Clinical trial NCT03919669
Conditions: Alzheimer Disease Mild Cognitive Impairment
Sponsor: University of Wisconsin, Madison
Start date: 2019-04-02; Completion date: 2022-05-19
Enrollment: 27 participants; Allocation: NA; Intervention model: SINGLE_GROUP

Brief summary:
This is a longitudinal, observational study evaluating the imaging characteristics of the tau PET radioligand \[18F\]MK-6240 in Alzheimer's disease (AD), Mild Cognitive Impairment (MCI) and Healthy Volunteer (HV) subjects. Up to 42 subjects, including approximately 28 MCI/mild AD subjects, up to 5 moderate AD subjects, and 9 similarly aged HV subjects will be consented and screened. Imaging procedures include \[11C\]PiB to evaluate amyloid deposition, \[18F\]MK-6240 PET, and structural MRI. All subjects complete an evaluable baseline \[18F\]MK-6240 PET scan, as well as scans at 6, 12 and 24 months post-baseline. If unable to complete the 6 month, 12 month, or 24 month visit, an 18 month and/or 30 month visit may instead be scheduled, totaling a maximum of four time points.

Detailed description:

Arms: arm 1: All subjects will complete PET imaging sessions evaluating the tau PET radioligand \[18F\]MK-6240 at baseline, as well as at 6, 12 and 24 months post-baseline.

If unable to complete the 6 month, 12 month, or 24 month visit, an 18 month and/or 30 month visit may instead be scheduled, totaling a maximum of four time points.
Interventions: intervention 1: All Subjects
Intervention descriptions: intervention 1: All subjects will be given the experimental tau PET radioligand \[18F\]MK-6240

Protocol documents:
Prot_000.pdf: 
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Longitudinal evaluation of [18F]MK-6240 as a novel tau PET radiotracer in 
patients with Alzheimer’s disease dementia or mild cognitive impairment 
compared to healthy volunteers 
 
NCT:03919669 
 
 
Principal Investigator: 
Sterling Johnson, PhD 
Professor of Medicine, University of Wisconsin-Madison  
Associate Director for Research, Wisconsin Alzheimer’s Institute 
Associate Director, Wisconsin Alzheimer’s Disease Research Center 
  
This investigator initiated trial is supported by: 
 
Sponsor:  
Cerveau Technologies, Inc. 
 
+1 (617) 610-5828 
 
60 State Street, Suite 700 
 
Boston, MA 02109 
 
 
 
 
Sponsor Contact:    
Joanna Shuping 
 
 
 
 
+1 (937) 926-5252 
 
 
 
 
js@enigmabiomedicalgroup.com  
Sponsor of IND:  
Brad Christian, PhD, University of Wisconsin-Madison holds the IND for [F-18]MK6240 (IND# 
134, 516) and Sterling Johnson, PhD holds the IND for [C-11]PiB (IND# 107,114) 
 
 


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TABLE OF CONTENTS 
 
STUDY TEAM ROSTER .............................................................................................................. 4 
1 
Protocol Synopsis ............................................................................................................... 5 
2 
BACKGROUND AND RATIONALE .................................................................................... 9 
2.1 
Background ............................................................................................................................. 9 
2.2 
Rationale for choice of amyloid imaging radiotracer: ..................................................... 10 
2.3 
Rationale for imaging tau with [F-18]MK6240 ................................................................... 12 
2.4 
Human Safety and Tolerability ............................................................................................ 12 
3 
Study Purpose ................................................................................................................... 12 
4 
Study Objectives ............................................................................................................... 13 
4.1 
Primary Objective ................................................................................................................. 13 
4.2 
Secondary Objectives .......................................................................................................... 13 
5 
STUDY DESIGN .................................................................................................................. 13 
5.1 
Study Location: ..................................................................................................................... 14 
5.2 
Enrollment Window and Study Duration: .......................................................................... 14 
6 
SELECTION AND ENROLLMENT OF PARTICIPANTS .................................................. 14 
6.1 
Inclusion Criteria (for all subjects) ..................................................................................... 14 
6.2 
Inclusion Criteria for Healthy Volunteers .......................................................................... 15 
6.3 
Inclusion Criteria for Subjects with a Diagnosis of MCI or Dementia due to AD ......... 15 
6.4 
Exclusion Criteria ................................................................................................................. 15 
6.5 
Study Enrollment Procedures ............................................................................................. 16 
7 
STUDY PROCEDURES ...................................................................................................... 18 
7.1 
Description of Evaluations and Procedures ..................................................................... 18 
7.1.1 
Consenting Procedure ......................................................................................................... 18 
7.1.2 
Screening Evaluation ........................................................................................................... 19 
7.1.3 
Physical and Neurological Examination ............................................................................ 19 
7.1.4 
Vital signs .............................................................................................................................. 19 
7.1.5 
Height and weight ................................................................................................................. 20 
7.1.6 
Clinical Scales ....................................................................................................................... 20 
7.1.6.1 
Mini-Mental Status Exam (MMSE) ................................................................................... 20 
7.1.6.2 
Clinical Dementia Rating Scale (CDR) ........................................................................... 20 
7.1.6.3 
Alzheimer’s Disease Assessment Scale – Cognitive Subscale (ADAS-cog) ............ 20 
7.1.7 
The MRI Protocol: ................................................................................................................. 21 
7.1.8 
Radiology Review of MRI:.................................................................................................... 22 
7.1.9 
PiB at Screening: .................................................................................................................. 22 
7.1.10 
[18F]MK-6240 ...................................................................................................................... 23 
7.1.11 
Data obtained from referral sources: ............................................................................. 24 
7.1.12 
Discontinuation of Study Treatment and Premature Subject Withdrawal ................. 24 
7.2 
Study Completion ................................................................................................................. 25 
7.3 
Data Sharing: ........................................................................................................................ 25 
7.4 
Data Banking ......................................................................................................................... 27 


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8 
SAFETY Considerations ................................................................................................... 27 
8.1 
Adverse Events ..................................................................................................................... 27 
8.2 
Adverse Events and Serious Adverse Events Monitoring .............................................. 27 
8.3 
Follow-up for Adverse Events ............................................................................................. 28 
8.4 
Risk benefit discussion for pertinent study procedures ................................................. 28 
9 
Data Handling and record keeping ................................................................................. 29 
9.1 
Study Monitoring .................................................................................................................. 29 
9.1.1 
Internal Audit and Data Safety Monitoring: ....................................................................... 29 
9.2 
Database Management and Quality Control...................................................................... 29 
9.2.1 
Data Collection Forms ......................................................................................................... 29 
9.3 
Data management tools ....................................................................................................... 29 
9.3.1 
REGGIE – CRM database ..................................................................................................... 29 
9.3.2 
PANDA and PACS................................................................................................................. 30 
9.3.3 
BOOKED: ............................................................................................................................... 30 
10 
STATISTICAL CONSIDERATIONS ............................................................................... 31 
10.1 
Subject Demographics and Other Baseline Characteristics ........................................... 31 
10.2 
Image Analysis ...................................................................................................................... 31 
10.3 
Statistical Analysis ............................................................................................................... 31 
10.4 
Sample Size ........................................................................................................................... 32 
11 
PARTICIPANT RIGHTS AND CONFIDENTIALITY ...................................................... 32 
11.1 
Institutional Review Board (IRB) Review ........................................................................... 32 
11.2 
Informed Consent Forms ..................................................................................................... 32 
11.3 
Participant Confidentiality ................................................................................................... 32 
11.4 
Study Discontinuation ......................................................................................................... 33 
12 Clinicaltrials.gov .................................................................................................................... 34 
13 
REFERENCES ................................................................................................................ 35 
 
 


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STUDY TEAM ROSTER  
Principal Investigator: 
 Sterling Johnson, PhD 
 
Professor of Medicine 
 
Wisconsin ADRC Imaging Core Leader  
 
Clinical Sciences Center 
 
600 Highland Avenue, K6/438, Madison, WI 53792 
 
608-262-9549  
 
email address: scj@medicine.wisc.edu    
 
Co-Investigator: 
 Brad Christian, PhD 
 
Professor of Medical Physics 
 
Waisman Center 
 
1500 Highland Avenue, Room T231, Madison WI, 53705 
 
Telephone: 608-890-0750 
 
email address:  bchristian@wisc.edu  
Main responsibilities/Key roles:  Dr. Christian leads the PET 
imaging components of the study and holds the IND for 
MK6240. 
 
Other investigators: 
Charles Stone MD, PET responsible physician 
 
Nathaniel Chin, MD, ADRC Medical Director 
 
Robert Przybelski, MD, Geriatrician 
 
 
 
 


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1 
PROTOCOL SYNOPSIS 
TITLE 
Longitudinal evaluation of [18F]MK-6240 as a novel tau PET radiotracer in subjects 
with Alzheimer’s disease or mild cognitive impairment compared to healthy 
volunteers  
TEST PRODUCT 
[18F]MK-6240  
STUDY CENTER 
University of Wisconsin School of Medicine and Public Health 
TRIAL OBJECTIVES  
The overall goal of this protocol is to characterize the longitudinal change in tau 
burden using [18F]MK-6240.  Data from this study may be used to inform the design 
of future therapeutic trials utilizing [18F]MK-6240 as a marker of disease 
progression.  
The primary objectives of this study are: 
• 
To characterize the longitudinal change in [18F]MK-6240 brain uptake 
at 26 (6 months) and 52 (12 months) weeks compared to baseline in 
subjects with Alzheimer’s disease (AD) dementia, mild cognitive 
impairment (MCI) and healthy volunteers (HV).   This comparison may 
include 78 (18 month) week measures, if the 26 or 52 week measures 
are not available, in order to attain 6 month and 12 month intervals.     
• 
To correlate the changes in [18F]MK-6240 uptake and changes in 
clinical cognitive assessments (MMSE, ADAS-cog and CDR) 
The secondary objectives of this study are: 
• 
To characterize the longitudinal change in [18F]MK-6240 brain uptake 
at 104 (24 months) weeks compared to baseline in subjects with AD 
dementia, MCI and healthy volunteers.   This comparison may include 
130 (30 month) week measures, if two or more [18F]MK-6240 scans 
are not available. 
• 
To evaluate cross-sectional comparison of [18F]MK-6240 uptake in 
AD, MCI and HV at baseline 26, 52 and 104 weeks.   This may include 
78 (18 month) and/or 130 (30 month) week measures, if the 26, 52, or 
104 week measures are not available.    
 
STUDY DESIGN 
This is a longitudinal, observational study evaluating the imaging characteristics of 
the tau PET radioligand [18F]MK-6240 in AD, MCI and HV subjects. Up to 42 
subjects including approximately 28 MCI/mild AD subjects, up to 5 moderate AD 
subjects, and 9 similarly aged HV subjects will be consented and screened.  
Imaging procedures include [11C]PiB, [18F]MK-6240 PET and structural MRI.  
All subjects who complete at least one [18F]MK-6240 PET imaging session will be 
considered enrolled in the study. As many as 28 MCI/mild AD subjects, 5 moderate 
AD subjects, and 9 similarly aged HV subjects may complete an evaluable 
baseline [18F]MK-6240 PET scan to enable at least 23 subjects (15 MCI/mild AD, 
3 moderate AD, 5  HV subjects) to complete the 24 month follow up.  Subjects who 
discontinue prior to completing the 12-month or 18-month [18F]MK-6240 PET scan 
may be replaced in the study until a total of 15 patients (MCI/AD) complete the 12 
month PET imaging session. Subjects that complete the 12-month visit but wish to 
abandon the study before the 24-month visit will be given the option to have a final 
evaluation any time between 18 and 24 months. 
All subjects will provide informed consent at enrollment before any study 
procedures are performed.  The Screening procedures will occur within 60 days 
prior to baseline [18F]MK-6240 imaging and will include a brief cognitive 


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assessment, review of medical history and medications, physical examination, 
[11C]PiB PET imaging and brain MRI. 
 
 
[11C]PiB and MRI IMAGING: 
As part of the Screening Visit, subjects will complete structural brain MRI imaging 
which will be used for eligibility evaluation, co-registration with PET imaging and 
volumetric analysis.   
If an evaluable PiB scan has been acquired and is available for use in this study 
and occurred within 12 months of screening, the scan will not be repeated. 
Otherwise, [11C]PiB PET imaging will be obtained at screening to evaluate for 
amyloid deposition. Subjects will be considered amyloid positive if [11C]PiB DVR 
(distribution volume ratio) imaging demonstrates amyloid deposition based on 
qualitative read or DVR index value >1.20.  
For the [11C]PIB PET imaging session, subjects will receive a single IV bolus 
injection target dose of 15 mCi ± 20% of [11C]PIB and scanned dynamically for 70 
minutes.  For participants who may not be able to tolerate this long scan, a 20 
minute scan will be offered after 50 minutes of uptake. 
 
[18F]MK-6240 PET IMAGING VISITS:  
Subjects will complete [18F]MK-6240 PET imaging at four time points:  Baseline, 6 
months, 12 months and 24 months.  If unable to complete the 6 month, 12 month, 
or 24 month visit, an 18 month and/or 30 month visit may instead be scheduled, 
totaling a maximum of four time points.  [18F]MK-6240 is administered 
intravenously at a target dose of 185 MBq (5 mCi ) plus or minus 20%.  Image 
acquisition will occur from 70 to 110 minutes post-injection.  Repeat of up to two 
[18F]MK-6240 PET imaging scans may be completed if needed.  Repeat scans will 
be prioritized for the Baseline and 12 month visits.    
A physician or physician representative will evaluate the subject for adverse events 
prior to leaving the imaging center and will discharge subjects when determined 
medically stable.  A follow-up phone call to the subject will be conducted by study 
staff within 4 days (±2 days) post-injection of [18F]MK-6240 to confirm subject well-
being and to collect information regarding new adverse or ongoing events.    
The primary outcome for [18F]MK-6240 imaging will be the standardized uptake 
value ratio (SUVR).  The reference region is the inferior cerebellum gray matter. A 
standardized volume of interest (VOI) template will be used to quantitatively 
measure [18F]MK-6240 tracer uptake in regions with expected tau pathology.   
INCLUSION/ 
EXCLUSION 
CRITERIA 
Healthy volunteer subjects and MCI/AD patients who are medically stable and 
meet the inclusion criteria and do not meet any of the exclusion criteria will be 
eligible for enrollment into the study. 
 
Inclusion Criteria for All Subjects 
• 
Signed and dated written informed consent must be obtained from the 
subject to enter the study and before any assessment is performed. 
• 
Pregnancy: Participant is not pregnant at the time of the PET and MRI 
imaging exams. Urine pregnancy tests will be conducted as needed with 
pre-menopausal women who are of child-bearing potential. 


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• 
Willing and able to undergo study procedures and study schedule 
• 
Availability of a study partner who has frequent and sufficient contact 
with the subject and is able to provide accurate information regarding 
the subject’s cognitive and functional abilities for the CDR, agrees to 
accompany the subject and provide information at visits or is available 
by phone. The study partner must have sufficient cognitive capacity, in 
the judgment of the investigator, to accurately report upon the subject’s 
behavior and cognitive and functional abilities.  
• 
Males and females between the age of 50 and 85 (inclusive).  
• 
Healthy with no clinically relevant finding on physical examination at 
screening and upon reporting for the Baseline [18F]MK-6240  imaging 
visit. 
 
Inclusion Criteria for Healthy Volunteer Subjects (HV) 
• 
Normal Cognition based on cognitive results at screening.  
• 
Healthy with no clinically relevant finding on physical examination at 
screening and upon reporting for the Baseline [18F]MK-6240 imaging 
visit. 
• 
CDR global score =0 
 
Inclusion Criteria for Subjects with a Diagnosis of MCI or Dementia Due to 
AD 
• 
Have screening [11C]PiB PET imaging demonstrating amyloid binding 
based on qualitative read or DVR index value >1.20. 
• 
MMSE score 26-30 (inclusive), CDR global score 0.5 for subjects with 
MCI 
• 
MMSE score 22-26 (inclusive), CDR global score 0.5 or 1 for subjects 
with mild dementia due to AD  
• 
MMSE score 16-21 (inclusive), CDR global score 1-2 for subjects with 
moderate dementia due to AD  
• 
Subjects with MCI must meet 2018 research criteria for MCI (Jack et al., 
2018). 
• 
Subjects with dementia must meet 2018 research criteria for dementia 
(Jack et al., 2018). 
• 
A structural brain MRI with no evidence of non-AD disease to account 
for dementia or MRI exclusion criteria. 
 
Exclusion Criteria (for all subjects) 
• 
Lack of capacity to provide informed consent at study entry. 
• 
Subject has received an investigational drug or device within 30 days of 
screening.  Other experimental PET radiotracer drugs are not excluded. 
• 
For women, pregnant, lactating or breastfeeding or intention to become 
pregnant. 
• 
Evidence of unstable or untreated clinically significant gastrointestinal, 
cardiovascular, hepatic, renal, hematological, neoplastic, endocrine, 
alternative neurological, immunodeficiency, pulmonary, or other disorder 
or disease. Stable, treated chronic medical conditions like hypertension, 
hypercholesterolemia, diabetes mellitus, non-metastatic dermatologic or 
prostatic cancer, etc. are acceptable as long as they do not, in the study 
investigator’s opinion, contribute to cognitive dysfunction or limit 
participation in study procedures. 
• 
Any illness or other consideration that makes it unlikely that the subject 
will be able to complete the 26-month study. 


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• 
Current or prior history (within past 5 years) of significant alcohol or 
substance abuse as determined by the investigator. 
• 
Psychiatric disorders that may interfere with the study including current 
major Axis I DSM-V disorders including but not limited to severe Major 
depression, current or history of bipolar I disorder, or schizophrenia.  
• 
Non-English speakers or subjects who are unable to comprehend study 
materials are excluded at entry 
• 
MRI exclusion criteria include: Findings that may be responsible for 
neurologic status of the subject such as significant evidence of 
cerebrovascular disease with multiple infarcts, infectious disease, 
space-occupying lesion, normal pressure hydrocephalus, CNS trauma, 
or any other structural abnormality that may impact cognition or image 
analysis, as judged by the investigator. 
• 
MRI-incompatible implants or devices such as certain cardiac 
pacemakers or defibrillators, insulin pumps, cochlear implants, metallic 
ocular foreign body, implanted neural stimulators, CNS aneurysm clips 
and other medical implants that have not been certified for MRI, or 
history of claustrophobia in MRI that prevents completion of MRI 
protocol. 
• 
Treatment with any therapeutic molecule that targets Aβ or tau within 12 
months prior to screening.  
 
LENGTH OF STUDY  
For each subject participating, the duration of study participation will be 
approximately 26 months including a 60-day screening period and 24-month 
longitudinal assessment period.   The longitudinal assessment period may be 
extended to include a 30-month visit, if prior visits are missing.  If a 30-month visit 
is scheduled, the total duration will be approximately 32 months. 
INVESTIGATIONAL 
AGENTS  
[18F]MK-6240 and [11C]PiB are investigational PET radiotracers that will be 
synthesized in accordance with FDA IND applications for each tracer. 
All subjects will receive one injection of [11C]PiB (at screening only) and up to four 
injections of [18F]MK-6240 during the course of their participation in this 26-32 month 
study.   Repeat of up to two [18F]MK-6240 PET imaging scans may be completed 
if needed.  Repeat scans will be prioritized for the Baseline and 12 month visits.     
STATISTICAL 
METHODS 
 
DEMOGRAPHICS 
The demographic and baseline characteristics will be summarized according to the 
clinical group (HV, MCI and AD) using descriptive statistics for continuous 
variables and using frequency count and percentage for discrete variables.   
 
 
ANALYSIS OF STUDY 
OBJECTIVES 
 
 
 
 
 
 
 
The change in [18F]MK-6240 uptake (e.g. composite and regional SUVR, voxel 
based statistics or change in tau distribution) will be determined by estimating the 
change from Baseline to each follow-up visit (6, 12 and 24 months).   If the 6, 12, 
or 24 month visit measures are not available, this may include 18 and/or 30 month 
visit measures. The change in [18F]MK-6240 uptake will be compared among the 
groups (AD, MCI and HV subjects) aligned on intervals of 6, 12, 18 and 24 months.  
The relationship between the change in [18F]MK-6240 uptake (e.g. composite and 
regional SUVR, voxel based statistics or change in tau distribution) and change in 
clinical severity or cognitive outcomes will be analyzed in AD dementia, MCI and 


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2 
BACKGROUND AND RATIONALE  
2.1 Background 
Neurofibrillary tangles begin during the preclinical phase of AD, and by the time of very mild 
dementia neurofibrillary tangles are well formed in predictable staged patterns (Braak & 
Braak, 1990; Braak, Braak, & Bohl, 1993). However, the rate of temporal change in 
neurofibrillary tangle burden in individual cases is poorly understood.  
Up until recently, the information about the temporal and spatial signal from neurofibrillary 
tangle (tau related) pathology in AD has come from neuropathology studies of brain bank cases 
(Gomez-Isla et al., 1996) and in life from CSF tau protein levels which have no spatial 
information and suffer from lack of standardized assays from lab to lab (Mattsson et al., 2013).  
The advent of tau positron emission tomography (PET) imaging using compounds (Chien et 
al., 2014; Maruyama et al., 2013; Villemagne et al., 2014) such as [F-18]AV1451 and now [F-
18]MK6240 (Hostetler et al., 2016; Lohith et al., 2018) hold promise of making major 
breakthroughs in diagnosing AD accurately and characterizing its rate of progression. Our 
group has published one of the first clinical papers (Betthauser et al., 2018) on MK-6240 
describing its temporal properties and imaging characteristics. World-wide the field has now 
conducted over 4000 exams with this compound and find it safe with no radioligand-related 
serious adverse events and strong binding to AD-relevant brain regions in amyloid positive 
subjects in a pattern consistent with the neuropathology literature (see Figure 1). 
 
 
HV subjects.  In addition, the correlation between baseline [18F]MK-6240 uptake 
and baseline clinical endpoints will be evaluated in all subjects. 
Cross-sectional comparisons will be made among the clinical groups (AD, MCI and 
HV subjects) at Baseline, 6, 12 and 24 months for the following measures: [18F]MK-
6240 uptake (composite and regional SUVR), neuropsychological testing (MMSE, 
CDR, ADAS-cog), MRI markers of atrophy such as hippocampal volume.   If the 6, 
12, or 24 month visit measures are not available, this cross-sectional comparison 
may include 18 and/or 30 month measures. 
 
 
 


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Molecular imaging biomarkers have the 
potential to play a key diagnostic role in 
tauopathies.  Tau protein has been 
identified as one of the key pathological 
features of AD. Tau is the primary protein 
composing neurofibrillary tangles and 
unlike beta-amyloid deposition, post-
mortem 
studies 
have 
shown 
that 
neurofibrillary tangle density correlates 
with neurodegeneration and cognitive 
impairment. Thus, a PET imaging agent 
that binds to aggregated tau has the 
potential to serve as a biomarker for 
disease severity or neurodegeneration 
and may be useful for monitoring disease 
progression in therapeutic trials. PET is 
able to detect the spatial distribution of 
the radioactive compound in the brain 
and can be used as an objective, sensitive, and accurate method to quantify the concentration 
of the target site in different brain regions. Using these PET techniques, β-amyloid aggregates 
have been successfully imaged in several studies in AD patients using high affinity 11-C and 
18-F-labeled PET tracers such as PiB or florbetapir (see Johnson, 2018 for a review; 
Villemagne et al., 2013; Villemagne et al., 2012).  
2.2 Rationale for choice of amyloid imaging radiotracer: 
[11C]PIB is the first of the amyloid imaging agents and is still considered the best of these 
agents for its overall imaging properties including lower non-specific off-target white matter 
binding and its large dynamic range (Villemagne et al., 2012).  [11C]PIB utilizes carbon 11 which 
is fast-decaying (20 minute half-life). While a distinct advantage for such a fast-decaying tracer 
is a much lower radiation exposure to the body, its short half life makes it unwieldy for wide 
commercial distribution. Thus, even though [11C]PIB offers the best image characteristics and 
lowest radiation exposure (about 3mSv which is less than 1/3rd of the dosage of newer F18 
agents, about 10mSV), it was never feasible to produce commercially in large scale and FDA 
approval was not ever sought by its developers. Each dose must be manufactured locally under 
IND.  Since its initial discovery in 2004, four other agents have been discovered ([18F]NAV, 
[18F]florbetapir, [18F]florbetaben, [18F]flutemetamol) and three of these have gone through 
the requisite process to obtain FDA approval—[18F]florbetapir, [18F]florbetaben, and 
[18F]flutemetamol. All of the FDA approved tracers have inferior imaging properties when 
compared to PIB, but to their advantage they are also Fluorine-18 based with a much longer 
half-life (~110 minutes) which allows them to be manufactured at central specialized 
manufacturing sites and distributed regionally throughout the country. (This is similar 
conceptually to how hospitals such as the UWHC purchase [18]FDG for clinical use from an 
external vendor.) 
 
Fig. 1. [18F]MK-6240 parametric SUVR (70-90 min) images in PiB(+) 
individuals organized by image-based Braak stages. [18F]MK-6240 
spatial binding patterns in PiB(+) individuals recapitulated patterns 
consistent with neuropathological staging of Alzheimer’s disease, 
including in the hippocampus. The PiB(+) dementia case in the far 
rightward column was clinical diagnosed with probable AD dementia 
(not informed by these biomarkers) but exhibited only circumscribed 
[18F]MK-6240 signal in the entorhinal region.  


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While the F18 radiotracers have improved the accessibility to amyloid imaging for research 
and gradual clinical use, PIB remains the gold standard to which other amyloid radiotracers 
are compared (Klunk et al., 2015). This is due to 1) its wider dynamic range which may 
improve its sensitivity to earlier stages of amyloid elevation 2) its relatively better target-
specific binding pattern such that it binds largely only to the fibrillar amyloid plaques, while 
F18 agents are more lipophilic and characteristically bind to off-target myelin-containing brain 
regions including very high binding in the white matter and thalamus making it difficult to 
accurately visually rate and quantify signal that is due to true amyloid signal versus off-target 
‘spill in’ effects into tissue of interest.  
In a series of studies, PiB has demonstrated high agreement with histopathology for 
identifying amyloid plaques (Bacskai et al., 2007; Ikonomovic et al., 2008; Joie et al., 2018; 
Leinonen et al., 2008).  PiB differentiates AD cases from controls in vivo (Klunk et al., 2004), 
and predicts subsequent cognitive decline in cognitively normal adults (Clark et al., 2018; 
Clark et al., 2016; Donohue et al., 2017), and conversion to dementia in patients with MCI 
(Chen et al., 2014; Frings et al., 2018; Hatashita & Wakebe, 2017; Iaccarino et al., 2017; 
Kemppainen et al., 2014; Kikukawa et al., 2018; Trzepacz et al., 2014; Wolk et al., 2009).  
Comparison to Florbetaben 
Villemagne et al. (Villemagne et al., 2012) compared 20 people (10 AD dementia and 10 
controls) with [11C]PIB and [18F]Florbetaben. The correlation of global amyloid burden as 
estimated with each tracer was r=.97. However the effect-size was nearly uniformly higher 
(by 10%) for PIB than florbetaben.  
 
Comparison to Florbetapir 
Wolk and colleagues (Wolk et al., 2012) compared [11C]PiB to [18F]Florbetapir in 12 AD 
cases and 14 healthy control subjects of similar age. Global beta-amyloid composite scores 
were computed in parallel fashion and correlated. The Pearson coefficient was r= .78. The 
area under the curve for separating cases from controls was 1.0 for PIB and .90 for 
florbetapir. The authors concluded that florbetapir provides comparable information to PiB. 
 
Comparison to Flutemetamol 
At least five studies have compared agreement between PIB and [18F]Flutemetamol and all 
report very strong robust agreement (Adamczuk et al., 2016; Leinonen et al., 2013; Lowe et 
al., 2017; Mountz et al., 2015; Vandenberghe et al., 2010).  Mountz et al. (2015) report a 
correlation greater than 0.90 in global amyloid burden and strong agreement (.82 kappa 
coefficient) for visual rating.  Adamzuck found the concordance between PIB and 
flutemetamol of =94% for amyloid positivity and r=.84 for the global index score 
semiquantitative composite.  Leinonen et al (2013) and Vandenberghe et al. (2010) reported 
correlations of .97 and .90 respectively.  


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Summary: PIB is the standard for comparison for the F18 amyloid agents. PiB corresponds 
strongly to amyloid pathology at autopsy, separates cases from controls with AUCs at or near 
1.0 (Lowe et al., 2017) and PIB elevation in controls and MCI is correlated with high 
specificity to later decline and conversion to dementia. The F18 agents are strongly 
correlated to PiB. The higher radiation dose of the F18 agents, and their higher off-target 
binding to white matter (lipophilicity) make them less optimal than PiB for detecting and 
quantifying amyloid plaques in vivo in a clinical research setting.  
 
2.3 Rationale for imaging tau with [F-18]MK6240 
The ability to image brain amyloid has offered an important advance for the diagnosis of 
neurodegenerative conditions (Jack et al., 2018; Johnson, 2018).  In contrast to Aβ-rich neuritic 
and diffuse amyloid plaques, the density and distribution of pathological tau, aggregated in 
neurofibrillary tangles, increases with AD-related cognitive impairment and correlates with 
neurodegeneration.  But the spatiotemporal rate of progression in the brain within individual 
people is not well understood. This information is needed in order to appropriately plan 
intervention trials. Furthermore, first generation tau tracers such as AV1451 and THK5351 
have been shown to have off-target binding effects in regions relevant to AD, which poses 
challenges to treatment trials wishing to demonstrate target engagement with those 
compounds. 
   
[18F]MK-6240 has been developed as a highly specific positron emitting radiopharmaceutical 
for in vivo imaging of tau protein aggregates (Hostetler et al., 2016; Lohith et al., 2018). [18F]MK-
6240 has been previously evaluated by several groups including ours demonstrating 
substantial NFT deposition in the AD subjects and no or little evidence for tau binding in the 
HV subjects in the absence of amyloid. This study aims to evaluate the longitudinal change in 
tau burden using [18F]MK-6240 PET imaging in relation to cognitive and functional metrics.  
2.4 Human Safety and Tolerability 
[18F]MK-6240 has been evaluated in over  1000 subjects world-wide in several studies including 
over 240 at the UWSMPH and is well tolerated with no known radioligand-related serious 
adverse events. 
3 
STUDY PURPOSE 
The overall goal of this study is to evaluate the longitudinal change in the uptake of [18F]MK-
6240. The data obtained will be vital in forming hypotheses for future larger studies, particularly 
for hypotheses about effect sizes that may inform future large scale clinical trials. 
 


Version 4, August 26, 2021 
 
                                           
Page 13 of 36 
4 
STUDY OBJECTIVES 
4.1 Primary Objective 
The primary objectives of this study are: 
• To characterize the longitudinal change in [18F]MK-6240 brain uptake at 26 and 52 
weeks compared to baseline in subjects with dementia due to AD, mild cognitive 
impairment (MCI) and healthy volunteers (HV).  This comparison may include 78 (18 
month) week measures, if the 26 or 52 week measures are not available, in order to 
attain 6 month and 12 month intervals.       
• To correlate the changes in [18F]MK-6240 uptake and changes in clinical cognitive 
assessments (MMSE, ADAS-cog and CDR).   
4.2 Secondary Objectives 
The secondary objectives of this study are: 
• To characterize the longitudinal change in [18F]MK-6240 brain uptake at 104 (24 
months) weeks compared to baseline in subjects with dementia due to AD, mild 
cognitive impairment and healthy volunteers.  This comparison may include 130 (30 
month) week measures, if two or more prior [18F]MK-6240 scans are not available. 
• To evaluate cross-sectional comparison of [18F]MK-6240 uptake in AD, MCI and HV 
at baseline 26, 52 and 104 weeks.  This cross-sectional comparison may include 78 
(18 month) and/or 130 (30 month) week measures, if the 26, 52, or 104 week 
measures are not available.     
 
5 
STUDY DESIGN 
This is a longitudinal, observational study evaluating the imaging characteristics of the tau PET 
radioligand [18F]MK-6240 in AD, MCI and HV subjects. Up to 28 MCI/mild AD subjects, up to 5 
Table 1. Overview of study design and timeline 
Screening 
Baseline 
6 month1 
12 month1 
18 Month3 
24 month2 
30 Month3 
Within -60 to -1 
days of baseline 
0 weeks (day 0) 
26 weeks (±60 
days) 
52 weeks (±60 
days) 
78 weeks (±60 
days) 
104 weeks (±60 
days) 
130 weeks (±60 
days) 
Cognitive 
Testing (MMSE, 
CDR, ADAS-
cog) 
No Cognitive 
Testing 
Cognitive 
Testing (MMSE, 
CDR) 
Cognitive 
Testing (MMSE, 
CDR, ADAS-
cog) 
Cognitive 
Testing (MMSE, 
CDR, ADAS-
cog4) 
Cognitive 
Testing (MMSE, 
CDR, ADAS-
cog) 
Cognitive 
Testing (MMSE, 
CDR,  ADAS-
cog5) 
MRI (T1, T2) 
No MRI 
MRI 
MRI 
MRI 
MRI 
MRI 
Amyloid Imaging 
(11C-PiB) 
No Amyloid 
Imaging 
No Amyloid 
Imaging 
No Amyloid 
Imaging 
No Amyloid 
Imaging 
No Amyloid 
Imaging 
No Amyloid 
Imaging 
No [18F]MK-6240 
PET Imaging 
[18F]MK-6240 
PET Imaging 
[18F]MK-6240  
PET Imaging 
[18F]MK-6240 
PET Imaging 
[18F]MK-6240 
PET Imaging 
[18F]MK-6240 
PET Imaging 
[18F]MK-6240 
PET Imaging 
Footnotes: 
1: If the 6 and/or 12 month visit is not completed, an 18 and/or 30 month visit may be completed, totaling a maximum of 4 timepoints. 
2: If the 24 month visit is not completed, a 30 month visit may be completed   
3: The 18 month and/or 30 month visit may be scheduled if 6 month, 12 month, and/or 24 month visit is missing 
4: ADAS-cog will be completed at 18 month visit if 12 month visit is not completed 
5: ADAS-cog will be conducted at the final visit including the 30-month visit 
 


Version 4, August 26, 2021 
 
                                           
Page 14 of 36 
moderate AD subjects, and up to 9 similarly aged HV subjects will be enrolled at the University 
of Wisconsin-Madison. Recruitment as well as screening and longitudinal clinical activities, 
including MRI, [11C]PiB and [18F]MK-6240 PET imaging, will be completed. The general design 
of the study is provided in Table 1.  
 
The overall goal of this protocol is to evaluate the longitudinal change in uptake of [18F]MK-
6240, an NFT targeted radiopharmaceutical.  Data from this study may be used to inform the 
design of future therapeutic trials utilizing [18F]MK-6240 as a marker of disease progression.  
 
Participants will be recruited from the Wisconsin Alzheimer’s Disease Research Center 
(ADRC), the Wisconsin Registry for Alzheimer’s Prevention (WRAP) as well as from the 
community. Pertinent standard lab tests and findings from the referral source (such as 
diagnosis, medical history and prior cognitive results) will be reviewed to assess eligibility.  
5.1 Study Location:  
The study will take place at the University of Wisconsin-Madison medical campus including the 
following sites: 
 
Waisman Center Laboratory for Brain Imaging and Behavior: where the MRI and PET/CT brain 
imaging will take place and radiolabeling, and chemistry occur.  
 
University Hospital and Clinics or WIMR where wide-bore MRI scanners are located that will 
be utilized if participant size prohibits the standard 3T scanners. 
 
Alzheimer’s Disease Research Center (ADRC) Imaging Core in the Clinical Sciences Center 
(University Hospital) which is adjacent to WIMR and across the street from Waisman Center.  
At the ADRC Imaging Core Directed by Dr. Johnson, the images will be backed up and 
maintained and processed using standardized pipelines.  
 
5.2 Enrollment Window and Study Duration:  
Recruitment and enrollment will require approximately 6 months. The study duration is 
26 months inclusive of 2 months for screening and baseline activities and 24 months of 
follow-up activities.  The longitudinal assessment period may be extended to include a 
30-month visit, if needed.  If a 30-month visit is scheduled, the total duration will be 
approximately 32 months.   
6 
SELECTION AND ENROLLMENT OF PARTICIPANTS  
Healthy volunteers and subjects diagnosed with mild cognitive impairment (MCI) and 
dementia cases will be enrolled who meet the following criteria. 
6.1 Inclusion Criteria (for all subjects) 
• Signed and dated written informed consent must be obtained from the subject to enter 


Version 4, August 26, 2021 
 
                                           
Page 15 of 36 
the study and before any assessment is performed. 
• Pregnancy: Participant is not pregnant at the time of the PET and MRI imaging 
exams.  Urine pregnancy tests will be conducted as needed with pre-menopausal 
women who are of child-bearing potential.  
• Willing and able to undergo the study procedures and study schedule. 
• Availability of a study partner whohas frequent and sufficient contact with the subject 
and is able to provide accurate information regarding the subject’s cognitive and 
functional abilities for the CDR, agrees to accompany the subject and provide 
information at visits or is available by phone. The study partner must have sufficient 
cognitive capacity, in the judgment of the investigator, to accurately report upon the 
subject’s behavior and cognitive and functional abilities.  
• Males and females between the age of 50 and 85 (inclusive).  
• Healthy with no clinically relevant finding on physical examination at screening and 
upon reporting for the Baseline [18F]MK-6240  imaging visit. 
6.2 Inclusion Criteria for Healthy Volunteers 
• Normal cognition based on cognitive results at screening 
• Healthy with no clinically relevant findings on physical examination at screening and 
upon reporting for the baseline visit 
• CDR global score = 0 
6.3 Inclusion Criteria for Subjects with a Diagnosis of MCI or Dementia due to AD 
• Have screening [11C]PiB PET imaging demonstrating amyloid binding based on 
qualitative read or DVR index value >1.20. 
• MMSE score 26-30 (inclusive), CDR global score 0.5 for subjects with MCI 
• MMSE score 22-26 (inclusive), CDR global score 0.5 or 1 for subjects with mild 
dementia due to AD  
• MMSE score 16-21 (inclusive), CDR global score 1-2 for subjects with moderate 
dementia due to AD  
• Subjects with MCI must meet 2018 research criteria for MCI (Jack et al., 2018). 
• Subjects with dementia must meet 2018 research criteria for dementia (Jack et al., 
2018). 
• A structural brain MRI with no evidence of non-AD disease to account for dementia or 
MRI exclusion criteria. 
 
6.4 Exclusion Criteria  
Candidates meeting any exclusion criteria at screening are not eligible for inclusion: 
• Lack of decisional capacity to provide informed consent at study entry. 
• Subject has received an investigational drug or device within 30 days of screening.  
Other experimental PET radiotracer drugs are not excluded. 
• For women, pregnant, lactating or breastfeeding or intention to become pregnant. 


Version 4, August 26, 2021 
 
                                           
Page 16 of 36 
• Evidence of unstable or untreated clinically significant gastrointestinal, cardiovascular, 
hepatic, renal, hematological, neoplastic, endocrine, alternative neurological, 
immunodeficiency, pulmonary, or other disorder or disease. Stable, treated chronic 
medical conditions like hypertension, hypercholesterolemia, diabetes mellitus, non-
metastatic dermatologic or prostatic cancer, etc. are acceptable as long as they do 
not, in the study investigator’s opinion, contribute to cognitive dysfunction or limit 
participation in study procedures. 
• Any illness or other consideration that makes it unlikely that the subject will be able to 
complete the 26-month study. 
• Current or prior history (within past 5 years) of significant alcohol or substance abuse 
as determined by the investigator. 
• Psychiatric disorders that may interfere with the study including current major Axis I 
DSM-V disorders including but not limited to severe Major depression, current or 
history of bipolar I disorder, or schizophrenia.  
• Non-English speakers or subjects who are unable to comprehend study materials are 
excluded at entry 
• MRI exclusion criteria include: Findings that may be responsible for neurologic status 
of the subject such as significant evidence of cerebrovascular disease with multiple 
infarcts, infectious disease, space-occupying lesion, normal pressure hydrocephalus, 
CNS trauma, or any other structural abnormality that may impact cognition or image 
analysis, as judged by the investigator. 
• MRI-incompatible implants or devices such as certain cardiac pacemakers or 
defibrillators, insulin pumps, cochlear implants, metallic ocular foreign body, implanted 
neural stimulators, CNS aneurysm clips and other medical implants that have not 
been certified for MRI, or history of claustrophobia in MRI that prevents completion of 
MRI protocol. 
• Treatment with any therapeutic molecule that targets Aβ or tau within 12 months prior 
to screening. 
 
6.5 Study Enrollment Procedures  
• 
Physicians who hold UW memory clinics may refer their clinically diagnosed cases of 
MCI or dementia by asking their patient to fill out a permission to contact form which 
includes the patient’s name and contact details and declares an interest in learning 
more about the study. A study information sheet is also provided. Following return of 
permission to contact form, the patient will be contacted by the study team, and the 
study will be explained per the phone screening script. The phone screening script 
also contains an oral consent and HIPPA authorization for medical records review. 
The study team will conduct the eligibility checklist with the patient and will access 
medical records with oral consent. Medical records may be requested with oral 


Version 4, August 26, 2021 
 
                                           
Page 17 of 36 
consent to evaluate eligibility including current diagnoses and medications, cognitive 
status, and prior head imaging.   
• 
For ADRC clinical core(2015-0030) and WRAP (2016-0634) participants, the 
applicable source study staff will conduct database screens for participants who meet 
criteria for older controls or patient groups. Dr. Johnson, the PI of this protocol, is also 
PI of WRAP and an investigator for the ADRC clinical core protocol. 
• 
From this general pool, case records will be examined further for eligibility criteria. 
Candidates who are ostensibly eligible on the record review will be contacted by a 
source study staff member via letter or phone and invited to participate. Reasons for 
non-participation of eligible unscreened candidates will be logged. 
• 
Interested candidates will be phone screened. If all eligibility criteria are met, the 
participant will have the in person screening visit to involve cognition, physical exam 
and MRI and PiB.  A screening log will be kept to record reasons for screen failures. A 
waiver of written consent is requested for the phone screen. Interested candidates will 
undergo verbal consent before screening information is collected via phone. 
• 
Informed consent is required prior to procedures. Only individuals with capacity to 
consent at screening will be included.  For participants diagnosed with Alzheimer’s 
disease, this will be assessed by study clinicians or psychologists using a brief 
interview format based on questions on the Consent form. For all others, this is with 
the study coordinator.  After enrollment, subjects who decline to the point where they 
no longer have capacity to consent will be allowed to continue because they initially 
expressed this desire on the enrollment consent form.   
• 
In the event that reconsent is needed during the course of the study, capacity will be 
reassessed at that time.  If a participant is found to lack decisional capacity to consent 
based on the brief interview, they will be allowed to continue because they initially 
expressed this desire on the enrollment consent form.  In this case, assent (the 
participant’s desire to continue to participate or not participate in the research) will 
always be obtained, as well as surrogate consent.  The surrogate would be sought in 
the following order of priority: participant’s research power of attorney/research 
advance directive, guardian or healthcare power of attorney, or next of kin.  Next of 
kin includes (in the following order): spouse, adult child, parent, adult sibling, 
grandparent, adult grandchild, or a close friend of the participant.  Participant’s assent 
will always operate as a veto to the participant’s participation, despite the surrogate’s 
preference.    
 
 Table 2. Schedule of Events 
 
Screening 
Assessments 
Baseline 
(BL) 
6 Month 
Assessments5 
12 Month 
Assessments5 
18 Month 
Assessments4 
24 Month 
Assessments6 
30 Month 
Assessments4 
Early 
Termination 
Assessments 
  
  
Within 60 
d of 
Screening 
26 w from BL 
(±60 days) 
52 w from BL  
(±60 days) 
78 w from BL 
(±60 days)  
104 w from BL 
(± 60 days) 
130 w from BL 
(±60 days) 
  
Inclusion/Excl
usion Criteria 
X 
X 
X 
X 
X 
X 
X 
X 
Demography 
and Smoking 
History 
X 
X 
X 
X 
X 
X 
X 
X 


Version 4, August 26, 2021 
 
                                           
Page 18 of 36 
Informed 
Consent 
X 
XAN 
XAN 
XAN 
XAN 
XAN 
XAN 
XAN 
Medical 
History  
X 
 
 
 
 
 
 
 
Physical & 
Neurologic 
Examination1 
X 
XAN 
XAN 
XAN 
XAN 
XAN 
XAN 
XAN 
Medications 
review 
X 
X 
X 
X 
X 
X 
X 
X 
Height/weight 
X 
X 
X 
X 
X 
X 
X 
X 
MMSE & CDR 
X 
 
X 
X 
X 
X 
X 
X 
ADAS-cog 
X 
 
 
X 
X3 
X 
X 
X 
Vital Signs 
(blood 
pressure, 
pulse rate, 
respiratory 
rate) 
X 
X 
X 
X 
X 
X 
X 
X 
Review NIA-
AA AD/MCI 
criteria 
X 
 
 
 
 
 
 
 
Pregnancy 
Test (if 
applicable) 2 
X 
X 
X 
X 
X 
X 
X 
X 
Brain MRI (T1, 
T2) 
X 
 
X 
X 
X 
X 
X 
X 
[11C]PiB 
X 
 
 
 
 
 
 
 
[18F]MK-6240 
 
X 
X 
X 
X 
X 
X 
X 
Adverse event 
assessment 
X 
X 
X 
X 
X 
X 
X 
X 
F/U phone call 
within 4 days 
X 
X 
X 
X 
X 
X 
X 
X 
Footnotes: 
AN: As needed 
1: Physical exam at screening may be performed at investigator’s discretion to ensure eligibility 
2:Pregnancy test administered to WOCBP, as defined by ADRC pregnancy testing SOP 
3: ADAS-cog will be completed at 18 month visit if 12 month visit is not completed 
4: The 18 month and/or 30 month visit may be scheduled if 6 month, 12 month, and/or 24 month visit is missing 
5: If the 6 and/or 12 month visit is not completed, an 18 and/or 30 month visit may be completed, totaling a maximum of 4 timepoints. 
6: If the 24 month visit is not completed, a 30 month visit may be completed   
 
 
7 
STUDY PROCEDURES 
7.1 Description of Evaluations and Procedures 
Procedures including screening/eligibility procedures and study visits are according to the 
schedule of events in Table 2. 
7.1.1 Consenting Procedure 
Before any study procedures are performed, informed consent will be obtained. A single 
consent form and process will be used for the screening and main study visits.  The study 
coordinator or one of the study investigators will obtain written informed consent and the 
original document retained by the study team. At each subsequent visit the procedures for the 
visit are explained together with their major risks and the subject is asked if they wish to 
continue. It is always reiterated that the subject may change their mind at any point for any 
reason and stop participating.  In the event that reconsent is needed during the course of the 
study, capacity will be reassessed at that time.  If a participant is found to lack decisional 


Version 4, August 26, 2021 
 
                                           
Page 19 of 36 
capacity to consent based on the brief interview, they will be allowed to continue because they 
initially expressed this desire on the enrollment consent form.  In this case, assent (the 
participant’s desire to continue to participate or not participate in the research) will always be 
obtained, as well as surrogate consent.  The surrogate would be sought in the following order 
of priority: participant’s research power of attorney/research advance directive, guardian or 
healthcare power of attorney, or next of kin.  Next of kin includes (in the following order): 
spouse, adult child, parent, adult sibling, grandparent, adult grandchild, or a close friend of the 
participant.  Participant’s assent will always operate as a veto to the participant’s participation, 
despite the surrogate’s preference.     
7.1.2  Screening Evaluation 
Screening procedures will occur within 60 days prior to the Baseline assessment with [18F]MK-
6240 PET imaging, and will include collection demographic and other health related information 
(age, gender, ethnicity, race,), cognitive testing (MMSE, CDR and ADAS-cog), review of 
medical history and medications, tobacco use including smoking status (active or not), pack-
year, duration of smoking, consumption during the last 6 months (#pack per day), physical and 
neurological examination. All subjects will complete these clinical assessments to ensure the 
subject is medically stable to complete the study protocol.  In addition, [11C]PiB PET/CT imaging 
will be completed for all subjects and serves as part of the screening process to confirm 
presence of amyloid deposition. Brain MRI (structural T1, T2) will be obtained at screening for 
eligibility evaluation and analysis of neurodegeneration.  
 
7.1.3 Physical and Neurological Examination 
A brief physical and neurological examination will include the examination of general 
appearance, neck (including thyroid), lungs, heart, lymph nodes, vascular and neurological.  
The physical exam at screening may be performed at the investigator’s discretion to ensure 
the participant’s eligibility.  A recent physical exam from the referring physician may be used to 
ensure eligibility throughout the course of the study.  
Information for all physical and neurological examinations will be included in the source 
documentation. Significant findings that are present prior to injection of [18F]MK-6240 will be 
included in the medical history in the subject's source documents. Significant findings noted 
after injection of [18F]MK-6240, which meet the definition of an adverse event will be recorded 
as an adverse event. 
Urine pregnancy tests will be conducted as needed with pre-menopausal women who are of 
child-bearing potential. 
7.1.4 Vital signs 
Vital signs include BP, respiratory rate, and pulse measurements. Vital signs will be obtained 
before and after each PET imaging procedure.  


Version 4, August 26, 2021 
 
                                           
Page 20 of 36 
7.1.5 Height and weight 
Height and body weight (in indoor clothing) will be measured at the screening and main study 
visits. 
7.1.6 Clinical Scales 
7.1.6.1 Mini-Mental Status Exam (MMSE) 
The MMSE is a sensitive, valid and reliable 30-point questionnaire that is used extensively in 
clinical and research settings to measure cognitive impairment.  It is commonly used as 
screening tool for dementia. It is also used to estimate the severity and progression of cognitive 
impairment and to follow the course of cognitive changes in an individual over time; thus, 
making it an effective way to document an individual's response to treatment.  
Administration of the test takes between 5–10 minutes and examines functions including 
registration, attention and calculation, recall, language, ability to follow simple commands and 
orientation. This test is not a mental status examination. The standard MMSE form, which is 
currently published by Psychological Assessment Resources, is based on its original 1975 
conceptualization, with minor subsequent modifications by the authors. 
7.1.6.2 Clinical Dementia Rating Scale (CDR) 
The CDR was developed at the Memory and Aging Project at Washington University School of 
Medicine in 1979 for the evaluation of staging severity of dementia. It was developed primarily 
for use in persons with dementia of the Alzheimer type (the equivalent of probable Alzheimer’s 
Disease) and it can also be used to stage dementia in other illnesses as well.  
The information from which the CDR score is derived consists of a standard set of information 
collected in a clinical instrument that uses other well-known scales for some of its foundation.  
The CDR Global Score will be used in this study as an eligibility criterion.  In assigning a Global 
CDR, the six domains that are used to construct the overall CDR table are each scored 
individually. The six domains are: Memory, Orientation, Judgment and Problem-solving, 
Community Affairs, Home and Hobbies, and Personal Care. In rating each of these domains, 
the assessment should be based on the subject’s cognitive ability to function in these areas. If 
they are limited in performing activities at home because of physical frailty, this should not 
affect their scoring on the CDR, which again should be rated on their cognitive ability alone. 
Each domain is rated on a 5-point scale of functioning as follows: 0, no impairment; 0.5, 
questionable impairment; 1, mild impairment; 2, moderate impairment; and 3, severe 
impairment (personal care is scored on a 4-point scale without a 0.5 rating available). 
7.1.6.3 Alzheimer’s Disease Assessment Scale – Cognitive Subscale (ADAS-cog) 
The ADAS-Cog is one of the most frequently used tests to measure cognition in clinical trials 
in AD. The ADAS-Cog is a more thorough battery than the Mini Mental State Exam, and 
primarily measures language and verbal episodic memory. The ADAS-Cog consists of 13 items 
and takes approximately 25 minutes to administer.  The ADAS was developed as a two-part 
scale: one that measured cognitive functions and one that measured non-cognitive functions 


Version 4, August 26, 2021 
 
                                           
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such as mood and behavior.  Most current research, including this study, uses the ADAS-Cog, 
which is the sub-scale that measures cognitive ability. 
 
7.1.7 The MRI Protocol:   
If the participant otherwise meets all inclusion and no exclusion criteria, the MRI will be 
performed.  This procedure includes a T1-weighted anatomic volume, and a T2weighted fluid 
attenuated inversion recovery (FLAIR) scan to determine whether the brain is normal.  These 
sequences do not take the place of a clinical MRI examination. If clinically significant 
abnormalities are found, the participant is excluded and referred for further clinical follow-up.  
 
The MRI exams will be performed using a 3T MRI scanner at the Waisman Center or WIMR 
using the standardized ADRC MRI. Alternatively, a UW Hospital wide bore scanner may be 
utilized for MRI for larger participants.  The scan duration is typically 45 minutes and no longer 
than 75 minutes and consists of established as well as innovative locally developed scan 
sequences.  
 
The MRI procedure is considered complete if a T1-weighted volume and FLAIR scan are 
successfully acquired. When feasible, additional scans will be acquired. The additional 
sequences will make it possible to conduct exploratory comparisons. Sequences may include: 
 
T1w Brain Volume: This sequence that provides high-resolution isotropic 1 mm voxels for 
volume and region quantification. This sequence is required and used for quantifying the PET 
images. 
T2 Fluid attenuated inversion recovery (FLAIR): This is a 3D volume acquisition and is 
sensitive to ischemic disease and other pathology. This scan will be used to quantify white 
matter hyper-intensity lesion burden.  
Other non-required MRI sequences.  Additional sequences from the ADRC/WRAP standard 
protocol may be used to maintain continuity with prior and future MRIs with the program. These 
are performed when time schedule and tolerability permit and will be used to conduct 
exploratory analyses.  
T2-weighted volume and susceptibility weighted scans: These are product sequences and 
are used for tissue segementation and for radiology reads respectively. 
Quantitative T1 Mapping with MPNRAGE [experimental]: This is a locally developed 
anatomical sequence for detailed T1-mapping and tissue segmentation. This is a non-standard 
sequence conducted in Research mode.  
Diffusion Imaging [experimental] A diffusion-weighted may be performed used for whole brain 
advanced DTI studies. Diffusion encoding will be performed using multiple shells and multiple 
directions requisite for NODDI and advanced DTI modeling of white matter tracts.  
Pseudo-continuous arterial spin labeling (pCASL) [experimental] provides a perfusion 
weighted scan used to assess flow and aspects of neurovascular function.  


Version 4, August 26, 2021 
 
                                           
Page 22 of 36 
4D flow [experimental]: We will use a novel high-resolution flow-sensitive MRI approach to 
quantify macroscopic CBF in all extracranial and intracranial arteries in a single acquisition. 
The method developed at UW uses radial undersampling and significantly reduces otherwise 
prohibitively long scan times for a vascular examination uses no exogenous contrast agent. 
The method allows for coverage of the entire brain, providing high spatial resolution (0.6 mm 
isotropic) and flow dynamics within a 7-minute exam. This is a non-standard sequence 
conducted in Research mode.  
The scans above that are labeled as experimental are being conducted as a research tool. 
Safety and efficacy of the scans themselves are not being evaluated.  Similarly, when MRI is 
acquired on the MRI750 model at Waisman or at WIMR, a 32 channel NOVA head coil will be 
used. This coil is non product and thus experimental. The study is not evaluating the safety or 
efficacy of the head coil.  
Quality review: MRI and PET scans will be checked immediately after acquisition for technical 
quality (motion and other artifact) of the T1-weighted sequence and if needed this may be 
rescanned either during the same MRI session or at a rescheduled session. Images are 
uploaded to the Wisconsin ADRC imaging lab immediately after the session and the post-
processing procedures are implemented including an additional quality check by the study 
team.  
7.1.8 Radiology Review of MRI:  
All MR images receive radiological review from the MRI Service of our ADRC (Neuroradiologist 
Howard Rowley or a similarly qualified neuroradiologist) within 30 days, to screen for clinical 
abnormalities that may not have been previously detected; any significant findings are referred 
for clinical follow-up. 
7.1.9 PiB at Screening:   
[11C]PiB is synthesized using our standard methods.  N-methylation of the 6-OH-BTA-0 
precursor (ABX, Inc.) is accomplished using [C-11]methyl triflate produced via an automated 
chemistry module and subsequently purified using HPLC.  Typical yields of final [C-11]PiB 
product are in excess of 2 GBq, with specific activities of 150 – 600 GBq/umol.   
 
PiB PET/CT Scanning: Participants are positioned head first, supine with the canthomeatal line 
parallel to the in-plane field of view. A CT scan is acquired for attenuation correction. A 70 
minute dynamic [C-11]PiB PET acquisition is then initiated with the injection of a 15 mCi target 
dose of [C-11]PiB bolus, injected over 30 s. For participants who may not be able to tolerate 
this long scan, a 20 minute scan will be offered after 50 minutes of uptake. Dynamic acquisition 
frames included 5 x 2 min and 12 x 5 min for a total of 17 time frames.  The PET data are 
reconstructed using a filtered back-projection algorithm (DIFT) with sinogram trimming to a 
voxel size of 2.57mm x 2.57mm x 2.43mm and matrix dimension of 128 x 128 x 63 and 
corrected for random events, attenuation of annihilation radiation, deadtime, scanner 
normalization and scatter radiation with attenuation correction.  The reconstructed time series 
PET data are realigned to correct for subject motion during the course of the study and a 
denoising algorithm is applied to the voxel-based time series (Christian, Vandehey, Floberg, & 


Version 4, August 26, 2021 
 
                                           
Page 23 of 36 
Mistretta, 2010; Floberg et al., 2012). The PET time-series is coregistered into the space 
defined by the T1-weighted MRI scan based upon coregistration with the time-integrated (i.e. 
sum image) [C-11]PET scan using mutual information. 
 
PiB Distribution volume Ratio Maps: The data are transformed into voxel-wise parametric 
images representing [C-11]PiB binding using the cerebellar cortex as a reference region of 
negligible binding (Price et al., 2005). The cerebellar time-activity curve is extracted from the 
PET data using a cerebellar gray matter (GM) mask image derived from the coregistered T1-
weighted MRI using FreeSurfer software.  Voxel-based parametric images using Logan 
graphical analysis are created as described previously (Lopresti et al., 2005).  For the Logan 
graphical method (Logan et al., 1996), linear regression was applied to the transformed data 
using the 35- to 70-min (7 points) interval and a mean efflux constant of 0.149 min-1. Using 
SPM12, the DVRs are also spatially normalized to the International Consortium for Brain 
Mapping 152 atlas (ICBM 152, i.e. MNI space) and smoothed with an 8 mm full width at half 
maximum Gaussian kernel and entered into voxel-wise group analyses. 
The CT component of the PET/CT scan may be repeated up to one time per study timepoint.  
The CT attenuation correction scan may be repeated if the scan fails for some reason, or if the 
participant must get off of the scanner bed.  
 
7.1.10 [18F]MK-6240  
Descriptive name: 6-Fluoro-3-(1H-pyrrolo[2,3-c]pyridin-1-yl)isoquinolin-5-amine.  
 
The synthesis and PET/CT scanning with MK6240 will be done consistent with the Investigators 
Brochure and the IND. F-18 is created with the GE PETrace cyclotron at WIMR.  Radiolabeling 
is performed using automated research chemistry synthesis units for C-11 methylation 
(Scansys), F-18 nucleophilic substitution (ELIXSYS, Synthera, Scansys, CTI CPCU). Analytic 
equipment includes HPLC, GC, TLC and Endosafe-PTS for performing radiopharmaceutical 
quality assurance. For this project, a dedicated HPLC system will be committed to the synthesis 
of [F-18]MK6240. 
 
A 5 mCi dose ±20% of MK6240 bolus is injected over 30 second infusion at Baseline, 6, 12, 
and 24 months. If the 6, 12, or 24 month visit is missing, this may also occur at 18 and/or 30 
months, totaling a maximum of 4 timepoints.  Scanning occurs for up to 40 minutes starting at 
70 minutes post-injection.  Repeat of up to two [18F]MK-6240 PET imaging scans over the 
course of the study may be completed if needed, if the patient remains under the annual 
radiation allowance.  Repeat scans will be prioritized for the Baseline and 12 month visits. 
Scans will be repeated only one time per study timepoint (e.g. the baseline scan would only be 
repeated up to one time).  Scans may be repeated if the participant moves during the scan 
such that the images aren’t useable for analysis, or if the participant can’t tolerate the full 
imaging session such that the required imaging frames aren’t acquired. SUVR images will be 
generated using the inferior cerebellum as the reference region of nondisplaceable uptake.  


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The SUVR maps will be coregistered to structural T1-weighted MRI images for voxel- and ROI-
based analysis. Details about dosimetry are provided in the investigators brochure.  
 
The CT component of the PET/CT scan may be repeated up to one time per study timepoint.  
The CT attenuation correction scan may be repeated if the scan fails for some reason, or if the 
participant must get off of the scanner bed.  
 
7.1.11 Data obtained from referral sources:   
This study recruits from the Wisconsin ADRC, WRAP and local UW memory clinics, and 
relevant information pertinent to subject selection and screening will be obtained regarding 
cognitive diagnosis and medical history.  
 
Data collection from source study and clinical referral source 
This study recruits from WRAP and Wisconsin ADRC and local UW memory clinics, and 
relevant information from those sources may be used to determine eligibility. Information to be 
collected includes the following: 
Diagnosis: From the memory clinics this would include physician summary reports with 
diagnostic information.  From the ADRC and WRAP this would include diagnostic consensus 
conference summaries and reports.  Primary diagnoses (such as MCI or dementia due to AD) 
and any relevant secondary diagnoses (such as vascular disease) would be captured. 
Rationale: Diagnosis is a main grouping variable. 
Medical history will be accessed as part of the subject selection and screening process. For 
the clinic this may include the memory clinic physician summaries/notes and for the 
ADRC/WRAP would include clinician and self-reported medical history survey results.  The 
rationale is to identify people who are eligible.  
Prior imaging: Although we will collect an MRI under this protocol, results/reports from prior 
MRIs conducted for WRAP or ADRC in the past 24 months may be used to guage eligibilty. 
Rationale: To avoid screening someone whose may be ineligible based on the existing MRI. 
Genetics:  APOE genetic status will be collected from the ADRC and WRAP source cohorts 
rather than repeating it.  
 
7.1.12 Discontinuation of Study Treatment and Premature Subject Withdrawal 
Subjects who discontinue prior to completing the 12-month or 18 month [18F]MK-6240 PET 
scan will be eligible for replacement in the study until a total of at least 15 MCI/AD subjects 
complete the 12 month PET imaging session.  Subjects that complete the 12-month visit but 
wish to abandon the study before the 24-month visit will be given the option to have a final 
evaluation (including all the original assessments and imaging) any time between 18 and 24 
months. 


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Subjects may voluntarily withdraw from the study for any reason at any time. They will be 
considered withdrawn if they state an intention to withdraw, fail to return for visits, or become 
lost to follow-up for any other reason.  
If premature withdrawal occurs, the study team will make every effort to determine the primary 
reason for a subject’s premature withdrawal from the study and document this information. In 
addition, the study team will ask the subject to return for an Early Terminations Visit for a final 
evaluation.  
Subjects may develop adverse events or abnormalities in vital signs, physical or neurological 
examination, or laboratory determinations during their participation in the study. If these occur, 
the investigator may discontinue a subject from the study if, in his/her clinical judgment, 
continued participation would result in undue risk or further worsening of the condition. 
For subjects who are lost to follow-up (i.e. those subjects whose status is unclear because they 
fail to appear for study visits without stating an intention to withdraw), the investigator will show 
due diligence by documenting attempts to contact the subject, e.g. dates of telephone calls, 
registered letters, or other attempts to communicate. 
7.2 Study Completion 
The study will be complete when the last subject (including replacement subjects) completes 
the final visit and follow up phone call. 
7.3 Data Sharing:  
 
Banked images and their meta-data from this study will be managed by the ADRC imaging 
core and provided to authorized ADRC and WRAP investigators. Images from ADRC 
participants may be uploaded to the National Alzheimer’s Coordinating Center or other NIH-
specified repository. The images from applicable subjects will also be shared back with the 
source protocols and with the ADRC UP protocol (2013-0178) to address the major specific 
aims of the UP project. Once the data are shared with repositories and with the source 
protocols, the data may be used to address future unspecified research by WRAP and ADRC 
investigators. Other investigators who wish to use these data may apply via established 
resource request mechanisms to the ADRC and WRAP, and the respective executive 
committees will evaluate the merit of the request and decide how these and other ADRC or 
WRAP data are shared. Investigators from within the ADRC and WRAP, other departments 
within UW, institutions outside UW, and private companies may submit applications requesting 
the data. Only coded data are shared with researchers that are not listed as key personnel on 
the projects. Dr. Johnson holds ultimate responsibility for data sharing oversight, and will review 
all requests. He will ensure that local IRB policies are followed prior to releasing data. 
 
Data shared with the study sponsor, Cerveau Technologies, Inc.:  
Only data collected under this protocol will be shared with the study sponsor. 
-MK-6240 Tau Brain PET Image 
-Brain MR Images 


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-Unique Subject Identifier  
-Amyloid image and status 
-Cognitive metrics consisting of MMSE, ADAS-COG and CDR 
-Weight/Height 
-Scan time 
-MK-6240 dose 
-Scan date 
-Clinical diagnosis 
-Age, gender, race/ethnicity 
-Smoking status 
All data shared with Cerveau will be coded by participant ID. Cerveau maintains safety data for 
all sites using the MK6240 drug, and is responsible for Investigational Drug Brochure updates. 
 
StatKing Clinical Services (TrialMaster) 
The Electronic Data Capture (TrialMaster) will be hosted by StatKing Clinical Services, will be 
used to record all visit data. Data to be recorded include visit dates, dates of informed consent 
and enrollment, demography, health and smoking history, pregnancy test results if applicable, 
height/weight, APOE Status, vital signs, cognitive test scores, MRI sequence details, PET scan 
details, drug dosing details, AEs, concomitant medications, and follow-up call results. 
TrialMaster is in compliance with 21 CFR Part 11, electronic records, electronic signatures and 
predicate rules.  Compliance is achieved through a combination of SOP adherence and a 
structured validation system. Security of the EDC system includes the use of passwords that 
limit user access according to their job responsibilities.  Access to the data at the clinical site 
is restricted to authorized personnel only. Usernames and passwords are sent in two separate 
emails to personalized email addresses only. 
 
BIOCLINICA 
Bioclinica will provide secure storage of the study images and will be responsible for 
transferring MRI and PET images to the sponsor. Bioclinica will perform study start-up 
activities, prepare materials and forms which will be used for training and collection of images 
and perform image data quality control. Bioclinica will also prepare the study procedure 
manuals to ensure consistent image acquisition and transfer via SMART Submit, Bioclinica’ s 
electronic image submission system. SMART submit is in compliance with 21 CFR Part 11, 
electronic records, electronic signatures and predicate rules.  Compliance is achieved through 
a combination of SOP adherence and a structured validation system. Security of this system 
includes the use of passwords that limit user access according to their job responsibilities. In 
addition, ongoing calibration of PET scanners will be monitored by the collection of quarterly 
report sheets. Throughout the study an image data back-up will be performed on data storage 
systems.  Off-site image data back-up will also be performed.  Other electronic data (electronic 
CRFs, audit trails, database contents, electronic documents, etc.) will be stored on a dedicated 


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database server and saved daily throughout the study. Access to the data at the clinical site is 
restricted to authorized personnel only.  
7.4 Data Banking 
Data banking is a required component of the study; participants must agree to data banking at 
the time of consent. Participants may request to have their data withdrawn from the bank, at 
which point study personnel will remove their data from the bank and will discontinue using it 
for further research. Data collected from this study will be stored on Department of Medicine 
computer servers that are password-protected. Banked data is coded with a subject ID. Only 
study personnel have access to the key linking subject ID and identifiable subject information. 
Unless staff are listed as key personnel on this study, they will not be given access to the code 
linking subject identity with subject ID. 
 
8 
SAFETY CONSIDERATIONS  
8.1 Adverse Events 
An adverse event (AE) is any unfavorable and unintended diagnosis, symptom, sign (including 
an abnormal laboratory finding), syndrome or disease which either occurs during the study, 
having been absent at baseline, or if present at baseline, appears to worsen. Adverse events 
will be recorded regardless of their relationship to the study.  
A serious adverse event (SAE) is generally defined as any untoward medical occurrence that 
results in death, is life threatening, requires inpatient hospitalization or prolongation of existing 
hospitalization, results in persistent or significant disability/incapacity, or is a congenital 
anomaly. 
Serious adverse events will be reported by the investigator to the Sponsor, FDA, and IRB within 
the required timeframes after learning of the event.  
8.2 Adverse Events and Serious Adverse Events Monitoring  
Given that this longitudinal study involves procedures that will occur at 6-12 month intervals 
and does not include chronic treatment with an investigational agent, adverse events (AEs) 
and serious adverse events (SAEs) will only be captured during the study visit before and after 
PiB and MK6240 scans.  The participant will receive a phone call within 4 days from the study 
team for the purpose of ascertaining their wellbeing and information on any adverse events 
that occur within 24 hours after the scan. If any adverse events are discovered, a clinician will 
continue to follow up with the participant until resolved. 
 
The PI will be apprised of any adverse events and will report any SAEs experienced in the 
study to the IRB, FDA and sponsor per the relevant regulations.  Although no study related 
adverse events are expected (based on our past experience), we will examine AEs for study 
related trends.  If needed, we would modify the consent form after consulting with the IRB.   


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8.3 Follow-up for Adverse Events 
The investigator is obliged to follow subjects with AE’s until the events have subsided, the 
conditions are considered medically stable, or the participants are no longer available for follow 
up. Subjects who discontinue due to adverse events will be treated and followed according to 
established medical practice. 
8.4 Risk benefit discussion for pertinent study procedures 
MRI – There are no known biologic risks associated with MRI scanning.  Participants will be 
screened by study staff prior to the scan to verify they do not have any contraindications for 
MRI. Subjects with the following should not participate in MRI studies: metallic implants, such 
as prostheses, shrapnel, or aneurysm clips, or persons with electronic implants, such as 
cardiac pacemakers. The magnetic field generated by the MRI machine can cause a 
displacement or malfunctioning of these devices. Potential side effects of the scan include 
headache or anxiety due to claustrophobia and/or noise, and risk of injury due to other 
unapproved metal being brought into the scanner room.  To minimize the level of noise, all 
subjects will be fitted with disposable earplugs.  Communication with the participant is still 
possible during the scan.  In addition, fatigue and physical discomfort due to the length of the 
scan session are possible.  An abbreviated scan sessions consisting of the T1-weighted scan 
and FLAIR scan is sufficient for fulfilling the MRI component of this protocol.  
 
PET/CT Imaging ([F-18]MK6240 and [C-11]PiB radiotracers) – PET/CT imaging involves 
exposure to small amounts of ionizing radiation, which has no known or expected harmful 
effects. 
No 
serious 
adverse 
effects 
or 
concerning 
trends 
attributable 
to 
the 
radiopharmaceuticals used in this study have been reported.  However, the possibility exists 
for a rare reaction to any of the substances or procedures to which the subject is exposed.  
Based on data from 6378 administrations of MK6240, the most commonly occurring adverse 
events possibly related to injection of MK6240 include headache (occurred in 10 out of 6378 
participants, or 0.16%) and dizziness (occurred in 2 out of 6378 participants, or 0.03%).  The 
following occurred in only one participant out of 6378, or 0.02%: abdominal distention (bloating 
or swelling in the belly area), injection site bruising, arthralgia (joint pain), dysgeusia (altered 
sense of taste), parosmia (altered sense of smell), insomnia (difficulty falling asleep), and 
dysuria (discomfort when urinating).  All reported adverse events were considered mild in 
intensity, and resolved shortly after the scan.  A PET/CT scanner will be used and a low dose 
CT transmission scan is acquired for attenuation correction (0.4mSv).  The whole body 
radiation dose of 26.9mSv received by the subjects from PET/CT [F-18]MK6240 (5.9mSv for 
each of 4 visits is 23.6mSv) and [C-11]PiB (3.3mSv) scans will be below the guidelines 
established in 21CFR §361.1 for whole body (Annual Limit - 50mSv), active blood forming 
organs, lens of eye and gonads (5 rad) and target organ (15 rad).  Specifics regarding the 
effective human radiation dosimetry for a subject undergoing [F-18]MK6240 and PiB are 
provided in the Investigators Brochure for each ligand.  
Repeat of up to two [18F]MK-6240 PET imaging scans over the course of the study may be 
completed if needed, if the patient remains under the annual radiation allowance.  Each 
additional [18F]MK-6240 PET imaging scan would expose the participant to an additional 
5.9mSv.  Repeat scans will be prioritized for the Baseline and 12 month visits. Scans will be 


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repeated only one time per study timepoint (e.g. the baseline scan would only be repeated up 
to one time).  The CT component of the PET/CT scan may be repeated up to one time per 
study timepoint (0.4mSv per additional CT scan).   
 
9 
DATA HANDLING AND RECORD KEEPING 
9.1 Study Monitoring 
9.1.1 Internal Audit and Data Safety Monitoring:   
The Study Monitoring Plan describes the strategy, responsibilities, and quality management 
activities in place to ensure adequate protection of the rights, welfare, and safety of human 
subjects and the quality and integrity of the resulting data, in compliance with applicable laws, 
regulations, policies, and guidance.   
 
This observational cohort study does not require an external DSMC. The radioligands are 
delivered in tracer quantities that have no known pharmacological effect.  However, as 
described in the Study Monitoring Plan, the investigator and clinical team will review the AE 
logs and any Study Monitoring findings to determine if there are trends or side effects that are 
study related that may warrant changes to the protocol and/or consent form. 
9.2 Database Management and Quality Control 
9.2.1 Data Collection Forms 
The study coordinator works with the participant at the study visit to collect all relevant data. 
Electronic case report forms will be generated to record the data. Source documents and all 
participant specific data are stored hard copy in an individual binder. 
9.3 Data management tools 
9.3.1 CoRRIE – CRM database 
Directly identifiable information and indirectly identifiable information (identified by Study ID 
number) will be stored in CoRRIE.  
 
CoRRIE is a contact database that will be used to record participant contacts, correspondence 
and scheduling. It is used by all ADRC-linked studies. It is a web-based, electronic database 
that is password-protected.  
In addition to storing the names of those who enroll in this study, the CoRRIE database will 
also help the staff to manage their contacts with participants. The database allows for the 
storage of participants’ relationship to our program by stating which studies in our program they 
are enrolled in or have been enrolled in the past. The database also allows us to track and 
assign activities that take place during the course of research (phone calls, letters, screenings).  


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This helps to ensure that participants are not needlessly contacted, and overall improves the 
customer service provided to our participants by the members of our research program.  The 
purpose of storing this data is for programmatic cohesion in working with subjects with memory 
problems across our program. It is important to know which subjects are enrolled in which 
studies so that we may provide appropriate coordination of their study visits. 
 
Universal Identifier 
An internal ID number is generated by the ADRC CoRRIE database and will have “RMRaic00” 
added to it to create a unique participant identifier that will remain with the participant from 
study to study. This number will be used to label brain images collected in affiliated ADRC 
protocols. This will allow physicians who are reviewing the brain scans to look for brain changes 
over time. 
9.3.2 PANDA and PACS 
Image data management tool:  Image data are electronically transferred and stored on servers 
at the ADRC imaging core (PI is Dr. Johnson) and metadata inserted into an imaging database 
called PANDA. Image headers by protocol do not contain identifying information. Additionally, 
each image is automatically inspected, and any PHI removed. These resources are maintained 
by the Department of Medicine.  Some derived numeric image data, cognitive and 
questionnaire data may be maintained in PANDA. User access is protocol specific such that 
only users authorized to see this study’s data will have access.  
MRI images labeled with only study IDs as identifiers are also uploaded to the Dept of 
Radiology PACS directly from the scanner for radiology over-reads.  
9.3.3 BOOKED:   
Directly identifiable information and indirectly identifiable information (identified by Study ID 
number) will be stored in Booked. A participant scheduling web application, Booked, has been 
developed by extending the Booked (PHP) free, open source project. The Booked application 
can prevent double booking of staff and resources, provides email notification to staff when 
they are added to appointments, provides email notification if an appointment has been 
cancelled, and email reminders before an appointment starts. Staff can be linked to multiple 
roles in appointments. The calendar view can be filtered by resource, staff and study 
participant. The appointments are color coded by appointment type and staff member. Booked 
reports can track cancelled appointments, cancellation reason, appointment types, resource 
usage, staff hour totals, and staff appointment counts.  Booked is limited to https ssl 
connections. Only users granted protocol specific permissions can login to Booked and view 
study participant information. It is also important to note that the Booked software is installed 
on the DOM production server in the DOM server room; therefore, all Booked data will be on 
the DOM server. Access to Booked via the web is limited to UW Networks. Booked is a free, 
open source project; therefore, there are no connections or relationships with the Booked 
software manufacturer. Participant Name, phone number and ADRC Registry ID (2016-0735) 
are identifiers used in Booked. Booked is an appointment scheduling application, so the 


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participant name, phone and Study ID are needed to identify the participant. These identifiers 
will only be visible to users who are on the protocols that the participant is enrolled in. 
 
10 
STATISTICAL CONSIDERATIONS  
10.1 Subject Demographics and Other Baseline Characteristics 
The demographic and baseline characteristics will be summarized according to the clinical 
group (HV, MCI, mild or moderate AD) using descriptive statistics for continuous variables and 
using frequency count and percentage for discrete variables.   
10.2 Image Analysis  
The MRI and [18F]MK-6240 PET images will be co-registered for anatomy-based definition of 
regions of interest (ROI) for analysis of regional [18F]MK-6240 binding/uptake. The [18F]MK-
6240 PET analysis will include application of spatially standardized region of interest (ROI) 
templates to assess tracer uptake and quantification.  Standard uptake values (SUV) and 
Standardized Uptake Value Ratios (SUVR) will be calculated for the areas and will serve as 
the primary imaging outcome measure.   
10.3 Statistical Analysis 
Descriptive statistics will be used to describe the tau deposition (e.g. composite and regional 
SUVR, voxel based statistics or change in tau distribution) using [18F]MK-6240 PET.  
The Baseline [18F]MK-6240 binding will be compared among the AD subjects at different stages 
of the disease, and HV groups descriptively, quantitatively and visually by graphical plots. 
[18F]MK-6240 binding in AD at different stages of the disease, and HV binding across multiple 
regions will be compared. Within the AD groups, the distribution and binding of [11C]PiB will be 
compared to the [18F]MK-6240 binding across multiple regions.  
The primary objective of this imaging trial is to evaluate the longitudinal change in [18F]MK-
6240. Composite and regional SUVRs will be determined for each of the [18F]MK-6240 imaging 
sessions (Baseline, 6-month, 12-month, and 24-month).  This may also include 78 (18 month) 
and/or 130 (30 month) week measures, if the 26, 52, or 104 week measures are not available 
in order to assess change over intervals of 6, 12, 18 and 24 months.    The analysis will include, 
but not be limited to, the following regions of interest: inferolateral temporal cortex, posterior 
cingulate, frontal cortex, parietal cortex, occipital cortex, mesial temporal cortex and anterior 
cingulate. To help control type 1, a composite inferomedial region will be used as the primary 
outcome. Change in tau regional deposition and/or volume of deposition as measured by 
[18F]MK-6240 (e.g. composite and regional SUVR, voxel based statistics or change in tau 
distribution) will be determined by estimating the change from baseline to each follow-up visit 
using an appropriate repeated measures metric. The change in tau burden will be compared 
among the groups (HV, prodromal, mild and moderate AD).   
The relationship between the change in tau deposition by [18F]MK-6240 (e.g. composite and 
regional SUVR, voxel based statistics or change in tau distribution) and change in clinical 


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biomarker measures will be examined in prodromal, mild and moderate AD subjects.  In 
addition, the correlation between baseline tau burden and AD severity based on clinical scales, 
venous blood biomarkers in prodromal, mild and moderate AD subjects will be evaluated. 
10.4 Sample Size 
The sample size for this study was determined by practical considerations and is not based on 
statistical power calculations.  Up to 42 subjects maybe enroll in this study or no less than 15 
MCI/mild AD subject, 3 moderate AD subjects and 5 similarly aged healthy volunteers all with 
a least the 12 month scan.   
11 
PARTICIPANT RIGHTS AND CONFIDENTIALITY  
11.1 Institutional Review Board (IRB) Review 
This protocol and the informed consent document and any subsequent modifications will be 
reviewed and approved by the University of Wisconsin-Madison Health Sciences IRB.   
11.2 Informed Consent Forms 
A signed consent form will be obtained from each participant. The consent form will describe 
the purpose of the study, the procedures to be followed, and the risks and benefits of 
participation. A copy will be given to each participant and this fact will be documented in the 
participant’s record. Only participants with cognitive capacity to provide consent will enroll in 
this study. 
 
11.3 Participant Confidentiality  
Any data, specimens, forms, reports, MRI and PET images, and other records will be identified 
only by a participant identification number (Participant ID, PID) to maintain confidentiality.  All 
records will be kept in a locked file cabinet.  All computer entry and networking programs will 
be done using PIDs only. Information will not be released without written permission of the 
participant, except as necessary for monitoring by IRB, the FDA, the NIA, and the OHRP.  
 
Privacy and Data Storage 
 
Physical data will be kept in locked cabinets in our lab which has space at the UW Hospital. 
Other data will be kept on the Department of Medicine's secure server. Only individuals in our 
lab will have access to these computers and any PHI. Any data shared with individuals outside 
of our lab (i.e. papers or presentations) will be anonymized. Each subject will also have an 
individual study number to code their study data. Names are never entered at the scanner 
console, only study number. Study number is used on data collection forms.  
 
Directly identifiable information and indirectly identifiable (identified by study ID number) 
information will be stored in CoRRIE and Booked. 
 


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CoRRIE is an electronic database/contact management system that stores information 
(inclusive of PHI) from the 'First Contact Form' as described in 2016-0735 and tracks study 
participation. The electronic database is web-based, though only accessible within the DOM 
server, and password-protected. Data are not stored in temporary files. Registered accounts 
must be approved by our research staff supervisors, and access/activity in the database will 
be monitored. Only those listed on the 2016-0735 protocol will be allowed access. Data will 
be kept in a web-based electronic database stored on the DOM server, with access only 
allowed to authorized research personnel. 
 
Booked is a participant visit scheduling web application that has been developed by 
extending the Booked (PHP) free, open source project. Booked software has been installed 
on the DOM production server in the DOM server room. All Booked data will be on the DOM 
server. Access to Booked via the web is limited to UW DOM Networks. Booked is a free, 
open source project; therefore, there are no connections or relationships with the Booked 
software manufacturer and data will not be stored online with the software manufacturer. 
Booked is limited to https ssl connections. Only users granted protocol specific permissions 
can log in to Booked and view study participant information. Booked is an appointment 
scheduling application, so the participant name, phone number, and Registry ID are needed 
to identify the participant. These identifiers will only be visible to users who are on the 
protocols which the participant is enrolled in. The DOM IT department has been consulted 
with regard to HIPAA security requirements. 
 
PANDA (PAN = Greek prefix meaning ‘all’; Data Archive) is a data and imaging management 
tool that has received IRB approval for use in other ADRC and WRAP linked protocols. Data 
and images are electronically transferred to PANDA, which is maintained by the ADRC 
imaging core. The PANDA is a Ruby on Rails application using a MySQL backend database, 
which provides secure web interfaces to a repository of MRI, PET and project-specific 
variables including neuropsychology, lab results, questionnaires, and participant properties. 
Security of the database uses best practice guidelines. Viewing and editing data are 
separately granted permissions and are access-controlled at the project level. Editing of data 
will be locked to all but the DBA. In all cases this also requires a user to be listed on the IRB-
approved protocol (via ARROW study team list). For security, all login and query downloads 
are logged and traceable by user and date. Further, any logged query, including table fields 
and selection criteria, may be reconstructed at a later date for auditing if needed. The DBA 
has an interface to view the queries by user/time. As imaging data cannot be uploaded, it is 
the image metadata that are uploaded into the SQL database; the images themselves are 
stored on a secure DOM server in the imaging core. Data are transferred to database users 
using https downloads of queries in CSV text files that can subsequently be imported into 
statistical analysis software. 
 
11.4 Study Discontinuation  
The study may be discontinued at any time by the investigator, the IRB, the sponsor, or by 
regulatory agencies including the FDA as part of their duties to ensure that research 


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participants are protected. 
 
12 CLINICALTRIALS.GOV 
A description of this clinical trial will be available on http://www.ClinicalTrials.gov, as required 
by U.S. Law. This website will not include information that can identify participants of this 
study. At most, the website will include a summary of the results.  
 
 


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13 
REFERENCES 
Betthauser, T. J., Cody, K. A., Zammit, M. D., Murali, D., Converse, A. K., Barnhart, T. E., Stone, C. 
K., Rowley, H. A., Johnson, S. C., & Christian, B. T. (2018). In vivo characterization and 
quantification of neurofibrillary tau PET radioligand [F18]MK-6240 in humans from 
Alzheimer's disease dementia to young controls. Journal of Nuclear Medicine, in press. 
doi:10.1101/290064 
Braak, H., & Braak, E. (1990). Neurofibrillary changes confined to the entorhinal region and an 
abundance of cortical amyloid in cases of presenile and senile dementia. Acta Neuropathol 
(Berl), 80(5), 479-486.  
Braak, H., Braak, E., & Bohl, J. (1993). Staging of Alzheimer-related cortical destruction. European 
Neurology, 33(6), 403-408.  
Chien, D. T., Szardenings, A. K., Bahri, S., Walsh, J. C., Mu, F., Xia, C., Shankle, W. R., Lerner, A. J., 
Su, M. Y., Elizarov, A., & Kolb, H. C. (2014). Early clinical PET imaging results with the 
novel PHF-tau radioligand [F18]-T808. J Alzheimers Dis, 38(1), 171-184. doi:10.3233/JAD-
130098 
Christian, B. T., Vandehey, N. T., Floberg, J. M., & Mistretta, C. A. (2010). Dynamic PET denoising 
with HYPR processing. J Nucl Med, 51(7), 1147-1154. doi:10.2967/jnumed.109.073999 
Floberg, J. M., Mistretta, C. A., Weichert, J. P., Hall, L. T., Holden, J. E., & Christian, B. T. (2012). 
Improved kinetic analysis of dynamic PET data with optimized HYPR-LR. Med Phys, 39(6), 
3319-3331. doi:10.1118/1.4718669 
Gomez-Isla, T., Price, J. L., McKeel, D. W., Jr., Morris, J. C., Growdon, J. H., & Hyman, B. T. (1996). 
Profound loss of layer II entorhinal cortex neurons occurs in very mild Alzheimer's disease. J 
Neurosci, 16(14), 4491-4500.  
Hostetler, E. D., Walji, A. M., Zeng, Z., Miller, P., Bennacef, I., Salinas, C., Connolly, B., Gantert, L., 
Haley, H., Holahan, M., Purcell, M., Riffel, K., Lohith, T. G., Coleman, P., Soriano, A., 
Ogawa, A., Xu, S., Zhang, X., Joshi, E., Della Rocca, J., Hesk, D., Schenk, D. J., & Evelhoch, 
J. L. (2016). Preclinical Characterization of 18F-MK-6240, a Promising PET Tracer for In 
Vivo Quantification of Human Neurofibrillary Tangles. J Nucl Med, 57(10), 1599-1606. 
doi:10.2967/jnumed.115.171678 
Jack, C. R., Jr., Bennett, D. A., Blennow, K., Carrillo, M. C., Dunn, B., Haeberlein, S. B., Holtzman, 
D. M., Jagust, W., Jessen, F., Karlawish, J., Liu, E., Molinuevo, J. L., Montine, T., Phelps, C., 
Rankin, K. P., Rowe, C. C., Scheltens, P., Siemers, E., Snyder, H. M., Sperling, R., & 
Contributors. (2018). NIA-AA Research Framework: Toward a biological definition of 
Alzheimer's disease. Alzheimers Dement, 14(4), 535-562. doi:10.1016/j.jalz.2018.02.018 
Johnson, S. C. (2018). Brain imaging in dementia and antecedent conditions. In G. E. Smith (Ed.), 
APA Handbook of Dementia. Washington D. C.: APA. 
Logan, J., Fowler, J. S., Volkow, N. D., Wang, G. J., Ding, Y. S., & Alexoff, D. L. (1996). Distribution 
volume ratios without blood sampling from graphical analysis of PET data. J Cereb Blood 
Flow Metab, 16(5), 834-840. doi:10.1097/00004647-199609000-00008 
Lohith, T. G., Bennacef, I., Vandenberghe, R., Vandenbulcke, M., Salinas-Valenzuela, C., Declercq, 
R., Reynders, T., Telan-Choing, F., Riffel, K., Celen, S., Serdons, K., Bormans, G., Tsai, K., 
Walji, A., Hostetler, E. D., Evelhoch, J. L., Van Laere, K., Forman, M., Stoch, A., Sur, C., & 
Struyk, A. (2018). First-in-human brain imaging of Alzheimer dementia patients and elderly 


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controls with (18)F-MK-6240, a PET tracer targeting neurofibrillary tangle pathology. J Nucl 
Med. doi:10.2967/jnumed.118.208215 
Lopresti, B. J., Klunk, W. E., Mathis, C. A., Hoge, J. A., Ziolko, S. K., Lu, X., Meltzer, C. C., 
Schimmel, K., Tsopelas, N. D., DeKosky, S. T., & Price, J. C. (2005). Simplified quantification 
of Pittsburgh Compound B amyloid imaging PET studies: a comparative analysis. J Nucl Med, 
46(12), 1959-1972. doi:46/12/1959 [pii] 
Maruyama, M., Shimada, H., Suhara, T., Shinotoh, H., Ji, B., Maeda, J., Zhang, M. R., Trojanowski, J. 
Q., Lee, V. M., Ono, M., Masamoto, K., Takano, H., Sahara, N., Iwata, N., Okamura, N., 
Furumoto, S., Kudo, Y., Chang, Q., Saido, T. C., Takashima, A., Lewis, J., Jang, M. K., Aoki, 
I., Ito, H., & Higuchi, M. (2013). Imaging of tau pathology in a tauopathy mouse model and in 
Alzheimer patients compared to normal controls. Neuron, 79(6), 1094-1108. 
doi:10.1016/j.neuron.2013.07.037 
Mattsson, N., Andreasson, U., Persson, S., Carrillo, M. C., Collins, S., Chalbot, S., Cutler, N., Dufour-
Rainfray, D., Fagan, A. M., Heegaard, N. H., Robin Hsiung, G. Y., Hyman, B., Iqbal, K., 
Lachno, D. R., Lleo, A., Lewczuk, P., Molinuevo, J. L., Parchi, P., Regeniter, A., Rissman, R., 
Rosenmann, H., Sancesario, G., Schroder, J., Shaw, L. M., Teunissen, C. E., Trojanowski, J. 
Q., Vanderstichele, H., Vandijck, M., Verbeek, M. M., Zetterberg, H., Blennow, K., Kaser, S. 
A., & Alzheimer's Association, Q. C. P. W. G. (2013). CSF biomarker variability in the 
Alzheimer's Association quality control program. Alzheimers Dement, 9(3), 251-261. 
doi:10.1016/j.jalz.2013.01.010 
Price, J. C., Klunk, W. E., Lopresti, B. J., Lu, X., Hoge, J. A., Ziolko, S. K., Holt, D. P., Meltzer, C. C., 
Dekosky, S. T., & Mathis, C. A. (2005). Kinetic modeling of amyloid binding in humans using 
PET imaging and Pittsburgh Compound-B. J Cereb Blood Flow Metab, 25(11), 1528-1547.  
Villemagne, V. L., Burnham, S., Bourgeat, P., Brown, B., Ellis, K. A., Salvado, O., Szoeke, C., 
Macaulay, S. L., Martins, R., Maruff, P., Ames, D., Rowe, C. C., Masters, C. L., & Australian 
Imaging Biomarkers Lifestyle Research Group. (2013). Amyloid beta deposition, 
neurodegeneration, and cognitive decline in sporadic Alzheimer's disease: a prospective cohort 
study. Lancet Neurol, 12(4), 357-367. doi:10.1016/S1474-4422(13)70044-9 
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Yates, P., Piguet, O., Pejoska, S., Dore, V., Yanai, K., Masters, C. L., Kudo, Y., Rowe, C. C., 
& Okamura, N. (2014). In vivo evaluation of a novel tau imaging tracer for Alzheimer's 
disease. Eur J Nucl Med Mol Imaging, 41(5), 816-826. doi:10.1007/s00259-013-2681-7 
Villemagne, V. L., Mulligan, R. S., Pejoska, S., Ong, K., Jones, G., O'Keefe, G., Chan, J. G., Young, 
K., Tochon-Danguy, H., Masters, C. L., & Rowe, C. C. (2012). Comparison of 11C-PiB and 
18F-florbetaben for Abeta imaging in ageing and Alzheimer's disease. Eur J Nucl Med Mol 
Imaging, 39(6), 983-989. doi:10.1007/s00259-012-2088-x 
 
 

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TABLE OF CONTENTS 
 
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TITLE 
Longitudinal evaluation of [18F]MK-6240 as a novel tau PET radiotracer in subjects 
with Alzheimer’s disease or mild cognitive impairment compared to healthy 
volunteers  
TEST PRODUCT 
[18F]MK-6240  
STUDY CENTER 
University of Wisconsin School of Medicine and Public Health 
TRIAL OBJECTIVES  
The overall goal of this protocol is to characterize the longitudinal change in tau 
burden using [18F]MK-6240.  Data from this study may be used to inform the design 
of future therapeutic trials utilizing [18F]MK-6240 as a marker of disease 
progression.  
The primary objectives of this study are: 
x 
To characterize the longitudinal change in [18F]MK-6240 brain uptake 
at 26 (6 months) and 52 (12 months) weeks compared to baseline in 
subjects with Alzheimer’s disease (AD) dementia, mild cognitive 
impairment (MCI) and healthy volunteers (HV).   
x 
To correlate the changes in [18F]MK-6240 uptake and changes in 
clinical cognitive assessments (MMSE, ADAS-cog and CDR) 
The secondary objectives of this study are: 
x 
To characterize the longitudinal change in [18F]MK-6240 brain uptake 
at 104 (24 months) weeks compared to baseline in subjects with AD 
dementia, MCI and healthy volunteers. 
x 
To evaluate cross-sectional comparison of [18F]MK-6240 uptake in 
AD, MCI and HV at baseline 26, 52 and 104 weeks  
 
STUDY DESIGN 
This is a longitudinal, observational study evaluating the imaging characteristics of 
the tau PET radioligand [18F]MK-6240 in AD, MCI and HV subjects. Up to 42 
subjects including approximately 28 MCI/mild AD subjects, up to 5 moderate AD 
subjects, and 9 similarly aged HV subjects will be consented and screened.  
Imaging procedures include [11C]PiB, [18F]MK-6240 PET and structural MRI.  
All subjects who complete at least one [18F]MK-6240 PET imaging session will be 
considered enrolled in the study. As many as 28 MCI/mild AD subjects, 5 moderate 
AD subjects, and 9 similarly aged HV subjects may complete an evaluable 
baseline [18F]MK-6240 PET scan to enable at least 23 subjects (14 MCI/mild AD, 
3 moderate AD, 6 HV subjects) to complete the 24 month follow up.  Subjects who 
discontinue prior to completing the 12-month [18F]MK-6240 PET scan may be 
replaced in the study until a total of 15 patients (MCI/AD) complete the 12 month 
PET imaging session. Subjects that complete the 12-month visit but wish to 
abandon the study before the 24-month visit will be given the option to have a final 
evaluation any time between 18 and 24 months. 
All subjects (or their legal authorized representative when applicable) will provide 
informed consent before any study procedures are performed.  The Screening 
procedures will occur within 60 days prior to baseline [18F]MK-6240 imaging and 
will include a brief cognitive assessment, review of medical history and 
medications, physical examination, [11C]PiB PET imaging and brain MRI. 
 


Version 2, May 18, 2020 
 
                                           
Page 4 of 13 
[11C]PiB and MRI IMAGING: 
As part of the Screening Visit, subjects will complete structural brain MRI imaging 
which will be used for eligibility evaluation, co-registration with PET imaging and 
volumetric analysis.   
If an evaluable PiB scan has been acquired and is available for use in this study 
and occurred within 12 months of screening, the scan will not be repeated. 
Otherwise, [11C]PiB PET imaging will be obtained at screening to evaluate for 
amyloid deposition. Subjects will be considered amyloid positive if [11C]PiB DVR 
(distribution volume ratio) imaging demonstrates amyloid deposition based on 
qualitative read or DVR index value >1.20.  
For the [11C]PIB PET imaging session, subjects will receive a single IV bolus 
injection target dose of 15 mCi r 20% of [11C]PIB and scanned dynamically for 70 
minutes. 
 
[18F]MK-6240 PET IMAGING VISITS:  
Subjects will complete [18F]MK-6240 PET imaging at four time points:  Baseline, 6 
months, 12 months and 24 months. [18F]MK-6240 is administered intravenously at 
a target dose of 185 MBq (5 mCi ) plus or minus 20%.  Image acquisition will occur 
from 70 to 120 minutes post-injection. 
A physician or physician representative will evaluate the subject for adverse events 
prior to leaving the imaging center and will discharge subjects when determined 
medically stable.  A follow-up phone call to the subject will be conducted by study 
staff within 4 days (±2 days) post-injection of [18F]MK-6240 to confirm subject well-
being and to collect information regarding new adverse or ongoing events.    
The primary outcome for [18F]MK-6240 imaging will be the standardized uptake 
value ratio (SUVR).  The reference region is the inferior cerebellum gray matter. A 
standardized volume of interest (VOI) template will be used to quantitatively 
measure [18F]MK-6240 tracer uptake in regions with expected tau pathology.   
INCLUSION/ 
EXCLUSION 
CRITERIA 
Healthy volunteer subjects and MCI/AD patients who are medically stable and 
meet the inclusion criteria and do not meet any of the exclusion criteria will be 
eligible for enrollment into the study. 
 
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x 
Signed and dated written informed consent must be obtained from the 
subject or the subject’s legally authorized representative or caregiver (if 
applicable) to enter the study and before any assessment is performed. 
x 
Pregnancy: Participant is not pregnant at the time of the PET and MRI 
imaging exams. Urine pregnancy tests will be conducted as needed with 
pre-menopausal women who are of child-bearing potential. 
x 
Willing and able to undergo study procedures and study schedule 
x 
Availability of a study partner who has frequent and sufficient contact 
with the subject and is able to provide accurate information regarding 
the subject’s cognitive and functional abilities, agrees to accompany the 
subject and provide information at visits, and signs the necessary 
consent form. The study partner must have sufficient cognitive capacity, 
in the judgment of the investigator, to accurately report upon the 
subject’s behavior and cognitive and functional abilities.  
x 
Males and females between the age of 50 and 85 (inclusive).  


Version 2, May 18, 2020 
 
                                           
Page 5 of 13 
x 
Healthy with no clinically relevant finding on physical examination at 
screening and upon reporting for the Baseline [18F]MK-6240  imaging 
visit. 
 
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x 
Normal Cognition based on cognitive results at screening.  
x 
Healthy with no clinically relevant finding on physical examination at 
screening and upon reporting for the Baseline [18F]MK-6240 imaging 
visit. 
x 
CDR global score =0 
 
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x 
Have screening [11C]PiB PET imaging demonstrating amyloid binding 
based on qualitative read or DVR index value >1.20. 
x 
MMSE score 26-30 (inclusive), CDR global score 0.5 for subjects with 
MCI 
x 
MMSE score 22-26 (inclusive), CDR global score 0.5 or 1 for subjects 
with mild dementia due to AD  
x 
MMSE score 16-21 (inclusive), CDR global score 1-2 for subjects with 
moderate dementia due to AD  
x 
Subjects with MCI must meet 2018 research criteria for MCI (Jack et al., 
2018). 
x 
Subjects with dementia must meet 2018 research criteria for dementia 
(Jack et al., 2018). 
x 
A structural brain MRI with no evidence of non-AD disease to account 
for dementia or MRI exclusion criteria. 

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x 
Subject has received an investigational drug or device within 30 days of 
screening. 
x 
For women, pregnant, lactating or breastfeeding or intention to become 
pregnant. 
x 
Evidence of unstable or untreated clinically significant gastrointestinal, 
cardiovascular, hepatic, renal, hematological, neoplastic, endocrine, 
alternative neurological, immunodeficiency, pulmonary, or other disorder 
or disease. Stable, treated chronic medical conditions like hypertension, 
hypercholesterolemia, diabetes mellitus, non-metastatic dermatologic or 
prostatic cancer, etc. are acceptable as long as they do not, in the study 
investigator’s opinion, contribute to cognitive dysfunction or limit 
participation in study procedures. 
x 
Any illness or other consideration that makes it unlikely that the subject 
will be able to complete the 24-month study. 
x 
Current or prior history (within past 5 years) of significant alcohol or 
substance abuse as determined by the investigator. 
x 
Psychiatric disorders that may interfere with the study including current 
major Axis I DSM-V disorders including but not limited to severe Major 
depression, current or history of bipolar I disorder, or schizophrenia.  
x 
Non-English speakers or subjects who are unable to comprehend study 
materials are excluded at entry 
x 
MRI exclusion criteria include: Findings that may be responsible for 
neurologic status of the subject such as significant evidence of 
cerebrovascular disease with multiple infarcts, infectious disease, 


Version 2, May 18, 2020 
 
                                           
Page 6 of 13 
space-occupying lesion, normal pressure hydrocephalus, CNS trauma, 
or any other structural abnormality that may impact cognition or image 
analysis, as judged by the investigator. 
x 
MRI-incompatible implants or devices such as certain cardiac 
pacemakers or defibrillators, insulin pumps, cochlear implants, metallic 
ocular foreign body, implanted neural stimulators, CNS aneurysm clips 
and other medical implants that have not been certified for MRI, or 
history of claustrophobia in MRI that prevents completion of MRI 
protocol. 
x 
Treatment with any therapeutic molecule that targets Aȡ or tau within 
12 months prior to screening.  
 
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For each subject participating, the duration of study participation will be 
approximately 26 months including a 60-day screening period and 24-month 
longitudinal assessment period. 
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[18F]MK-6240 and [11C]PiB are investigational PET radiotracers that will be 
synthesized in accordance with FDA IND applications for each tracer. 
All subjects will receive one injection of [11C]PiB (at screening only) and up to four 
injections of [18F]MK-6240 during the course of their participation in this 26 month 
study.  
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DEMOGRAPHICS 
The demographic and baseline characteristics will be summarized according to the 
clinical group (HV, MCI and AD) using descriptive statistics for continuous 
variables and using frequency count and percentage for discrete variables.   
 
 
ANALYSIS OF STUDY 
OBJECTIVES 
 
 
 
 
 
 
 
 
 
The change in [18F]MK-6240 uptake (e.g. composite and regional SUVR, voxel 
based statistics or change in tau distribution) will be determined by estimating the 
change from Baseline to each follow-up visit (6, 12 and 24 months).  The change 
in [18F]MK-6240 uptake will be compared among the groups (AD, MCI and HV 
subjects).   
The relationship between the change in [18F]MK-6240 uptake (e.g. composite and 
regional SUVR, voxel based statistics or change in tau distribution) and change in 
clinical severity or cognitive outcomes will be analyzed in AD dementia, MCI and 
HV subjects.  In addition, the correlation between baseline [18F]MK-6240 uptake 
and baseline clinical endpoints will be evaluated in all subjects. 
Cross-sectional comparisons will be made among the clinical groups (AD, MCI and 
HV subjects) at Baseline, 6, 12 and 24 months for the following measures: [18F]MK-
6240 uptake (composite and regional SUVR), neuropsychological testing (MMSE, 
CDR, ADAS-cog), MRI markers of atrophy such as hippocampal volume. 
 
 
 


Version 2, May 18, 2020 
 
                                           
Page 7 of 13 
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Neurofibrillary tangles begin during the preclinical phase of AD, and by the time of very mild 
dementia neurofibrillary tangles are well formed in predictable staged patterns (Braak & 
Braak, 1990; Braak et al., 1993). However, the rate of temporal change in neurofibrillary 
tangle burden in individual cases is poorly understood.  Until recently, the information about 
the temporal and spatial signal from neurofibrillary tangle (tau related) pathology in AD has 
come from neuropathology studies of brain bank cases (Gomez-Isla et al., 1996) and in life 
from CSF tau protein levels which have no spatial information and suffer from lack of 
standardized assays from lab to lab (Mattsson et al., 2013).  The advent of tau positron 
emission tomography (PET) imaging using compounds (Chien et al., 2014; Maruyama et al., 
2013; Villemagne et al., 2014) such as [F-18]AV1451 and now [F-18]MK6240 (Hostetler et 
al., 2016; Lohith et al., 2018) hold promise of making major breakthroughs in diagnosing AD 
accurately and characterizing its rate of progression. 
[18F]MK-6240 has been previously evaluated by several groups including ours (Betthauser 
et al., 2018) demonstrating substantial NFT deposition in the AD subjects and no or little 
evidence for tau binding in the HV subjects in the absence of amyloid. This study aims to 
evaluate the longitudinal change in tau burden using [18F]MK-6240 PET imaging in relation to 
cognitive and functional metrics.  

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The primary objectives of this study is: 
x To estimate rates of longitudinal change in [18F]MK-6240 brain uptake at 26 and 52 
weeks compared to baseline in subjects with dementia due to AD, mild cognitive 
impairment (MCI) and healthy volunteers (HV).   
x To correlate the changes in [18F]MK-6240 uptake and changes in clinical cognitive 
assessments (MMSE, ADAS-cog and CDR).   
 6HFRQGDU\2EMHFWLYHV
The secondary objectives of this study are: 
x To estimate rates of longitudinal change in [18F]MK-6240 brain uptake at 104 (24 
months) weeks compared to baseline in subjects with dementia due to AD, mild 
cognitive impairment and healthy volunteers. 
x To evaluate cross-sectional comparison of [18F]MK-6240 uptake in AD, MCI and HV 
at baseline 26, 52 and 104 weeks  

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This is a longitudinal, observational study evaluating the imaging characteristics of the tau PET 
radioligand [18F]MK-6240 in AD, MCI and HV subjects. Up to 28 MCI/mild AD subjects, up to 5 


Version 2, May 18, 2020 
 
                                           
Page 8 of 13 
moderate AD subjects, and up to 9 similarly aged HV subjects will be enrolled at the University 
of Wisconsin-Madison. Recruitment as well as screening and longitudinal clinical activities, 
including MRI, [11C]PiB and [18F]MK-6240 PET imaging, will be completed. The general design 
of the study is provided in 7DEOH.  
 
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The MRI, PiB and [18F]MK-6240 PET images will be co-registered for anatomy-based definition 
of regions of interest (ROI) for analysis of regional [18F]MK-6240 binding/uptake. The PET 
analyses will include application of spatially standardized region of interest (ROI) templates to 
assess tracer uptake and quantification.  Standardized Uptake Value Ratios (SUVR) will be 
calculated as described by Betthauser et al 2018 and ROIs extracted that represent Braak and 
Braak staging.  
Tau Braak and Braak stage equivalent regions of interest using the Harvard Oxford Brain atlas 
for defining regions of interest bilaterally: 
Stage I: entorhinal cortex average SUVR 
Stage II: Hippocampus and amygdala average SUVR 
Stage III: fusiform average SUVR 
Stage IV: Inferior temporal and middle temporal gyrus average SUVR 
Stage V: Superior temporal gyrus average SUVR 
Stage VI: Cuneus and pericalcarine cortex average SUVR 
 
Amyloid load:  
PIB Index: is comprised of the average signal extracted from the DVR image of eight bilateral 
ROIs including the anterior cingulate, posterior cingulate, precuneus, angular gyrus, 
supramarginal gyrus, superior temporal gyrus, middle temporal gyrus, medial orbital gyrus.  
Visual rating: As described in Johnson et al 2014 a rating of elevated, not elevated or 
indeterminate is assessed for each amyloid scan. 
 
MRI: 
Hippocampal volume: obtained using FIRST/FSL and adjusted for total intracranial volume 
using a regression approach. 
Total atrophy: expressed as a ratio of the volume of segmented CSF to the volume of 
segmented brain (gray + white matter). 
  


Version 2, May 18, 2020 
 
                                           
Page 9 of 13 
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General approach: Because the sample sizes are small, and because the goal of the project is 
to characterize rates of change by clinical status, the objectives of the analyses are largely 
descriptive in nature.  
 
The demographic and baseline characteristics will be summarized according to the clinical 
group (HV, MCI, mild or moderate AD) using descriptive statistics for continuous variables and 
using frequency count and percentage for discrete variables.  Plots of relevant variables will be 
examined for skewness and transformed as necessary prior to any analyses. 
Descriptive statistics and counts (with histograms when relevant) will be ascertained for the 
following variables by diagnostic group:   
Age, sex, education, race/ethnicity;  ADAS-Cog total score and ADAS-Cog13 subscore, MMSE 
score; CDR-sum and weighted scores; Amyloid status and PIB index score; MK6240 estimated 
Braak stage and SUVR values for each of six regions of interest representing each Braak 
Stage; hippocampal volume (corrected for total intracranial volume) and estimate whole brain 
atrophy (CSF volume to brain volume). 
 
The Baseline [18F]MK-6240 binding will be compared among the AD subjects at different stages 
of the disease, and HV groups descriptively, quantitatively and visually by graphical plots. A 
primary region of interest will be comprised of the average signal in the entorhinal cortex, 
amygdala, hippocampus, and anterior fusiform gyrus [18F]MK-6240binding in AD at different 
stages of the disease, and HV binding across multiple regions will be compared.Within the AD 
groups, the distribution and binding of [11C]PiB will be compared to the [18F]MK-6240 binding 
across multiple regions.  
 
Cross-sectional Spearman correlations will be computed by group at Baseline, 6, 12 and 24 
months for the following measures: [18F]MK-6240 uptake neuropsychological testing (MMSE, 
CDR-SB, ADAS-cog), hippocampal volume and whole brain atrophy. 
 
 /RQJLWXGLQDO$QDO\VLV
The primary objective of this imaging trial is to evaluate the longitudinal change in [18F]MK-
6240. Composite and regional SUVRs will be determined for each of the [18F]MK-6240 imaging 
sessions (Baseline, 6-month, 12-month, and 24-month) in the six specific regions 
(approximating Braak stages) as described above. Change in tau regional deposition as 
measured by [18F]MK-6240 will be determined by estimating the mean change from baseline 
to each follow-up visit for each ROI by diagnostic group. The mean change and standard 
deviation will be computed for each region and group. These regional means and SDs by region 
and group are the primary objectives of the project. The Kruskal-Wallis test will be performed 
to determine if rates of change differ by group. 


Version 2, May 18, 2020 
 
                                           
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The relationship between the change in tau deposition by [18F]MK-6240 and baseline PIB 
status will be assessed with Spearman correlation.   
 
 6DPSOH6L]H
The sample size for this study was determined by practical considerations and is not based on 
statistical power calculations.  Up to 42 subjects maybe enroll in this study or no less than 15 
MCI/mild AD subject, 3 moderate AD subjects and 5 similarly aged healthy volunteers all with 
a least the 12 month scan.   
 
 (1'32,176
The primary endpoint is change in MK6240 binding from baseline to 12 months in a composite 
region comprising the entorhinal cortex, amygdala, hippocampus and anterior fusiform. The 
secondary enpoints include 6 and 24 month change. 
 
 0,66,1*9$/8(6
Missing values in a longitudinal study of persons with dementia is expected. A closeout visit 
will be completed when possible. Imputation methods will be utilized and missingness will be 
assumed to be ‘not random’.  
 
 4&3/$16
 
Image Data: 
The principal investigator has oversight of image quality at the institution as established in the 
protocol and technical documents including the PET Imaging Manual, MR Imaging Manual, 
Image Charter and Data Transfer Specifications. The operations of the image core as hosted 
by Bioclinica will be conducted in accordance with Bioclinica’s standard operating procedures 
in accordance with the clinical protocol and technical documents. All image data will be 
submitted to the image core online through SMART Submitt as hosted by Bioclinica. The final 
database will be provided to the institution in accordance with the Data Transfer Specification. 
Clinical Data: 
All data will be submitted through the internet via the electronic data capture system hosted by 
Statking Clinical Services. Data for this study will be entered and accepted from the site into 
TrialMaster, a 21 CFR 11 compliant system in accordance with the User Completion Guidelines 
and managed by Statking Clinical Services in accordance with the Data Management Plan and 


Version 2, May 18, 2020 
 
                                           
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Statking Clinical Services SOPs. The electronic database will be locked upon completion of the 
last iCRFs, the last resolved query and the completion of the QC of the data. After the electronic 
database has been locked, per SCS’s SOPs, the final study database will be provided to the 
institution in accordance with the Data Transfer Plan. 
The institution will conduct quality oversight of all trial data in accordance with the monitoring 
plan perform quality control and quality assurance checks on the clinical study data.  
 
 352*5$00,1*3/$16
Statistics will be programmed in R and scripts will be made available for inspection/input and 
use by study sponsors and other stake holders. 
 
 
 
 
 


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
5()(5(1&(6
Betthauser, T. J., Cody, K. A., Zammit, M. D., Murali, D., Converse, A. K., Barnhart, T. E., 
Stone, C. K., Rowley, H. A., Johnson, S. C., & Christian, B. T. (2018). In vivo 
characterization and quantification of neurofibrillary tau PET radioligand [F18]MK-6240 
in humans from Alzheimer's disease dementia to young controls. Journal of Nuclear 
Medicine, in press. doi:10.1101/290064 
Braak, H., & Braak, E. (1990). Neurofibrillary changes confined to the entorhinal region and 
an abundance of cortical amyloid in cases of presenile and senile dementia. Acta 
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Chien, D. T., Szardenings, A. K., Bahri, S., Walsh, J. C., Mu, F., Xia, C., Shankle, W. R., 
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results with the novel PHF-tau radioligand [F18]-T808. J Alzheimers Dis, 38(1), 171-
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denoising with HYPR processing. J Nucl Med, 51(7), 1147-1154. 
doi:10.2967/jnumed.109.073999 
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Holtzman, D. M., Jagust, W., Jessen, F., Karlawish, J., Liu, E., Molinuevo, J. L., 
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Forman, M., Stoch, A., Sur, C., & Struyk, A. (2018). First-in-human brain imaging of 
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N., Okamura, N., Furumoto, S., Kudo, Y., Chang, Q., Saido, T. C., Takashima, A., 
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