A Three-Part Trial to Qualify [11C]MK-6884 Positron Emission Tomography for Use as a Biomarker for Regional M4 PAM Receptor Density Quantification in the Human Brain
Phase: PHASE1
Conditions: Alzheimer's Disease
Sponsor: Merck Sharp & Dohme LLC

Official Protocol Title: 
NCT number: 
NCT02621606  
Document Date: 
24-May-2017
A Three-Part Trial to Qualify [11C]MK-6884 Positron Emission 
Tomography for Use as a
Biomarker for Regional M4 PAM Receptor Density Quantification 
in the Human Brain.

Product:  MK-6884 
1
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24-May-2017
Confidential
THIS PROTOCOL AMENDMENT AND ALL OF THE INFORMATION RELATING 
TO IT ARE CONFIDENTIAL AND PROPRIETARY PROPERTY OF MERCK 
SHARP & DOHME CORP., A SUBSIDIARY OF MERCK &
CO., INC., 
WHITEHOUSE STATION, NJ, U.S.A.
SPONSOR:
Merck Sharp & Dohme Corp., a subsidiary of Merck & Co., Inc. 
(hereafter referred to as the Sponsor or Merck)
One Merck Drive
P.O. Box 100
Whitehouse Station, New Jersey, 08889-0100, U.S.A.
Protocol-specific Sponsor Contact information can be found in the Investigator Trial File 
Binder (or equivalent).
TITLE:
A Three-Part Trial to Qualify [11C]MK-6884 Positron Emission Tomography for Use as a 
Biomarker for Regional M4 PAM Receptor Density Quantification in the Human Brain
IND NUMBER:  127,788
EudraCT NUMBER:  2015-001631-20
 
 
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TABLE OF CONTENTS
SUMMARY OF CHANGES.................................................................................................. 9
1.0
TRIAL SUMMARY.................................................................................................. 11
2.0
TRIAL DESIGN........................................................................................................ 11
Trial Design ........................................................................................................... 11
2.1
Trial Diagram........................................................................................................ 14
2.2
3.0
OBJECTIVE(S) & HYPOTHESIS(ES).................................................................. 15
Primary Objective(s) & Hypothesis(es) .............................................................. 15
3.1
Secondary Objective(s) & Hypothesis(es)........................................................... 16
3.2
Exploratory Objective .......................................................................................... 16
3.3
4.0
BACKGROUND & RATIONALE.......................................................................... 16
Background ........................................................................................................... 16
4.1
Pharmaceutical and Therapeutic Background .................................................... 17
4.1.1
Rationale................................................................................................................ 17
4.2
Rationale for the Trial and Selected Subject Population .................................... 17
4.2.1
Rationale for Dose Selection/Regimen/Modification ......................................... 21
4.2.2
4.2.2.1
Maximum Dose/Exposure for This Trial..................................................... 22
4.2.2.2
Rationale for Dose Interval and Trial Design .............................................. 23
Rationale for Endpoints ...................................................................................... 24
4.2.3
4.2.3.1
Efficacy Endpoints....................................................................................... 24
4.2.3.2
Safety Endpoints .......................................................................................... 25
4.2.3.3
Planned Exploratory Biomarker Research................................................... 25
4.2.3.4
Future Biomedical Research........................................................................ 25
Benefit/Risk ........................................................................................................... 25
4.3
5.0
METHODOLOGY ................................................................................................... 26
Entry Criteria........................................................................................................ 26
5.1
Diagnosis/Condition for Entry into the Trial ...................................................... 26
5.1.1
Subject Inclusion Criteria.................................................................................... 26
5.1.2
Subject Exclusion Criteria .................................................................................. 29
5.1.3
 
 
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Trial Treatment(s) ................................................................................................ 35
5.2
Dose Selection .................................................................................................... 35
5.2.1
5.2.1.1
Dose Selection (Preparation) ....................................................................... 35
Timing of Dose Administration .......................................................................... 36
5.2.2
Trial Blinding/Masking....................................................................................... 36
5.2.3
Randomization or Treatment Allocation............................................................ 36
5.3
Stratification.......................................................................................................... 36
5.4
Concomitant Medications/Vaccinations (Allowed & Prohibited).................... 36
5.5
Rescue Medications & Supportive Care............................................................. 39
5.6
Diet/Activity/Other Considerations..................................................................... 39
5.7
Diet...................................................................................................................... 39
5.7.1
Fruit Juice Restrictions ....................................................................................... 39
5.7.2
Alcohol, Caffeine, Tobacco, Activity Restrictions ............................................. 39
5.7.3
5.7.3.1
Alcohol......................................................................................................... 39
5.7.3.2
Caffeine........................................................................................................ 40
5.7.3.3
Tobacco........................................................................................................ 40
5.7.3.4
Activity ........................................................................................................ 40
Contraception and Pregnancy Testing ................................................................ 40
5.7.4
5.7.4.1
Contraception............................................................................................... 40
5.7.4.2
Pregnancy Testing........................................................................................ 41
Other ................................................................................................................... 41
5.7.5
Subject Withdrawal/Discontinuation Criteria................................................... 41
5.8
Subject Replacement Strategy............................................................................. 42
5.9
Beginning and End of the Trial ........................................................................... 42
5.10
Clinical Criteria for Early Trial Termination ................................................... 43
5.11
6.0
TRIAL FLOW CHART ........................................................................................... 44
Trial Flow Chart Part I........................................................................................ 44
6.1.1
Trial Flow Chart Part II....................................................................................... 47
6.1.2
Trial Flow Chart Part III ..................................................................................... 50
6.1.3
7.0
TRIAL PROCEDURES ........................................................................................... 53
Trial Procedures ................................................................................................... 53
7.1
Administrative Procedures.................................................................................. 53
7.1.1
 
 
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7.1.1.1
Informed Consent......................................................................................... 53
7.1.1.1.1
General Informed Consent.................................................................... 53
7.1.1.1.2
Consent and Collection of Specimens for Future Biomedical 
Research................................................................................................ 54
7.1.1.2
Inclusion/Exclusion Criteria ........................................................................ 54
7.1.1.3
Subject Identification Card .......................................................................... 54
7.1.1.4
Medical History ........................................................................................... 54
7.1.1.5
Prior and Concomitant Medications Review ............................................... 54
7.1.1.5.1
Prior Medications.................................................................................. 54
7.1.1.5.2
Concomitant Medications..................................................................... 54
7.1.1.6
Assignment of Screening Number............................................................... 55
7.1.1.7
Assignment of Treatment/Randomization Number ..................................... 55
7.1.1.8
Trial Compliance (Medication/Diet/Activity/Other) ................................... 55
Clinical Procedures/Assessments........................................................................ 55
7.1.2
Laboratory Procedures/Assessments .................................................................. 57
7.1.3
7.1.3.1
Laboratory Safety Evaluations (Hematology, Chemistry and Urinalysis) .. 58
7.1.3.2
Pharmacokinetic/Pharmacodynamic Evaluations ........................................ 59
7.1.3.2.1
Blood Collection for [11C]MK-6884 Tracer Kinetics (Parts I and II) .. 59
7.1.3.2.2
Blood Collection for Plasma Donepezil or Rivastigmine (Part III)...... 59
7.1.3.2.3
Blood Collection for Plasma AChE Activity (Part III)......................... 59
7.1.3.3
Planned Genetic Analysis Sample Collection.............................................. 59
7.1.3.4
Future Biomedical Research Sample Collection ......................................... 59
Other Procedures................................................................................................. 60
7.1.4
7.1.4.1
Withdrawal/Discontinuation........................................................................ 60
7.1.4.1.1
Withdrawal From Future Biomedical Research ................................... 60
7.1.4.2
Blinding/Unblinding .................................................................................... 60
7.1.4.3
Domiciling ................................................................................................... 60
7.1.4.4
Calibration of Critical Equipment................................................................ 61
Visit Requirements.............................................................................................. 61
7.1.5
7.1.5.1
Screening (Part I, Part II and Part III).......................................................... 61
7.1.5.2
Treatment Period (Part I, Part II, and Part III)............................................. 61
7.1.5.3
Post-Trial...................................................................................................... 66
7.1.5.4
Critical Procedures Based on Trial Objectives: Timing of Procedure......... 66
 
 
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7.1.5.5
Trial 
Design/Dosing/Procedures Modifications Permitted 
within 
Protocol Parameters ..................................................................................... 67
Assessing and Recording Adverse Events .......................................................... 68
7.2
Definition of an Overdose for This Protocol and Reporting of Overdose to 
7.2.1
the Sponsor.......................................................................................................... 69
Reporting of Pregnancy and Lactation to the Sponsor ....................................... 69
7.2.2
Immediate Reporting of Adverse Events to the Sponsor.................................... 70
7.2.3
7.2.3.1
Serious Adverse Events ............................................................................... 70
7.2.3.2
Events of Clinical Interest............................................................................ 71
Evaluating Adverse Events ................................................................................. 72
7.2.4
Sponsor Responsibility for Reporting Adverse Events ...................................... 75
7.2.5
8.0
STATISTICAL ANALYSIS PLAN ........................................................................ 75
Statistical Analysis Plan Summary ..................................................................... 75
8.1
Statistical Analysis Plan ....................................................................................... 76
8.2
Hypotheses.......................................................................................................... 76
8.2.1
Analysis Endpoints ............................................................................................. 76
8.2.2
Approaches to Analyses...................................................................................... 77
8.2.3
Statistical Methods.............................................................................................. 77
8.2.4
Multiplicity ......................................................................................................... 80
8.2.5
Power .................................................................................................................. 80
8.2.6
9.0
LABELING, PACKAGING, STORAGE AND RETURN OF CLINICAL 
SUPPLIES ................................................................................................................. 80
Investigational Product ........................................................................................ 80
9.1
Packaging and Labeling Information ................................................................. 80
9.2
Supply of Precursor and Synthesis/Labeling of [11C]MK-6884......................... 80
9.2.1
Clinical Supplies Disclosure................................................................................. 81
9.3
Storage and Handling Requirements.................................................................. 81
9.4
Discard/Destruction/Returns and Reconciliation .............................................. 81
9.5
10.0
ADMINISTRATIVE AND REGULATORY DETAILS....................................... 82
Confidentiality....................................................................................................... 82
10.1
Confidentiality of Data ....................................................................................... 82
10.1.1
Confidentiality of Subject Records ..................................................................... 82
10.1.2
 
 
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Confidentiality of Investigator Information........................................................ 82
10.1.3
Confidentiality of IRB/IEC Information............................................................. 83
10.1.4
Compliance with Financial Disclosure Requirements....................................... 83
10.2
Compliance with Law, Audit and Debarment ................................................... 83
10.3
Compliance with Trial Registration and Results Posting Requirements ........ 85
10.4
Quality Management System............................................................................... 85
10.5
Data Management................................................................................................. 86
10.6
Publications ........................................................................................................... 86
10.7
11.0
LIST OF REFERENCES......................................................................................... 87
12.0
APPENDICES........................................................................................................... 88
Merck Code of Conduct for Clinical Trials........................................................ 88
12.1
Collection and Management of Specimens for Future Biomedical 
12.2
Research................................................................................................................. 90
Pharmacogenetics 
Informational 
Brochure 
for 
IRBs/IECs 
& 
12.3
Investigational Site Staff ...................................................................................... 94
Approximate Blood/Tissue Volumes Drawn/Collected by Trial Visit and 
12.4
by Sample Types ................................................................................................. 103
12-Lead Electrocardiogram Abnormality Criteria ......................................... 104
12.5
Algorithm for assessing Out-of-Range laboratory Values.............................. 106
12.6
13.0
SIGNATURES......................................................................................................... 107
Sponsor's Representative ................................................................................... 107
13.1
Investigator.......................................................................................................... 107
13.2
 
 
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LIST OF TABLES
Table 1
Study Design Scheme ............................................................................................. 15
Table 2
Trial Treatments...................................................................................................... 35
Table 3
Sample Allocation Schedule................................................................................... 36
Table 4
Laboratory Tests ..................................................................................................... 58
Table 5
Part I Procedures..................................................................................................... 62
Table 6
Part II Procedures.................................................................................................... 64
Table 7
Part III Procedures. ................................................................................................. 65
Table 8
Evaluating Adverse Events..................................................................................... 73
Table 9
Product Descriptions............................................................................................... 80
 
 
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LIST OF FIGURES
Figure 1
Study Design Part I ............................................................................................. 14
Figure 2
Study Design Part II............................................................................................ 14
Figure 3
Study Design Part III .......................................................................................... 15
 
 
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SUMMARY OF CHANGES
PRIMARY REASON(S) FOR THIS AMENDMENT:
Section Number (s)
Section Title(s)
Description of Change (s)
Rationale
5.1.3
Subject 
Exclusion 
Criteria: Part III
Updated exclusion criterion # 19 
regarding 
prior 
exposure 
to 
radiation to exclude subjects who 
underwent a radiological exam with 
a radiation burden exceeding 30 
mSv (change from 10 mSv).
Updated eligibility criterion to align with 
the level of radiation burden associated 
with 
radiological 
exams 
typically 
conducted at the Part III trial site. This 
change was made to expand on the 
potential pool of study participants who are 
under the care of the Part III
trial 
investigator.
6.1.3
Trial Flow Chart Part III
Removal of predose urine/blood 
drug screen and footnote “h”
associated with this procedure
Removed non-critical study procedure to 
reduce unnecessary burden on Alzheimer’s 
Disease (AD) study participants. Based on 
the nature of the study population, it is 
expected that any negative drug screen test 
results from the Screening Visit will not 
change prior to dosing for subjects already 
deemed eligible for the trial.  
 
 
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ADDITIONAL CHANGE(S) FOR THIS AMENDMENT:
Section Number (s)
Section Title (s)
Description of Change (s)
Rationale
4.2.2
Rationale 
for 
Dose 
Selection/ 
Regimen/Modification
Updated to include acceptable yearly 
limit
(Effective Dose [ED] <50 
mSv) for radiation exposure in the 
US.
Update to reflect acceptable annual limits 
for radiation dose in the geographic region 
where Part III is to be conducted.
6.1.3
Trial Flow Chart Part III
For footnotes “b” and “c” pertaining 
to the timing of vital signs and ECG 
measurements, the timing for end of 
scanning session is corrected to read 
“(~90 minutes post-dose)” instead of 
“(~2 hours post-dose)”.
Correction to align with PET scan 
duration (up to ~ 90 minutes) planned for 
Part III
7.1.4.3
Domiciling
Clarification that subjects in Part III 
of the study will report to the 
research center on Day 1 (whereas 
subjects in Part I of the study will 
report to the research center on Day 
-1)
Update 
to 
reflect 
operational 
logistics/study conduct at Part III trial site
7.1.5.1
Screening (Part I, Part II 
and Part III)
Clarified that screening can occur 
within the 4 week visit window.
Clarification on timing of screening 
procedures
7.1.5.2
Treatment Period (Part I, 
Part II, and Part III)
For Part III, Table 7 Clarified the 
sequence of procedures related to 
blood collections
Update 
to 
reflect 
operational 
logistics/study conduct at Part III trial site
 
 
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1.0 TRIAL SUMMARY
Abbreviated Title
[11C]MK-6884 Positron Emission Tomography Tracer Validation 
Trial
Trial Phase
Phase I
Clinical Indication
Alzheimer’s Disease (AD)
Trial Type
Interventional
Type of control
No treatment control
Route of administration
Intravenous (IV)
Trial Blinding
Unblinded Open-label
Treatment Groups
Part I: Single IV dose of approximately 370 MBq (~10 mCi, ≤ 4.9 µg) 
[11C]MK-6884 (healthy subjects)
Part II: Two separate IV doses of approximately 370 MBq (~10 mCi, 
≤ 4.9 µg) per dose [11C]MK-6884 (healthy elderly subjects)
Part III: Single IV dose of approximately 370 MBq (~10 mCi, ≤ 4.9 
µg) [11C]MK-6884 (moderate to severely impaired Alzheimer’s 
Disease patients)
Number of trial subjects
Up to 26 subjects will be enrolled.
Estimated duration of trial
The Sponsor estimates that the trial will require approximately 20
months from the time the first subject signs the informed consent until 
the last subject’s last study-related phone call or visit.
Duration of Participation
Each subject will participate in the trial for approximately 6-7 weeks
from the time the subject signs the Informed Consent Form (ICF) 
through the final contact (Parts I-III).  After a screening phase of 4
weeks, each subject will be receiving assigned treatment for 
approximately 1 day (Parts I and III) or up to 2 days (Part II).  After 
the end of treatment each subject will be followed for approximately
14 days for post study evaluation (Parts I-III).
2.0 TRIAL DESIGN
Trial Design
2.1
This is an open-label, 3-part study in healthy subjects (Parts I and II) and moderate to 
severely impaired Alzheimer’s disease (AD) patients (Part III) to be conducted in 
conformance with Good Clinical Practices.  The objective of the study is to investigate the 
safety and utility of [11C]MK-6884 as a research probe for quantifying regional receptor 
density of M4 muscarinic acetylcholine Positive Allosteric Modulators (PAMs) in the brain 
by Positron Emission Tomography (PET). All aspects of this study have been designed to 
qualify for conduct as a "microdose" study in accordance with ICH M3 (R2).
Only tracer doses (≤4.9 μg/dose) of [11C]MK-6884 will be administered during this 
investigation. No other drugs or chemical substances will be administered (except lidocaine 
for arterial catheter insertion).
 
 
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Part I
Part I is designed to investigate the safety and tolerability of [11C]MK-6884 and to estimate 
the radiation absorbed per unit of administered radioactivity in the whole body and internal 
organs of healthy subjects.  A single previously defined (IV dose of ~370 MBq (~10 mCi, ≤ 
4.9 µg) [11C]MK-6884 will be administered to subjects (estimate based on Rhesus study, not 
confirmed in human) followed by a series of whole body PET scans, clinical examinations 
and laboratory safety evaluations.  [11C]MK-6884 radiation doses for subsequent subjects 
may be adapted upwards or downwards after analysis of the actual dosimetry results of the 
initial subject(s), but will not exceed acceptable yearly limits for radiation exposure (see 
Section 7.1.5.5 for further details on adaptation of doses). A minimum of 3 subjects will be 
tested in Part I, but up to 3 additional subjects may be tested at the discretion of the 
investigator and Sponsor, if necessary (e.g., unexpected levels of variability, technical 
problems, etc).
Part II
Part II will only initiate if the Investigator and Sponsor agree there are no indications of 
medically meaningful radiochemical toxicity or undue radiation risks after an initial review 
of safety data from Part I (including clinical, clinical laboratory and radiation safety data).
Part II [11C]MK-6884 radiation doses may be adapted if indicated, based on actual data found 
during Part I (see Section 7.1.5.5 for further details on adaptation of doses).
Part II will begin the process of validating and qualifying [11C]MK-6884 as a M4 PAM tracer 
in humans. The parameter of interest to be quantified from the PET baseline scans will be 
nondisplaceable binding potential (BPND) or distribution volume (VT), an index of receptor 
availability. If needed, additional methods may also be employed, to more robustly 
characterize the tracer kinetics in both healthy and AD subjects. The possibility of reliably 
quantifying M4 receptor availability will be determined by measurement of the intra-subject 
baseline test-retest [T-RT] variability or within-subject coefficient of variation. A baseline 
magnetic resonance imaging (MRI) scan of the brain will be obtained for region-of-interest 
(ROI) delineation. Subjects will be administered 2 separate single IV doses of approximately 
370 MBq (10 mCi, ≤ 4.9 µg) [11C]MK-6884 with a brain PET/CT scan performed after each 
dose.  PET images of the brain will be obtained for up to approximately 90 minutes after 
each administration of [11C]MK-6884.  There will be a wash-out of at least 3 hours between
each drug administration to allow for most of the radioactivity from the first scan to decay 
prior to starting the second scan.  In case of technical difficulties, the duration between the 
two scans may be adjusted at the investigator’s discretion.  A minimum of 6 subjects will be 
tested in Part II.  Up to 4 additional subjects may be tested if unexpected levels of variability 
are observed in the first 6 subjects of Part II.  
Part III
In parallel with Part II, Part III will begin the process of validating and qualifying [11C]MK-
6884 as a M4 PAM PET tracer in AD patients based on the results of Part I and in 
comparison to an age matched population of healthy elderly subjects in Part II (i.e., the AD 
patients enrolled in Part III will be in the same age range [55 to 85 years of age, inclusive] as 
 
 
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the healthy elderly subjects enrolled into Part II).  Specifically, Part III will initiate upon 
completion of at least 3 healthy subjects in Part II for the validation of a reference region 
approach.  A baseline MRI scan of the brain will be obtained for ROI delineation and to 
ensure the MRI scan is consistent with a diagnosis of moderate to severe AD.  A cohort of up 
to 10 (target N=7 completing) moderate to severely impaired AD patients will be 
administered a single IV dose of approximately 370 MBq (10 mCi, ≤ 4.9 µg) [11C]MK-6884.  
A single brain scan will be performed after the dose, and positron emission images of the 
brain will be obtained for approximately 90 minutes after the administration of [11C]MK-
6884 to verify the BPND of the [11C]MK-6884 ligand. The scan duration can be shortened to 
approximately 60 minutes in the event that the AD patient cannot endure the 90 minutes 
scan..
Parts I, II, and III
Each part will be conducted with separate study populations (up to 6 healthy subjects for Part 
I; up to 10 elderly healthy subjects for Part II; up to 10 AD patients for Part III).  
Clinical and laboratory safety evaluations will be performed up to ~3 hours following 
administration of each dose of [11C]MK-6884.
In Part I, venous blood sampling will be 
performed during the PET scans for optimization of methods for measurement of the 
radiolabeled tracer metabolites. In Part II, arterial blood sampling for measurement of the 
radioligand concentration (and its metabolites) will be performed during the PET scans in
order to quantify the tracer kinetic modeling methods. This method utilizes an input function 
and will enable assessment of the possibility of performing the quantitative analysis of 
[11C]MK-6884 in subsequent studies without the need for arterial blood sampling. The 2 
doses of [11C]MK-6884 for scans 1 and 2 will be separated by sufficient time to allow for 
most of the radioactivity from the first scan to decay prior to starting the second scan. Scans 
1 and 2 will be performed on the same day or on separate (preferably consecutive) days. In 
case of technical difficulties, the duration between the two scans may be adjusted at the 
investigator's discretion. Imaging analysis will be initiated upon the completion of the first 3 
healthy subjects. If the reference region is validated to accurately assess tracer binding 
(BPND) and there is no need for continued arterial line monitoring of radioligand 
concentration and its metabolites, arterial blood sampling for measurement of radioactivity 
concentration and its metabolites will not be performed during the scanning session 
following administration of [11C]MK-6884 for the rest of the Part II subjects. A minimum of 
6 subjects will be tested in Part II, but this part has also been designed with some flexibility 
to allow for dosing of up to 4 additional subjects if unexpected levels of noise or variability 
are observed in the first 6 subjects of Part II.
In each Part, final clinical assessment will be conducted either shortly after the completion of 
the final scan (i.e., the second scan in Part II) or just prior to discharge which may be at ~ 24 
hours post final dose (if the subject is kept overnight at the investigator’s discretion). All 
adverse experiences will be reported from the signing of the informed consent through 14 
days post final dose. Assessment for potential adverse experiences will be conducted at ~24 
hours post dose either by phone or at the clinic, followed by an additional phone call 
conducted at 14 days post final dose. See Section 6.0 for additional details.
 
 
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Specific procedures to be performed during the trial, as well as their prescribed times and 
associated visit windows, are outlined in the Trial Flow Chart - Section 6.0. Details of each 
procedure are provided in Section 7.0 – Trial Procedures.
Because this is a Phase I assessment of MK-6884 in humans, the pharmacokinetic, 
pharmacodynamic and safety profiles of the compound are still being elucidated. This 
protocol is therefore written with some flexibility to accommodate the inherent dynamic 
nature of Phase I clinical trials. Please refer to Section 7.1.5 – Visit Requirements for 
examples of modifications permitted within the protocol parameters.
Trial Diagram
2.2
The trial design is depicted in Figure 1, Figure 2, Figure 3, and Table 1.
Figure 1
Study Design Part I 
Figure 2
Study Design Part II 
 
 
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Figure 3
Study Design Part III
Table 1
Study Design Scheme
Part Ia
Single IV dose of [11C]MK-6884
Whole Body PET scan
Part IIa,b
Brain MRI 
scan
Single IV dose of 
[11C]MK-6884
Brain PET scan
Single 
IV 
dose 
of 
[11C]MK-6884c
Brain PET scan
Part IIIa,b
Brain MRI 
scan
Single IV dose of [11C]MK-6884
Brain PET scan
a Up to 26 subjects (Parts I, II, and III) will be allocated to receive [11C]MK-6884. A single subject may only participate 
in one Part of the study.
b The suggested dose in Parts II and III may be adjusted based on evaluation of safety, tolerability and radiation 
dosimetry data from Part I.
c The second IV dose of [11C]MK-6884 will be administered at least 3 hours following the first administration.
3.0 OBJECTIVE(S) & HYPOTHESIS(ES)
Primary Objective(s) & Hypothesis(es)
3.1
Part I
1) Objective: To investigate the safety and tolerability of a single intravenous dose of 
[11C]MK-6884 administered to healthy adult subjects.
2) Objective: To estimate the whole body and internal organ radiation absorbed dose 
following administration of a single intravenous dose of [11C]MK-6884 in healthy 
adult subjects.
Hypothesis: Dosimetry calculations based on Part 1 data will support multiple 
[11C]MK-6884 injections in humans.
 
 
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Part II
1) Objective: To evaluate the safety and tolerability of two intravenous doses of 
[11C]MK-6884 administered to healthy elderly subjects.
2) Objective: To evaluate [11C]MK-6884 kinetics throughout the brain following 
intravenous administration and determine an index of baseline M4 receptor 
availability.
3) Objective: To evaluate intra-subject T-RT variability of the M4 receptor availability 
in brain following intravenous administration of two serial doses of [11C]MK-6884.
Hypothesis: The average intra-subject T-RT variability of M4 receptor density index 
measured from [11C]MK-6884 PET data is acceptable (≤ 20%).
Part III
1) Objective: To investigate the safety and tolerability of a single intravenous dose of 
[11C]MK-6884 administered to AD patients.
2) Objective: To determine [11C]MK-6884 regional brain distribution and index of 
baseline M4 receptor availability in AD patients
Secondary Objective(s) & Hypothesis(es)
3.2
There are no secondary objectives (or hypotheses) for this study.
Exploratory Objective
3.3
Parts I, II, and III
To explore the relationship between genetic variation and response to the treatment(s) 
administered.  Variation across the human genome may be analyzed for association with 
clinical data collected in this study.  
Part III only
To explore the relationship between [11C]MK-6884 brain regional M4 receptor density index, 
peripheral AChE activity, and AChEI concentration  
4.0 BACKGROUND & RATIONALE
Background
4.1
Refer to the Investigator’s Brochure (IB) for detailed background information on MK-6884.
Modulating the cholinergic system by specifically targeting the M4 muscarinic acetylcholine 
receptor (mAChR) is a novel approach to treat behavioral and perhaps certain cognitive 
symptoms in patients with Alzheimer’s disease (AD) and schizophrenia (SCZ). Clinical 
studies using xanomeline (a M1/M4 preferring mAChR agonist) have established that 
 
 
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targeting the muscarinic cholinergic system is a viable treatment for alleviating psychosis and 
behavioral disturbance symptoms in AD [1] and SCZ patients [2]. However, xanomeline, like 
other muscarinic agonists, ultimately failed in clinical development due to lack of adequate 
receptor subtype selectivity resulting in adverse side effects by activation of peripheral 
mAChRs. The development of an M4 PAM may overcome the challenges of developing 
selective orthosteric muscarinic agonists. 
Preclinical data have demonstrated that the binding affinity of a PAM to the target is directly 
dependent on the endogenous cholinergic tone, indicating the clinical utility of such a PET 
tracer is influenced by the level of cholinergic tone in AD. Although a substantial loss of 
cholinergic neurons in the cerebral cortex is an universal feature of advanced AD, 
histological data suggest the cholinergic neuron pathways of the striatum remain relatively 
intact.  
An evaluation of the binding sensitivity of a M4 PAM tracer to the potential difference in 
cholinergic tone in AD patients will inform the clinical development of a therapeutic.  
[11C]MK-6884, a novel PET ligand, has been preclinically qualified for target engagement of 
M4 PAMs and is being developed as a clinical research tool to facilitate the clinical 
development of M4 PAMs for AD.
Pharmaceutical and Therapeutic Background
4.1.1
[11C]MK-6884 is a novel PET ligand that is being developed as a clinical research tool to 
facilitate the clinical development of M4 PAMs for AD. MK-6884 selectively binds to and 
potentiates M4 receptor at its allosteric site as a PAM, with in vitro properties suitable for an 
M4 PAM PET tracer: high affinity (Ki < 5 nM), moderate lipophilicity (logP < 3.5), and low 
susceptibility for human P-glycoprotein (P-gp) (BA/AB ratio < 2).  It has been preclinically 
qualified for assessment of target engagement of M4 PAMs through determination of the 
occupancy and efficacy relationship and assessment of changes in cholinergic tone in non-
human primates. [11C]MK-6884 is anticipated to enable quantitative measurement of M4 
receptor occupancy (RO) in the brain as a function of drug pharmacokinetics (PK). 
The dosimetry and test-retest validation study with [11C]MK-6884 will be the first 
administration of MK-6884 or [11C]MK-6884 in humans.  Safety pharmacology, toxicology 
and radiation safety studies have been performed with [11C]MK-6884 in preclinical species 
and provide no contraindication to the initiation of clinical trials with in humans with this 
compound via the IV route.
[11C]MK-6884 is a non-biological, small molecule, low mass, high specific activity tracer 
that is classified by the Food and Drug Administration (FDA) as a Type 1 
radiopharmaceutical [3] and the European Union (EU) as a Class IIb radiopharmaceutical [4]
and is suitable for microdosing per ICH M3(R2) guidance for PET tracers.
Rationale
4.2
Rationale for the Trial and Selected Subject Population
4.2.1
Preclinical PET studies show [11C]MK-6884 provides a large M4 PAM specific signal in 
monkey brain, and in vitro data suggests human M4 density is sufficiently high for 
[11C]MK-6884 to provide a useful specific signal in in vivo PET studies. This first 
 
 
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investigation in humans is an open label, three part study designed to assess whether the 
safety, tolerability and signal characteristics (radiation dosimetry, signal magnitude, and T-
RT variability) of [11C]MK-6884 support its utility to interrogate M4 PAM RO.  
This 3-part study will be conducted in healthy adult male subjects and female subjects and 
also in age-matched moderate to severe AD patients (i.e., same age range as the healthy 
elderly).  Each part of the study will be conducted in a separate study population. The study 
design for [11C]MK-6884 conforms to standards in the field for measuring radiation 
dosimetry, baseline quantitative reproducibility (test-retest variability) and assessing 
radiopharmacological safety. It is intended for use in a small number of human subjects who 
will participate in medical research studies. It is not intended for development as a diagnostic 
imaging agent. It will not be developed for commercialization.
All aspects of this study have been designed to qualify for conduct as a microdose study in 
accordance with ICH M3 (R2) guidance.
Part I
Part I is designed to investigate the safety and tolerability of [11C]MK-6884 and estimate the 
radiation absorbed per unit of administered radioactivity. Safety will be assessed based on 
series of physical examinations, vital signs, ECGs and clinical safety laboratory 
measurements. Radiation safety will be assessed by estimating the radiation absorbed doses 
per unit administered radioactivity in the whole body and its internal organs. After tracer 
injection, dynamic whole body PET scans will be acquired for up to 6 physical half -lives of 
the radioisotope [half-life of carbon-11 (11C) is ~ 20 minutes]. The effective dose 
concentration of radioactivity in several organs will be measured as a function of time and 
used for radiation dose calculations. [11C]MK-6884 doses for subsequent subjects may be 
adapted after analysis of the actual dosimetry results of the initial subject(s) in this part of the 
study. [11C]MK-6884 administration to subsequent subjects will be separated by at least one 
day from the initial subject(s). 
Venous blood will be drawn for metabolite assessment and the relative [11C]MK-6884
fraction in plasma to optimize methods for measuring the radioactive material available for 
delivery to the brain.
The brain uptake information from the whole-body dosimetry scan will be used to perform an 
initial assessment of whether the tracer has suitable uptake in the regions of interest.
A minimum of 3 subjects will be tested in Part I, but up to 3 additional subjects may be 
tested, for a total of 6 subjects, if unexpected technical difficulties or levels of noise are 
encountered, at the discretion of the Investigator and Sponsor.
Rationale for Requirement for Mental Status Assessment of Older Subjects/Patients:
Parts II and III will enroll subjects between the ages of 55 to 85 years of age (inclusive) at the 
first visit. To control for the potential that subjects in Part II may harbor potentially 
confounding minor or undocumented dementia, healthy elderly subjects enrolled in Part II 
must demonstrate a Mini Mental State Exam (MMSE) score ≥ 27.  In Part III, the moderately
 
 
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to severely impaired AD patients to be enrolled must demonstrate a MMSE score ≤ 20, in 
addition to other qualifying mental and physical assessments, to affirm the etiology of the 
patient’s dementia as consistent with AD.
Part II:
Part II of this study will begin the process of validating and qualifying [11C]MK-6884 as a 
M4 PAM tracer in humans. Part II will only be initiated if there is no indication of
radiochemical toxicity, undue radiation risk or medically meaningful effect on physiology
observed during Part I based on review of the safety and radiation safety data. [11C]MK-6884 
doses administered in Part II may be adapted to insure that the maximum exposure remains 
below the yearly limit of 10 mSv and within the acceptable limits for healthy human 
volunteers (see Section 4.2.2, Rationale for Dose Selection). The possibility of reliably 
quantifying M4 receptor availability will be determined by measuring the intra-subject -TRT
variability. Subjects will be administered 2 separate IV doses of [11C]MK-6884 separated by 
sufficient time (at least 3 hours) to allow most of the radioactivity from the first 
administration to decay prior to administering the second dose. The 2 doses will be 
administered preferably on the same day in order to limit the number of arterial punctures to 
one per evaluation. An alternate day for the second dose may be scheduled in case of
technical difficulties at the discretion of the investigator.
An MRI scan of the brain will be obtained for ROI delineation. Positron emission images 
will be acquired for up to 2.0 hours after the administration of [11C]MK-6884. It is expected 
that 90 minutes will be sufficient to characterize the regional cerebral tracer kinetic curves. 
The scanning duration may be adjusted based on available data. In addition, a CT scan, to 
enable attenuation correction, will be performed either before or after the PET scan. Arterial 
blood sampling for quantification of total radioactivity and the relative [11C]MK-6884
fraction in plasma will be performed to provide a measure of radioactive material available in 
the brain. Arterial input function methodology is invasive and a non-invasive approach is 
preferable. In order to perform future studies non-invasively, a reference region (region in the 
brain devoid of M4 receptor) is necessary and will be assessed in this study. Clinical and 
laboratory safety evaluations will also be performed following administration of each dose of 
[11C]MK-6884.
A minimum of 6 subjects will be tested in Part II, but up to 4 additional subjects may be
tested, for a total of 10 subjects, if unexpected levels of noise or variability are encountered, 
at the discretion of the Investigator and Sponsor.
Part III:
Rationale for enrollment of moderate to severely impaired AD patients:  Early work 
indicates the binding affinity of an M4 PAM is influenced by the endogenous receptor 
agonist ACh tone such that the binding affinity of a PAM increases in proportion to ambient 
cholinergic tone. Importantly, there may not be sufficient endogenous ACh to observe M4 
PAM binding in AD, which is marked by decreased cholinergic tone in some neuronal 
populations as disease progresses. This risk may be mitigated to some degree by the 
observation that the major localization of M4 is relatively intact in the striatal regions of the 
 
 
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brain in AD.  However, should reductions in cholinergic tone be steep in these regions, this 
may have a significant impact on the utility of treatment based on an M4 PAM. Nonetheless, 
the use of an M4 PAM to treat cognitive and behavioral symptoms of AD may be appropriate 
to all stages of disease, should adequate ACh tone exist to support PAM binding.  Thus, AD 
patients with moderate to severe symptomatology will be enrolled in Part III to support 
evaluation of the ability a PAM to bind to the M4 receptor given the ambient ACh tone found 
across the range of disease severity.
Rationale for Requirement that AD Patients be Maintained on an AChEI Inhibitor:
Inhibitors of acetylcholine esterase exert a cognition enhancing effect through the elevation 
of presynaptic acetylcholine (ACh) levels.  AD patients administered such inhibitors are 
anticipated to possess a synaptic ACh tone that is greater than patients who are not on such 
inhibitors. Further, a majority of patients with moderate to severe AD symptoms are 
anticipated to be prescribed such inhibitors.  As [11C]MK-6884 is a M4 PAM whose binding 
potency is sensitive to ACh tone, patients administered AChEIs should offer the best
potential to quantify a PET signal in such patients.  Consequently, AD patients enrolled in 
Part III will be required to be maintained on a stable dose of a qualifying AChEI for at least 4 
weeks prior to screening and throughout participation in the study.  A target minimum of 3 
patients stably maintained on donepezil is highly desired for enrollment to ensure that 
sufficient AD patients on this AChEI are investigated to support the Part III exploratory 
objective.
Rationale for Use of Specific AChEIs:  The data obtained from AD patients on an AChEI 
will be used to support conclusions about ACh tone in these patients.  To this end, it is 
reasonable to restrict the selection of AChEIs allowable at enrollment to those capable of 
supporting a similar level of acetylcholine esterase inhibition under normal conditions of use.  
Allowable AChEIs for Part III are donepezil and rivastigmine.  Galantamine in particular, is 
not allowed as this agent harbors additional modes of interactions with the ACh signaling 
system that may confound the analysis of M4 PAM binding [3].
Part III Study conduct: In parallel with Part II, Part III will begin the process of validating 
and qualifying [11C]MK-6884 as a M4 PAM PET tracer in AD patients, based on the results 
of Part I and in comparison to age matched (i.e., same age range from 55 to 85 years of age) 
healthy elderly subjects in Part II.  
A baseline MRI scan of the brain will be obtained for ROI delineation and to ensure the MRI 
scan is consistent with a diagnosis of moderate to severe AD.  Each moderate to severe AD 
patient enrolled in this part will be administered a single IV dose of approximately 370 MBq 
(~10 mCi, ≤ 4.9 µg) [11C]MK-6884.  A single brain scan will be performed after the dose, 
and positron emission images of the brain will be obtained for approximately 90 minutes 
after the administration of [11C]MK-6884 to verify the BPND of the [11C]MK-6884 ligand.  
The scan duration in AD patients can be shortened to approximately 60 min in the event an
AD patient cannot endure the 90 minutes scan. 
A minimum of 7 moderate to severely impaired AD patients will be tested in Part III, but up 
to 3 additional AD patients may be tested, for a total of 10 AD patients, if unexpected levels 
of noise or variability are encountered, at the discretion of the Investigator and Sponsor.
 
 
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Rationale for Dose Selection/Regimen/Modification
4.2.2
The radioactive dose required to produce acceptable image quality in human brain is not 
known. The current study will begin the process of determining if specific binding can be 
reliably measured at acceptable radiation doses in humans.  
Nonhuman primate studies and dose selection: A pre-clinical PET study in rhesus monkey 
has been performed which demonstrated a high uptake of [11C]MK-6884 in the brain with the 
largest uptake in the striatum, providing a useful specific signal. In vitro saturation binding 
studies with [3H]MK-6884 in monkey and human brain striatum homogenate indicate that 
similar concentration (Bmax) of M4 receptors may be present in humans and therefore the
human M4 PAM receptor density is sufficiently high for [ 11C]MK-6884 to provide a useful 
specific signal in in vivo PET studies. 
As directed by the eCTA Guidance [ICH Topic M3 (R2)], the total dose will not exceed
100 µgs and will not exceed 5 administrations with a washout between doses of 6 or more 
half-lives. Each dose will not exceed 1/100th of the NOAEL, as determined in a toxicology 
trial in rats after proper scaling. Dose selection for safety assessment of [11C]MK-6884 was 
based upon assumptions of tracer specific activity and injection dose. A maximum 
cumulative mass associated with [11C]MK-6884 to be given to a 60 kg human adult subject 
undergoing a single PET scan is estimated to be 4.9 µg.
A whole-body distribution PET study conducted with [11C]MK-6884 in three rhesus 
monkeys suggest that the level of radiation absorbed should allow for multiple doses of  
[11C]MK-6884 that may be required for clinical PET occupancy studies.
Organs found to 
have high absorbed radiation dose included gallbladder (0.034 ± 0.020 mSv/MBq), small 
intestine (0.016 ± 0.016 mSv/MBq), and liver (0.014 ± 0.007 mSv/MBq). The overall ED by 
[11C]MK-6884 was estimated to be 0.0038 ± 0.0002 mSv/MBq, which is in the typical range 
for 11C-labeled PET tracer.  
The preliminary measurement of the radiation absorbed dose from [ 11C]MK-6884 to 
Standard Reference Man was estimated with data from these three nonhuman primates. 
Based on this, administration of one 370 MBq (10 mCi) dose or two 370 MBq (10 mCi) 
doses of [11C]MK-6884 is predicted to result in a human Effective Dose (ED) of 1.9 mSv or 
2.9 mSv, respectively (accounting for 1 WB CT  resulting 0.5 mSv/scan in Part I and two 
head CTs resulting ~0.05 mSv/scan in Part II).
Thus the radiation dose to human in the 
planned studies is predicted to be within acceptable yearly limits (ED < 10 mSv) for healthy 
subjects. This is thought to represent a dose that conforms to the As Low As Reasonably 
Achievable (ALARA) principle of radiation exposure. Based on pre-clinical studies this dose 
should provide the minimum image quality necessary to quantify tracer binding in the brain 
while minimizing tracer exposure for healthy subjects. This is well below the desired yearly 
limit of ED = 10 mSv. 
[11C]MK-6884 will always be administered in an open-label manner. For each scan, 
patients/subjects will be administered an anticipated IV dose of ≤ 4.9 µg of MK-6884 based 
on assumptions of a 6 mCi single injection of a tracer with minimum specific activity of 500 
Ci/mmol, as explained in Section 4.2.2.1 - Maximum Doses/Exposure for This Trial. In 
general, cyclotron produced 11C tracers have been offering specific activity much higher than 
 
 
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500 Ci/mmol. Therefore, the administration of 10 mCi dose of [11C]MK-6884 is anticipated 
to result in a maximum mass dose below 4.9 µg. The actual doses that will be administered 
during all parts will be adjusted based on the specific activity not to exceed the maximum 
mass of 4.9 µg and maximum allowed radiation exposure of 10 mSv per year in Europe or 50 
mSv per year in the United States. 
Part I is a first-in-human study designed to investigate the safety and tolerability of
[11C]MK-6884 and estimate the radiation absorbed. Subjects will be administered a single IV 
dose of 370 MBq (10 mCi, 4.9 µg) [11C]MK-6884 followed by a series of whole body PET 
scans, clinical examinations and laboratory safety evaluations. This dose was selected based 
on the results from whole-body distribution PET studies in rhesus monkeys. The selected 
radioactive starting dose for Part I of 370 MBq (10 mCi, 4.9 µg) per scan would result in a 
human ED of 1.9 mSv. The dose in Part I for subsequent subjects may be adjusted 
downwards or upwards based on mass dose limitation and dosimetry results learned from the 
initial Part I subjects.
Parts II and III will be initiated if there are no indications of medically meaningful 
radiochemical toxicity or undue radiation risks observed during Part I based on the initial 
review of safety data, including the clinical, clinical laboratory, and radiation safety data, as 
agreed by the Investigator and Sponsor. In Part II, subjects will receive 2 doses of [11C]MK-
6884. In Part III, AD patients will receive a single dose of [11C]MK-6884.  The administered 
dose in Parts II and III will be adjusted if indicated by the results from Part I.
As this is a Phase I assessment of MK-6884 in humans, and the pharmacokinetic, 
pharmacodynamic and safety profiles of the compound are still being evaluated, 
modifications to the dose or dosing regimen may be required to achieve the scientific goals 
of the trial objectives and/or to ensure appropriate safety monitoring of the trial subjects.  
Details 
of 
allowed 
modifications 
are 
provided 
in 
Section 
7.1.5.5 
-
Trial 
Design/Dosing/Procedures Modifications Permitted within Protocol Parameters.
4.2.2.1
Maximum Dose/Exposure for This Trial
This study will be conducted under a microdosing paradigm, in accordance with the ICH M3 
(R2) guidance. As per Guidance, the total dose should not exceed 100 μg and each dose 
should not exceed 1/100th of the NOAEL and 1/100th of the pharmacologically active dose 
after proper scaling. 
Dose selection for safety assessment of [11C]MK-6884 is based upon assumptions that a 
maximum cumulative mass associated with [11C]MK-6884 to be given to a 60 kg human 
adult subject undergoing a single PET scan would be 4.9 µg. This estimate is derived from 
the molecular weight of MK-6884 (411.5 kD) and assumptions of a 6 mCi single injection of 
a tracer with minimum specific activity of 500 Ci/mmol. Therefore, the maximal single 
human dose for a 60 kg adult human would be 0.08 µg/kg. MK-6884 safety and toxicity 
studies were designed to assess up to 1000-fold margins from this maximal human single 
dose. 
 
 
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To support the safety of MK-6884, a 7-day toxicity study in rat has been performed. 
MK-6884 was administered IV up to 80 μg/kg/day (1000x the maximal anticipated human 
dose). In this study there were no adverse effects attributed to treatment with MK-6884 at 
any dose. The NOAEL of 80 μg/kg/day provides a 1000-fold margin over the maximal 
clinical dose of 4.9 g. This is well below the <1/100th of the NOEL and within the ICH M3 
(R2) guidance. Thus, toxicology study results provide no contraindications to the conduct of 
the clinical PET studies with MK-6884.
To support that the maximal clinical MK-6884 dose of 4.9 µg is also ≤ 1/100th of the 
pharmacologically active dose, an amphetamine-induced hyperactivity assay has been 
performed, which is a highly sensitive assay to pharmacological inhibition of M4 PAM 
activity. MK-6884 at 100X the projected maximal clinical single dose of 4.9 μg did not 
induce a significant pharmacodynamics effect in rhesus macaque in this amphetamine-
induced hyperactivity model. Thus, the results of this non-clinical study support the conduct 
of clinical PET studies with a maximum MK-6884 dose of 4.9 µg, consistent with ICH 
M3(R2) guidance. 
4.2.2.2
Rationale for Dose Interval and Trial Design
MK-6884, a PET tracer for non-invasive visualization of M4 PAM, is not considered a 
compound with higher potential for risk of harm to volunteers according to the publication 
"Guideline on Strategies to Identify and Mitigate Risks for First-in-Human Clinical Trials 
with Investigational Medicinal Products" (European Medicine Agency guidance released 
July 2007).  It is not a biological molecule, does not exhibit highly species-specific action, 
nor is it directed towards immune system targets.  Safety assessment toxicity trials and 
ancillary pharmacology trials with MK-6884 provide no contraindications to the initiation of 
clinical trials in people with this compound via the IV route. [11C]MK-6884 doses for 
subsequent subjects may be adapted after analysis of the actual dosimetry results of the initial 
subject(s) in this part of the study. [11C]MK-6884 administration to subsequent subjects will 
be separated by at least one day from the initial subject(s). No dose-limiting toxicities were 
observed in 7-day toxicity trials, and substantial preclinical safety margins were obtained 
over initial human doses.
 
 
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Rationale for Endpoints
4.2.3
4.2.3.1
Efficacy Endpoints
In order to assess the potential efficacy of [11C]MK-6884 as a radiopharmaceutical tracer for 
M4 PAM receptor binding, the following endpoints have been selected to establish the 
validity and reliability of [11C]MK-6884:
1. In Parts II and III, index/Indices of M4 PAM receptor availability will be determined by 
kinetic modeling of the dynamic PET data. Indices that may be measured include: (1) 
total volume of distribution (VT); (2) non-displaceable binding potential (BPND); and/or 
standard uptake value ratio (SUVR). The VT is the ratio at equilibrium of the 
concentration of radioligand in a region of tissue to that in plasma. VT will be assessed 
using the metabolite corrected tracer plasma curve obtained from arterial blood sampling 
during the corresponding scan (relative [11C]MK-6884 fraction in plasma), to provide a 
measure of the radioactive material available to the brain. BPND is the ratio at 
equilibrium of specifically bound radioligand to that of a non-displaceable radioligand in 
tissue. The measurement of BPND assumes the presence of a reference region (region in 
the brain devoid of M4 PAM binding site), and does not require arterial sampling. 
SUVR is a semi-quantitative measure of tracer uptake estimated using a reference region 
with low/no tracer binding. SUVR is calculated as the ratio of the average tracer uptake
over a given time period in the target region relative to a reference region. In order to 
perform the future studies non-invasively, using the reference region method, further 
PET studies with arterial sampling after pre-treatment with a M4 PAM (not part of this 
protocol) will be needed to validate the
reference region method for tracer 
quantification. If needed, additional methods may also be employed, to more robustly 
characterize the tracer kinetics in both healthy and AD subjects. 
2. In Part II, intra-subject T-RT variability of the receptor availability indices will be 
assessed by the comparing the outcome indices of two scans obtained in the same 
subject (N≥6). Less than 10% T-RT variability is ideal and less than 20% T-RT 
variability is acceptable on average for a PET tracer.
3. In Part III, a pre-scan blood sample appropriate for determination of erythrocyte 
acetylcholinesterase (RBC-AChE) activity and for determination of donepezil or 
rivastigmine concentration (as appropriate to the AD patient enrolled) will be taken. 
These samples will enable correlation of the pharmacodynamic effects of the AChEI, as 
assessed by RBC-AChE activity, with peripheral AChEI concentrations and [11C]MK-
6884 binding in AD patients.  Collectively, this data will inform the design of a model 
that can predict the effective dose range of M4 PAMs in clinical development for 
treatment of behavioral disturbances in AD patients.
 
 
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4.2.3.2
Safety Endpoints
Systemic Safety
Safety and tolerability will be assessed throughout the study by monitoring subjects for 
clinical adverse experiences. Physical examinations, vital signs, 12-lead electrocardiograms 
(ECG) and laboratory safety tests will be performed periodically to detect any medically 
meaningful effects of the tracer on physiology. 
Radiation Safety
This study also includes quantitative assessments of radiation exposure to the whole body 
and its internal organs, including the brain. In Part I, whole body PET scans will estimate 
[11C]MK-6884 tracer radiation exposure and organ distribution (Effective Dose Equivalent, 
Effective Dose and radiation absorbed doses to individual organs).
4.2.3.3
Planned Exploratory Biomarker Research
Planned Genetic Analysis
Understanding genetic determinants of drug response is an important endeavor during 
medical research. This research will evaluate whether genetic variation within a clinical trial 
population correlates with response to the treatment(s) under evaluation. If genetic variation 
is found to predict efficacy or adverse events, the data might inform optimal use of therapies 
in the patient population. This research contributes to understanding genetic determinants of 
efficacy and safety associated with the treatments in this study.
4.2.3.4
Future Biomedical Research
The Sponsor will conduct Future Biomedical Research on DNA specimens collected for 
future biomedical research during this clinical trial.
Such research is for biomarker testing to address emergent questions not described elsewhere 
in the protocol (as part of the main trial) and will only be conducted on specimens from 
appropriately consented subjects. The objective of collecting specimens for Future 
Biomedical Research is to explore and identify biomarkers that inform the scientific 
understanding of diseases and/or their therapeutic treatments. The overarching goal is to use 
such information to develop safer, more effective drugs/vaccines, and/or to ensure that 
subjects receive the correct dose of the correct drug/vaccine at the correct time.  The details 
of this Future Biomedical Research sub-trial are presented in Section 12.2 - Collection and 
Management of Specimens for Future Biomedical Research.  Additional informational 
material for institutional review boards/ethics committees (IRBs/ERCs) and investigational 
site staff is provided in Section 12.3.
Benefit/Risk
4.3
Subjects in clinical trials generally cannot expect to receive direct benefit from 
treatment/vaccination during participation, as clinical trials are designed to provide 
information about the safety and effectiveness of an investigational medicine.
 
 
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Additional details regarding specific benefits and risks for subjects participating in this 
clinical trial may be found in the accompanying Investigators Brochure (IB) and Informed 
Consent documents.
5.0 METHODOLOGY
Entry Criteria
5.1
Diagnosis/Condition for Entry into the Trial
5.1.1
Healthy male and female subjects (at least one of each gender) between the ages of 18 and 55 
(inclusive) will be enrolled in Part I. Healthy elderly male and female subjects (at least one 
of each gender) between the ages of 55 and 85 years (inclusive) will be enrolled in Part II of 
this trial.  In Part III, male and female moderate to severely impaired AD patients (MMSE 
score ≤20) between the ages of 55 and 85 years (inclusive) will be enrolled in this trial.
Subject Inclusion Criteria
5.1.2
In order to be eligible for participation in this trial, the subject must:
Part I, II, and III:
1.
Provide written informed consent/assent for the trial. The subject may also provide 
consent/assent for Future Biomedical Research. However, the subject may participate 
in the main trial without participating in Future Biomedical Research. For AD patients 
in Part III, if the investigator determines that the patient is unable to provide their own 
informed consent, the patient’s legal representative must understand the study 
procedures and provide written informed assent for the patient, in accordance with 
local requirements.
2.
Be male or non-pregnant and non-breast feeding female of 18 to 55 years (inclusive)
(Part I) or 55 to 85 (inclusive) (Parts II and III) years of age at the pre-trial (screening) 
visit; further:
a.
If male and has intercourse with females of childbearing potential, subject 
must be willing to use a condom from the first dose of study medication until 
3 months post the last dose of study medication.  The use of a condom is an 
additional safety measure to the use of a contraceptive by the subject’s 
partner.  Female partners must additionally use one of the following methods: 
hormonal contraception, intra-uterine device, diaphragm, cervical cap.
b. If female with reproductive potential: subject must demonstrate a serum β-
human chorionic gonadotropin (β –hCG) level consistent with the nongravid 
state at the pretrial (screening) visit and agree to use (and/or have their partner 
use) two (2) acceptable methods of birth control beginning at the pretrial 
(screening) visit, throughout the trial (including washout intervals between 
treatment periods/panels) and until 2 weeks after the last dose of trial drug in 
the last treatment period.  Acceptable methods of birth control are defined in 
Section 5.7.4.1.
 
 
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c.
If female of non-childbearing potential, subject/patient can be:
i. A postmenopausal female: subject/patient is without menses for at 
least 1 year and has a follicle stimulating hormone (FSH) value in the 
postmenopausal range upon pretrial (screening) evaluation,
OR
ii. A female who is status post hysterectomy, oophorectomy or tubal 
ligation.  
NOTE: These procedures must be confirmed with medical records. In the 
absence of documentation, hysterectomy may be confirmed by pelvic exam or 
if necessary by ultrasound; oophorectomy may be confirmed by hormone 
levels, particularly FSH in the post-menopausal range, but tubal ligation 
subjects without records should be excluded.  Information must be captured 
appropriately within the site's source documents.
3. Have a Body Mass Index (BMI) ≤35 kg/m2, inclusive with height no greater than 195 
cm and weight no greater than 136 kg.  BMI = weight (kg)/height (m)2.
4. Be judged to be in good health (Part I) or be generally healthy (Parts II and III) based on 
medical history, physical examination, vital sign measurements and ECG performed prior 
to randomization.  Appendix 12.5 provides a table of 12-Lead Electrocardiogram 
Abnormality Criteria.
5. Be judged to be in good health based on laboratory safety tests (Section 7.1.3.1) obtained 
at the screening visit and prior to administration of the initial dose of trial drug. Section 
12.6 provides an algorithm for the assessment of out-of-range laboratory values. 
6. Have a negative urinary drug screen upon inclusion Exception: Subject with positive 
results may participate in the trial as long as the result can be rationalized as a 
consequence of concurrent use of a medication as permitted per protocol (see Section 
5.5).
7. Be a nonsmoker and/or has not used nicotine or nicotine-containing products (e.g., 
nicotine patch) for at least approximately 3 months. 
8. Be willing to comply with the trial restrictions (see Section 5.7 for a complete summary 
of trial restrictions).
Additional Inclusion Criteria for Part II only:
9. Be willing to allow the investigator(s) to place an arterial catheter in the radial artery and
is assessed via physical examination (Allen Test and/or Doppler Study) to be a good 
candidate for arterial catheter placement.
10. Mini Mental Status Examination (MMSE) score ≥ 27.
11. No history of subjective memory or other cognitive complaints
 
 
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12. No objective evidence of memory or cognitive impairment
Additional Inclusion Criteria for Part III only:
13. Subjects must have moderate to severe Alzheimer’s disease as defined by:
a.
Mini Mental Status Examination (MMSE) score ≤ 20
b. Meet the National Institute of Neurological and Communicative Diseases and 
Stroke/Alzheimer’s Disease and Related Disorders Association (NINCDS-
ADRDA) criteria for probable AD
c.
Meet Diagnostic and Statistical Manual of Mental Disorders, 5th Edition 
(DSM-V) criteria for AD
d. Rosen-Modified Hachinski score ≤4
e.
MRI scan obtained at screening is consistent with a diagnosis of AD.
14. Each subject must have a clear history of cognitive and functional decline over at least 
one year that is either:
a.
documented in medical records, or
b. documented by history from an informant who knows the subject well.
15. Be on a stable dose of an acetylcholinesterase inhibitor for symptomatic treatment of AD.  
Allowable AChEIs are donepezil and rivastigmine.  Other AChEIs require prior 
consultation with the SPONSOR.  The dose must be stable for at least the last 4 weeks 
before screening, and the subject must be willing to remain on the same dose for the 
duration of the trial.  The treatment dose at screening should not be changed during the 
trial unless medically necessary.  Additional treatments for AD that are not specified in 
the protocol should not be initiated during the trial.  The subject and caregiver must agree 
that they do not plan to discontinue treatment or initiate additional AD treatments during 
the trial unless medically necessary. Every effort should be made to enroll a minimum 
of 3 subjects already on a stable dose of donepezil. 
16. Each subject must have a reliable trial partner/caregiver (i.e., spouse, sibling, child, close 
friend) such that he/she is knowledgeable of the subject’s condition and progress.
a.
The trial partner/caregiver must be able to understand the nature of the trial 
and adhere to trial requirements (e.g., visit schedules, evaluations).
b. If appropriate, the trial partner/caregiver must be willing to accompany the 
subject to all visits.  However, at the discretion of the investigator, the trial 
partner/caregiver may not be required to accompany the subject to all visits 
(Note: Trial partner/caregiver is not required to stay in-house).
 
 
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c.
Trial partner/caregiver must be able to provide information to study 
investigator/staff via telephone contact.
Subject Exclusion Criteria
5.1.3
The subject must be excluded from participating in the trial if the subject:
Part I:
1. Is under the age of legal consent.
2. Is mentally or legally incapacitated, has significant emotional problems at the time of 
pretrial (screening) visit or expected during the conduct of the trial or has a history of 
clinically significant psychiatric disorder of the last 5 years.
Subjects who have had 
situational depression may be enrolled in the trial at the discretion of the investigator.
3. Has a history of clinically significant endocrine, gastrointestinal, cardiovascular, 
hematological, hepatic, immunological, renal, respiratory, genitourinary or major 
neurological (including stroke and chronic seizures) abnormalities or diseases.  Subjects 
with a history of uncomplicated kidney stones, as defined as spontaneous passage and no 
recurrence in the last 5 years, or childhood asthma may be enrolled in the trial at the 
discretion of the investigator
4. Has a history of cancer (malignancy).  
Exceptions: (1) Subjects with adequately treated non-melanomatous skin carcinoma or 
carcinoma in situ of the cervix may participate in the trial; (2) Subjects with other 
malignancies which have been successfully treated ≥10 years prior to the pretrial 
(screening) visit where, in the judgment of both the investigator and treating physician, 
appropriate follow-up has revealed no evidence of recurrence from the time of treatment 
through the time of the pretrial (screening) visit (except those cancers identified at the 
beginning of exclusion criterion 4); or, (3) Subjects, who, in the opinion of the trial 
investigator, are highly unlikely to sustain a recurrence for the duration of the trial.
5. Has a history of significant multiple and/or severe allergies (e.g. food, drug, latex 
allergy), or has had an anaphylactic reaction or significant intolerability to prescription or 
non-prescription drugs or food.
6. Is positive for hepatitis B surface antigen, hepatitis C antibodies or HIV.
7. Had major surgery, donated or lost 1 unit of blood (approximately 500 mL) within 4 
weeks prior to the pretrial (screening) visit. 
8. Has participated in another investigational trial within 4 weeks (or 5 half-lives), 
whichever is greater, prior to the pretrial (screening) visit.  The window will be derived 
from the date of the last visit in the previous trial.  
9. Has QTc interval ≥ 470 msec (for males) or ≥ 480 msec (for females).
 
 
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10. Is unable to refrain from or anticipates the use of any medication, including prescription 
and non-prescription drugs or herbal remedies beginning approximately 2 weeks (or 5 
half-lives) prior to administration of the initial dose of trial drug, throughout the trial 
(including washout intervals between treatment periods), until the post-trial visit.  There 
may be certain medications that are permitted, see Section 5.5.
11. Consumes greater than 3 glasses of alcoholic beverages (1 glass is approximately 
equivalent to: beer [354 mL/12 ounces], wine [118 mL/4 ounces], or distilled spirits [29.5 
mL/1 ounce]) per day.  Patients that consume 4 glasses of alcoholic beverages per day 
may be enrolled at the discretion of the investigator.
12. Consumes 
excessive 
amounts, 
defined 
as 
greater 
than 
6 
servings 
(1 serving is approximately equivalent to 120 mg of caffeine) of coffee, tea, cola, energy-
drinks, or other caffeinated beverages per day.
13. Is currently a regular or recreational user of cannabis, any illicit drugs or has a history of 
drug (including alcohol) abuse within approximately 3 months.
14. Has participated in a PET study or other study involving administration of a radioactive 
substance or ionizing radiation within 12 months prior to the screening visit, or has 
undergone an extensive radiological examination within this period with a radiation 
burden over 10 mSv (such as a CT-scan exam or a nuclear medical examination).
15. Suffers from claustrophobia or an inability to tolerate confinement in small places and 
would be unable to undergo MRI or PET scanning.
16. Is any concern by the investigator regarding (1) the safe participation of the subject in the 
trial, (2) the ability of the subject to tolerate procedures (for example, subjects with vague 
low back pain syndromes or subclinical hyperactivity spectrum disorders), or (3) for any 
other reason the investigator considers the subject inappropriate for participation in the 
trial.
17. Is or has an immediate family member (e.g., spouse, parent/legal guardian, sibling or 
child) who is investigational site or sponsor staff directly involved with this trial.
Part II
1. Is under the age of legal consent.
2. Is mentally or legally incapacitated, has significant emotional problems at the time of 
pretrial (screening) visit or expected during the conduct of the trial or has a history of 
clinically significant psychiatric disorder of the last 5 years.
Subjects who have had 
situational depression may be enrolled in the trial at the discretion of the investigator.
3. Has a history of clinically significant endocrine, gastrointestinal, cardiovascular, 
hematological, hepatic, immunological, renal, respiratory, genitourinary or major 
neurological (including stroke and chronic seizures) abnormalities or diseases that is not 
adequately controlled through a stable medication regimen.  Subjects with a history of 
uncomplicated kidney stones, as defined as spontaneous passage and no recurrence in the 
last 5 years, or childhood asthma may be enrolled in the trial at the discretion of the 
investigator
 
 
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4. Has been administered an AChEI for any purpose within the prior 3 months or anticipates 
a requirement for administration of an AChEI for any purpose during the course of the 
study investigations.  
5. Has incidental findings on an MRI scan that is pathognomonic for an active disease or 
pathological process that requires medical intervention.
6. Has implanted or embedded metal objects, or fragments in the head or body that would 
present a risk during the MRI scanning procedure, or have worked with ferrous metals 
either as a vocation or hobby (for example, as a sheet metal worker, welder, or machinist) 
in such a way that might have led to unknown, indwelling metal fragments that could 
cause injury if they moved in response to placement in the magnetic field. 
7. Has a history of cancer (malignancy).  
Exceptions: (1) Subjects with adequately treated non-melanomatous skin carcinoma or 
carcinoma in situ of the cervix may participate in the trial; (2) Subjects with other 
malignancies which have been successfully treated ≥10 years prior to the pretrial 
(screening) visit where, in the judgment of both the investigator and treating physician, 
appropriate follow-up has revealed no evidence of recurrence from the time of treatment 
through the time of the pretrial (screening) visit (except those cancers identified at the 
beginning of exclusion criterion 4); or, (3) Subjects, who, in the opinion of the trial 
investigator, are highly unlikely to sustain a recurrence for the duration of the trial.
8. Has a history of significant multiple and/or severe allergies (e.g. food, drug, latex 
allergy), or has had an anaphylactic reaction or significant intolerability to prescription or 
non-prescription drugs or food. For Part II, this includes any known allergy to 
lidocaine which may be used as an anesthetic for the placement of the arterial 
catheter.
9. Is positive for hepatitis B surface antigen, hepatitis C antibodies or HIV.
10. Had major surgery, donated or lost 1 unit of blood (approximately 500 mL) within 4 
weeks prior to the pretrial (screening) visit. 
11. Has participated in another investigational trial within 4 weeks (or 5 half-lives), 
whichever is greater, prior to the pretrial (screening) visit.  The window will be derived 
from the date of the last visit in the previous trial.  
12. Has QTc interval ≥ 470 msec (for males) or ≥ 480 msec (for females).
13. Is unable to refrain from or anticipates the use of any prescription and non-prescription 
herbal remedies beginning approximately 2 weeks (or 5 half-lives) prior to administration 
of the initial dose of trial drug, throughout the trial (including washout intervals between 
treatment periods), until the post-trial visit. Of note, subject should be excluded from 
Part II if he/she currently uses aspirin (ASA) or aspirin-containing medications (> 
80 mg/day ASA), or non-steroidal anti-inflammatory drugs (NSAIDS), which cannot 
be discontinued 2 weeks prior to dosing and throughout the course of the study. 
There are certain medications that are permitted, see Section 5.5.
 
 
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14. Consumes greater than 3 glasses of alcoholic beverages (1 glass is approximately 
equivalent to: beer [354 mL/12 ounces], wine [118 mL/4 ounces], or distilled spirits [29.5 
mL/1 ounce]) per day.  Patients that consume 4 glasses of alcoholic beverages per day 
may be enrolled at the discretion of the investigator.
15. Consumes 
excessive 
amounts, 
defined 
as 
greater 
than 
6 
servings 
(1 serving is approximately equivalent to 120 mg of caffeine) of coffee, tea, cola, energy-
drinks, or other caffeinated beverages per day.
16. Is currently a regular or recreational user of cannabis, any illicit drugs or has a history of 
drug (including alcohol) abuse within approximately 3 months.
17. Has participated in a PET study or other study involving administration of a radioactive 
substance or ionizing radiation within 12 months prior to the screening visit, or has 
undergone an extensive radiological examination within this period with a radiation 
burden over 10 mSv (such as a CT-scan exam or a nuclear medical examination).
18. Suffers from claustrophobia or an inability to tolerate confinement in small places and 
would be unable to undergo MRI or PET scanning.
19. Is any concern by the investigator regarding (1) the safe participation of the subject in the 
trial, (2) the ability of the subject to tolerate procedures (for example, subjects with vague 
low back pain syndromes or subclinical hyperactivity spectrum disorders), or (3) for any 
other reason the investigator considers the subject inappropriate for participation in the 
trial.
20. Is or has an immediate family member (e.g., spouse, parent/legal guardian, sibling or 
child) who is investigational site or sponsor staff directly involved with this trial.
Part III:
1. Is under the age of legal consent.
2. Is mentally or legally incapacitated, has significant emotional problems at the time of 
pretrial (screening) visit or expected during the conduct of the trial or has a history of 
clinically significant psychiatric disorder of the last 5 years (with the exception of AD).
Subjects who have had situational depression may be enrolled in the trial at the discretion 
of the investigator.
3. Has a history of clinically significant endocrine, gastrointestinal, cardiovascular, 
hematological, hepatic, immunological, renal, respiratory, genitourinary or major 
neurological (including stroke and chronic seizures) abnormalities or diseases is not 
adequately controlled through a stable medication regimen.  Subjects with a history of 
uncomplicated kidney stones, as defined as spontaneous passage and no recurrence in the 
last 5 years, or childhood asthma may be enrolled in the trial at the discretion of the 
investigator.
 
 
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4. Has been administered galantamine for any purpose within the prior 7 days or anticipates 
a requirement for administration of galantamine for any purpose during the course of the 
study investigations.
5. Has incidental findings on an MRI scan that is pathognomonic for an active disease other 
than AD or pathological process that requires medical intervention.
6. Has implanted or embedded metal objects, or fragments in the head or body that would 
present a risk during the MRI scanning procedure, or have worked with ferrous metals 
either as a vocation or hobby (for example, as a sheet metal worker, welder, or machinist) 
in such a way that might have led to unknown, indwelling metal fragments that could 
cause injury if they moved in response to placement in the magnetic field. 
7. Has a history (within 2 years of the prestudy/screening visit) or current evidence of any 
neurological or neurodegenerative disorder other than AD that is associated with transient 
or sustained alterations in cognition.
8. Has a history (within 2 years prior to the prestudy visit) or current evidence of a 
psychotic disorder, or a major depressive disorder by DSM-V criteria
9. Has a history of cancer (malignancy).  
Exceptions: (1) Subjects with adequately treated non-melanomatous skin carcinoma or 
carcinoma in situ of the cervix may participate in the trial; (2) Subjects with other 
malignancies which have been successfully treated ≥10 years prior to the pretrial 
(screening) visit where, in the judgment of both the investigator and treating physician, 
appropriate follow-up has revealed no evidence of recurrence from the time of treatment 
through the time of the pretrial (screening) visit (except those cancers identified at the 
beginning of exclusion criterion 4); or, (3) Subjects, who, in the opinion of the trial 
investigator, are highly unlikely to sustain a recurrence for the duration of the trial.
10. Has a history of significant multiple and/or severe allergies (e.g. food, drug, latex 
allergy), or has had an anaphylactic reaction or significant intolerability to prescription or 
non-prescription drugs or food.
11. Is positive for hepatitis B surface antigen, hepatitis C antibodies or HIV.
12. Had major surgery, donated or lost 1 unit of blood (approximately 500 mL) within 4 
weeks prior to the pretrial (screening) visit. 
13. Has participated in another investigational trial within 4 weeks (or 5 half-lives), 
whichever is greater, prior to the pretrial (screening) visit.  The window will be derived 
from the date of the last visit in the previous trial.  
14. Has QTc interval ≥ 470 msec (for males) or ≥ 480 msec (for females).
 
 
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15. Is unable to refrain from or anticipates the use of any prescription and non-prescription 
herbal remedies beginning approximately 2 weeks (or 5 half-lives) prior to administration 
of the initial dose of trial drug, throughout the trial (including washout intervals between 
treatment periods), until the post-trial visit.  There are certain medications that are 
permitted, see Section 5.5.
16. Consumes greater than 3 glasses of alcoholic beverages (1 glass is approximately 
equivalent to: beer [354 mL/12 ounces], wine [118 mL/4 ounces], or distilled spirits [29.5 
mL/1 ounce]) per day.  Patients that consume 4 glasses of alcoholic beverages per day 
may be enrolled at the discretion of the investigator.
17. Consumes excessive amounts, defined as greater than 6 servings (1 serving is 
approximately equivalent to 120 mg of caffeine) of coffee, tea, cola, energy-drinks, or 
other caffeinated beverages per day.
18. Is currently a regular or recreational user of cannabis, any illicit drugs or has a history of 
drug (including alcohol) abuse within approximately 3 months.
19. Has participated in a PET study or other study involving administration of a radioactive 
substance or ionizing radiation within 12 months prior to the screening visit, or has 
undergone an extensive radiological examination within this period with a radiation 
burden over 30 mSv (such as a CT-scan exam or a nuclear medical examination).
20. Suffers from claustrophobia or an inability to tolerate confinement in small places and 
would be unable to undergo MRI or PET scanning.
21. Is any concern by the investigator regarding (1) the safe participation of the subject in the 
trial, (2) the ability of the subject to tolerate procedures (for example, subjects with vague 
low back pain syndromes or subclinical hyperactivity spectrum disorders), or (3) for any 
other reason the investigator considers the subject inappropriate for participation in the 
trial.
22. Is or has an immediate family member (e.g., spouse, parent/legal guardian, sibling or 
child) who is investigational site or sponsor staff directly involved with this trial.
 
 
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Trial Treatment(s)
5.2
The treatments to be used in this trial are outlined below in 
Table 2
Trial Treatments
PET Tracer
Dose/Potency
Dose 
Frequency
Route of 
Administration
Part
Use
[11C]MK-6884
~370 MBq (~10 mCi) 
containing ≤4.9 µg MK-6884a
Single dose
bolus IV 
injection
Part Ia
experimental
[11C]MK-6884
~370 MBq (~10 mCi) per 
dose, each containing ≤4.9 µg
MK-6884
Two doses 
(at least 3
hours 
apart)
bolus IV 
injection
Part IIb
experimental
[11C]MK-6884
~370 MBq (~10 mCi) 
containing ≤4.9 µg MK-6884
Single dose
bolus IV 
injection
Part IIIb
experimental
a [11C]MK-6884 doses for subjects may be adapted upwards or downwards after analysis of the actual 
dosimetry results of the initial subject(s) in this part of the study (see Section 7.1.5.5 for further details on 
adaptation of doses). 
b [11C]MK-6884 doses may be adapted upwards or downwards if indicated by the actual data found during 
Part I (see Section 7.1.5.5 for further details on adaptation of doses).
Trial treatment should begin on the day of treatment allocation/randomization or as close as 
possible to the date on which the subject is allocated/assigned.
All supplies indicated in Table 2 above will be provided centrally by the Sponsor or locally 
by the trial site, subsidiary or designee, depending on local country operational or regulatory 
requirements.
For any commercially available product that is provided by the trial site, subsidiary or 
designee every attempt will be made to source these supplies from a single lot/batch number. 
The trial site will be responsible for recording the lot number, manufacturer and expiry date 
of any locally purchased product.
The investigator shall take responsibility for and shall take all steps to maintain appropriate 
records and ensure appropriate supply, storage, handling, distribution and usage of trial 
treatments in accordance with the protocol and any applicable laws and regulations.
Dose Selection
5.2.1
5.2.1.1
Dose Selection (Preparation)
The rationale for selection of doses to be used in this trial is provided in Section 4.0 –
Background & Rationale.  There are no specific calculations or evaluations required to be 
performed in order to administer the proper dose to each subject.
 
 
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Timing of Dose Administration
5.2.2
[11C]MK-6884 tracer will be prepared and dosed per the instructions outlined in the site 
Master Batch Record.
Trial Blinding/Masking
5.2.3
This is an open-label trial; therefore, the Sponsor, investigator and subject will know the 
treatment administered.
Randomization or Treatment Allocation
5.3
A sample allocation schedule is provided in Table 3.
Table 3
Sample Allocation Schedule
Study Part
Maximum Sample Size 1
Treatment
Part I
N=6
A single IV [11C]MK-6884 dose
Part II
N=10
Two separate IV [11C]MK-6884
doses
Part III
N=10
A single IV [11C]MK-6884 dose
1Sample size for Part I ranges from 3-6; sample size for Part II ranges from 6-10; and sample size for Part III 
ranges from 7-10.
Subjects participating in this trial will be allocated by non-random assignment.
Stratification
5.4
No stratification based on age, sex or other characteristics will be used within each study part 
in the trial.
Concomitant Medications/Vaccinations (Allowed & Prohibited)
5.5
If a subject does not discontinue all prior medications within 14 days or 5 half-lives of the 
first dose of trial medication, he/she may be included in the study if the investigator can 
rationalize that the specific use of a prior medication is not clinically relevant within the 
context of the trial.
Concurrent use of any prescription or non-prescription medication, or concurrent vaccination,
during the course of the trial (i.e., after randomization or treatment allocation) must first be 
discussed between the investigator and Sponsor prior to administration, unless appropriate 
medical care necessitates that therapy or vaccination should begin before the investigator and 
Sponsor can consult.  The subject will be allowed to continue in the trial if both the Sponsor 
and the investigator agree.
Parts I, II, and III: Paracetamol/acetaminophen may be used for minor ailments without 
prior consultation with the Sponsor.
 
 
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Part II: Lidocaine will be permitted for arterial catheter placement.
In addition, the following concomitant medications/vaccinations are permitted:
1. Low dose ASA (i.e., ≤ 81 mg ASA once daily)
2. All biologics & vaccines
3. Vitamin supplements 
4. Medical foods/supplement (eg, Axona®, Souvenaid® ) 
5. Hormone replacement therapy
6. Lipid lowering drugs
7. Erectile dysfunction treatments
8. Diabetes medications (insulin, metformin, sulfonylureas, DPP4 inhibitors, GLP-1 
analogs, etc.)
9. Antihypertensives (ACE inhibitors, Angiotensin II receptor antagonists; B blockers, 
calcium channel blockers, direteics)
10. Analgesics/Narcotics: Current use of ≤ 2 doses/week or prior short-term use (<1 month) 
of more than 2 doses/week for temporary conditions is acceptable (e.g., codeine, 
morphine, hydromorphone, oxycodone, propoxyphene (Darvon) and its variations, & 
combination products that contain a narcotic).
11. Sedative/benzodiazepines: Use of the following medications is acceptable if stable for at 
least one month before the Screening Visit: trazodone, mirtazapine, zaleplon ≤ 5 mg, 
zopiclone ≤ 7.5 mg, eszopiclone ≤ 3 mg, zolpidem ≤ 5 mg, or lorazepam ≤ 1.0 mg.  For 
other medications in this category not specified here, please contact the Sponsor for 
guidance.
12. Pregabalin and gabapentin: Treatment for neuropathic pain
13. Anti-inflammatory drugs such as corticosteroids: Low dose oral treatment with the 
equivalent of 10 mg prednisone or less, short-term (<3 weeks) oral treatment with the 
equivalent of 60 mg prednisone or less, if needed for management of rash, local 
injections into joints or bursae, topical use, inhaled or nasal use
Part III: Acetylcholinesterase inhibitors (i.e., donepezil, rivastigmine), 
In addition, the following concomitant medications/vaccinations are permitted:
1. All biologics & vaccines
2. Vitamin supplements 
 
 
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3. Medical foods/supplement (eg, Axona®, Souvenaid® ) 
4. NMDA antagonists (e.g., memantine)
5. Hormone replacement therapy
6. Lipid lowering drugs
7. Erectile dysfunction treatments
8. Diabetes medications (insulin, metformin, sulfonylureas, DPP4 inhibitors, GLP-1 
analogs, etc)
9. Antihypertensives (ACE inhibitors, Angiotensin II receptor antagonists; B blockers, 
calcium channel blockers, direteics)
10. Neuroleptics: asenapine, aripiprazole, olanzapine, quetiapine, risperidone, ziprasidone
11. Analgesics/Narcotics: Current use of ≤ 2 doses/week or prior short-term use (<1 month) 
of more than 2 doses/week for temporary conditions is acceptable (e.g., codeine, 
morphine , hydromorphone, oxycodone, propoxyphene (Darvon) and its variations, & 
combination products that contain a narcotic).
12. Sedative/benzodiazepines: Use of the following medications is acceptable if stable for at 
least one month before the Screening Visit: trazodone, mirtazapine, zaleplon ≤ 5 mg, 
zopiclone ≤ 7.5 mg, eszopiclone ≤ 3 mg, zolpidem ≤ 5 mg, or lorazepam ≤ 1.0 mg.  For 
other medications in this category not specified here, please contact the Sponsor for 
guidance
13. Antidepressants:  bupropion, citalopram (40 mg or less), escitalopram, fluoxetine, 
mirtazapine, paroxetine, sertraline, venlafaxine. Use of 50 mg or less at night of 
nortriptyline or desipramine during the trial is acceptable
14. Carbidopa/levodopa and dopamine agonists are allowed for treating restless legs 
syndrome
15. Pregabalin and gabapentin: Treatment for neuropathic pain
16. Anti-inflammatory drugs such as corticosteroids: Low dose oral treatment with the 
equivalent of 10 mg prednisone or less, short-term (<3 weeks) oral treatment with the 
equivalent of 60 mg prednisone or less, if needed for management of rash, local 
injections into joints or bursae, topical use, inhaled or nasal use
Medications or vaccinations specifically prohibited in the exclusion criteria are not allowed 
during the ongoing trial.  If there is a clinical indication for any medication or vaccination
specifically prohibited during the trial, discontinuation from trial therapy or vaccination may 
be required.  The investigator should discuss any questions regarding this with the Sponsor.  
The final decision on any supportive therapy or vaccination rests with the investigator and/or 
 
 
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the subject's primary physician.  However, the decision to continue the subject on trial 
therapy or vaccination schedule requires the mutual agreement of the investigator, the 
Sponsor and the subject.
Listed below are specific restrictions for concomitant therapy or vaccination during the 
course of the trial:
1. Part II only: currently uses aspirin or aspirin-containing medications (>80 mg/day), or 
non-steroidal anti-inflammatory drugs (NSAIDS), which cannot be discontinued 2 weeks 
prior to dosing and throughout the course of the study.
2. Part II only: all AChEI inhibitors
3. Part III only: galantamine and restrictions to dose level as noted above
Rescue Medications & Supportive Care
5.6
No rescue or supportive medications are specified to be used in this trial.
Diet/Activity/Other Considerations
5.7
Diet
5.7.1
Fasting requirements for trial procedures, such as but not limited to laboratory safety 
evaluations are specified in Section 7.0.
Subjects will fast from all food and drinks, except water, for at least 4 hours prior to
screening, predose, and poststudy laboratory safety evaluations.  In Part II, subjects are 
allowed to have a light non-fat meal (provided by the investigator) when two tracer 
administrations are performed on same day.
Fruit Juice Restrictions
5.7.2
Subjects will refrain from the consumption of grapefruit juice, grapefruits and grapefruit 
products beginning approximately 2 weeks prior to administration of the initial dose of trial 
drug, throughout the trial and until the post-trial visit.
Subject also will refrain from the consumption of all fruit juices 24 hours prior to and after 
trial drug administration(s).  All other days during the trial, consumption of fruits and fruit 
juices (except for grapefruit, grapefruit juices, and grapefruit products) is allowed. 
Alcohol, Caffeine, Tobacco, Activity Restrictions
5.7.3
5.7.3.1
Alcohol
Subjects will refrain from consumption of alcohol 24 hours prior to the pre- and post-trial 
visits and from 24 hours prior to and after trial drug administration(s). At all other times, 
alcohol consumption is limited to no more than approximately 3 alcoholic beverages or 
 
 
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equivalent (1 glass is approximately equivalent to: beer [354 mL/12 ounces], wine [118 mL/4 
ounces], or distilled spirits [29.5 mL/1 ounce]) per day.
5.7.3.2
Caffeine
Subjects will refrain from consumption of caffeinated beverages from 12 hours prior to the 
pre- and post-trial visits and from 12 hours prior to and after trial drug administration(s). At 
all other times, caffeinated beverages or xanthine-containing products will be limited to no 
more than 6 units per day amounts (>6 units: 1 unit=120 mg of caffeine).
5.7.3.3
Tobacco
Smoking and/or the use of nicotine containing products is not permitted during this trial.
5.7.3.4
Activity
Subjects will avoid unaccustomed strenuous physical activity (i.e., weight lifting, running, 
bicycling, etc.) from the pre-trial (screening) visit until administration of the initial dose of 
trial drug, throughout the trial (including washout intervals between treatments in Part II) and 
until the post-trial visit.
Contraception and Pregnancy Testing 
5.7.4
5.7.4.1
Contraception
Women of childbearing potential can be enrolled.  However, two (2) acceptable methods of 
barrier contraception must be used beginning at the pretrial visit, throughout the trial 
(including washout intervals between treatment periods/panels) and until 2 weeks after the 
last dose of trial drug in the last treatment period.  Acceptable methods of birth control are 
two (2) of the following:  intrauterine device (IUD-with or without local hormone release), 
diaphragm, spermicides, cervical cap, contraceptive sponge, and/or condoms.  Abstinence is 
an alternative life style and subjects practicing abstinence may be included in the trial.
Alternatively, women may use an appropriate hormonal contraception instead of one of the 
two barrier methods.  Appropriate hormonal contraception may include any marketed 
contraceptive agent that contains an estrogen and/or a progestational agent (including oral, 
subcutaneous, transdermal, intrauterine, or intramuscular agents).  If hormonal contraception 
is used as one of the methods, hormonal contraceptives must have been used for at least 2 
months prior to initial administration of trial drug for subjects to be eligible for enrollment 
into the trial. Subjects must be completely informed of the unknown risks of pregnancy and 
agree not to become pregnant during the time they are participating in this trial.  
If there is any question that a subject will not be reliable in the use of appropriate 
contraceptive methods, they should not be entered into the trial.
Male subjects who have intercourse with females of child-bearing potential must agree to use 
a medically acceptable method of contraception during the trial and for 3 months after the 
last dose of trial drug. If their partner is pregnant: males must agree to use a condom and no 
 
 
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additional method of contraception is required for the pregnant partner. If their partner is of 
child-bearing potential: males should use a condom with spermicide. Spermicides alone are 
not an acceptable method of contraception. Their partner must additionally be using one of 
the following methods: hormonal contraception, intra-uterine device, diaphragm with 
spermicide, cervical cap with spermicide or female condom with spermicide. Male subject 
must also agree to not donate sperm during the study and for 3 months following the last 
dose of trial medication.
5.7.4.2
Pregnancy Testing
Female subjects of childbearing potential will be tested for serum -human chorionic 
gonadotropin (hCG) at pretrial and for urine - hCG at predose.  In the case of a positive or 
borderline serum β-hCG pregnancy test at the pretrial visit, the subject must not enter the 
trial; in the case of a positive urine β-hCG pregnancy test during the trial, a serum β-hCG 
pregnancy test should be performed and confirmed positive.  If the pregnancy has been 
confirmed the subject must be discontinued from the trial immediately and the pregnancy 
must be reported the Sponsor as outlined in Section 7.2.2.    
Other
5.7.5
For potential subjects in Parts II and III (which require a baseline MRI scan), X-rays may be 
acquired, if indicated, as part of the screening procedures to confirm absence of indwelling 
metal fragments.
Investigators and designees may conduct other evaluations as medically indicated should 
adverse events occur or unanticipated problems arise that could have an impact on the health 
or wellbeing of the research volunteers. Diagnostic evaluations and treatment interventions 
should be rendered according to the standard of local medical care in the country in which 
each site is located.
Subject Withdrawal/Discontinuation Criteria
5.8
Subjects may withdraw consent at any time for any reason or be dropped from the trial at the
discretion of the investigator should any untoward effect occur.  In addition, a subject may be 
withdrawn by the investigator or the Sponsor if enrollment into the trial is inappropriate, the 
trial plan is violated, or for administrative and/or other safety reasons.  Specific details 
regarding discontinuation or withdrawal procedures; including specific details regarding 
withdrawal from Future Biomedical Research, are provided in Section 7.1.4 – Other 
Procedures.
A subject must be discontinued from the trial for any of the following reasons:
●
The subject or legal representative (such as a parent or legal guardian) withdraws 
consent.

The subject has a medical condition or personal circumstance which, in the opinion of 
the investigator and/or Sponsor, places the subject at unnecessary risk through 
 
 
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continued participation in the trial or does not allow the subject to adhere to the 
requirements of the protocol.

The subject has a positive urine drug screen at any time during the course of the trial.
Subject Replacement Strategy
5.9
If a subject discontinues from the trial, a replacement subject may be enrolled if deemed 
appropriate by the investigator and Sponsor.  The replacement subject will generally receive 
the same treatment or treatment sequence (as appropriate) as the subject being replaced. The 
replacement subject will be assigned a unique treatment/randomization number. The trial site 
should contact the Sponsor for the replacement subject’s treatment/randomization number.
Beginning and End of the Trial
5.10
The overall trial begins when the first subject signs the informed consent form.  The overall 
trial ends when the last subject completes the last study-related phone-call or visit,
discontinues from the trial or is lost to follow-up (i.e. the subject is unable to be contacted by 
the investigator).
A trial may be paused during review of newly available preclinical/clinical safety, 
pharmacokinetic, pharmacodynamic, efficacy or biologic data or other items of interest, prior 
to a final decision on continuation or termination of the trial.  It may be necessary to keep the 
trial open for gathering/reviewing of additional supportive data to optimally complete the 
objective(s) of the trial.  If necessary, the appropriate amendment(s) to the protocol and/or 
appropriate communication(s) will be generated.  The overall trial end will then not be 
identified until the Sponsor has made the decision to end the trial following this review 
period.  The Competent Authority(ies) and Institutional Review Board(s)/Independent Ethics 
Committee(s) [IRB(s)/IEC(s)] will be appraised of the maximum duration of the trial beyond 
the last subject out and the justification for keeping the trial open.
 
 
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Clinical Criteria for Early Trial Termination
5.11
There are no pre-specified criteria for terminating the trial early.
A primary objective of this early Phase I trial is to identify the maximum safe and well-
tolerated dose and/or dosing regimen that achieve pharmacokinetic, pharmacodynamic and/or 
biologic targets in humans based on preclinical or early clinical data.  Therefore, it is possible 
that trial subjects may not receive all doses specified in the protocol if this objective is 
achieved at lesser dose levels in this trial.  This would not be defined as early termination of 
the trial, but rather an earlier than anticipated achievement of the trial objective(s).  If a 
finding (e.g., pharmacokinetic, pharmacodynamic, efficacy, biologic targets, etc.) from 
another preclinical or clinical trial using the trial treatment(s), comparator(s), drug(s) of the 
same class, or methodology(ies) used in this trial, results in the trial(s) or program being 
stopped for non-safety reasons, this also does not meet the definition of early trial 
termination.
Early trial termination is defined as a permanent discontinuation of the trial due to 
unanticipated concerns of safety to the trial subjects arising from clinical or preclinical trials 
with the trial treatment(s), comparator(s), drug(s) of the same class or methodology(ies) used 
in this trial.
 
 
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6.0 TRIAL FLOW CHART
Trial Flow Chart Part I
6.1.1
Screening 
(-4 weeks prior to Day 1)
Predose
Treatment 
Post-trial a
Post-trial Call 
(at least 14 days post dose)
Administrative Procedures
Informed Consent
X
Informed Consent for Future Biomedical Research 
X
Review Inclusion/Exclusion Criteria
X
X
Subject Identification Card
X
Medical History
X
Concomitant Medication Review
X
X
X
X
X
Clinic Procedures/Assessments
Full Physical Examination
X
X
X
Height
X
Weight
X
X
X
Vital Signs (supine heart rate, blood pressure)b
X
X
X
X l
Vital Signs (respiratory rate, oral/tympanic  body 
temperature)
X
X
Orthostatic Vital Signs (heart rate, blood pressure) b
X
X
Xl
12-Lead Electrocardiogramc
X
X
X
Xl
[11C]MK-6884 Administration
Xi
Whole Body PET/CT scan
Xj
Adverse Events monitoring
X
X
X
Xm
X
Discharge from PET centerd
X
Follow-up Phone Calle
X
X
 
 
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Screening 
(-4 weeks prior to Day 1)
Predose
Treatment 
Post-trial a
Post-trial Call 
(at least 14 days post dose)
Laboratory Procedures/Assessments
Hematologyf
X
X
X l
Urinalysisf
X
X
X l
Chemistryf
X
X
X l
Serum β-Human Chorionic Gonadotropin (β-hCG) –
(WOCBP Only) 
X
Serum Follicle Stimulating Hormone (FSH) – (Post-
Menopausal Females Only)
X
Urine β-Human Chorionic Gonadotropin (β-hCG) –
(WOCBP Only)
X
Urine/Blood Drug Screen –(per site SOP)
X
X g
HIV/Hepatitis Screen (per site SOP) 
X
Blood for Genetic Analysish
X
Tracer Kinetics
Venous Blood Sampling to measure the metabolite fraction 
in plasma
Xk
 
 
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a Post-study procedures to be conducted prior to discharge (either after the scanning session, or the next day at ~ 24 hours). Some post study procedures (safety labs, ECGs,
and vital signs [HR, BP] are to be performed shortly after completion of the scan; if the post study procedure is performed on the same day as the scanning session, it does 
not need to be repeated at the time of discharge, provided the post study procedure itself is not the reason for delaying the discharge to the next day.
b Obtain Pre-dose (within 4 hours prior to administration), and at approximately 5 minutes and 60 minutes post-dose, and at the end of the scanning session (~2 hours post-
dose). Orthostatic vital signs will be performed following supine assessments at predose and end of scanning session only.
c Subjects should be resting supine for 10min prior to ECG. Obtain Pre-dose (within 4 hours prior to administration), and at approximately 5 minutes and 60 minutes post-
dose, and at the end of the scanning session (~2 hours post-dose).
d Time of discharge may be shortly after completion of the scan (i.e., up to ~3 hours post dose), or subjects may be required to stay overnight on the day of scanning, at the 
discretion of the investigator and discharge the next day.
e Telephone interview conducted at ~24 hours post-dose (if subject was not kept overnight) and at 14 days post-dose to follow up for all adverse experiences.
f Laboratory safety tests (hematology, chemistry and urinalysis will be collected in the fasted state (at least 4 hours)). On treatment days, blood samples should be drawn pre-
dose (up to 24 hours Pre-dose) and at the end of the scanning session.
g The urine/blood drug screen may be performed up to 24 hours Pre-dose. 
h This sample should be drawn for planned analysis of the association between genetic variants in DNA and drug response. If there is either a documented law or regulation 
prohibiting collection, or if the IRB/IEC does not approve the collection of the sample for these purposes, then this sample will not be collected at that site. If the sample is 
collected, leftover extracted DNA will be stored for future biomedical research if the subject signs the FBR consent. If the planned genetic analysis is not approved, but FBR 
is approved and consent is given, this sample will be collected for the purpose of FBR.
I Time = 0. The study medication will be given as a bolus injection.
j PET emission scan will be initiated immediately along with the initiation of tracer injection with acquisition up to 2 hours Post-dose. A CT scan will be performed as part of 
the PET study to enable attenuation correction of the PET emission scan. The CT scan may be performed before or after the PET scan.
k Venous blood samples for measuring metabolites in plasma will be collected at the following time points: 5, 15, 30, 45, 60 and 90,  minutes post-dose. After each sample, 
the line will be flushed with saline. The time points and/or number of samples may be adjusted as necessary. Additional blood samples may be taken if necessary, adhering 
to maximum blood volume limits (see appendix Section 12.4). The clinical site SOP will be followed for collection and analysis of plasma samples.
l Shortly after scan completion
m Assessment for potential adverse experiences should be conducted at ~ 24 post dose either by phone or in the clinic.
 
 
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Trial Flow Chart Part II
6.1.2
Screening 
(-4 weeks prior to Day 1)
Predoseq
Treatment 
Post-triala
Post-trial Call
(at least 14 days post last dose)
Administrative Procedures
Informed Consent
X
Informed Consent for Future Biomedical Research 
X
Inclusion/Exclusion Criteria
X
X
Subject Identification Card
X
Medical History
X
Concomitant Medication Review
X
X
X
X
X
Clinic Procedures/Assessments
Allen Test or Doppler Study (for radial artery 
assessment) b
X
Mini Mental Status Examination (MMSE)
X
Full Physical Examination
X
X
X
Height
X
Weight
X
X
X
Vital Signs (supine heart rate, blood pressure)c
X
X
Xc
Xo
Vital Signs (respiratory rate, oral/tympanic body 
temperature)
X
X
Orthostatic Vital Signs (heart rate, blood pressure)
c
X
X
X
Xo
12-Lead Electrocardiogramd
X
X
X
Xo
Brain MRIe
X
[11C]MK-6884 Administration
Xk
Brain PET/CT Scan
Xl
Adverse Events monitoring
X
X
X
X p
X
 
 
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Screening 
(-4 weeks prior to Day 1)
Predoseq
Treatment 
Post-triala
Post-trial Call
(at least 14 days post last dose)
Discharge from PET centerf
X
Follow-up Phone Callg
X
X
Laboratory Procedures/Assessments
Hematologyh
X
X
X o
Urinalysish
X
X
X o
Chemistryh
X
X
X o
Serum β-Human Chorionic Gonadotropin (β-hCG) 
(If applicable) 
X
Serum Follicle Stimulating Hormone (FSH) –
(Post-Menopausal Females Only)
X
Urine β-Human Chorionic Gonadotropin (β-hCG) 
– (WOCBP Only)
X
Urine/Blood Drug Screen –(per site SOP)
X
X i
HIV/Hepatitis Screen (per site SOP) 
X
Blood for Genetic Analysisj
X
Tracer Kinetics
Arterial Blood Sampling (for tracer metabolism-
counts and metabolites)r
Xm
Arterial Blood sampling (for radioactivity in 
whole blood and plasma)r
Xn
 
 
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a Post-study procedures to be conducted prior to discharge (either after the scanning session, or the next day at ~ 24 hours). Some of the post study procedures (safety labs, ECGs, 
and vital signs [HR, BP]) should be done shortly after completion of the scan; if the post study procedure is done on the same day as the scanning session, it does not need to be 
repeated at the time of discharge, provided the post study procedure itself is not the reason for delaying the discharge to the next day.
b Assessment of the radial artery will be performed via the Allen Test first. The Doppler Study may be conducted if the Allen Test appears abnormal and at the discretion of the 
Investigator.
c Obtain Pre-dose (within 4 hours prior to administration), and at approximately 5 minutes and 60 minutes post-dose, and at the end of each scanning session (~2 hours post-dose). 
Orthostatic vital signs will be performed following supine assessments at predose and end of each scanning session only. The predose assessments for the second scan may be 
omitted if the scans are performed on the same day.
d Subjects should be resting supine for 10min prior to ECG. Obtain Pre-dose (within 4 hours prior to administration), and at approximately 5 minutes and 60 minutes post-dose, 
and at the end of each scanning session (~2 hours post-dose). If both scans are done at the same day, the pre-dose ECG will only be performed prior to the first scan.
e MRI to be performed after all other screening assessments of screening 1 are found acceptable. A separate screening visit may be scheduled for the MRI as needed. In case of 
technical problems, the MRI scan may be repeated.
f Time of discharge may be shortly after completion of the scan (i.e. up to ~3 hours post dose), or subjects may be required to stay overnight on the day of scanning, at the 
discretion of the investigator and discharge the next day.
g Telephone interview conducted at ~24 post last dose (if subject is not kept overnight) and at 14 days post-dose (after second IV dose) to follow up for all adverse experiences.
h Laboratory safety tests (hematology, chemistry and urinalysis) will be collected in the fasted state (at least 4 hours) .  PT/aPTT will be measured at screening. On scan days, 
blood samples should be drawn before the first dose (up to 24 hours Pre-dose) and at the end of the second scan (prior to discharge). If the 2 scans are done on separate non-
consecutive days, blood samples should be drawn each day prior to dosing (within 24 hours Pre-dose) and at the end of each scan. If the 2 scans are done on consecutive days, 
blood samples should be drawn prior to the first scan and at the end of the second scan (total 2 blood draws).
i The urine/blood drug screen may be performed within 24 hours prior to dosing.
j This sample should be drawn for planned analysis of the association between genetic variants in DNA and drug response. If there is either a documented law or regulation 
prohibiting collection, or if the IRB/IEC does not approve the collection of the sample for these purposes, then this sample will not be collected at that site. If the sample is 
collected, leftover extracted DNA will be stored for future biomedical research if the subject signs the FBR consent. If the planned genetic analysis is not approved, but FBR is 
approved and consent is given, this sample will be collected for the purpose of FBR.
k Two bolus injections of [11C]MK-6884 will be given with a minimum interval of 3 hr. Time = 0 relative to each injection.
l PET emission scan will be initiated immediately along with the initiation of each tracer injection with acquisition up to ~90 minutes post-dose. A CT scan will be performed as 
part of the PET study to enable attenuation correction of the PET emission scan. The CT scan may be performed before or after the PET scan. (Scanning duration time may be 
adjusted based on data from Part I and initial data from Part II).
m Arterial blood samples will be collected for metabolite measurements at approximately 5, 15, 30, 45, 60 and 90minutes post-dose for each scan. After each sample, the line will 
be flushed. The time points and/or number of samples taken may be adjusted as necessary, adhering to the maximum blood volume limits (See Appendix 12.4). The clinical site 
SOP will be followed for collection and analysis of blood samples.
n Arterial blood samples will be collected for radioactivity in whole blood and plasma. For each scan, arterial samples will be taken at approximately 10, 20, 30, 40, 50, 60, 70, 80, 
90, 100, 120 and 150 seconds, and 3, 5, 15, 30, 45, 60, 75, and 90 minutes post-dose. The time points and/or number of samples taken may be adjusted as necessary, adhering to 
maximum blood volume limits (See Appendix 12.4) The clinical site SOP will be followed for collection and analysis of blood samples.
o Shortly after scan completion
p Assessment for potential adverse experiences should be conducted at ~ 24 post dose either by phone or in the clinic.
q Pre-dose procedures to be performed only prior to the first scan if both scans are done at the same day. 
r Arterial blood sampling may not be performed based on data from the initial group of subjects (at least N=3).
 
 
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Trial Flow Chart Part III
6.1.3
Screening 
(-4 weeks prior to Day 1)
Predose
Treatment 
Post-triala
Post-trial Call
(at least 14 days post last dose)
Administrative Procedures
Informed Consent/Assent
X
Informed Consent/Assent for Future Biomedical 
Research 
X
Review Inclusion/Exclusion Criteria
X
X
Subject Identification Card
X
Medical History
X
Concomitant Medication Review
X
X
X
X
X
Clinic Procedures/Assessments
Mini Mental Status Examination (MMSE)
X
Rosen-Modified Hachinski Scoring
X
Full Physical Examination
X
X
X
Height
X
Weight
X
X
X
Vital Signs (supine heart rate,blood pressure) b
X
X
X
Xl
Vital Signs (respiratory rate, oral/tympanic  body 
temperature)
X
X
Orthostatic Vital Signs (heart rate, blood pressure)b
X
X
Xl
12-Lead Electrocardiogram c
X
X
X 
Xl
Brain MRI d
X
[11C] MK-6884 Administration
X j
Brain PET/CT scan
X k
Adverse Events monitoring
X
X
X
X m
X
Discharge from PET center e
X
 
 
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Screening 
(-4 weeks prior to Day 1)
Predose
Treatment 
Post-triala
Post-trial Call
(at least 14 days post last dose)
Follow-up Phone Call f
X
X
Laboratory Procedures/Assessments
Hematology g
X
X
Xl
Urinalysis g
X
X
Xl
Chemistry g
X
X
Xl
Serum β-Human Chorionic Gonadotropin (β-hCG) (if 
applicable) 
X
Serum Follicle Stimulating Hormone (FSH) – (Post-
Menopausal Females Only)
X
Urine β-Human Chorionic Gonadotropin (β-hCG) –
(WOCBP Only)
X
Urine/Blood Drug Screen –(per site SOP)
X
HIV/Hepatitis Screen (per site SOP) 
X
Blood for Genetic Analysis i
X
Pharmacokinetic/Pharmacodynamic Evaluations
Blood Sample for Plasma Donepezil or Rivastigmine n
X
Blood Sample for RBC-AChE Activity n
X
 
 
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a Post-study procedures to be conducted prior to discharge (either after the scanning session, or the next day at ~ 24 hours). Some of the post study procedures (safety labs, 
ECGs, and vital signs [HR, BP]) should be done shortly after completion of the scan; if the post study procedure is done on the same day as the scanning session, it does not 
need to be repeated at the time of discharge, provided the post study procedure itself is not the reason for delaying the discharge to the next day.
b Obtain Pre-dose (within 4 hours prior to administration), and at approximately 5 minutes and 60 minutes post-dose, and at the end of the scanning session (~90 minutes post-
dose). Orthostatic vital signs will be performed following supine assessments at predose and end of scanning session only.
c Subjects should be resting supine for 10min prior to ECG. Obtain Pre-dose (within 4 hours prior to administration), and at approximately 5 minutes and 60 minutes post-dose, 
and at the end of the scanning session (~90 minutes post-dose).
d MRI to be performed after all other screening assessments of screening 1 are found acceptable. A separate screening visit may be scheduled for the MRI as needed. In case of 
technical problems, the MRI scan may be repeated.
e Time of discharge may be shortly after completion of the scan (i.e. up to ~3 hours post dose), or subjects may be required to stay overnight on the day of scanning, at the 
discretion of the investigator and discharge the next day.
f Telephone interview conducted at ~24 ours post-dose (if patient is not kept overnight) and at 14 days post-dose to follow up for all adverse experiences.
g Laboratory safety tests (hematology, chemistry and urinalysis will be collected in the fasted state (at least 4 hours). On treatment days, blood samples should be drawn pre-dose 
(up to 24 hours Pre-dose) and at the end of the scanning session.
i This sample should be drawn for planned analysis of the association between genetic variants in DNA and drug response. If there is either a documented law or regulation 
prohibiting collection, or if the IRB/IEC does not approve the collection of the sample for these purposes, then this sample will not be collected at that site. If the sample is 
collected, leftover extracted DNA will be stored for future biomedical research if the subject signs the FBR consent. If the planned genetic analysis is not approved, but FBR is 
approved and consent is given, this sample will be collected for the purpose of FBR.
j Time = 0. The study medication will be given as a bolus injection.
k PET emission scan will be initiated immediately along with the initiation of tracer injection with acquisition up to ~ 90 minutes post-dose. A CT scan will be performed as part 
of the PET study to enable attenuation correction of the PET emission scan. The CT scan may be performed before or after the PET scan. (Scanning duration time may be 
shortened to approximately 60 minutes based on data from Part II),
l Shortly after scan completion.
m Assessment for potential adverse experiences should be conducted at ~ 24 post dose either by phone or in the clinic.
n Venous blood samples will be collected no more than 90 minutes before administration of study drug [11C] MK-6884. One sample will be collected for either donepezil or 
rivastigmine (depending on the subject’s concomitant medication). Refer to the Operations Manual for collection, preparation, storage and shipment of plasma samples.
 
 
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7.0 TRIAL PROCEDURES
Trial Procedures
7.1
The Trial Flow Chart - Section 6.0 summarizes the trial procedures to be performed at each 
visit.  Individual trial procedures are described in detail below.  It may be necessary to 
perform these procedures at unscheduled time points if deemed clinically necessary by the 
investigator.
Furthermore, additional evaluations/testing may be deemed necessary by the investigator and 
or the Sponsor for reasons related to subject safety. In some cases, such evaluation/testing 
may be potentially sensitive in nature (e.g., HIV, Hepatitis C, etc.), and thus local regulations 
may require that additional informed consent be obtained from the subject.  In these cases, 
such evaluations/testing will be performed in accordance with those regulations.
Administrative Procedures
7.1.1
7.1.1.1
Informed Consent
The investigator or qualified designee must obtain documented consent from each potential 
subject or each subject’s legally acceptable representative prior to participating in a clinical 
trial or Future Biomedical Research.
7.1.1.1.1 General Informed Consent
Consent must be documented by the subject’s dated signature or by the subject’s legally 
acceptable representative’s dated signature on a consent form along with the dated signature 
of the person conducting the consent discussion. 
A copy of the signed and dated consent form should be given to the subject before 
participation in the trial.
The initial informed consent form, any subsequent revised written informed consent form 
and any written information provided to the subject must receive the IRB/ERC’s 
approval/favorable opinion in advance of use.  The subject or his/her legally acceptable 
representative should be informed in a timely manner if new information becomes available 
that may be relevant to the subject’s willingness to continue participation in the trial.  The 
communication of this information will be provided and documented via a revised consent 
form or addendum to the original consent form that captures the subject’s dated signature or 
by the subject’s legally acceptable representative’s dated signature.
Specifics about a trial and the trial population will be added to the consent form template at 
the protocol level.  
The informed consent will adhere to IRB/ERC requirements, applicable laws and regulations 
and Sponsor requirements.
 
 
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7.1.1.1.2 Consent and Collection of Specimens for Future Biomedical Research
The investigator or qualified designee will explain the Future Biomedical Research consent 
to the subject, answer all of his/her questions, and obtain written informed consent before 
performing any procedure related to the Future Biomedical Research sub-trial.  A copy of the 
informed consent will be given to the subject.
7.1.1.2
Inclusion/Exclusion Criteria
All inclusion and exclusion criteria will be reviewed by the investigator or qualified designee 
to ensure that the subject qualifies for the trial.
7.1.1.3
Subject Identification Card
All subjects will be given a Subject Identification Card identifying them as participants in a 
research trial.  The card will contain trial site contact information (including direct telephone 
numbers) to be utilized in the event of an emergency.  The investigator or qualified designee 
will provide the subject with a Subject Identification Card immediately after the subject 
provides written informed consent.
The subject identification card also contains contact information for the emergency 
unblinding call center so that a health care provider can obtain information about trial 
medication/vaccination in emergency situations where the investigator is not available.
7.1.1.4
Medical History
A medical history will be obtained by the investigator or qualified designee.
7.1.1.5
Prior and Concomitant Medications Review
7.1.1.5.1 Prior Medications
The investigator or qualified designee will review prior medication use, including any 
protocol-specified washout requirement, and record prior medication taken by the 
subject/patient within 14 days before starting the trial.
For AD subjects enrolled on a stable dose of an acetylcholinesterase inhibitor (donepezil or 
rivastigmine), the dose and dose schedule of their AChEI medication will be used for 
pharmacokinetic (PK)_and pharmacodynamics (PD) evaluations in conjunction with the 
blood assays. The site staff will record the time when the last dose of AChEI was taken 
prior to blood sampling for the PK and PD assays.
7.1.1.5.2 Concomitant Medications
The investigator or qualified designee will record medication, if any, taken by the subject 
during the trial.
 
 
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7.1.1.6
Assignment of Screening Number
All consented subjects will be given a unique screening number that will be used to identify 
the subject for all procedures that occur prior to randomization or treatment allocation.  Each 
subject will be assigned only one screening number.  Screening numbers must not be re-used 
for different subjects.
Any subject who is screened multiple times will retain the original screening number 
assigned at the initial screening visit.
Specific details on the screening visit requirements (screening/rescreening) are provided in 
Section 7.1.5.1.  
7.1.1.7
Assignment of Treatment/Randomization Number
All eligible subjects will be randomly allocated and will receive a treatment/randomization 
number.  The treatment/randomization number identifies the subject for all procedures 
occurring after treatment allocation/randomization.  Once a treatment/randomization number 
is assigned to a subject, it can never be re-assigned to another subject.
A single subject cannot be assigned more than 1 treatment/randomization number.
7.1.1.8
Trial Compliance (Medication/Diet/Activity/Other)
Administration of trial medication will be witnessed by the investigator and/or trial staff.
Clinical Procedures/Assessments
7.1.2
Physical Exam
The physical exam assessments will be defined and conducted per the site SOP.
Allen Test or Doppler Study (Part II)
This will be done at Screening for Part II subjects only in order to assess the radial artery for 
blood sampling.
Body Weight and Height
Body weight and height will be obtained with the subjects shoes off, jacket or coat removed.
Body Mass Index (BMI)
BMI equals a person's weight in kilograms divided by height in meters squared.
(BMI=kg/m2). Body weight and height will be obtained with the subjects shoes off, jacket or 
coat removed. BMI can be rounded to the nearest whole number.
 
 
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12-Lead ECG
Special care must be taken for proper lead placement by qualified personnel. Skin should be
clean and dry prior to lead placement. Subjects may need to be shaved to ensure proper lead
placement.
Subjects should be resting in the supine position for at least 10 minutes prior to each ECG
measurement. Subject position during ECG collection (e.g., supine) should be consistent
throughout the study.
The correction formula to be used for QTc is Fredericia.
If repeat ECGs are required the clinical site will decide whether to leave the electrodes in
place or mark the position of the electrodes for subsequent ECGs. To mark the position of the 
electrodes, 12-lead electrode sites will be marked on the skin of each subject with an ECG 
skin marker pen to ensure reproducible electrode placement.
Body Temperature
Body temperature will be measured with an oral or tympanic thermometer. The same method 
(e.g. oral or tympanic) must be used for all measurements for each individual subject and 
should be the same for all subjects.
Vital Sign Measurements (Heart Rate and Blood Pressure)
Subjects should be resting in a supine position for at least 10 minutes prior to having vital
sign measurements obtained. Supine vital signs will include heart rate (HR) and blood
pressure (BP). The correct size of the blood pressure cuff and the correct positioning on the
subjects' arm is essential to increase the accuracy of blood pressure measurements. The same
method (e.g., manual or automated) must be used for all measurements for each 
individualsubject and should be same for all subjects.
Orthostatic vital signs (HR and BP) will also be obtained. Subjects should be resting in a
supine position for at least 10 minutes and then stand upright for 2 minutes prior to
measurement of orthostatic vital signs.
Imaging Procedures
Whole Body (WB) PET/CT Scan (Part I)
In Part I only, WB PET imaging will be performed according to the clinical site SOP on a
PET/CT camera. Whole-body CT transmission scan will be obtained for attenuation 
correction before or after the emission PET scan. Following [11C]MK-6884 administration, a 
series of whole body PET images will be obtained according to the clinical site SOP. The 
acquisition will be conducted over about ~2 hours. The acquisition duration may be 
shortened at the discretion of the investigator.
 
 
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Magnetic Resonance Imaging (MRI) (Parts II and III)
In Parts II and III only, a MRI scan of the brain will be obtained per the clinic SOPs to enable
regions of interest (ROIs) delineation. The MRI visit may take place at any time during the 
screening period after all other screening assessments from the Screening 1 visit are deemed 
acceptable. The MRI may be waived at the discretion of the investigator if the subject/patient
has had a previous MRI performed within the past year at the same local imaging center 
where the current study is being conducted.
Brain PET/CT Scan (Parts II and III)
In Parts II and III only, the brain scans will be performed according to the clinical site SOPs 
on a PET/CT or PET camera. For each scanning session, subjects will be positioned on the 
scanner bed with the head within the center of axial and transaxial field of view. The head 
will be restrained to reduce movement artifacts during the scan. A transmission scan of the 
brain will be obtained either before or after the PET scan to enable attenuation correction of 
the emission scan. [11C]MK-6884 will be administered by IV injection while the subject is 
lying supine on the imaging table. The brain PET scan will be initiated along with the 
initiation of tracer injection. Serial dynamic imaging frames will be obtained up to a total 
duration of approximately 90 minutes for each session according to clinical site SOPs. The 
acquisition duration may be shortened at the discretion of the investigator.
Part III Only: every effort should be made to get a full dynamic scan for 90 minutes (if 
required based on available data from the ongoing trial). If an AD subject is unable to
tolerate the full duration of 90 minutes, as determined by the investigator, or an unexpected 
intolerance event occurs at or after 60 minutes into a full scan, the scan can be concluded at 
or after 60 minutes. PET data for such a shortened scan should be reconstructed following the 
same protocol as a normal scan, without inclusion of the truncated time frames.
Venous (Parts I and III) and Arterial (Part II) Blood Sampling
Intravenous (IV) and radial arterial catheters will be placed in Part I and Part II subjects, 
respectively, for blood sampling. In Part III, venous blood samples will be drawn from AD 
subjects as outlined in Section 6.1.3 Trial Flow Chart. The number of blood samples may be 
changed, if necessary, adhering to maximum blood volume limits (See Appendix 12.4). The
clinical site SOP will be followed for collection and analysis of blood samples.
Part II Only: no more than 2 arterial lines, preferably in different hands, may be placed in 
any one subject over the course of the entire study.
Laboratory Procedures/Assessments
7.1.3
Details regarding specific laboratory procedures/assessments to be performed in this trial are 
provided below. The total amount of blood/tissue to be drawn/collected over the course of 
the trial (from pre-trial to post-trial visits), including approximate blood/tissue volumes 
drawn/collected by visit and by sample type per subject can be found in Section 12.4.
 
 
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7.1.3.1
Laboratory Safety Evaluations (Hematology, Chemistry and Urinalysis)
Laboratory tests for hematology, chemistry and urinalysis are specified in Table 4.
Table 4
Laboratory Tests
Hematology
Chemistry
Urinalysis
Other
Hematocrit
Albumin
Blood
Serum  β-Human 
Chorionic 
Gonadotropin (β-hCG) 
(If applicable)
Hemoglobin
Alkaline phosphatase
Glucose
Urine β-Human 
Chorionic 
Gonadotropin (β-hCG) 
(If applicable)
Platelet count
Alanine aminotransferase 
(ALT)
Protein
Follicle Stimulating 
Hormone (FSH) (if 
applicable)
WBC (total and 
differential)
Aspartate aminotransferase 
(AST)
Specific gravity 
Hepatitis
PT/aPTT
(Part II
screening only)
Bicarbonate
Microscopic exam, 
if abnormal results 
are noted
HIV
Calcium
Urine/Blood
Drug 
Screen (per site SOP)
Chloride
Creatinine
Glucose
Phosphorus
Potassium
Sodium
Total Bilirubin  
Direct Bilirubin, if total 
bilirubin is elevated above 
the upper limit of normal
Total protein
Urea/Blood Urea Nitrogen
(BUN)
 
 
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In each Part, subjects will fast from all food and drink except water for at least 4 h prior to 
screening, pre-dose and post-trial laboratory safety evaluations.
7.1.3.2
Pharmacokinetic/Pharmacodynamic Evaluations
Quantification of tracer in plasma will be performed to obtain the input function for PET
tracer kinetic modeling. In addition, the decision as to which Part III samples collected will 
be assayed for exploratory evaluations will be collaboratively determined by the appropriate 
departments within the Sponsor’s organization.
7.1.3.2.1 Blood Collection for [11C]MK-6884 Tracer Kinetics (Parts I and II)
Prior to dosing, IV catheter will be placed for Part I subjects and radial arterial catheters will 
be placed for Part II subjects for arterial blood sampling. The clinical site SOP will be 
followed for collection and analysis of blood samples. Samples will be collected and 
analyzed on site. 
7.1.3.2.2 Blood Collection for Plasma Donepezil or Rivastigmine (Part III)
Blood sample for determination of plasma donepezil or rivastigmine levels should be taken 
no more than 90 minutes prior to [11C]MK-6884 administration. Sample collection, storage 
and shipment instructions for plasma samples will be provided in the Operations Manual.
7.1.3.2.3 Blood Collection for Plasma AChE Activity (Part III)
Blood samples for determination of erythrocyte acetylcholinesterase (RBC-AChE) activity 
should be taken no more than 90 minutes prior to [11C]MK-6884 administration. Sample 
collection, storage and shipment instructions for plasma samples will be provided in the 
Operations Manual.
7.1.3.3
Planned Genetic Analysis Sample Collection
Sample collection, storage and shipment instructions for Planned Genetic Analysis samples 
will be provided in the appendix Section 12.2
7.1.3.4
Future Biomedical Research Sample Collection
The following specimens are to be obtained as part of Future Biomedical Research:
Leftover DNA for future research.
 
 
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Other Procedures
7.1.4
7.1.4.1
Withdrawal/Discontinuation
The investigator or trial coordinator must notify the Sponsor when a subject has been 
discontinued/withdrawn from the trial.  If a subject discontinues for any reason at any time 
during the course of the trial, the subject may be asked to return to the clinic (or be 
contacted) for a post-trial visit (approximately 14 days after the last dose of trial drug is 
given) to have the applicable procedures conducted.  However, the investigator may decide 
to perform the post-trial procedures at the time of discontinuation or as soon as possible after 
discontinuation.  If the post-trial visit occurs prior to 14 days after the last dose of trial drug
is given , the investigator should perform a follow-up phone call 14 days after the last  dose 
of trial drug  to determine if any adverse events have occurred since the post-trial clinic visit.  
Any adverse events which are present at the time of discontinuation/withdrawal should be 
followed in accordance with the safety requirements outlined in Section 7.2 - Assessing and 
Recording Adverse Events.
7.1.4.1.1 Withdrawal From Future Biomedical Research
Subjects may withdraw their consent for Future Biomedical Research and have their 
specimens and all derivatives destroyed.   Subjects may withdraw consent at any time by 
contacting the principal investigator for the main trial.  If medical records for the main trial 
are still available, the investigator will contact the Sponsor using the designated mailbox 
(clinical.specimen.management@merck.com), and a form will be provided by the Sponsor to 
obtain appropriate information to complete specimen withdrawal.  Subsequently, the 
subject's specimens will be removed from the biorepository and be destroyed.  A letter will 
be sent from the Sponsor to the investigator confirming the destruction. It is the 
responsibility of the investigator to inform the subject of completion of destruction.  Any 
analyses in progress at the time of request for destruction or already performed prior to the 
request being received by the Sponsor will continue to be used as part of the overall research 
trial data and results.   No new analyses would be generated after the request is received.
In the event that the medical records for the main trial are no longer available (e.g., if the 
investigator is no longer required by regulatory authorities to retain the main trial records) or 
the specimens have been completely anonymized, there will no longer be a link between the 
subject’s personal information and their specimens.  In this situation, the request for 
specimen destruction cannot be processed.
7.1.4.2
Blinding/Unblinding
This is an open label trial; there is no blinding for this trial.
7.1.4.3
Domiciling
Parts I and III: Subjects will report to the research center on Day -1 (Part I) or on Day 1 
(Part III) and will be discharged after completion of all post-dose study procedures following 
the scanning session on Day 1. At the discretion of the investigator, subjects may be 
 
 
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requested to stay longer or return to the unit in the event of a technical failure that prevents 
tracer administration or scanning.
Part II: Subjects will report to the research center on Day -1 and will be discharged after
completion of all post-dose study procedures following Scan 1 and Scan 2. At the discretion
of the investigator, subjects may be requested to stay longer or return to the unit in the event
of a technical failure that prevents tracer administration or scanning.
7.1.4.4
Calibration of Critical Equipment
The investigator or qualified designee has the responsibility to ensure that any critical device
or instrument used for a clinical evaluation/test during a clinical trial that provides important 
information about inclusion/exclusion criteria and/or safety or efficacy parameters shall be 
suitably calibrated and maintained to ensure that the data obtained is reliable and/or 
reproducible.  Documentation of equipment calibration must be retained as source 
documentation at the trial site.
Critical Equipment for this trial includes:
MRI/PET/CT Scanners and related imaging equipment, equipment for measuring blood 
pressure, ECG machine, HPLC system, Gamma Counter, Centrifuge.
Visit Requirements
7.1.5
Visit requirements are outlined in Section 6.0 - Trial Flow Chart.   Specific procedure-related 
details are provided above in Section 7.1 - Trial Procedures.
7.1.5.1
Screening (Part I, Part II and Part III)
Within approximately 4 weeks prior to randomization, potential subjects will be evaluated to 
determine that they fulfill the entry requirements as set forth in Section 5.1.
Screening procedures may be repeated after consultation with the Sponsor. In Parts II and III, 
a baseline MRI scan of the brain will be obtained for region-of-interest (ROI) delineation and 
to make sure the MRI scan is consistent with a diagnosis of AD (Part III only).
7.1.5.2
Treatment Period (Part I, Part II, and Part III)
In Parts I, II, and III, dosing and study procedures may be conducted any time during the day 
as the PET scan outcome measures are relatively resistant to the impact of diurnal variations 
in physiology.
Part I
Pre-dose
An IV catheter will be placed for injection of the radiotracer and venous blood sampling.
 
 
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Dosing/Scanning
A single, open-label dose of ≤ 4.9 μg [11C]MK-6884 with a radiation dose ~370 MBq will be
administered by IV injection through an indwelling venous catheter while the subject is lying
supine on the imaging table. Immediately following the [11C]MK-6884 administration, a
series of whole body PET images will be obtained over a period of up to approximately 120
minutes. CT scans will be obtained at each bed position, for attenuation correction.
The sequence of procedures that should be followed in Part I (refer to Study Flowchart in 
Section 6.0) is outlined in Table 5.
Table 5
Part I Procedures
Time Period
Description
-90 to -10 minutes
-All procedures requiring needle sticks will be 
completed, including antecubital venous lines.
-Subjects should be asked to micturate immediately 
prior to the next time period.
Approximately 30 minutes pre-dose
-Subjects will rest supine on the imaging table while 
baseline vital signs and ECGs are obtained per the 
study flowchart (Section 6.0).
-Venous blood sample will be drawn before tracer 
administration 
for 
baseline 
laboratory 
safety 
evaluations (up to 24 hours prior).
-A whole body CT scan is obtained (the time of the 
CT scan can be at the discretion of the investigator, 
target within 5 min before acquisition)
Time “0”
[11C]MK-6884 administration, PET scan initiated
0 to ~ 120 minutes
Subjects will be asked to remain motionless on the 
imaging table while the scans are acquired.
-HR, BP, and 12-lead ECGs will be obtained during 
this time period per the study flowchart (Section 6.0)
-Venous blood samples will be collected for 
measurement of radioactivity associated with the 
parent tracer and its metabolites (Section 6.0)
End of scanning sessions
HR, BP, EGG and blood for laboratory safety 
evaluations will be collected per the study flowchart 
(Section 6.0). Indwelling venous catheter will be 
removed.
 
 
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All images will be acquired using the HI-Rez Biography PET/CT scanner. First, a CT scout
will be acquired to set the axial field of view (FOV). The axial FOV should extend from the 
top of the head to the middle of the thighs (~ 8 bed positions). Then, a low current CT will be 
acquired for both PET attenuation correction and anatomical information. Following the CT 
3D PET images will be acquired sequentially for an overall study duration of approximately 
2 hours.
WB 1-3: 30s/bed (~4 min per WB)
WB 4-6: 60s/bed (~8 min per WB)
WB 7-8: 120s/bed (~16 min per WB)
WB 9: 240s/bed (~32 min per WB)
After this sequence of PET acquisitions, the subject will be moved out of the camera and will
be encouraged to void their urine. The actual times of scanning and the acquisition sequence
may be varied by the investigator, as indicated by the data that emerges during the course of
the study – See Section 7.1.5.5. In order to use the whole body PET images for dosimetry
calculations, the dose calibrator and PET scanner will be cross-calibrated.
Catheters will be removed after all of the procedures requiring venous access have been
completed.
Postdose
Subjects may stay overnight at the discretion of the investigator.
Part II
Pre-dose
Prior to administration of [11C]MK-6884, a trained staff member will place an arterial
catheter in a radial artery for the collection of blood samples.  A topical anesthetic may be 
used to reduce some of the discomfort associated with insertion of the catheter. The staff 
member placing the line may also inject a small amount of lidocaine subcutaneously to 
further reduce any discomfort when the actual catheter is placed. The IV catheter for tracer 
injection will be placed contralateral to the radial arterial catheter and the IV catheter for 
arterial blood sampling.
Dosing/Scanning
A low-dose CT scan of the brain will be performed to enable attenuation correction of the
emission scan. Separate single, open-label doses of [11C]MK-6884 will be administered by
IV injection through an indwelling venous catheter while the subject is lying supine on the
imaging table (dose may be adapted based on the data from Part I). The brain PET scan will
be initiated along with the initiation of the tracer injection. The sequence of procedures that 
should be followed in Part II (refer to Study Flowchart in Section 6.0) is outlined in Table 6.
 
 
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Table 6
Part II Procedures
Time Period
Description
-90 to -10 minutes
-All procedures requiring needle sticks will be 
completed, including antecubital venous and arterial 
lines.
-Subjects should be asked to micturate immediately prior 
to the next time period.
Approximately 30 minutes 
pre-dose
-Subjects will rest supine on the imaging table while 
baseline vital signs and ECGs are obtained per the study 
flowchart (Section 6.0).
-Venous blood samples will be drawn before tracer 
administration for baseline laboratory safety evaluations 
(up to 24 hours prior). This is done prior to the first dose 
only if both doses are done on the same day or if both 
doses are done on consecutive days. If the second dose is 
done on a different non-consecutive day, blood samples 
should be obtained for baseline laboratory safety 
evaluations prior to the second scan as well.
-A brain attenuation CT scan is obtained (the time of the 
CT scan can be at the discretion of the investigator)
Time “0”
[11C]MK-6884 administration1, PET scan initiated
0 - ~90 min
-Subjects will be asked to remain motionless on the 
imaging table while the scans are acquired.
-HR, BP, and 12-lead ECGs will be obtained during this 
time period per the study flowchart (Section 6.0)
-Arterial blood samples  will be collected for tracer 
metabolism counts per the study flowchart (Section 6.0)
-
Arterial blood samples will be collected for 
radioactivity counts per the study flow chart (Section 
6.0).
End of scanning session
- HR, BP, and ECG will be collected per the study flow 
chart (Section 6.0). Indwelling catheter will be removed.
-Venous blood samples will be drawn for laboratory 
safety evaluations. This is done at the end of the second 
scan only if both doses/scans are done on the same day
or if both doses/scans are done on consecutive days. If 
the second scan is done on a different non-consecutive 
day, blood samples should be obtained at the end of the 
first scan as well for laboratory safety evaluations.
1 Sequence procedures for the second dose (to be administered at least 3 hours after the first dose) will follow the time frame 
as for the first dose. If second dose/scanning session occurs on a different day due to difficulties performing both scans in 
one day, then all procedures starting from row 1 of this table will be followed.
 
 
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A brain PET scan will be initiated immediately following each dosing. For each scanning 
session, subjects will be positioned on the scanner bed with the head within the center of
axial and transaxial fields of view. The head will be restrained to reduce movement artifacts
during the scan. Baseline sensory conditions (dimmed room lighting, reduced noise) will be
imposed and maintained throughout the session.
Catheters will be removed after all of the procedures requiring arterial and venous access
have been completed.
Postdose
Subjects may stay overnight after the day of scanning at the discretion of the investigator.
Part III
Pre-dose
An IV catheter will be placed for injection of the radiotracer.
Dosing/Scanning
In Part III, a single IV dose of approximately 370 MBq (10 mCi, ≤ 4.9 μg) [11C]MK-6884 
will be administered.  A single brain scan will be performed after the dose, and positron 
emission images of the brain will be obtained for approximately 90 minutes after the 
administration of [11C]MK-6884 to verify the BPND of the [11C]MK-6884 ligand.  
The sequence of procedures that should be followed in Part III (refer to Study Flowchart in 
Section 6.0) is outlined in Table 7.
Table 7
Part III Procedures.
Time
Description
Approximately 2 hours to 90 minutes 
pre-dose
-Venous blood sample will be drawn before tracer 
administration 
for 
baseline 
laboratory 
safety 
evaluations.
-90 to -10 minutes
-Note all procedures requiring needle sticks 
(including antecubital venous
lines) will be 
completed 
-Venous bloods sample will be drawn for 
evaluation of plasma donepezil/rivastigmine 
level and RBC-AChE activity during this period. 
-Subjects should be asked to micturate immediately 
prior to the next time period.
Approximately 30 minutes pre-dose
-Subjects will rest supine on the imaging table while 
baseline vital signs and ECGs are obtained per the 
study flowchart (Section 6.0).
-A brain attenuation CT scan is obtained (the time of 
the CT scan can be at the discretion of the 
investigator) 1
Time “0”
[11C]MK-6884
administration, 
PET/CT
scan 
initiated
 
 
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Time
Description
0 to ~ 90 minutes
Subjects will be asked to remain motionless on the 
imaging table while the scans are acquired.1
-HR, BP, and 12-lead ECGs will be obtained during 
this time period per the study flowchart (Section 6.0)
End of scanning sessions
HR, BP, ECG and blood for laboratory safety 
evaluations will be collected per the study flowchart 
(Section 6.0). Indwelling venous catheter will be 
removed.
1 Every effort should be made to get a full dynamic scan for 90 minutes (if required based on available data from the 
ongoing trial). If an AD subject cannot tolerate the full duration of 90 minutes, as determined by the investigator, or, an 
unexpected intolerance event occurs at or after 60 minutes into a full scan, the scan can be concluded at or after 60 minutes. 
PET data for such a shortened scan should be reconstructed following the same protocol as a normal scan, without 
inclusion of the truncated time frames.
A brain PET scan will be initiated immediately following dosing. For the scanning session, 
subjects will be positioned on the scanner bed with the head within the center of axial and 
transaxial fields of view. The head will be restrained to reduce movement artifacts during the 
scan. Baseline sensory conditions (dimmed room lighting, reduced noise) will be imposed 
and maintained throughout the session. 
Catheters will be removed after all of the procedures requiring venous access have been
completed.
Postdose
Subjects may stay overnight at the discretion of the investigator.
7.1.5.3
Post-Trial
Post-study procedures will be performed either shortly after the last scanning session, or just 
prior to discharge which may be at ~ 24 hours post final dose (if the subject is kept overnight 
at the investigator’s discretion) (see the Study Flowchart in Section 6.0).  Assessment for 
potential adverse experiences will be conducted at ~24 hours post dose either by phone or at 
the clinic, followed by an additional phone call conducted at 14 days post final dose.
7.1.5.4
Critical Procedures Based on Trial Objectives: Timing of Procedure 
For this trial, the blood sample collections for [11C]MK-6884/tracer kinetics (in Parts I and 
II) and the PET scans (in Parts I, II, and III) are the critical procedures. 
At any postdose time point, the blood sampling for tracer kinetics and PET scans need to be
performed as close to the exact time point as possible. When multiple procedures are
scheduled for the same time, the collection of venous (Part I) or arterial (Part II) blood
samples will have the highest priority. All other procedures should be completed as close to
the prescribed/scheduled time as possible. Trial procedures can be performed prior or after
the prescribed/scheduled time.
 
 
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The order of priority can be changed during the trial with joint agreement of the investigator
and the Sponsor Clinical Director.
Any nonscheduled procedures required for urgent evaluation of safety concerns take
precedence over all routine scheduled procedures.
7.1.5.5
Trial Design/Dosing/Procedures Modifications Permitted within Protocol 
Parameters
This is a Phase I assessment of MK-6884 in humans, and the pharmacokinetic, 
pharmacodynamic and safety profiles of the compound is still being elucidated.  This 
protocol is written with some flexibility to accommodate the inherent dynamic nature of 
Phase I clinical trials.  Modifications to the dose, dosing regimen and/or clinical or laboratory 
procedures currently outlined below may be required to achieve the scientific goals of the 
trial objectives and/or to ensure appropriate safety monitoring of the trial subjects.  
As such, some alterations from the currently outlined radiation dose and/or dosing regimen 
may be permitted based on newly available data, but the tracer mass dose as well as yearly 
effective dose may not exceed those limits currently outlined in the protocol. Specifically, 
any upward titration in the radiation dose for Parts II and III may occur if needed based on 
Part I data as long as it remains below the yearly acceptable limits of radiation exposure. 

Repeat of or adjustment in the dose of the trial drug administered in any given 
period/panel

Omission of one part of the study or a dose within Part II

Adjustment of the dosing interval (Part II)

Instructions to take trial drug with or without food or drink may also be modified based
on newly available data

Changes to the time interval between dosing and PET scans

Changes to the scanning protocol

Changes to tracer kinetics sampling timepoints 
If it is determined that incomplete or aberrant data has been captured during the PET 
measurements at any post-randomization trial visit, the subject may be asked to repeat the 
treatment/scan. The evaluation to determine whether the treatment/scan is to be repeated will 
be done on an individual basis per subject, and the decision will be reached by mutual 
agreement of the Sponsor and investigator. Up to two (2) treatment/scan per subject may be 
repeated. Repeating treatment/scan may result in an increase of the subject's cumulative 
exposure and/or may increase the total blood volume with approximately 50 mL per repeat 
in Part I, approximately 90 mL in Part II, and approximately 33 mL in Part III. The resulting 
exposure or blood volume increases will be deemed acceptable by the Sponsor and 
investigator for that subject. The total blood volume collected should remain <500 mL. A 
subject may be discontinued from the trial and be replaced at the investigator’s discretion 
after one failed repeat treatment/scan. 
 
 
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The blood sampling scheme for tracer kinetics currently outlined in the protocol may be 
modified during the trial based on newly available data (e.g., to obtain data closer to the time 
of peak plasma concentrations).  If indicated, these collected samples may also be assayed in 
an exploratory manner for metabolites and/or additional pharmacodynamic markers.
Up to additional 50 mL of blood may be drawn for safety, pharmacokinetic, and/or 
pharmacodynamic analyses.  The total blood volume withdrawn from any single subject will 
not exceed the maximum allowable volume during his/her participation in the entire trial 
(Section 12.4). 
The timing of procedures for assessment of safety procedures (e.g., vital signs, ECG, safety 
laboratory tests, etc.) currently outlined in the protocol may be modified during the trial 
based on newly available safety, tolerability, pharmacokinetic or pharmacodynamic data 
(e.g., to obtain data closer to the time of peak plasma concentrations).  Additional laboratory 
safety tests may be added to blood samples previously drawn to obtain additional safety 
information (e.g., adding creatinine kinase to serum chemistry panel that was already drawn. 
These changes will not increase the number of trial procedures for a given subject during 
his/her participation in the entire trial. 
It is understood that the current trial may employ some or none of the alterations described 
above.  Any alteration made to this protocol to meet the trial objectives must be detailed by 
the Sponsor in a letter to the Trial File and forwarded to the investigator for retention.  The 
letter may be forwarded to the IRB/ERC at the discretion of the investigator.
Assessing and Recording Adverse Events
7.2
An adverse event is defined as any untoward medical occurrence in a patient or clinical 
investigation subject administered a pharmaceutical product and which does not necessarily 
have to have a causal relationship with this treatment. An adverse event can therefore be any 
unfavourable and unintended sign (including an abnormal laboratory finding, for example), 
symptom, or disease temporally associated with the use of a medicinal product or protocol-
specified procedure, whether or not considered related to the medicinal product or protocol-
specified procedure.  Any worsening (i.e., any clinically significant adverse change in 
frequency and/or intensity) of a preexisting condition that is temporally associated with the 
use of the Sponsor’s product, is also an adverse event.
Changes resulting from normal growth and development that do not vary significantly in 
frequency or severity from expected levels are not to be considered adverse events.  
Examples of this may include, but are not limited to, teething, typical crying in infants and 
children and onset of menses or menopause occurring at a physiologically appropriate time.
Sponsor's product includes any pharmaceutical product, biological product, device, 
diagnostic agent or protocol-specified procedure, whether investigational (including placebo 
or active comparator medication) or marketed, manufactured by, licensed by, provided by or 
distributed by the Sponsor for human use.
 
 
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Adverse events may occur during clinical trials, or as prescribed in clinical practice, from 
overdose (whether accidental or intentional), from abuse and from withdrawal.
For randomized subjects only, all adverse events that occur after the consent form is signed 
but before treatment allocation/randomization must be reported by investigator if they are the 
result of a protocol-specified intervention, including but not limited to washout or 
discontinuation of usual therapy, diet, placebo treatment or a procedure. From the time of 
treatment allocation/randomization through 14 days following cessation of treatment, all 
adverse events must be reported by the investigator. Such events will be recorded at each 
examination on the Adverse Event case report forms/worksheets.  The reporting timeframe 
for adverse events meeting any serious criteria is described in section 7.2.3.1. The 
investigator will make every attempt to follow all subjects with non-serious adverse events 
for outcome.
Electronic reporting procedures can be found in the EDC data entry guidelines. Paper 
reporting procedures can be found in the Investigator Trial File Binder (or equivalent).
Definition of an Overdose for This Protocol and Reporting of Overdose to the 
7.2.1
Sponsor
The subject has taken (accidentally or intentionally) any drug administered as part of the 
protocol and exceeding the dose as prescribed by the protocol. It is up to the investigator or 
the reporting physician to decide whether a dose is to be considered an overdose, in 
consultation with the Sponsor.
The targeted radiation doses of [11C]MK-6884 are specified in the protocol. The actual 
radiation dose administered will be as specified per protocol, with a deviation of up to 10% 
greater than prescribed deemed acceptable, per local standards.
If an adverse event(s) is associated with (“results from”) the overdose of Sponsor's product or 
vaccine, the adverse event(s) is reported as a serious adverse event, even if no other 
seriousness criteria are met.
If a dose of Sponsor's product or vaccine meeting the protocol definition of overdose is taken 
without any associated clinical symptoms or abnormal laboratory results, the overdose is 
reported as a non-serious Event of Clinical Interest (ECI), using the terminology “accidental 
or intentional overdose without adverse effect.”
All reports of overdose with and without an adverse event must be reported by the 
investigator within 24 hours to the Sponsor either by electronic media or paper. Electronic 
reporting procedures can be found in the EDC data entry guidelines. Paper reporting 
procedures can be found in the Investigator Trial File Binder (or equivalent).
Reporting of Pregnancy and Lactation to the Sponsor
7.2.2
Although pregnancy and lactation are not considered adverse events, it is the responsibility of 
investigators or their designees to report any pregnancy or lactation in a subject 
(spontaneously reported to them) that occurs during the trial. 
 
 
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Pregnancies and lactations that occur after the consent form is signed but before treatment 
allocation/randomization must be reported by the investigator if they cause the subject to be 
excluded from the trial, or are the result of a protocol-specified intervention, including but 
not limited to washout or discontinuation of usual therapy, diet, placebo treatment or a 
procedure. Pregnancies and lactations that occur from the time of treatment 
allocation/randomization through 14 days following cessation of Sponsor’s product must be 
reported by the investigator. All reported pregnancies must be followed to the 
completion/termination of the pregnancy. Pregnancy outcomes of spontaneous abortion, 
missed abortion, benign hydatidiform mole, blighted ovum, fetal death, intrauterine death, 
miscarriage and stillbirth must be reported as serious events (Important Medical Events). If 
the pregnancy continues to term, the outcome (health of infant) must also be reported. 
Such events must be reported within 24 hours to the Sponsor either by electronic media or 
paper. Electronic reporting procedures can be found in the EDC data entry guidelines. Paper 
reporting procedures can be found in the Investigator Trial File Binder (or equivalent).
Immediate Reporting of Adverse Events to the Sponsor
7.2.3
7.2.3.1
Serious Adverse Events
A serious adverse event is any adverse event occurring at any dose or during any use of 
Sponsor's product that:
●
Results in death;
●
Is life threatening;
●
Results in persistent or significant disability/incapacity;
●
Results in or prolongs an existing inpatient hospitalization;
●
Is a congenital anomaly/birth defect;
●
Is another important medical event.
Note: In addition to the above criteria, adverse events meeting either of the below criteria, 
although not serious per ICH definition, are reportable to the Sponsor in the same timeframe 
as SAEs to meet certain local requirements. Therefore, these events are considered serious by 
the Sponsor for collection purposes.
●
Is a cancer;
●
Is associated with an overdose.
Refer to Table 8 for additional details regarding each of the above criteria.
For the time period beginning when the consent form is signed until treatment 
allocation/randomization, any serious adverse event, or follow up to a serious adverse event, 
including death due to any cause, that occurs to any subject must be reported within 24 hours 
to the Sponsor if it causes the subject to be excluded from the trial, or is the result of a 
protocol-specified intervention, including but not limited to washout or discontinuation of 
usual therapy, diet, placebo treatment or a procedure.
For the time period beginning at treatment allocation/randomization through 14 days 
following cessation of treatment, any serious adverse event, or follow up to a serious adverse 
 
 
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event, including death due to any cause, whether or not related to the Sponsor's product, must 
be reported within 24 hours to the Sponsor either by electronic media or paper. Electronic 
reporting procedures can be found in the EDC data entry guidelines. Paper reporting 
procedures can be found in the Investigator Trial File Binder (or equivalent).
Additionally, any serious adverse event, considered by an investigator who is a qualified 
physician to be related to the Sponsor's product that is brought to the attention of the 
investigator at any time outside of the time period specified in the previous paragraph also 
must be reported immediately to the Sponsor.
All subjects with serious adverse events must be followed up for outcome.
7.2.3.2
Events of Clinical Interest
Selected non-serious and serious adverse events are also known as Events of Clinical Interest 
(ECI) and must be reported to the Sponsor.
For the time period beginning when the consent form is signed until treatment 
allocation/randomization, any ECI, or follow up to an ECI, that occurs to any subject must be 
reported within 24 hours to the Sponsor if it causes the subject to be excluded from the trial, 
or is the result of a protocol-specified intervention, including but not limited to washout or 
discontinuation of usual therapy, diet, placebo treatment or a procedure.
For the time period beginning at treatment allocation/randomization through 14 days 
following cessation of treatment, any ECI, or follow up to an ECI, whether or not related to 
the Sponsor’s product, must be reported within 24 hours to the Sponsor, either by electronic 
media or paper.  Electronic reporting procedures can be found in the EDC data entry 
guidelines.  Paper reporting procedures can be found in the Investigator Trial File Binder (or 
equivalent).
Events of clinical interest for this trial include:
1. an overdose of Sponsor's product, as defined in Section 7.2.1 - Definition of an 
Overdose for This Protocol and Reporting of Overdose to the Sponsor, that is not 
associated with clinical symptoms or abnormal laboratory results. 
2. an elevated AST or ALT lab value that is greater than or equal to 3X the upper limit 
of normal and an elevated total bilirubin lab value that is greater than or equal to 2X 
the upper limit of normal and, at the same time, an alkaline phosphatase lab value that 
is less than 2X the upper limit of normal, as determined by way of protocol-specified 
laboratory testing or unscheduled laboratory testing.*
*Note:  These criteria are based upon available regulatory guidance documents. The 
purpose of the criteria is to specify a threshold of abnormal hepatic tests that must trigger 
an additional evaluation for an underlying etiology. The trial site guidance for assessment 
and follow up of these criteria can be found in the Investigator Trial File Binder (or 
equivalent).
 
 
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It may also be appropriate to conduct additional evaluation for an underlying etiology in 
the setting of abnormalities of liver blood tests including AST, ALT, bilirubin, and 
alkaline phosphatase that do not meet the criteria noted above. In these cases, the decision 
to proceed with additional evaluation will be made through consultation between the 
study investigators and the Sponsor Clinical Director. However, abnormalities of liver 
blood tests that do not meet the criteria noted above are not ECIs for this trial.
Evaluating Adverse Events
7.2.4
An investigator who is a qualified physician will evaluate all adverse events with respect to 
the elements outlined in Table 8. The investigator’s assessment of causality is required for 
each adverse event.  Refer to Table 8 for instructions in evaluating adverse events.
 
 
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Table 8
Evaluating Adverse Events
Maximum
Mild
awareness of sign or symptom, but easily tolerated  (for pediatric trials, awareness of symptom, but easily tolerated)
Intensity
Moderate
discomfort enough to cause interference with usual activity (for pediatric trials, definitely acting like something is wrong)
Severe
incapacitating with inability to work or do usual activity (for pediatric trials, extremely distressed or unable to do usual activities)
Seriousness
A serious adverse event (AE) is any adverse event occurring at any dose or during any use of Sponsor's product that:
†Results in death; or
†Is life threatening; or places the subject, in the view of the investigator, at immediate risk of death from the event as it occurred [Note: This does not include an 
adverse event  that, had it occurred in a more severe form, might have caused death.]; or
†Results in a persistent or significant disability/incapacity (substantial disruption of one’s ability to conduct normal life functions); or
†Results in or prolongs an existing inpatient hospitalization (hospitalization is defined as an inpatient admission, regardless of length of stay, even if the 
hospitalization is a precautionary measure for continued observation.   (Note: Hospitalization for an elective procedure to treat a pre-existing condition that has not 
worsened is not a serious adverse event.  A pre-existing condition is a clinical condition that is diagnosed prior to the use of a Merck product and is documented in the 
patient’s medical history.); or
†Is a congenital anomaly/birth defect  (in offspring of subject taking the product regardless of time to diagnosis); or
Is a cancer (although not serious per ICH definition, is reportable to the Sponsor within 24 hours to meet certain local requirements); or
Is associated with an overdose (whether accidental or intentional).  Any adverse event associated with an overdose is considered a serious adverse event for 
collection purposes. An overdose that is not associated with an adverse event is considered a non-serious event of clinical interest and must be reported within 24 
hours.
Other important medical events that may not result in death, not be life threatening, or not require hospitalization may be considered a serious adverse event when, 
based upon appropriate medical judgment, the event may jeopardize the subject and may require medical or surgical intervention to prevent one of the outcomes listed 
previously (designated above by a †).
Duration
Record the start and stop dates of the adverse event.  If less than 1 day, indicate the appropriate length of time and units
Action taken 
Did the adverse event cause the Sponsor's product to be discontinued?
Relationship to 
Sponsor's 
Product
Did the Sponsor's product cause the adverse event?   The determination of the likelihood that the Sponsor's product caused the adverse event will be provided by an 
investigator who is a qualified physician.  The investigator’s signed/dated initials on the source document or worksheet that supports the causality noted on the AE 
form, ensures that a medically qualified assessment of causality was done.  This initialed document must be retained for the required regulatory time frame.  The 
criteria below are intended as reference guidelines to assist the investigator in assessing the likelihood of a relationship between the test drug and the adverse event 
based upon the available information
The following components are to be used to assess the relationship between the Sponsor's product and the AE; the greater the correlation with the components 
and their respective elements (in number and/or intensity), the more likely the Sponsor's product caused the adverse event:
Exposure
Is there evidence that the subject was actually exposed to the Sponsor's product such as:  reliable history, acceptable compliance assessment (pill 
count, diary, etc.), expected pharmacologic effect, or measurement of drug/metabolite in bodily specimen?
Time Course
Did 
the 
AE 
follow 
in 
a 
reasonable 
temporal 
sequence 
from 
administration 
of 
the 
Sponsor's 
product? 
Is the time of onset of the AE compatible with a drug-induced effect (applies to trials with investigational medicinal product)?
Likely Cause
Is the AE not reasonably explained by another etiology such as underlying disease, other drug(s)/vaccine(s), or other host or environmental 
factors
 
 
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Relationship
The following components are to be used to assess the relationship between the Sponsor's product and the AE:  (continued)
to Sponsor's 
Product
(continued) 
Dechallenge
Was the Sponsor's product discontinued or dose/exposure/frequency reduced?
      If yes, did the AE resolve or improve?
           If yes, this is a positive dechallenge.    If no, this is a negative dechallenge.
(Note:  This criterion is not applicable if:  (1) the AE resulted in death or permanent disability; (2) the AE resolved/improved despite 
continuation of the Sponsor's product; (3) the trial is a single-dose drug trial); or (4) Sponsor's product(s) is/are only used one time.)
Rechallenge
Was the subject re-exposed to the Sponsor's product in this trial?
      If yes, did the AE recur or worsen?
          If yes, this is a positive rechallenge.    If no, this is a negative rechallenge.
(Note:  This criterion is not applicable if:  (1) the initial AE resulted in death or permanent disability, or (2) the trial is a single-dose drug trial); 
or (3) Sponsor's product(s) is/are used only one time.)
NOTE:  IF A RECHALLENGE IS PLANNED FOR AN ADVERSE EVENT WHICH WAS SERIOUS AND WHICH MAY HAVE BEEN 
CAUSED BY THE SPONSOR'S PRODUCT, OR IF RE-EXPOSURE TO THE SPONSOR'S PRODUCT POSES ADDITIONAL POTENTIAL 
SIGNIFICANT RISK TO THE SUBJECT THEN THE RECHALLENGE MUST BE APPROVED IN ADVANCE BY THE SPONSOR
CLINICAL DIRECTOR AND THE INSTITUTIONAL REVIEW BOARD/INDEPENDENT ETHICS COMMITTEE.
Consistency 
with Trial 
Treatment 
Profile
Is the clinical/pathological presentation of the AE consistent with previous knowledge regarding the Sponsor's product or drug class 
pharmacology or toxicology?
The assessment of relationship will be reported on the case report forms /worksheets by an investigator who is a qualified physician according to his/her best clinical judgment, including 
consideration of the above elements.
Record one of the following:
Use the following scale of criteria as guidance (not all criteria must be present to be indicative of a Sponsor's product relationship).
Yes, there is a reasonable 
possibility of Sponsor's product 
relationship.
There is evidence of exposure to the Sponsor's product.  The temporal sequence of the AE onset relative to the administration of the Sponsor's 
product is reasonable.  The AE is more likely explained by the Sponsor's product than by another cause. 
No, there is not a reasonable 
possibility of Sponsor's product 
relationship
Subject did not receive the Sponsor's product OR temporal sequence of the AE onset relative to administration of the Sponsor's product is not 
reasonable OR the AE is more likely explained by another cause than the Sponsor’s product.  (Also entered for a subject with overdose without 
an associated AE.)
 
 
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Sponsor Responsibility for Reporting Adverse Events
7.2.5
All Adverse Events will be reported to regulatory authorities, IRB/IECs and investigators in 
accordance with all applicable global laws and regulations, i.e., per ICH Topic E6 (R1) 
Guidelines for Good Clinical Practice.
8.0 STATISTICAL ANALYSIS PLAN
The statistical analysis of the data obtained from this study will be conducted by, or under the 
direct auspices of, the Clinical Pharmacology Statistics Department in collaboration with the 
Pharmacology Imaging and Clinical Pharmacology Departments of the Sponsor.
Statistical Analysis Plan Summary
8.1
This section contains a brief summary of the statistical analyses for this trial. Full detail is in 
the Statistical Analysis Plan (SAP) (Section 8.2).
Statistical Methods
Safety (All Parts)
Incidence of adverse experiences will be descriptively summarized. Summary statistics
and plots will be generated for the change from baseline values in the vital signs, ECG 
parameters,
and
selected
laboratory
safety
parameters
for
subjects,
as
deemed
clinically appropriate. Depending on the safety parameter, the difference from baseline
will either be computed on the original scale (raw change from baseline) or on the log
scale and back- transformed for reporting (percent change from baseline). 
Summary
statistics for the raw laboratory safety tests, ECGs, and/or vital signs may also be
computed, as deemed clinically appropriate.
Primary (Pharmacodynamics; Parts I, II, and III)
Whole body and internal organ radiation dose will be evaluated by whole body PET scans 
(Part I). Efficacy measurements to investigate M4 PAM receptor availability and its inter-
subject variability in healthy subjects (Part II) will be evaluated via two administrations of 
[11C]MK-6884 and brain PET scanning and will include: (1) volume of distribution, or one 
of its surrogate (2) test-retest variability of volume of distribution, or one of its surrogate. 
Efficacy measurements to investigate M4 PAM receptor availability and its inter-subject 
variability  in AD patients (Part III) will be evaluated via single administration of   
[11C]MK-6884 and brain PET scanning and will include: (1) binding potential, or one of its 
surrogate.
Power
Up to 26 (N=3-6 in Part I, N=6-10 in Part II, and N=7-10 in Part III) subjects will be 
included in the study. Given the investigational nature of this study no sample size 
calculation has been performed.
 
 
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Statistical Analysis Plan
8.2
The statistical analysis of the data obtained from this study will be conducted by, or under the 
direct auspices of, the Early Clinical Development Statistics Department in collaboration 
with the Pharmacology Imaging and Translational Medicine Departments of the Sponsor.
The analysis of the data obtained in Part I of this study will be the responsibility of the 
Leuven PET center. The analysis of the data obtained in Part II and Part III of the study will 
be the responsibility of the Merck Translational Imaging Biomarkers Department.
If, after the study has begun, changes are made to the statistical and image analysis plan 
stated below, then these deviations to the plan will be listed, along with an explanation as to 
why they occurred, in the Clinical Study Report (CSR).
Hypotheses
8.2.1
Part I
Primary
1. Dosimetry calculations based on Part 1 data will support multiple [ 11C]MK-6884 
injections in humans.
Part II
Primary
1. The average intra-subject T-RT variability of M4 receptor density index measured from 
[11C]MK-6884 PET data is acceptable (≤ 20%).
Analysis Endpoints
8.2.2
Primary (Safety)
Safety and tolerability will be assessed throughout the study by monitoring subjects for 
clinical adverse experiences. Physical examinations, vital signs, 12-lead electrocardiograms 
(ECG) and laboratory safety tests will be performed periodically to detect any medically 
meaningful effects of the tracer on physiology. 
Primary (Pharmacodynamics)
Whole body and internal organ radiation dose will be evaluated by whole body PET scans 
(Part I). Efficacy measurements to investigate M4 PAM receptor availability and its inter-
subject variability in healthy subjects (Part II) will be evaluated via two administrations of 
[11C]MK-6884 and brain PET scanning and will include: (1) volume of distribution, or one of 
its surrogate (2) test-retest variability of volume of distribution, or one of its surrogate. 
Efficacy measurements to investigate M4 PAM receptor availability and its inter-subject 
 
 
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variability  in AD patients (Part III) will be evaluated via single administration of [11C]MK-
6884 and brain PET scanning and will include: (1) binding potential, or one of its surrogate. 
Approaches to Analyses
8.2.3
The following populations are defined for the analysis and reporting of data. All subjects 
will be reported, and their data analyzed, according to the treatment(s) they actually received.
All Subjects as Treated (AST) - All subjects who received at least one dose of the 
investigational drug. This population will be used for assessments of safety and tolerability.
Per-Protocol (PP) – The set of data generated by the subset of subjects who comply with the 
protocol sufficiently to ensure that these data will be likely to exhibit the effects of treatment, 
according to the underlying scientific model. Compliance covers such considerations as 
exposure to treatment, availability of measurements and absence of major protocol 
deviations. Major protocol deviations will be identified to the extent by individuals
responsible for data collection/compliance, and its analysis and interpretation. 
Any
subjects or data values excluded from analysis will be identified, along with their reason
for exclusion, in the CSR. At the end of the study, all subjects who are compliant with
the study procedure as aforementioned and have available data from at least one treatment
will be included in the primary analysis dataset. This population will be used for 
assessments of pharmacodynamics.
Statistical Methods
8.2.4
Safety (All Parts)
Incidence of adverse experiences will be descriptively summarized. Summary statistics
and plots will be generated for the change from baseline values in the vital signs, 
ECG parameters, and selected laboratory safety parameters for subjects, as deemed
clinically appropriate. Depending on the safety parameter, the difference from baseline
will either be computed on the original scale (raw change from baseline) or on the log
scale and back- transformed for reporting (percent change from baseline). 
Summary
statistics for the raw laboratory safety tests, ECGs, and/or vital signs may also be
computed, as deemed clinically appropriate.
Pharmacodynamics
Part I
The whole body and internal organ radiation burden associated with a single IV dose of 
[11C]MK-6884 (~ 370 MBq, < 4.9 μg) administered to healthy subjects will be estimated 
using methods from the site. The primary measure of radiation safety will be the Effective 
Dose (ED), a weighted composite measure of the radiation absorbed doses in multiple 
compartments. 
 
 
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Part II
Brain extraction and grey and white matter segmentation will be performed in each subject’s 
MRI scan.  A human brain atlas will be aligned to the extracted subject MRI brain via a non-
linear registration algorithm.
[11C]MK-6884 dynamic PET images will be corrected for decay, scatter, random 
coincidences, photon attenuation and motion (frame to frame registration). The test PET scan
will be aligned to the extracted subject MRI brain via a rigid registration algorithm. The 
aligned brain atlas will then be applied to the motion corrected PET dynamic data to generate 
time activity curves (TACs) of several brain regions, including (but not limited to) striatum, 
cortex, and cerebellum. The retest PET scan will be coregistered to the first scan and TACs 
will be generated using the previously defined ROIs for that subject.
At least the following analyses will be used for [11C]MK-6884 binding quantification (index 
of M4 PAM receptor availability) in human brain from both test and retest scans:
a) Regional volumes of distribution (VT) will be estimated by means of compartmental 
modeling and an arterial input function which represent the parent concentration of 
[11C]MK-6884 in plasma. A one or two tissue compartment model will be selected on the 
basis of a model selection metric (e.g. AIC).  Additional tests such as VT time stability 
will also be performed to guide the selection of an appropriate scanning time and to 
support the development of simplified quantification techniques such as standardized 
uptake value ratios.
b) Non-displaceable binding potential (BPND) will be estimated for target M4 receptor rich 
region(s) based on tissue-ratio (transient equilibrium) method, as well as simplified 
reference tissue model (SRTM), with a suitable reference region that is devoid of M4 
receptors. Based on preclinical studies in NHP PET and human brain autoradiography 
study, striatum (putamen and caudate) and cerebellum has been identified as the M4 
receptor rich and poor regions, respectively. To validate the accuracy/bias in 
measurements, the BPND derived from both tissue-ratio method and SRTM will be 
compared to that derived from volumes of distribution. i.e.
-1.
c) Standardized uptake value ratio (SUVR) will also be evaluated as part of the development 
of a simplified quantification strategy for [11C]MK-6884. Standardized uptake value 
(SUV) represent the activity in the brain (or brain region) obtained during an specific 
time window normalized by total injected activity and whole body weight.  SUVR is a 
semi-quantitative measure of specific tracer uptake using a reference region which 
accounts for the non-displaceable signal present in the target region(s) (e.g. striatum).
 
 
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d) If needed, additional methods may also be employed, to more robustly characterize the
tracer kinetics in both healthy and AD subjects 
Part III
Brain extraction and grey and white matter segmentation will be performed in each subject’s 
MRI scan.  A human brain atlas will be aligned to the extracted subject MRI brain via a non-
linear registration algorithm.
[11C]MK-6884 dynamic PET images will be corrected for decay, scatter, random 
coincidences, photon attenuation and motion (frame to frame registration). The PET scan will
be aligned to the extracted subject MRI brain via a rigid registration algorithm. The aligned 
brain atlas will then be applied to the motion corrected PET dynamic data to generate time 
activity curves (TACs) of several brain regions, including (but not limited to) striatum, 
cortex, and cerebellum.
As AD subjects will undergo PET scans without arterial input function, the analyses that will 
be used for [11C]MK-6884 binding quantification (index of M4 PAM receptor availability) in 
brain include BPND and/or SUVR and will be determined as described in Part II. These 
parameters will be determined on an individual as well as on average basis.
Blood samples for AChE plasma concentration and RBC-AChE activity will be measured 
prior to [11C]MK-6884 dosing. The information on plasma concentration and RBC-AChE 
activity will be used to explore quantitative relationships between BPND vs. plasma 
concentration and BPND vs. RBC-AChE activity using regression analysis or non-linear 
mixed effect modeling.  The measured plasma concentration and RBC-AChE activity will 
 
 
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also be compared to pharmacokinetic/pharmacodynamics relationships described in the 
scientific literature, which may facilitate further analysis of the data.
Multiplicity
8.2.5
No multiplicity adjustment is needed. Only one of the hypotheses will be formally evaluated. 
Power
8.2.6
Up to 26 (N=3-6 in Part I, N=6-10 in Part II, and N=7-10 in Part III) subjects will be 
included in the study. Given the investigational nature of this study no sample size 
calculation has been performed.
9.0 LABELING, PACKAGING,
STORAGE AND RETURN OF CLINICAL 
SUPPLIES
Investigational Product
9.1
The investigator shall take responsibility for and shall take all steps to maintain appropriate 
records and ensure appropriate supply, storage, handling, distribution and usage of 
investigational product in accordance with the protocol and any applicable laws and 
regulations.
Table 9
Product Descriptions
Product Name & Potency
Dosage Form
[11C]MK-6884 370 MBq (10 mCi)
containing ≤4.9 μg MK-6884
A sterile solution
All other supplies not indicated in Table 9 above will be provided centrally by the Sponsor or 
locally by the trial site, subsidiary or designee, depending on local country operational or 
regulatory requirements.
For any commercially available product that is provided by the trial site, subsidiary or 
designee every attempt will be made to source these supplies from a single lot/batch number. 
The trial site will be responsible for recording the lot number, manufacturer and expiry date 
of any locally purchased product.
Packaging and Labeling Information
9.2
Clinical supplies will be affixed with a clinical label in accordance with regulatory 
requirements.
Supply of Precursor and Synthesis/Labeling of [11C]MK-6884
9.2.1
Merck Research Laboratories (MRL) will supply the local radiochemistry synthesis 
laboratory with the radiopharmaceutical precursor to MK-6884. [11C]MK-6884 will be 
generated from the precursor compound after a final synthetic step.
 
 
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MRL will also supply a nonradioactive version of MK-6884 to be used as an analytical 
standard during quality control procedures, and a Certificate of Analysis describing the 
precursor as well as the nonradioactive standard, will be provided.
Radiolabeling and sterile solution compounding will be conducted under the appropriate 
cGMP standards for clinical PET materials at this stage of development. The final 
compounded product will be in a sterile solution containing up to 10% (v/v) ethanol, 10 mM 
sodium phosphate buffer, pH 7 in 0.9% sodium chloride for injection. 
The 
radiopharmaceutical formulation will be prepared shortly before administration by the local 
radiochemistry synthesis laboratory. Unit doses that pass quality control procedures for 
radiochemical purity will be dispensed to physicians in the PET unit, using standard 
operating 
procedures 
for 
the 
production, 
transfer, 
and 
administration 
of 
radiopharmaceuticals.
A qualified staff member who is authorized to administer unsealed radioactive material to 
human beings may inject the radiopharmaceutical formulation intravenously after confirming 
that the batch passed all necessary quality control procedures and verifying that the radiation 
dose is correct.
Clinical Supplies Disclosure
9.3
This trial is open-label; therefore, the subject, the trial site personnel, the Sponsor and/or 
designee are not blinded. Treatment (name, strength or potency) is included in the label text; 
random code/disclosure envelopes or lists are not provided.
Storage and Handling Requirements
9.4
Clinical supplies must be stored in a secure, limited-access location under the storage 
conditions specified on the label.  
Receipt and dispensing of trial medication must be recorded by an authorized person at the 
trial site.
Clinical supplies may not be used for any purpose other than that stated in the protocol.
Discard/Destruction/Returns and Reconciliation
9.5
The investigator is responsible for keeping accurate records of the clinical supplies received 
from the Sponsor or designee, the amount dispensed to and returned by the subjects and the 
amount remaining at the conclusion of the trial. For all trial sites, the local country Sponsor 
personnel or designee will provide appropriate documentation that must be completed for 
drug accountability and return, or local discard and destruction if appropriate.   Where local 
discard and destruction is appropriate, the investigator is responsible for ensuring that a local 
discard/destruction procedure is documented.
 
 
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10.0 ADMINISTRATIVE AND REGULATORY DETAILS
Confidentiality
10.1
Confidentiality of Data
10.1.1
By signing this protocol, the investigator affirms to the Sponsor that information furnished to 
the investigator by the Sponsor will be maintained in confidence, and such information will 
be divulged to the institutional review board, ethics review committee (IRB/ERC) or similar 
or expert committee; affiliated institution and employees, only under an appropriate 
understanding of confidentiality with such board or committee, affiliated institution and 
employees.  Data generated by this trial will be considered confidential by the investigator, 
except to the extent that it is included in a publication as provided in the Publications section 
of this protocol.
Confidentiality of Subject Records
10.1.2
By signing this protocol, the investigator agrees that the Sponsor (or Sponsor representative), 
IRB/ERC, or regulatory authority representatives may consult and/or copy trial documents in 
order to verify worksheet/case report form data.  By signing the consent form, the subject 
agrees to this process.  If trial documents will be photocopied during the process of verifying 
worksheet/case report form information, the subject will be identified by unique code only; 
full names/initials will be masked prior to transmission to the Sponsor.
By signing this protocol, the investigator agrees to treat all subject data used and disclosed in 
connection with this trial in accordance with all applicable privacy laws, rules and 
regulations.
Confidentiality of Investigator Information
10.1.3
By signing this protocol, the investigator recognizes that certain personal identifying 
information with respect to the investigator, and all subinvestigators and trial site personnel, 
may be used and disclosed for trial management purposes, as part of a regulatory 
submissions, and as required by law.  This information may include:
1. name, address, telephone number and e-mail address;
2. hospital or clinic address and telephone number;
3. curriculum vitae or other summary of qualifications and credentials; and
4. other professional documentation.
Consistent with the purposes described above, this information may be transmitted to the 
Sponsor, and subsidiaries, affiliates and agents of the Sponsor, in your country and other 
countries, including countries that do not have laws protecting such information.  
Additionally, the investigator’s name and business contact information may be included 
when reporting certain serious adverse events to regulatory authorities or to other 
investigators.  By signing this protocol, the investigator expressly consents to these uses and 
disclosures.
 
 
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If this is a multicenter trial, in order to facilitate contact between investigators, the Sponsor 
may share an investigator’s name and contact information with other participating 
investigators upon request.
Confidentiality of IRB/IEC Information
10.1.4
The Sponsor is required to record the name and address of each IRB/IEC member that 
reviews and approves this trial. The Sponsor is also required to document that each IRB/IEC 
meets regulatory and ICH GCP requirements by requesting and maintaining records of the 
names and qualifications of the IRB/IEC members and to make these records available for 
regulatory agency review upon request by those agencies.
Compliance with Financial Disclosure Requirements
10.2
Financial Disclosure requirements are outlined in the US Food and Drug Administration 
Regulations, Financial Disclosure by Clinical Investigators (21 CFR Part 54).  It is the 
Sponsor's responsibility to determine, based on these regulations, whether a request for 
Financial Disclosure information is required.  It is the investigator's/subinvestigator's 
responsibility to comply with any such request.  
The investigator/subinvestigator(s) agree, if requested by the Sponsor in accordance with 21 
CFR Part 54, to provide his/her financial interests in and/or arrangements with the Sponsor to 
allow for the submission of complete and accurate certification and disclosure statements.  
The investigator/subinvestigator(s) further agree to provide this information on a 
Certification/Disclosure Form, commonly known as a financial disclosure form, provided by 
the Sponsor. The investigator/subinvestigator(s) also consent to the transmission of this 
information to the Sponsor in the United States for these purposes.  This may involve the 
transmission of information to countries that do not have laws protecting personal data.
Compliance with Law, Audit and Debarment
10.3
By signing this protocol, the investigator agrees to conduct the trial in an efficient and 
diligent manner and in conformance with this protocol; generally accepted standards of Good 
Clinical Practice (e.g., International Conference on Harmonization of Technical 
Requirements for Registration of Pharmaceuticals for Human Use Good Clinical Practice: 
Consolidated Guideline and other generally accepted standards of good clinical practice); and 
all applicable federal, state and local laws, rules and regulations relating to the conduct of the 
clinical trial.
The Code of Conduct, a collection of goals and considerations that govern the ethical and 
scientific conduct of clinical investigations sponsored by Merck, is provided in Section 12.1 -
Merck Code of Conduct for Clinical Trials.
The investigator also agrees to allow monitoring, audits, IRB/ERC review and regulatory 
authority inspection of trial-related documents and procedures and provide for direct access 
to all trial-related source data and documents.
 
 
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The investigator agrees not to seek reimbursement from subjects, their insurance providers or 
from government programs for procedures included as part of the trial reimbursed to the 
investigator by the Sponsor.
The investigator shall prepare and maintain complete and accurate trial documentation in 
compliance with Good Clinical Practice standards and applicable federal, state and local 
laws, rules and regulations; and, for each subject participating in the trial, provide all data, 
and, upon completion or termination of the clinical trial, submit any other reports to the 
Sponsor as required by this protocol or as otherwise required pursuant to any agreement with 
the Sponsor.
Trial documentation will be promptly and fully disclosed to the Sponsor by the investigator 
upon request and also shall be made available at the trial site upon request for inspection, 
copying, review and audit at reasonable times by representatives of the Sponsor or any 
regulatory authorities.  The investigator agrees to promptly take any reasonable steps that are 
requested by the Sponsor as a result of an audit to cure deficiencies in the trial documentation 
and worksheets/case report forms.
The investigator must maintain copies of all documentation and records relating to the 
conduct of the trial in compliance with all applicable legal and regulatory requirements.  This 
documentation includes, but is not limited to, the protocol, worksheets/case report forms, 
advertising for subject participation, adverse event reports, subject source data, 
correspondence with regulatory authorities and IRBs/ERCs, consent forms, investigator’s 
curricula vitae, monitor visit logs, laboratory reference ranges, laboratory certification or 
quality control procedures and laboratory director curriculum vitae.  By signing this protocol, 
the investigator agrees that documentation shall be retained until at least 2 years after the last 
approval of a marketing application in an ICH region or until there are no pending or 
contemplated marketing applications in an ICH region or until at least 2 years have elapsed 
since the formal discontinuation of clinical development of the investigational product.  
Because the clinical development and marketing application process is variable, it is 
anticipated that the retention period can be up to 15 years or longer after protocol database 
lock. The Sponsor will determine the minimum retention period and notify the investigator 
when documents may be destroyed.  The Sponsor will determine the minimum retention 
period and upon request, will provide guidance to the investigator when documents no longer 
need to be retained.  The sponsor also recognizes that documents may need to be retained for 
a longer period if required by local regulatory requirements. All trial documents shall be 
made available if required by relevant regulatory authorities. The investigator must consult 
with and obtain written approval by the Sponsor prior to destroying trial and/or subject files.  
ICH Good Clinical Practice guidelines recommend that the investigator inform the subject’s 
primary physician about the subject’s participation in the trial if the subject has a primary 
physician and if the subject agrees to the primary physician being informed.
The investigator will promptly inform the Sponsor of any regulatory authority inspection 
conducted for this trial.
 
 
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Persons debarred from conducting or working on clinical trials by any court or regulatory 
authority will not be allowed to conduct or work on this Sponsor’s trials.  The investigator 
will immediately disclose in writing to the Sponsor if any person who is involved in 
conducting the trial is debarred or if any proceeding for debarment is pending or, to the best 
of the investigator’s knowledge, threatened.
In the event the Sponsor prematurely terminates a particular trial site, the Sponsor will 
promptly notify that trial site’s IRB/IEC.
According to European legislation, a Sponsor must designate an overall coordinating 
investigator for a multi-center trial (including multinational).  When more than one trial site 
is open in an EU country, Merck, as the Sponsor, will designate, per country, a national 
principal coordinator (Protocol CI), responsible for coordinating the work of the principal 
investigators at the different trial sites in that Member State, according to national 
regulations.  For a single-center trial, the Protocol CI is the principal investigator.  In 
addition, the Sponsor must designate a principal or coordinating investigator to review the 
trial report that summarizes the trial results and confirm that, to the best of his/her 
knowledge, the report accurately describes the conduct and results of the trial [Clinical Study 
Report (CSR) CI].  The Sponsor may consider one or more factors in the selection of the 
individual to serve as the Protocol CI and or CSR CI (e.g., availability of the CI during the 
anticipated review process, thorough understanding of clinical trial methods, appropriate 
enrollment of subject cohort, timely achievement of trial milestones).  The Protocol CI must 
be a participating trial investigator.
Compliance with Trial Registration and Results Posting Requirements
10.4
Under the terms of the Food and Drug Administration Modernization Act (FDAMA) and the 
Food and Drug Administration Amendments Act (FDAAA), the Sponsor of the trial is solely 
responsible for determining whether the trial and its results are subject to the requirements 
for submission to the Clinical Trials Data Bank, http://www.clinicaltrials.gov.  Merck, as 
Sponsor of this trial, will review this protocol and submit the information necessary to fulfill 
these requirements.  Merck entries are not limited to FDAMA/FDAAA mandated trials. 
Information posted will allow subjects to identify potentially appropriate trials for their 
disease conditions and pursue participation by calling a central contact number for further 
information on appropriate trial locations and trial site contact information.    
By signing this protocol, the investigator acknowledges that the statutory obligations under 
FDAMA/FDAAA are that of the Sponsor and agrees not to submit any information about this 
trial or its results to the Clinical Trials Data Bank.
Quality Management System
10.5
By signing this protocol, the Sponsor agrees to be responsible for implementing and 
maintaining a quality management system with written development procedures and 
functional area standard operating procedures (SOPs) to ensure that trials are conducted and 
data are generated, documented, and reported in compliance with the protocol, accepted 
 
 
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standards of Good Clinical Practice, and all applicable federal, state, and local laws, rules and 
regulations relating to the conduct of the clinical trial.
Data Management
10.6
The investigator or qualified designee is responsible for recording and verifying the accuracy 
of subject data.  By signing this protocol, the investigator acknowledges that his/her 
electronic signature is the legally binding equivalent of a written signature.  By entering 
his/her electronic signature, the investigator confirms that all recorded data have been 
verified as accurate.
Detailed information regarding Data Management procedures for this protocol will be 
provided separately.
Publications
10.7
This trial is intended for publication, even if terminated prematurely. Publication may include 
any or all of the following: posting of a synopsis online, abstract and/or presentation at a 
scientific conference, or publication of a full manuscript.  The Sponsor will work with the 
authors to submit a manuscript describing trial results within 12 months after the last data 
become available, which may take up to several months after the last subject visit in some 
cases such as vaccine trials.  However, manuscript submission timelines may be extended on 
OTC trials.  For trials intended for pediatric-related regulatory filings, the investigator agrees 
to delay publication of the trial results until the Sponsor notifies the investigator that all 
relevant regulatory authority decisions on the trial drug have been made with regard to 
pediatric-related regulatory filings. Merck will post a synopsis of trial results for approved 
products on www.clinicaltrials.gov by 12 months after the last subject's last visit for the 
primary outcome, 12 months after the decision to discontinue development, or product 
marketing (dispensed, administered, delivered or promoted), whichever is later.
These timelines may be extended for products that are not yet marketed, if additional time is 
needed for analysis, to protect intellectual property, or to comply with confidentiality 
agreements with other parties.  Authors of the primary results manuscript will be provided 
the complete results from the Clinical Study Report, subject to the confidentiality agreement. 
When a manuscript is submitted to a biomedical journal, the Sponsor's policy is to also 
include the protocol and statistical analysis plan to facilitate the peer and editorial review of 
the manuscript.  If the manuscript is subsequently accepted for publication, the Sponsor will 
allow the journal, if it so desires, to post on its website the key sections of the protocol that 
are relevant to evaluating the trial, specifically those sections describing the trial objectives 
and hypotheses, the subject inclusion and exclusion criteria, the trial design and procedures, 
the efficacy and safety measures, the statistical analysis plan, and any amendments relating to 
those sections.  The Sponsor reserves the right to redact proprietary information.
For multicenter trials, subsequent to the multicenter publication (or after public disclosure of 
the results online at www.clinicaltrials.gov if a multicenter manuscript is not planned), an 
investigator and his/her colleagues may publish their data independently.  In most cases, 
publication of individual trial site data does not add value to complete multicenter results, 
 
 
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due to statistical concerns.  In rare cases, publication of single trial site data prior to the main 
paper may be of value.  Limitations of single trial site observations in a multicenter trial 
should always be described in such a manuscript.
Authorship credit should be based on 1) substantial contributions to conception and design, 
or acquisition of data, or analysis and interpretation of data; 2) drafting the article or revising 
it critically for important intellectual content; and 3) final approval of the version to be 
published. Authors must meet conditions 1, 2 and 3.  Significant contributions to trial 
execution may also be taken into account to determine authorship, provided that 
contributions have also been made to all three of the preceding authorship criteria.  Although 
publication planning may begin before conducting the trial, final decisions on authorship and 
the order of authors’ names will be made based on participation and actual contributions to 
the trial and writing, as discussed above. The first author is responsible for defending the 
integrity of the data, method(s) of data analysis and the scientific content of the manuscript.
The Sponsor must have the opportunity to review all proposed abstracts, manuscripts or 
presentations regarding this trial 45 days prior to submission for publication/presentation. 
Any information identified by the Sponsor as confidential must be deleted prior to 
submission; this confidentiality does not include efficacy and safety results. Sponsor review 
can be expedited to meet publication timelines.
11.0 LIST OF REFERENCES
1. Bodick NC, Offen WW, Levey AI, Cutler NR, Gauthier SG, Satlin A, Shannon HE, 
Tollefson GD, Rasmussen K, Bymaster FP, Hurley DJ, Potter WZ, Paul SM. Effects of 
xanomeline, a selective muscarinic receptor agonist, on cognitive function and 
behavioral symptoms in Alzheimer disease.  Arch Neurol. 1997 Apr;54(4):465-73.
2. Shekhar A1, Potter WZ, Lightfoot J, Lienemann J, Dubé S, Mallinckrodt C, Bymaster 
FP, McKinzie DL, Felder CC.  Selective muscarinic receptor agonist xanomeline as a 
novel treatment approach for schizophrenia. Am J Psychiatry. 2008 Aug;165(8):1033-9. 
3. European Commission on Radiation Protection 99. Guidance on radiation exposures in 
medical and biomedical research. 1998; Directorate-General, Environment Nuclear 
Safety and Civil Protection.
4. Lilienfeld, S. Galantamine--a novel cholinergic drug with a unique dual mode of action 
for the treatment of patients with Alzheimer's disease. CNS Drug Rev. 2002 
Summer;8(2):159-76.
 
 
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12.0 APPENDICES
Merck Code of Conduct for Clinical Trials
12.1
Merck*
Code of Conduct for Clinical Trials
I.
Introduction
A. Purpose
Merck, through its subsidiaries, conducts clinical trials worldwide to evaluate the safety and effectiveness of our 
products. As such, we are committed to designing, implementing, conducting, analyzing and reporting these trials in 
compliance with the highest ethical and scientific standards. Protection of subject safety is the overriding concern in 
the design of clinical trials. In all cases, Merck clinical trials will be conducted in compliance with local and/or 
national regulations and in accordance with the ethical principles that have their origin in the Declaration of Helsinki. 
B. Scope
Such standards shall be endorsed for all clinical interventional investigations sponsored by Merck irrespective of the 
party (parties) employed for their execution (e.g., contract research organizations, collaborative research efforts). This 
Code is not intended to apply to trials which are observational in nature, or which are retrospective. Further, this Code 
does not apply to investigator-initiated trials which are not under the control of Merck.
II. Scientific Issues
A. Trial Conduct
1. Trial Design
Except for pilot or estimation trials, clinical trial protocols will be hypothesis-driven to assess safety, efficacy 
and/or pharmacokinetic or pharmacodynamic indices of Merck or comparator products.  Alternatively, Merck may 
conduct outcomes research trials, trials to assess or validate various endpoint measures, or trials to determine 
subject preferences, etc.  
The design (i.e., subject population, duration, statistical power) must be adequate to address the specific purpose 
of the trial.  Research subjects must meet protocol entry criteria to be enrolled in the trial. 
2. Site Selection
Merck selects investigative sites based on medical expertise, access to appropriate subjects, adequacy of facilities 
and staff, previous performance in Merck trials, as well as budgetary considerations.  Prior to trial initiation, sites 
are evaluated by Merck personnel to assess the ability to successfully conduct the trial.
3. Site Monitoring/Scientific Integrity
Trial sites are monitored to assess compliance with the trial protocol and general principles of Good Clinical 
Practice.  Merck reviews clinical data for accuracy, completeness and consistency. Data are verified versus source 
documentation according to standard operating procedures.  Per Merck policies and procedures, if fraud, 
misconduct or serious GCP-non-Compliance are suspected, the issues are promptly investigated. When necessary, 
the clinical site will be closed, the responsible regulatory authorities and ethics review committees notified and 
data disclosed accordingly. 
B. Publication and Authorship
To the extent scientifically appropriate, Merck seeks to publish the results of trials it conducts.  Some early phase or 
pilot trials are intended to be hypothesis-generating rather than hypothesis testing.  In such cases, publication of 
results may not be appropriate since the trial may be underpowered and the analyses complicated by statistical issues 
of multiplicity.
Merck’s policy on authorship is consistent with the requirements outlined in the ICH-Good Clinical Practice 
guidelines. In summary, authorship should reflect significant contribution to the design and conduct of the trial, 
performance or interpretation of the analysis, and/or writing of the manuscript.  All named authors must be able to 
defend the trial results and conclusions.  Merck funding of a trial will be acknowledged in publications. 
 
 
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III. Subject Protection
A. IRB/ERC review
All clinical trials will be reviewed and approved by an independent IRB/ERC before being initiated at each site.  
Significant changes or revisions to the protocol will be approved by the IRB/ERC prior to implementation, except that 
changes required urgently to protect subject safety and well-being may be enacted in anticipation of IRB/ERC 
approval. For each site, the IRB/ERC and Merck will approve the subject informed consent form. 
B. Safety
The guiding principle in decision-making in clinical trials is that subject welfare is of primary importance.  Potential 
subjects will be informed of the risks and benefits of, as well as alternatives to, trial participation. At a minimum, trial 
designs will take into account the local standard of care.  Subjects are never denied access to appropriate medical care 
based on participation in a Merck clinical trial. 
All participation in Merck clinical trials is voluntary.  Subjects are enrolled only after providing informed consent for 
participation.  Subjects may withdraw from a Merck trial at any time, without any influence on their access to, or 
receipt of, medical care that may otherwise be available to them.
C. Confidentiality
Merck is committed to safeguarding subject confidentiality, to the greatest extent possible.  Unless required by law, 
only the investigator, sponsor (or representative) and/or regulatory authorities will have access to confidential medical 
records that might identify the research subject by name.  
D. Genomic Research
Genomic Research will only be conducted in accordance with informed consent and/or as specifically authorized by 
an Ethics Committee.
IV. Financial Considerations
A. Payments to Investigators
Clinical trials are time- and labor-intensive.  It is Merck’s policy to compensate investigators (or the sponsoring 
institution) in a fair manner for the work performed in support of Merck trials.   Merck does not pay incentives to 
enroll subjects in its trials.  However, when enrollment is particularly challenging, additional payments may be made 
to compensate for the time spent in extra recruiting efforts.
Merck does not pay for subject referrals.  However, Merck may compensate referring physicians for time spent on 
chart review to identify potentially eligible subjects.
B. Clinical Research Funding 
Informed consent forms will disclose that the trial is sponsored by Merck, and that the investigator or sponsoring 
institution is being paid or provided a grant for performing the trial.  However, the local IRB/ERC may wish to alter 
the wording of the disclosure statement to be consistent with financial practices at that institution.  As noted above, 
publications resulting from Merck trials will indicate Merck as a source of funding.
C. Funding for Travel and Other Requests
Funding of travel by investigators and support staff (e.g., to scientific meetings, investigator meetings, etc.) will be 
consistent with local guidelines and practices including, in the U.S., those established by the American Medical 
Association (AMA). 
V. Investigator Commitment
Investigators will be expected to review Merck’s Code of Conduct as an appendix to the trial protocol, and in signing 
the protocol, agree to support these ethical and scientific standards.
* In this document, "Merck" refers to Merck Sharp & Dohme Corp. and Schering Corporation, each of which is a 
subsidiary of Merck & Co., Inc.  Merck is known as MSD outside of the United States and Canada.  As warranted by 
context, Merck also includes affiliates and subsidiaries of Merck & Co., Inc."
 
 
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Collection and Management of Specimens for Future Biomedical Research
12.2
1. Definitions
a.
Biomarker:  A biological molecule found in blood, other body fluids, or tissues that is a 
sign of a normal or abnormal process or of a condition or disease.  A biomarker may be 
used to see how well the body responds to a treatment for a disease or condition.1
b. Pharmacogenomics:  The investigation of variations of DNA and RNA characteristics as 
related to drug/vaccine response.2
c.
Pharmacogenetics:  A subset of pharmacogenomics, pharmacogenetics is the influence of 
variations in DNA sequence on drug/vaccine response.2
d. DNA:  Deoxyribonucleic acid.
e.
RNA:  Ribonucleic acid.
2. Scope of Future Biomedical Research
The specimens collected in this trial as outlined in Section 7.1.3.3 – Future Biomedical 
Research Sample Collection will be used to study various causes for how subjects may 
respond to a drug/vaccine.  Future biomedical research specimen(s) will be stored to 
provide a resource for future trials conducted by the Sponsor focused on the study of 
biomarkers responsible for how a drug/vaccine enters and is removed by the body, how a 
drug/vaccine works, other pathways a drug/vaccine may interact with, or other aspects of 
disease. The specimen(s) may be used for future assay development and/or drug/vaccine 
development.
It is now well recognized that information obtained from studying and testing clinical 
specimens offers unique opportunities to enhance our understanding of how individuals 
respond to drugs/vaccines, enhance our understanding of human disease and ultimately 
improve public health through development of novel treatments targeted to populations 
with the greatest need.  All specimens will be used by the Sponsor or those working for 
or with the Sponsor.
3. Summary of Procedures for Future Biomedical Research
a.
Subjects for Enrollment
All subjects enrolled in the clinical trial will be considered for enrollment in the 
Future Biomedical Research sub-trial.
b. Informed Consent
Informed consent for specimens (i.e., DNA, RNA, protein, etc.) will be obtained 
during screening for protocol enrollment from all subjects or legal guardians, at a trial 
visit by the investigator or his or her designate.  Informed consent for Future 
Biomedical Research should be presented to the subjects on Visit 1.  If delayed, 
present consent at next possible Subject Visit. Informed consent must be obtained 
prior to collection of all Future Biomedical Research specimens.  Consent forms 
signed by the subject will be kept at the clinical trial site under secure storage for 
regulatory reasons.  
 
 
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A template of each trial site’s approved informed consent will be stored in the 
Sponsor’s clinical document repository. Each consent will be assessed for appropriate 
specimen permissions.  
c.
eCRF Documentation for Future Biomedical Research Specimens
Documentation of patient consent for Future Biomedical Research will be captured in 
the electronic Case Report Forms (eCRFs). Any specimens for which such an 
informed consent cannot be verified will be destroyed.
d. Future Biomedical Research Specimen Collections
Collection of specimens for Future Biomedical Research will be performed as 
outlined in the trial flow chart. In general, if additional blood specimens are being 
collected for Future Biomedical Research, these will usually be obtained at a time 
when the subject is having blood drawn for other trial purposes.
4. Confidential Subject Information for Future Biomedical Research 
In order to optimize the research that can be conducted with Future Biomedical Research 
specimens, it is critical to link subject' clinical information with future test results. In fact 
little or no research can be conducted without connecting the clinical trial data to the 
specimen. The clinical data allow specific analyses to be conducted. Knowing subject 
characteristics like gender, age, medical history and treatment outcomes are critical to 
understanding clinical context of analytical results.
To maintain privacy of information collected from specimens obtained for Future 
Biomedical Research, the Sponsor has developed secure policies and procedures. All 
specimens will be single-coded per ICH E15 guidelines as described below. 
At the clinical trial site, unique codes will be placed on the Future Biomedical Research 
specimens for transfer to the storage facility.  This first code is a random number which 
does not contain any personally identifying information embedded within it. The link (or 
key) between subject identifiers and this first unique code will be held at the trial site.  No 
personal identifiers will appear on the specimen tube.  
5. Biorepository Specimen Usage
Specimens obtained for the Merck Biorepository will be used for analyses using good 
scientific practices.  Analyses utilizing the Future Biomedical Research specimens may 
be performed by the Sponsor, or an additional third party (e.g., a university investigator) 
designated by the Sponsor. The investigator conducting the analysis will follow the 
Sponsor’s privacy and confidentiality requirements. Any contracted third party analyses 
will conform to the specific scope of analysis outlined in this sub-trial. Future Biomedical 
Research specimens remaining with the third party after specific analysis is performed 
will be reported to the Sponsor.
6. Withdrawal From Future Biomedical Research 
Subjects may withdraw their consent for Future Biomedical Research and have their 
specimens and all derivatives destroyed.   Subjects may withdraw consent at any time by 
contacting the principal investigator for the main trial. If medical records for the main 
trial are still available, the investigator will contact the Sponsor using the designated 
 
 
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mailbox (clinical.specimen.management@merck.com) and a form will be provided to 
obtain appropriate information to complete specimen withdrawal. Subsequently, the 
subject's specimens will be removed from the biorepository and be destroyed. 
Documentation will be sent to the investigator confirming the destruction. It is the 
responsibility of the investigator to inform the subject of completion of destruction.  Any 
analyses in progress at the time of request for destruction or already performed prior to 
the request being received by the Sponsor will continue to be used as part of the overall 
research trial data and results. No new analyses would be generated after the request is 
received.
In the event that the medical records for the main trial are no longer available (e.g., if the 
investigator is no longer required by regulatory authorities to retain the main trial 
records) or the specimens have been completely anonymized, there will no longer be a 
link between the subject’s personal information and their specimens. In this situation, the 
request for specimen destruction can not be processed. 
7. Retention of Specimens 
Future Biomedical Research specimens will be stored in the biorepository for potential 
analysis for up to 20 years from the end of the main study. Specimens may be stored for 
longer if a regulatory or governmental authority has active questions that are being 
answered. In this special circumstance, specimens will be stored until these questions 
have been adequately addressed.
Specimens from the trial site will be shipped to a central laboratory and then shipped to 
the Sponsor-designated biorepository. If a central laboratory is not utilized in a particular 
trial, the trial site will ship directly to the Sponsor-designated biorepository. The 
specimens will be stored under strict supervision in a limited access facility which 
operates to assure the integrity of the specimens.  Specimens will be destroyed according 
to Sponsor policies and procedures and this destruction will be documented in the 
biorepository database.
8. Data Security
Databases containing specimen information and test results are accessible only to the 
authorized Sponsor representatives and the designated trial administrator research 
personnel and/or collaborators. Database user authentication is highly secure, and is 
accomplished using network security policies and practices based on international 
standards (e.g., ISO17799) to protect against unauthorized access.
9. Reporting of Future Biomedical Research Data to Subjects
No information obtained from exploratory laboratory studies will be reported to the 
subject, family, or physicians. Principle reasons not to inform or return results to the 
subject include: Lack of relevance to subject health, limitations of predictive capability, 
and concerns regarding misinterpretation.
 
 
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If any exploratory results are definitively associated with clinical significance for subjects 
while the clinical trial is still ongoing, investigators will be contacted with information. 
After the clinical trial has completed, if any exploratory results are definitively associated 
with clinical significance, the Sponsor will endeavor to make such results available 
through appropriate mechanisms (e.g., scientific publications and/or presentations). 
Subjects will not be identified by name in any published reports about this study or in any 
other scientific publication or presentation.
10. Future Biomedical Research Study Population
Every effort will be made to recruit all subjects diagnosed and treated on Sponsor clinical 
trials for Future Biomedical Research.
11. Risks Versus Benefits of Future Biomedical Research 
For future biomedical research, risks to the subject have been minimized. No additional 
risks to the subject have been identified as no additional specimens are being collected 
for Future Biomedical Research (i.e., only leftover samples are being retained).
The Sponsor has developed strict security, policies and procedures to address subject data 
privacy concerns.  Data privacy risks are largely limited to rare situations involving 
possible breach of confidentiality.  In this highly unlikely situation there is risk that the 
information, like all medical information, may be misused.
12. Questions
Any questions related to the future biomedical research should be e-mailed directly to 
clinical.specimen.management@merck.com.
13. References
1. National Cancer Institute: http://www.cancer.gov/dictionary/?searchTxt=biomarker
2. International Conference on Harmonization: DEFINITIONS FOR GENOMIC 
BIOMARKERS, PHARMACOGENOMICS, PHARMACOGENETICS, GENOMIC 
DATA AND SAMPLE CODING CATEGORIES - E15; 
http://www.ich.org/LOB/media/MEDIA3383.pdf
 
 
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Pharmacogenetics Informational Brochure for IRBs/IECs & Investigational Site Staff
12.3
 
 
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Approximate Blood/Tissue Volumes Drawn/Collected by Trial Visit and by 
12.4
Sample Types
Part I
mL/collection
Number of draws
Total mL/ Test
Laboratory safety tests 
         Screening 
12.5
1
12.5
β-hCG or FSH (if applicable)
4.5
1
4.5
         Pre-dose
12.5
1
12.5
         Treatment
12.5
0
0
         Post-study
12.5
1
12.5
Blood for Planned Genetic Analysis
8.5
1
8.5
HIV/Hepatitis Screen 
5
1
5
Venous blood sampling (metabolite fraction in 
plasma)
4
6
24
Total Blood Volume Per Subject for Part I†
~ 79.5mL
Part II
mL/collection
Number of draws
Total mL/ Test
Laboratory safety tests 
         Screening
12.5 
1
12.5
         PT/aPTT
2.5
1
2.5
         β-hCG or FSH (if applicable)
4.5
1
4.5
         Pre-dose
12.5
1
12.5
         Treatment
12.5
0-2±
0-25
         Post-study
12.5
1
12.5
Blood for Planned Genetic Analysis
8.5
1
8.5
HIV/Hepatitis Screen
5
1
5
Arterial 
Blood 
Sampling 
(for 
tracer 
metabolism-counts and metabolites in whole 
blood and plasma and metabolites in plasma)
4
12
48
Arterial Blood Sampling (for radioactivity in 
whole blood and plasma)
2
40
80
Total Blood Volume Per Subject for Part II†
~186mL to 211 mL
Part III
mL/collection
Number of draws
Total mL/ Test
Laboratory safety tests
         Screening
12.5 
1
12.5
         β-hCG  or  FSH (if applicable)
4.5
1
4.5
         Pre-dose
12.5
1
12.5
         Treatment
12.5
0
0
         Post-study
12.5
1
12.5
Blood for donepezil or rivastigme plasma 
levels
4
1
4
Blood 
for 
erythrocyte-acetylcholinesterase 
activity
4
1
4
Blood for Planned Genetic Analysis
8.5
1
8.5
HIV/Hepatitis Screen
5
1
5
Total Blood Volume Per Subject for Part III†
~63.5 mL
† If additional pharmacokinetic/pharmacodynamic and/or safety analysis is necessary, additional blood (up to 50 mL) 
may be obtained.  Note: never to exceed 50 mL..
± For Part II, if the second dose is done on a separate non-consecutive day, the number of blood draws during treatment 
will be 2 (and would require an additional 25 mL volume of blood).
 
 
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12-Lead Electrocardiogram Abnormality Criteria
12.5
12-Lead Electrocardiogram Abnormality Criteria 
Screen Failure Criteria
Potentially Significant Post-Randomization 
Findings (clarification on action to take)
RHYTHM
Sinus 
Tachycardia
110 bpm
HR >110 bpm  and HR increase of ≥ 25 bpm from 
baseline and 
Sinus 
Bradycardia
< 40 bpm
HR < 40 bpm and HR decrease of ≥ 5 bpm from 
baseline
Sinus 
Pause/Arrest
> 2.0 seconds
> 2.0 seconds
Atrial premature 
complex
1 beat
3 beats
Ventricular 
premature 
complex
All
3 beats
Ectopic Atrial 
Rhythm 
None
None
Junctional 
Rhythm
Junctional Rhythm with HR < 40 bpm
Junctional Rhythm with HR < 40 bpm
Idioventricular 
Rhythm
All
All
Atrial 
Fibrillation
All
All
Atrial Flutter
All
All
Supraventricular 
Tachycardia
All
All
Ventricular 
Tachycardia
All
All
AXIS
Left 
Axis 
Deviation
RBBB with Left Anterior Hemiblock 
(LAHB)
New onset LAHB
Right 
Axis 
Deviation
RBBB with Left Posterior Hemiblock 
(LPHB)
New onset LPHB
CONDUCTION
1st degree A-V 
Block
PR 230 ms
PR 230 ms + increase of 15 ms; or PR increase 
of > 25%
2nd degree A-V 
Block
Mobitz Type II
Mobitz Type II
3rd degree A-V 
Block
All
All
LBBB   
All
All
RBBB   
RBBB with LAHB/LPHB as defined 
above
New onset RBBB (not including intermittent or 
rate-related)
Incomplete 
Right 
BBB 
(ICRBBB) 
(QRS<120 ms)
No exclusion
Nothing
 
 
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12-Lead Electrocardiogram Abnormality Criteria 
Screen Failure Criteria
Potentially Significant Post-Randomization 
Findings (clarification on action to take)
Short 
PR/ 
Preexcitation 
syndrome
Delta wave + PR <120 ms
Delta wave + PR <120 ms
Other 
Intra-
ventricular 
Conduction 
Delay
QRS 130 ms
QRS 130 ms + increase of 10 ms
QTc (B or F)
Male
QTc 470 ms
QTc 500 ms or increase of 60 ms from 
baseline
Female
QTc 480 ms
QTc 500 ms or increase of 60 ms from 
baseline
HYPERTROPHY
Atrial 
abnormalities
Definite evidence of P mitrale or P 
pulmonale
Definite evidence of P mitrale or P pulmonale
Ventricular abnorm Voltage criteria for LVH plus Strain 
Pattern
Voltage criteria  for LVH plus Strain Pattern
MYOCARDIAL  INFARCTION
Acute or Recent
All
All
Old
All
All
ST/T MORPHOLOGY
ST 
elevation 
suggestive 
of 
Myocardial 
Injury 
In 2 or more contiguous leads
In 2 or more contiguous leads
ST 
depression 
suggestive of
Myocardial 
Ischaemia 
In 2 or more contiguous  leads
In 2 or more contiguous  leads
T-wave 
Inversions 
suggestive 
of  
Myocardial 
Ischaemia 
In 2 or more contiguous  leads
In 2 or more contiguous leads
Non-specific 
ST-T changes 
(In 2 or more 
leads)
No exclusion
In 2 or more contiguous leads
PACEMAKER
All
All
Baseline is defined as Predose Day 1
ms=milliseconds, mm=millimeter
 
 
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Algorithm for assessing Out-of-Range laboratory Values
12.6
For all laboratory values obtained at prestudy (screening) visit and/or pre-dose evaluation:
A. If all protocol-specified laboratory values are normal, the subject may enter the study.
B. If a protocol specified laboratory value is outside of the parameter(s) outlined in the 
inclusion/exclusion criteria (including a repeat if performed), the subject will be excluded 
from the study.
C. If ≥1 protocol-specified laboratory value not specified in the inclusion/exclusion criteria 
is outside the normal range, the following choices are available:
1. The subject may be excluded from the study;
2. The subject may be included in the study if the abnormal value(s) is not clinically 
significant (NCS) (the investigator must annotate the laboratory value “NCS” on the 
laboratory safety test source document).
3. The subject may be included in the study if the abnormality is consistent with a pre-
existing medical condition which is not excluded per protocol (e.g., elevated 
eosinophil count in a subject with asthma or seasonal allergies) the medical condition 
should be annotated on the laboratory report or
4. The abnormal test may be repeated (refer items a. and b. below for continuation of 
algorithm for repeated values).
a.
If the repeat test value is within the normal range, the subject may enter the study.
b. If the repeat test value is still abnormal, the study investigator will evaluate the 
potential subject with a complete history and physical examination, looking 
especially for diseases that could result in the abnormal laboratory value in 
question.  If such diseases can be ruled out, and if the abnormal laboratory value 
is not clinically relevant, then the subject may enter the study.
D. If there is any clinical uncertainty regarding the significance of an abnormal value, the 
subject will be excluded from the study.
 
 
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13.0 SIGNATURES
Sponsor's Representative
13.1
TYPED NAME
TITLE
SIGNATURE
DATE SIGNED
Investigator
13.2
I agree to conduct this clinical trial in accordance with the design outlined in this protocol 
and to abide by all provisions of this protocol (including other manuals and documents 
referenced from this protocol).  I agree to conduct the trial in accordance with generally 
accepted standards of Good Clinical Practice.  I also agree to report all information or data in 
accordance with the protocol and, in particular, I agree to report any serious adverse events 
as defined in Section 7.0 – Assessing and Recording Adverse Events.  I also agree to handle 
all clinical supplies provided by the Sponsor and collect and handle all clinical specimens in 
accordance with the protocol.  I understand that information that identifies me will be used 
and disclosed as described in the protocol, and that such information may be transferred to 
countries that do not have laws protecting such information. Since the information in this 
protocol and the referenced Investigator’s Brochure is confidential, I understand that its 
disclosure to any third parties, other than those involved in approval, supervision, or conduct 
of the trial is prohibited.  I will ensure that the necessary precautions are taken to protect such 
information from loss, inadvertent disclosure or access by third parties.
TYPED NAME
TITLE
SIGNATURE
DATE SIGNED
 
 
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