Clinical trial NCT01953601
Conditions: Amnestic Mild Cognitive Impairment Alzheimer's Disease Prodromal Alzheimer's Disease
Sponsor: Merck Sharp & Dohme LLC
Start date: 2013-11-05; Completion date: 2018-04-17
Enrollment: 1454 participants; Allocation: RANDOMIZED; Intervention model: PARALLEL

Brief summary:
This study consists of two parts, Part 1 and Part 2. Part 1 assesses the efficacy and safety of verubecestat (MK-8931) compared with placebo administered for 104 weeks in the treatment of amnestic mild cognitive impairment (aMCI) due to Alzheimer's Disease (AD), also known as prodromal AD. Participants are randomized to receive placebo, or 12 mg or 40 mg verubecestat, once daily. The primary study hypothesis for Part 1 is that ≥1 verubecestat dose is superior to placebo with respect to the change from baseline in the Clinical Dementia Rating scale-Sum of Boxes (CDR-SB) score at 104 weeks. Participants completing Part 1 may choose to participate in Part 2, which is a long term double-blind extension to assess efficacy and safety of verubecestat administered for up to an additional 260 weeks. In Part 2, all participants receive either 12 mg or 40 mg verubecestat, once daily.

Detailed description:
As a result of protocol amendment, Study Part 2 will contain a Positron Emission Tomography (PET) imaging substudy to assess regional neurofibrillary tangle (NFT) expression.

Arms: arm 1: \[Part 1\] Verubecestat 12 mg once daily for 104 weeks in Part 1 (Base Study). \[Part 2\] Participants completing Part 1 and continuing to Part 2 (Extension Study) receive Verubecestat 12 mg once daily for an additional 260 weeks. arm 2: \[Part 1\] Verubecestat 40 mg once daily for 104 weeks in Part 1 (Base Study). \[Part 2\] Participants completing Part 1 and continuing to Part 2 (Extension Study) receive Verubecestat 40 mg once daily for an additional 260 weeks. arm 3: \[Part 1\] Placebo once daily for 104 weeks in Part 1 (Base Study). \[Part 2\] Participants completing Part 1 and continuing to Part 2 (Extension Study) receive Verubecestat 40 mg once daily for an additional 260 weeks.
Interventions: intervention 1: Verubecestat 12 mg (Parts 1 and 2) intervention 2: Verubecestat 40 mg (Parts 1 and 2) intervention 3: Placebo (Part 1)
Intervention descriptions: intervention 1: Verubecestat 12 mg oral tablet, given once daily. intervention 2: Verubecestat 40 mg oral tablet, given once daily. Verubecestat 40 mg given to participants in Arm C continuing to study Part 2. intervention 3: Placebo matching verubecestat, given once daily as an oral tablet.

Protocol documents:
Prot_SAP_000.pdf: 
Official Protocol Title: A Parallel-Group, Double-Blind, Long Term Safety and Efficacy 
Trial of MK-8931 (SCH 900931) in Subjects with Amnestic Mild 
Cognitive Impairment Due to Alzheimer’s Disease (Prodromal AD).
NCT number: 
NCT01953601 
11-DEC-2017
Document Date: 


Product:  MK-8931 (SCH 900931)
1
Protocol/Amendment No.: 019-17 
MK-8931-019-17 Final Protocol
11-Dec-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.
This protocol amendment is applicable only to France.
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, NJ 08889-0100, U.S.A.
Protocol-specific Sponsor Contact information can be found in the Investigator Trial File
Binder.
TITLE:
A Parallel-Group, Double-Blind, Long Term Safety and Efficacy Trial of MK-8931 (SCH 
900931) in Subjects with Amnestic Mild Cognitive Impairment Due to Alzheimer’s Disease 
(Prodromal AD).
This long term trial is an EXTENSION of the initial 104-week trial. 
This protocol amendment is applicable only to France.
IND NUMBER:  110,186
EudraCT NUMBER:  2015-002134-49
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TABLE OF CONTENTS
SUMMARY OF CHANGES................................................................................................ 10
1.0
TRIAL SUMMARY.................................................................................................. 12
2.0
TRIAL DESIGN........................................................................................................ 13
Trial Design ........................................................................................................... 13
2.1
Trial Diagram........................................................................................................ 14
2.2
3.0
OBJECTIVE(S) & HYPOTHESIS(ES).................................................................. 14
Primary Objective(s) & Hypothesis(es) .............................................................. 14
3.1
Secondary Objective(s) & Hypothesis(es)........................................................... 14
3.2
Other Objectives (e.g., Tertiary, Exploratory, etc.)........................................... 15
3.3
4.0
BACKGROUND & RATIONALE.......................................................................... 15
Background ........................................................................................................... 15
4.1
Pharmaceutical and Therapeutic Background .................................................... 15
4.1.1
Rationale................................................................................................................ 16
4.2
Rationale for the Trial and Selected Subject Population .................................... 16
4.2.1
4.2.1.1
Trial Design Rationale ................................................................................. 16
4.2.1.2
Rationale for Subject Population and Dose ................................................. 16
Rationale for Endpoints ...................................................................................... 17
4.2.2
4.2.2.1
Outcome Measures Rationale ...................................................................... 17
4.2.2.2
Safety Measures Rationale........................................................................... 18
4.2.2.3
Planned Biomarker Research....................................................................... 19
4.2.2.4
Future Biomedical Research........................................................................ 19
5.0
METHODOLOGY ................................................................................................... 19
Entry Criteria........................................................................................................ 19
5.1
Diagnosis/Condition for Entry into the Trial ...................................................... 19
5.1.1
Subject Inclusion Criteria.................................................................................... 20
5.1.2
Subject Exclusion Criteria .................................................................................. 20
5.1.3
Trial Treatments................................................................................................... 21
5.2
Dose Selection/Modification .............................................................................. 22
5.2.1
5.2.1.1
Dose Selection ............................................................................................. 22
 
 
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Timing of Dose Administration .......................................................................... 22
5.2.2
Trial Blinding/Masking....................................................................................... 22
5.2.3
Concomitant Medications/Vaccinations (allowed & prohibited) ..................... 23
5.3
Prohibited Medications ....................................................................................... 23
5.3.1
Allowed Medications .......................................................................................... 23
5.3.2
Rescue Medications & Supportive Care............................................................. 24
5.4
Diet/Activity/Other Considerations..................................................................... 24
5.5
Subject Withdrawal/Discontinuation Criteria................................................... 24
5.6
Subject Replacement Strategy............................................................................. 26
5.7
Beginning and End of the Trial ........................................................................... 26
5.8
Clinical Criteria for Early Trial Termination ................................................... 27
5.9
6.0
TRIAL FLOW CHART ........................................................................................... 28
7.0
TRIAL PROCEDURES ........................................................................................... 31
Trial Procedures ................................................................................................... 31
7.1
Administrative Procedures.................................................................................. 31
7.1.1
7.1.1.1
Informed Consent......................................................................................... 31
7.1.1.1.1
General Informed Consent.................................................................... 31
7.1.1.2
Inclusion/Exclusion Criteria ........................................................................ 32
7.1.1.3
Subject Identification Card .......................................................................... 32
7.1.1.4
Concomitant Medications Review............................................................... 32
7.1.1.4.1
Concomitant Medications..................................................................... 32
7.1.1.5
Trial Compliance (Medication/Diet/Activity/Other) ................................... 32
Clinical Procedures/Assessments........................................................................ 32
7.1.2
7.1.2.1
Trial Partner Attendance at Trial Visits....................................................... 32
7.1.2.2
Physical Assessments/Examinations ........................................................... 33
7.1.2.2.1
Vital Signs............................................................................................. 33
7.1.2.2.2
Body Weight (kg/lbs)............................................................................ 33
7.1.2.2.3
Directed Physical and Neurological Examinations .............................. 33
7.1.2.2.4
Skin Examinations ................................................................................ 33
7.1.2.2.5
12-Lead Electrocardiogram (ECG)....................................................... 34
7.1.2.2.6
Structural Magnetic Resonance Imaging (MRI)................................... 34
7.1.2.3
Cognitive and Clinical Assessments............................................................ 35
 
 
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7.1.2.3.1
Confirmation of Progression to Probable AD Dementia ...................... 36
7.1.2.3.2
Clinical Dementia Rating (CDR).......................................................... 36
7.1.2.3.3
Alzheimer’s Disease Assessment Scale Cognitive Subscale 
(ADAS-Cog)......................................................................................... 36
7.1.2.3.4
Controlled Oral Word Association Test (COWAT)............................. 36
7.1.2.3.5
Trail Making Test (A&B)..................................................................... 37
7.1.2.3.6
CERAD Verbal Fluency (CVF)............................................................ 37
7.1.2.3.7
Digit Span Test ..................................................................................... 37
7.1.2.3.8
Digit Symbol-Coding (DSC) ................................................................ 37
7.1.2.3.9
Alzheimer’s Disease Cooperative Study Activities of Daily Living 
Inventory (ADCS-ADLMCI).................................................................. 37
7.1.2.3.10 Mini-Mental State Examination (MMSE) ............................................ 37
7.1.2.3.11 Columbia Suicide Severity Rating Scale (C-SSRS)............................. 38
7.1.2.3.12 Neuropsychiatric Inventory (NPI) ........................................................ 38
7.1.2.3.13 Modified 
Resource 
Utilization in 
Dementia 
(RUD) 
Lite 
Questionnaire........................................................................................ 39
7.1.2.3.14 Health Economic Assessment (HEA)................................................... 39
7.1.2.3.15 EuroQol Five Dimension Questionnaire (EQ-5D) ............................... 39
7.1.2.3.16 Confusion Assessment Method (CAM)................................................ 39
Laboratory Procedures/Assessments .................................................................. 39
7.1.3
7.1.3.1
Laboratory Safety Evaluations (Hematology, Chemistry and Urinalysis) .. 39
Other Procedures................................................................................................. 40
7.1.4
7.1.4.1
Withdrawal/Discontinuation........................................................................ 40
7.1.4.2
Blinding/Unblinding .................................................................................... 40
Visit Requirements.............................................................................................. 41
7.1.5
Assessing and Recording Adverse Events .......................................................... 41
7.2
Definition of an Overdose for This Protocol and Reporting of Overdose to 
7.2.1
the Sponsor.......................................................................................................... 42
Reporting of Pregnancy and Lactation to the Sponsor ....................................... 42
7.2.2
Immediate Reporting of Adverse Events to the Sponsor.................................... 43
7.2.3
7.2.3.1
Serious Adverse Events ............................................................................... 43
7.2.3.2
Events of Clinical Interest............................................................................ 44
Evaluating Adverse Events................................................................................. 45
7.2.4
 
 
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Sponsor Responsibility for Reporting Adverse Events ...................................... 48
7.2.5
TRIAL GOVERNANCE AND OVERSIGHT ................................................... 48
7.3
Executive Oversight Committee ......................................................................... 48
7.3.1
Data Monitoring Committee ............................................................................... 48
7.3.2
Clinical Adjudication Committee ....................................................................... 48
7.3.3
8.0
STATISTICAL ANALYSIS PLAN ........................................................................ 49
Statistical Analysis Plan Summary ..................................................................... 49
8.1
Efficacy Analyses ............................................................................................... 49
8.1.1
Safety Analyses................................................................................................... 49
8.1.2
Power and Sample Size....................................................................................... 49
8.1.3
Interim Analyses ................................................................................................. 49
8.1.4
Statistical Analysis Plan ....................................................................................... 50
8.2
Responsibility for Analyses/In-House Blinding ................................................. 50
8.2.1
Hypotheses/Estimation ....................................................................................... 50
8.2.2
Analysis Endpoints ............................................................................................. 50
8.2.3
8.2.3.1
Efficacy Endpoints....................................................................................... 50
8.2.3.1.1
Primary Efficacy Endpoint ................................................................... 50
8.2.3.1.2
Exploratory Efficacy Endpoints............................................................ 51
8.2.3.2
Safety Endpoints .......................................................................................... 51
8.2.3.3
Derivations of Efficacy Endpoints............................................................... 51
Analysis Populations........................................................................................... 52
8.2.4
8.2.4.1
Efficacy Analysis Populations ..................................................................... 52
Safety Analysis Populations ............................................................................... 53
8.2.5
Statistical Methods.............................................................................................. 53
8.2.6
Statistical Methods for Efficacy Analyses .......................................................... 53
8.2.7
8.2.7.1
Primary Efficacy Analysis ........................................................................... 53
8.2.7.2
Exploratory Efficacy Analyses .................................................................... 55
8.2.7.3
Health Economic Endpoints ........................................................................ 56
8.2.7.4
Pharmacogenetic Analyses .......................................................................... 56
8.2.7.5
Accounting for Missing Data....................................................................... 56
8.2.7.6
Handling of Missing Items Within a Clinical Assessment .......................... 58
Statistical Methods for Safety Analyses ............................................................. 59
8.2.8
 
 
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Summaries of Baseline Characteristics, Demographics, and Other Analyses .... 61
8.2.9
8.2.9.1
Demographic and Baseline Characteristics ................................................. 61
Multiplicity ......................................................................................................... 62
8.2.10
Sample Size and Power Calculations.................................................................. 62
8.2.11
8.2.11.1 Sample Size and Power for Efficacy Analyses............................................ 62
8.2.11.1.1 Parameter Estimates.............................................................................. 62
8.2.11.1.2 Power Calculations ............................................................................... 63
Subgroup Analyses and Effect of Baseline Factors ............................................ 63
8.2.12
Interim Analyses ................................................................................................. 64
8.2.13
Compliance/Medication Adherence.................................................................... 64
8.2.14
Extent of Exposure.............................................................................................. 65
8.2.15
9.0
LABELING, PACKAGING, STORAGE AND RETURN OF CLINICAL 
SUPPLIES ................................................................................................................. 65
Investigational Product ........................................................................................ 65
9.1
Packaging and Labeling Information ................................................................. 65
9.2
Clinical Supplies Disclosure................................................................................. 66
9.3
Storage and Handling Requirements.................................................................. 66
9.4
Discard/Destruction/Returns and Reconciliation .............................................. 66
9.5
Standard Policies................................................................................................... 67
9.6
10.0
ADMINISTRATIVE AND REGULATORY DETAILS....................................... 67
Confidentiality....................................................................................................... 67
10.1
Confidentiality of Data ....................................................................................... 67
10.1.1
Confidentiality of Subject Records ..................................................................... 67
10.1.2
Confidentiality of Investigator Information........................................................ 67
10.1.3
Confidentiality of IRB/IEC Information............................................................. 68
10.1.4
Compliance with Financial Disclosure Requirements....................................... 68
10.2
Compliance with Law, Audit and Debarment ................................................... 68
10.3
Compliance with Trial Registration and Results Posting Requirements ........ 70
10.4
Quality Management System............................................................................... 71
10.5
Data Management................................................................................................. 71
10.6
Publications ........................................................................................................... 71
10.7
11.0
LIST OF REFERENCES......................................................................................... 72
 
 
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12.0
APPENDICES........................................................................................................... 76
Merck Code of Conduct for Clinical Trials........................................................ 76
12.1
Approximate Blood/Tissue Volumes Drawn/Collected by Trial Visit and 
12.2
by Sample Types ................................................................................................... 78
Predefined Limits of Change Criteria ................................................................ 79
12.3
List of Abbreviations ............................................................................................ 81
12.4
13.0
SIGNATURES........................................................................................................... 84
Sponsor's Representative ..................................................................................... 84
13.1
Investigator............................................................................................................ 84
13.2
 
 
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LIST OF TABLES
Table 1 Prohibited Medications............................................................................................ 21
Table 2 Trial Treatments....................................................................................................... 22
Table 3 Medications, Supplements, and Other Substances Allowed During the Trial......... 24
Table 4 Laboratory Tests ...................................................................................................... 40
Table 5 Evaluating Adverse Events...................................................................................... 46
Table 6 Analysis Strategy for Primary Endpoints ................................................................ 55
Table 7 Analysis Strategy for Safety Parameters.................................................................. 61
Table 8 Parameter Assumptions for CDR-SB ...................................................................... 62
Table 9 Power Calculations (MK-8931 40 mg / MK-8931 40 mg vs. Placebo / MK-
8931 40 mg)............................................................................................................. 63
Table 10 Product Descriptions................................................................................................ 65
 
 
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LIST OF FIGURES
Figure 1
Trial Design Diagram ......................................................................................... 14
 
 
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SUMMARY OF CHANGES
PRIMARY REASON(S) FOR THIS AMENDMENT:
Section 
Number (s)
Section Title(s)
Description of Change (s)
Rationale
1.0
2.1
4.2.1.2
5.1.3
7.1.2.3.1
Trial Summary
Trial Design
Rationale for Trial and Selected 
Subject Population
Subject Exclusion Criteria
Confirmation of Progression to 
Probable AD Dementia
Eligibility criteria modified to exclude 
subjects who progress to dementia due 
to AD based on investigator diagnosis
in the main 104 week study from 
entering the long term extension study.  
Results of the Phase 2/3 clinical study 
MK-8931-017 did not show a benefit in 
AD patients who initiated MK-8931 
treatment in the mild to moderate 
dementia stage. Therefore, the balance of 
benefit/risk no longer supports entry of 
subjects with AD dementia in the 
extension, where active treatment may be 
newly initiated. Regarding continued 
treatment of subjects who progress to 
dementia later in the trial, it is not known 
whether initiation of treatment at the 
prodromal stage would provide benefit to 
these subjects.
Therefore, despite the 
lack of efficacy in the 017 population of 
subjects with mild to moderate dementia, 
the sponsor believes that continued 
treatment of these subjects is warranted.
 
 
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ADDITIONAL CHANGE(S) FOR THIS AMENDMENT:
Section 
Number (s)
Section Title (s)
Description of Change (s)
Rationale
3.1
Primary Objective(s) and 
Hypothesis(es)
Added baseline timepoint.
Clarification
1.0 
2.1
5.8
Trial Summary
Trial Design
Beginning and End of the 
Trial
Added statement that study duration is 
5 years from when the first subject 
enrolls.
Clarification
7.1.4.2
9.3
Blinding/Unblinding
Clinical Supplies Disclosure
Updated text to provide clarity around 
emergency 
unblinding 
procedures. 
Updated text to describe who may be 
unblinded 
following 
emergency 
unblinding.
Clarification
 
 
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1.0 TRIAL SUMMARY
Abbreviated Title
A Long Term Safety and Efficacy Trial of MK-8931 (SCH 900931) in 
Subjects with Prodromal AD (APECS)
Trial Phase
III
Clinical Indication
Treatment of early (prodromal) AD
Trial Type
Interventional
Type of control
Not Applicable
Route of administration
Oral
Trial Blinding
Double-blind
Treatment Groups 
MK-8931 12 mg
MK-8931 40 mg
Number of trial subjects
All subjects who complete the initial 104 week trial and are willing and 
qualified to participate in the long term trial will be enrolled.  Subjects 
who progress to dementia due to AD in the main 104 week study will not
be permitted to move into the long term extension study. The actual 
number enrolled may vary depending on the number enrolled in the 104 
week trial, the dropout rate, and the number of eligible subjects who 
consent to enroll.  Based on the current sample size projection and 
estimated dropout rate (25%) for the initial 104 week trial, approximately 
912 subjects would be enrolled.  The total number of subjects enrolled in 
the extension will not exceed the total enrolled in the initial 104 week 
trial.
Estimated duration of trial
The duration of the long-term trial is expected to be up to approximately 
five years or until a) MK-8931 becomes commercially available 
(locally), or b) when the MK-8931 program is terminated (whichever 
comes first). Duration of the trial may be limited based on local 
regulation.
Duration of Participation
Expected maximum duration of no longer than 260 weeks (5 years after 
the first subject enrolls), with the duration of individual subject 
participation dependent on the timing of enrollment. Duration of 
participation may be limited based on local regulations. Subjects who do 
not complete the initial 104-week trial of MK-8931 protocol 019 will not 
be permitted to continue in this trial. In addition, subjects who are less 
than 75% compliant with trial medication during the initial 104-week 
trial will require Sponsor approval to participate in this trial.
Subjects will be followed for at least 14 days following cessation of 
treatment.
Randomization Ratio
Not applicable to this trial.
A list of abbreviations used in this document can be found in Section 12.4.
 
 
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2.0 TRIAL DESIGN
Trial Design
2.1
This is a long-term safety and efficacy study (up to 260 weeks) which will be available to 
subjects who have completed the initial 104-week trial of MK-8931-019. 
The initial 104-week trial is a double blind, randomized, parallel group, placebo controlled, 
multicenter trial in subjects with amnestic mild cognitive impairment (aMCI) due to 
Alzheimer's Disease (AD), referred to herein as prodromal AD. The initial 104-week trial, 
detailed in a separate amendment, includes two active dose arms of MK-8931 (12 mg and 40 
mg) and placebo. Duration of treatment is 104 weeks (24 months). MK-8931 is a potent 
-site APP cleaving enzyme 1 (BACE1) inhibitor being developed for the treatment of AD.
The initial 104-week trial will enroll subjects who meet criteria for prodromal AD, which is
defined as subjects who have aMCI and are positive for an AD biomarker.  The primary AD 
biomarker to be used for the inclusion criterion is cortical amyloid load measured with 
positron emission tomography (PET).  
At the end of the 104-week trial, subjects who have completed treatment and satisfy 
eligibility criteria may choose to participate in this trial, during which all subjects who 
received placebo during the initial 104-week trial will receive active drug. Subjects who 
progress to dementia due to AD in the main 104 week study will not be permitted to move 
into the long term extension study.
This trial will start with enrollment of the first subject who completes the initial 104-week 
trial and chooses to participate in the long term trial. The long term safety and efficacy trial 
will end 5 years after the first subject enrolls (260 weeks), or a) when the drug either 
becomes commercially available (locally), or b) when the MK-8931 program is terminated
(whichever comes first). The duration of the trial may be even shorter for subjects in 
particular regions, per local regulation. 
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.
This trial will use an independent, external Data Monitoring Committee (eDMC) to monitor 
safety at the appropriate frequency and for the duration required per the eDMC Charter.
 
 
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Trial Diagram
2.2
The trial design is depicted in Figure 1.
Figure 1
Trial Design Diagram
3.0 OBJECTIVE(S) & HYPOTHESIS(ES)
Primary Objective(s) & Hypothesis(es)
3.1
The two primary objectives are as follows:
1. To evaluate the safety and tolerability of MK-8931 in the long term treatment of 
prodromal Alzheimer’s Disease (AD).
2. To compare the efficacy of MK-8931 administered to subjects for 30 months to that 
of subjects administered placebo for 24 months followed by MK-8931 for 6 months 
using the change from baseline score CDR-SB score at Week 130.
For both of the primary objectives, subjects who received MK-8931 in the initial 104-week 
study will be compared to subjects who received placebo during that period (i.e. 40 mg / 40 
mg vs. pbo / 40 mg and 12 mg / 12 mg vs. pbo. /40 mg). It is noted that baseline refers to the
baseline from the initial 104-week trial.
Secondary Objective(s) & Hypothesis(es)
3.2
There are no secondary objectives or hypotheses for this long-term extension.
 
 
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Other Objectives (e.g., Tertiary, Exploratory, etc.)
3.3
Objectives: 
To compare the efficacy of MK-8931 administered to subjects for 24 months followed by 
long term treatment of MK-8931 to that of subjects administered placebo for 24 months 
followed by long term treatment of MK-8931 on 
1) cognition, function, disease progression, and health economic burden at multiple time 
points.
2) time to progression to probable AD dementia as determined by investigator-
diagnosis.
4.0 BACKGROUND & RATIONALE
Background
4.1
Refer to the Investigator’s Brochure (IB) for detailed background information on MK-8931.
Pharmaceutical and Therapeutic Background
4.1.1
Alzheimer’s Disease (AD) is a slowly developing neurodegenerative disease that is the 
leading cause of dementia world-wide.  Currently available treatments for AD are limited, 
and include acetylcholinesterase inhibitors (e.g., donepezil) and the low affinity N-methyl D-
aspartate (NMDA) receptor antagonist (memantine). These medicines modestly improve 
symptoms but do not alter disease progression.  Therefore, novel pharmacological agents that 
slow or halt the progression of AD are needed.
Alzheimer’s Disease is characterized by specific histopathological features including 
amyloid deposits (plaques), neurofibrillary tangles, and neuronal degeneration.  The 
“amyloid hypothesis” posits that amyloid β (Aβ) peptides aggregate into complexes, such as 
fibrils and plaques, which subsequently trigger the development of tau-related neurofibrillary 
tangles.  These tangles are thought to be the more proximal cause of neuronal degeneration.  
Aβ pathology appears to begin years before the onset of AD dementia and is thought at some 
point to trigger tau pathology, neural degeneration, and the subsequent gradual emergence of 
clinical symptoms.  As amyloid plaques continue to accumulate, tangle pathology spreads to 
a variety of brain regions, leading to progressive neuronal degeneration, brain atrophy, and 
cognitive decline.  As a result, early intervention to reduce Aβ accumulation when patients 
are in the prodromal phase, or even earlier, has gained increasing acceptance as a promising 
approach to reduce the incidence of AD.
Aβ peptides are produced when amyloid precursor protein (APP) is cleaved by three distinct 
proteases:  α secretase, BACE1 (β site APP cleaving enzyme 1, also known as β-secretase), 
and γ secretase.  Most APP is processed by α and γ secretases to generate nonamyloidogenic 
peptides.  However, 5-10% of APP is cleaved by BACE1 and γ secretase to generate 
pathogenic Aβ peptides (Aβ40 and Aβ42).  Deletion of BACE1 in mice eliminates Aβ in 
 
 
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both the plasma and the brain.  Thus, inhibition of BACE1 is a potential therapeutic strategy 
for slowing or halting progression of AD.
MK-8931 is a potent BACE1 inhibitor being developed for the treatment of AD.  It has been 
shown to reduce Aβ levels in the CSF and brain of rodents and primates.  MK-8931 also 
reduces Aβ in human CSF.  In Phase 1 trials, MK-8931 has been generally safe and well 
tolerated (see IB).  These results suggest that MK-8931 may reduce Aβ production in humans 
and could potentially slow progression in subjects with prodromal AD.  
Rationale
4.2
Rationale for the Trial and Selected Subject Population
4.2.1
4.2.1.1
Trial Design Rationale
This is a parallel group, multi-site, double-blind, long term safety and efficacy trial to 
provide access to MK-8931 before it is commercially available, to estimate the effects of 
delayed start of MK-8931, and to evaluate the safety and tolerability of two doses of MK-
8931 in extended treatment of prodromal AD. MK-8931 is hypothesized to exert disease-
modifying effects in subjects with prodromal AD. A delayed-start design may provide 
supportive evidence of disease modification in prodromal AD if the treatment effect is 
sustained and greater in the group of subjects that starts the active treatment earlier as 
compared to the group of subjects with a substantial delay in start of active treatment. Results 
from this long term trial will also provide data regarding the sample size necessary for 
delayed start studies with disease modifying therapeutics for AD. In addition, this long term 
trial will be used to further assess the long term effects of MK-8931 on disease progression, 
health economic effects and the safety and tolerability of MK-8931. Some Sponsor personnel 
will be unblinded following the completion of the initial 104-week trial. A separate group of 
Sponsor personnel will remain blinded during the long-term trial, in order to ensure the 
proper conduct of the trial in furtherance of the collection of quality efficacy data, including 
the 30-month timepoint to support the primary objective regarding efficacy. Details are 
included in the Sponsor’s blinding document.
4.2.1.2
Rationale for Subject Population and Dose 
The recent results from Protocol 017 indicate that MK-8931 is not effective when treatment 
is initiated in subjects with mild/moderate AD.  The amyloid hypothesis suggests, however, 
that earlier treatment with a BACE inhibitor (prior to the onset of dementia) could be 
beneficial even if ineffective at later stages. The initial 104-week trial of Protocol 019 in 
prodromal AD is still ongoing so the impact of BACE inhibition in this earlier stage of the 
disease is not yet known.  Given this uncertainty along with the 017 results, subjects who 
tolerated study medication, have not progressed to dementia and completed the initial 104-
week trial of Protocol 019 may enroll in this long term trial. However, subjects who have 
progressed to dementia will be excluded since the 017 results indicate increased adverse 
events in addition to no efficacy. 
 
 
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Subjects in the initial 104 week trial who progress to dementia during that time have a 2 out 
of 3 chance of being on active treatment with MK-8931.  Based on the view that these 
subjects could still benefit from MK-8931 since it was initiated before the onset of dementia, 
one alternative is to allow these subjects into the extension trial. However, since the blind 
will be maintained in the extension, it is not possible to include these subjects while 
excluding subjects who were on placebo during the initial 104-week trial.  Given the concern 
that the placebo treated subjects who progress to dementia would not benefit from treatment, 
the current protocol will exclude all subjects who have progressed to dementia.
Subjects who progress to dementia during this extension trial will be allowed to continue, 
since it is not known whether initiation of treatment at the prodromal stage would provide 
benefit to these subjects. Therefore, despite the lack of efficacy in the 017 population where 
treatment was initiated at the mild to moderate dementia stage, the sponsor believes that 
continued treatment of these subjects is warranted. 
Those subjects who did not complete treatment in the initial 104-week trial, but continued 
with and completed scheduled visits may be permitted to enroll in this long term trial based 
on the discretion of the Sponsor. Where required locally by IRBs/ECs (including sites in 
France), these subjects may enroll in the long term trial without Sponsor approval. Subjects 
who received the 12 mg or 40 mg dose during the 104-week trial will continue to receive the 
same dose in this long term trial. They will be referred to as the 12/12 and 40/40 groups 
respectively. Subjects who received placebo during the initial 104-week trial will receive the 
40 mg dose during this long term trial. They will be referred to as the placebo/40 group.
The 40-mg dose has been shown to substantially inhibit CSF Aβ. The 12-mg dose produces a 
more moderate reduction in CSF Aβ and is included since the long term safety of greater 
inhibition is unknown. Using PK/PD modeling and simulation, 12-mg and 40-mg doses are 
projected to reduce CSF Aβ by at least 50% and 75%, respectively, in more than 90% of 
subjects.  It is unknown how much Aβ lowering is optimal from the perspective of both 
safety/tolerability as well as efficacy. Subjects who received placebo during the initial 104-
week trial will be treated with the 40-mg dose in the long term trial to provide additional 
information about the long term safety of 40 mg of MK-8931 and to estimate the clinical 
effects of delayed start of this higher dose.
Rationale for Endpoints
4.2.2
4.2.2.1
Outcome Measures Rationale
As in the protocol for the initial 104-week trial, the primary outcome measure is the change 
from Baseline in the Clinical Dementia Rating Scale Sum of Boxes (CDR-SB) score at 130 
weeks.  The CDR-SB is highly relevant clinically and has been shown to worsen over time in 
this patient population.
Progression to probable AD dementia will be included in the long term trial as an exploratory 
objective. This study will use both NINCDS ARDRA and Diagnostic and Statistical Manual 
of Mental Disorders, 4th Edition, Text Revision (DSM-IV-TR) criteria to define probable 
AD dementia. Unlike the initial 104-week trial, cases of progression in the long term trial 
 
 
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will not be reviewed by an adjudication committee; therefore, the final decision on 
progression will be the opinion of the investigator or qualified designee. The progression
endpoint will provide useful information for patients and physicians for understanding the 
effects of MK-8931.
Other clinical measures include the following: a) the composite cognition score (based on the 
mean
of the three domain z-scores from tests of episodic memory, working 
memory/executive function, and attention/psychomotor speed) and b) the Alzheimer’s 
Disease Cooperative Study Activities of Daily Living Inventory (ADCS ADLMCI) (mild 
cognitive impairment [MCI] version) score. Previously conducted trials have demonstrated 
that cognition and function are relevant dimensions of clinical progression in this patient 
population. Regarding cognition, prior studies of MCI have used some version of the 
Alzheimer’s Disease Assessment Scale Cognitive subscale (ADAS-Cog). Because of the 
well-known issue with sensitivity of the ADAS-Cog, many studies have also included 
additional, standard cognitive tests. Several methods have been proposed to combine the 
ADAS-Cog with the additional tests to generate a composite cognition score. While intensive 
ongoing research may clarify the optimal approach, this protocol will calculate the average z-
score of three cognitive domains thought to be involved in prodromal AD based on modeling 
suggesting this is superior to the ADAS-Cog alone.
Additional clinical endpoints include scores from the 13-item ADAS-Cog with Delayed 
Word Recall and Number Cancellation tasks (ADAS Cog13), the Mini Mental State 
Examination (MMSE), the Neuropsychiatric Inventory (NPI), cognitive and functional 
subscales of the CDR-SB, and the Health Economic Outcomes (HEA, RUD lite, EQ-5D).
4.2.2.2
Safety Measures Rationale
Safety and tolerability will be assessed by clinical review of AEs, laboratory tests, vital signs, 
and ECG measurements. The same safety parameters and AEs designated as being of special 
interest during the initial 104-week trial will continue to be monitored in the long term trial, 
including delirium, and rash ECI (see Section 7.2.3.2).
Regarding MRI monitoring, the US FDA had noted the occurrence of imaging abnormalities 
believed to represent cerebral vasogenic edema in association with the investigational use of 
Aβ antibodies that are intended to treat AD by reducing β-amyloid in the brain. These 
imaging abnormalities, described in Salloway et al [36], have, in the majority of instances, 
been asymptomatic and their presence has been detected by routine MRI scans. Symptoms, 
when present,
include headache, worsening of cognitive function, alteration of 
consciousness, seizures, unsteadiness, and vomiting. In most instances, the occurrence of 
such imaging abnormalities, even when symptomatic, has not required treatment beyond 
discontinuation of the investigational compound; infrequently, high-dose steroid therapy has 
been administered in the presence of prominent symptoms. Previous regulatory guidance
required that all subjects have an MRI scan during Screening in order to qualify for the trial 
and routine MRI scans for safety monitoring. Following a comprehensive review of the 
existing data, the FDA has updated this guidance stating that serial clinical and MRI 
monitoring will no longer be required as a matter of course in clinical trials of small molecule 
 
 
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drugs that may affect β-amyloid. Therefore, routine MRI safety monitoring is not included in 
this trial. MRIs may be performed for safety monitoring if clinically indicated as determined 
by the investigator (e.g., in follow up to an AE). 
After initiation of the initial 104-week trial, the FDA issued guidance to sponsors indicating 
that all trials with BACE1 inhibitors that are longer than two weeks in duration must include 
routine monitoring of skin. Therefore, in order to gain additional data on those previously not 
exposed to MK-8931 during the initial 104-week trial, i.e. those subjects on placebo, routine 
skin examinations by a site physician will continue in this study. If no difference is seen in 
the occurrence of hypopigmentation between the placebo and MK-8931 groups after 300 
subjects/group are evaluated at six months in the MK-8931 program (P017 and P019), the 
eDMC may recommend the discontinuation of the routine skin examinations. Sites would 
continue to collect skin-related adverse events and refer subjects for further dermatologic 
evaluation as needed.
4.2.2.3
Planned Biomarker Research
As noted in the IB, rash has been observed in Phase I studies and may be a risk for patients 
who take MK-8931. Preliminary results from Phase I studies suggest that rash may be 
associated with specific HLA genotypes. To explore this issue further, DNA was collected
from all subjects in the initial 104-week study and stored for HLA genotyping if indicated. 
HLA genotyping will be performed on subjects who develop a rash in this trial and a 
matched control group who do not develop rash.
4.2.2.4
Future Biomedical Research
Some subjects in the initial 104-week study gave consent for using specimens for future 
biomedical research.  These included blood for genomics use, and CSF (in the optional CSF 
sub study).  Phenotypes generated from the current long term extension study may also be 
used in conjunction with biomedical specimens for research.
5.0 METHODOLOGY
Entry Criteria
5.1
Diagnosis/Condition for Entry into the Trial
5.1.1
Male/Female subjects who completed the initial 104-week trial.
 
 
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Subject Inclusion Criteria
5.1.2
In order to be eligible for participation in this trial, the subject must:
1. Have tolerated study medication and completed the initial 104-week trial. Subjects 
who did not complete the initial 104-weeks of treatment but continued with and 
completed scheduled visits may be permitted to continue in the long term extension at 
the discretion of the Sponsor. Subjects who repeatedly deviate from protocol 
requirements will not be permitted to continue in this extension. In addition, subjects 
who are less than 75% compliant with trial medication during the initial 104-week 
trial will not be permitted to continue in the long term extension, except in special 
circumstances, which require Sponsor approval (or, where required locally, approval 
of the investigator rather than the Sponsor).
2. Have a trial partner who is reliable and competent. The trial partner must have a close 
relationship with the subject, have face to face contact at least 3 days/week for a 
minimum of 6 waking hours/week (or more, based on local requirements), be willing 
to accompany the subject to all trial visits, and be willing to monitor compliance of 
the administration of the trial medication. The trial partner should understand the 
nature of the trial and adhere to trial requirements (e.g. dose, visit scheduled and 
evaluations). It is recommended that the trial partner accompany the subject to all trial 
visits.
3. Sign (or legal representative signature) the informed consent in accordance with local 
requirements, after the scope and nature of the trial have been explained.
4. Agree to inform their general practitioner of their participation in this study.
Note: PI will follow up with subject to ensure compliance and document notification 
of the general practitioner in subjects medical records.
Subject Exclusion Criteria
5.1.3
The subject must be excluded from participating in the trial if the subject:
1. Has progressed to dementia due to AD per investigator diagnosis in the initial 104-
week study.
2. Is in imminent risk of self harm, based on clinical interview or on the Columbia 
Suicidality Severity Rating Scale (C-SSRS), or of harm to others in the opinion of the 
investigator. Subjects who report suicidal ideation with intent, with or without a plan 
(e.g., suicidal ideation item 4 or 5 on the C-SSRS) in the past one (1) month or 
suicidal behavior in the past six (6) months should be excluded. Such subjects will be 
permitted to rescreen for entry into this study once in the Investigator’s opinion, this 
risk of harm to self or others is no longer present.
 
 
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3. Has developed a recent or ongoing, uncontrolled, clinically significant medical or 
psychiatric condition that precludes participation in this protocol in the judgment of 
the investigator.  
4. Based on results from the EOT Visit (Visit 12) in the initial 104-week trial has results 
of clinical laboratory tests (complete blood count [CBC], blood chemistries, and 
urinalysis) that are clinically unacceptable to the investigator. However, it is 
recognized that lab results will not be available at Visit 12/12B if they occur on the 
same day. Therefore, such subjects may be enrolled prior to receiving these results; 
upon their receipt of the lab results, if the PI feels they are clinically unacceptable the 
subject should be discontinued.
5. Based on the results from the EOT Visit (Visit 12) has results of a physical 
examination, and vital signs that are clinically unacceptable to the investigator.
6. Has developed a form of dementia that is not Alzheimer's Disease, including but not 
limited to, dementia due to HIV infection, head trauma, vascular disease, Parkinson's 
disease, frontotemporal dementia, or Huntington's disease, as determined by the 
investigator.
7. Anticipates receiving any of the treatments listed in Table 1 during the current trial.
Table 1
Prohibited Medications
Prohibited Medications, Supplements, and Other Substances
Anti-amyloid agents (e.g., tarenflurbil, tramiprosate)
Anti-amyloid antibodies (e.g., solanezumab)
Anti-amyloid vaccine 
(Subjects who received placebo only in a vaccine trial may participate in this trial.)
CYP3A4 inducers (strong) including: 
Rifampicin and St. John’s Wort, phenytoin, carbamazepine 
Exceptions: Use of the following is acceptable: topical use; short-term (<2 weeks) oral 
treatment during the trial; use of oral St. John’s Wort <300 mg three times a day during the 
trial, regardless of duration.
NOTE: This is not a complete list of excluded medications.  Contact the Sponsor if there is a 
question about a specific medication.
7. Has progressed to dementia due to AD per investigator diagnosis in the initial 104-
week study.
Trial Treatments
5.2
The treatments to be used in this trial are outlined below in Table 2.  
 
 
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Table 2
Trial Treatments
Drug
Dose/Potency
Dose 
Frequency
Route of 
Administration
Regimen/Treatment 
Period
Use
MK-8931
12 mg tablet
Once daily
Oral
Up to 260 weeks
Investigational
MK-8931
40 mg tablet
Once daily
Oral
Up to 260 weeks
Investigational
Subjects who received the 12 mg or 40 mg dose in the initial 104-week trial will continue to 
receive the same dose in this long term trial. Subjects who received placebo during the initial 
104-week trial will receive the 40 mg dose during this long term trial.
Dose Selection/Modification
5.2.1
5.2.1.1
Dose Selection
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.
Timing of Dose Administration
5.2.2
The trial medication should be administered by the subject, by the subject’s trial partner, or 
by a caregiver. Each subject should take one tablet at approximately the same time each day 
without regard to food. For each treatment group, one tablet equals one dose of trial 
medication as summarized below:

12/12 group: MK-8931 12 mg (one tablet)

40/40 and placebo/40 groups: MK-8931 40 mg (one tablet)
If a subject misses a dose, the subject may take the dose later in the day and should continue 
with the regular dosing schedule by taking the next dose at the usual time the next day. Any 
changes in dosing schedule should be noted by the subject or subject’s trial partner and 
recorded by the site at the next visit. Subjects should not take more than one dose on the 
same calendar day.
With the exceptions of any subjects enrolled to a dose that is dropped for reasons of safety or 
tolerability, there will be no adjustments to the dose of any subject in the trial.
Trial Blinding/Masking
5.2.3
A double-blind/masking technique will be used. MK-8931 12 and 40 mg tablets will be 
packaged identically so that treatment blind/masking is maintained for the subject and the 
investigator. The Sponsor will be unblinded at the completion of the initial 104-week trial.
 
 
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See Section 7.1.4.2, Blinding/Unblinding, for a description of the method of unblinding a 
subject during the trial, should such action be warranted.
Concomitant Medications/Vaccinations (allowed & prohibited)
5.3
Medications or vaccinations specifically prohibited in the exclusion criteria are not allowed 
during the ongoing trial.  Listed below are some specific restrictions for concomitant therapy 
or vaccination during the course of the trial.  If there is a clinical indication for one of these 
or other medications or vaccinations specifically prohibited during the trial, discontinuation 
from trial therapy or vaccination may be required.  The investigator should discuss any 
questions regarding this with the local Clinical Monitor.  The final decision on any 
supportive therapy or vaccination rests with the investigator and/or 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.
Prohibited Medications
5.3.1
The subject must not take the treatments listed in Table 1 during this trial.
During the trial, initiation of treatment with medications known to be associated with 
substantial increased risk of Stevens-Johnson Syndrome or toxic epidermal necrolysis should 
be avoided when possible. Subjects who have been safely treated with at least one routine 
course of treatment with these medications in the past are exempted from this requirement. 
Examples of such medications are included below.  The Sponsor should be consulted for 
questions about specific medications.

trimethoprim-sulfamethoxazole, azithromycin, allopurinol, phenobarbital, oxicam 
NSAIDS (e.g., celecoxib, valdecoxib, meloxicam), carbamazepine, phenytoin, 
valproic acid, nevirapine, lamotrigine, and chlormezanone
Allowed Medications
5.3.2
Medications, supplements, and other substances allowed during the trial include, but are not 
limited to, those listed in Table 3. Note that the use of any concomitant medication must 
relate to the documented medical history, prophylaxis, or an adverse event of the subject. 
Initiation and change of dose of cholinesterase inhibitors and memantine are allowed in 
this trial.
 
 
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Table 3
Medications, Supplements, and Other Substances Allowed During the Trial
Allowed Medications, Supplements, and Other Substances
Acetylcholinesterase inhibitors (e.g., donepezil, tacrine, rivastigmine, galantamine) 
Memantine 
Huperzine A
Vitamin E
Herbal supplements from Ginkgo biloba, ginseng, Huperzia serrata (Qian Ceng Ta)
Medical foods/supplements (e.g., Axona®, Souvenaid® )
Estrogens and estrogen-like compounds
Antihypertensives
Nonsteroidal anti-inflammatory drugs (NSAIDs)
Cycloxygenase 2 inhibitors
Neuroleptics
Antidepressants
Carbidopa/levodopa and dopamine agonists
Pregabalin and gabapentin
Rifampicin and St. John’s Wort: Topical use, short-term (<2 weeks) oral treatment during the 
trial, use of oral St. John’s Wort <300 mg three times a day during the trial, regardless of 
duration.
Selective H1 blockers, selective H2 blockers, and topical anti-pruritic treatments for 
treatment of rash during the trial, as specified in the Rash Guidance Document.
Rescue Medications & Supportive Care
5.4
No rescue or supportive medications are specified to be used in this trial.
Diet/Activity/Other Considerations
5.5
Subjects who are provided non-pharmacological treatments, such as day care, may continue
these through the trial. The frequency should not change unless medically indicated. Day 
care attendance on the day before clinic visits and cognitive testing should remain stable 
through the protocol. 
Subject Withdrawal/Discontinuation Criteria
5.6
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 
 
 
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regarding discontinuation or withdrawal procedures are provided in Section 7.1.4 – Other 
Procedures.
In this trial, a subject may temporarily discontinue from treatment under certain conditions
specified in the protocol (e.g. in follow-up to imaging abnormalities or rash; refer to Sections 
7.1.2.2.6 and Rash Guidance Document for details) but continue to participate in the 
regularly scheduled activities, as long as the subject does not withdraw consent.  Given the 
exploratory nature of this long term trial’s endpoints, subjects who permanently discontinue 
from treatment will be discontinued from the trial.
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 
continued participation in the trial or does not allow the subject to adhere to the 
requirements of the protocol.
A subject must be discontinued from treatment (but may continue to be monitored in the 
trial) for any of the following reasons:

Elevated ALT, AST, or T-BIL meeting any one of the following criteria:
o
ALT or AST ≥ 8 x ULN;
o
ALT or AST ≥ 5 and < 8 x ULN for more than 2 weeks;
o
ALT or AST ≥ 3 x ULN and T BIL ≥ 2 x ULN at the same visit;
o
ALT or AST ≥ 3 x ULN with the appearance of symptoms indicating hepatitis 
(e.g., worsening fatigue, nausea, vomiting, right upper quadrant pain or 
tenderness, fever, rash, or eosinophilia).    
Exception: If elevations are determined to be due to some other medical condition, 
subject may resume trial medication with Sponsor approval.

An imaging abnormality consistent with intraparenchymal macrohemorrhage appears 
(see details in Section 7.1.2.2.6); 

QTc prolongation (defined as QTc interval > 500 ms or QTc change from baseline > 
60 ms, based on the average of three measurements using the Fridericia formula for 
correction).

Exception: If QTc change from baseline (from Visit 1 of the initial 104-week trial) > 
60 ms is determined to be due to some other medical condition, or if subject has a 
new onset of bundle branch block, subject may continue treatment with Sponsor 
approval.
 
 
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
The subject develops a form of dementia that is not Alzheimer's Disease, including 
but not limited to dementia due to HIV infection, head trauma, vascular disease, 
Parkinson's disease, frontotemporal dementia, or Huntington's disease, as determined 
by the investigator.  

The subject develops a severe rash confirmed by a dermatologist. For the purpose of 
this program, a “severe rash” is defined as one of the following: 
o
A vesicular rash (i.e., one with blistering lesions) that is not clearly caused by 
herpes simplex virus or contact allergy such as poison ivy AND has EITHER 
a) extensive body surface area (BSA) involvement OR b) involves 
oral/mucosal surfaces. 
o
Stevens Johnson Syndrome, erythroderma, or toxic epidermal necrolysis
o
DRESS Syndrome. 

The subject develops an uncontrolled AND clinically significant rash defined as 
follows: 
o
A clinically significant rash (see Section 7.2.3.2) that is not controlled by 
topical medications or oral medications such as antihistamines (detailed in the 
Rash Guidance Document) AND causes intolerable symptoms attributed to 
study drug.

The subject’s trial partner is no longer willing or able to participate in the study and a 
suitable replacement trial partner cannot be found in a reasonable period of time.
Subject Replacement Strategy
5.7
A subject that discontinues from the trial will not be replaced.
Beginning and End of the Trial
5.8
Each subject is considered to be enrolled when the subject (or the subject’s legal 
representative) has provided written informed consent in accordance with local requirements. 
This long-term trial will start with enrollment of the first subject who completes the initial 
104-week trial and chooses to participate in the long term trial. This trial will end after 5 
years after the first subject enrolls (260 weeks), or a) when the drug either becomes 
commercially available (locally), or b) when the MK-8931 program is terminated (whichever 
comes first).  Duration of participation may also be limited based on local regulations. Each 
subject is considered to have ended participation in the trial when he/she has completed the 
last protocol-specified contact (e.g., visits or telephone contacts) or has prematurely 
discontinued from the trial. A subject will be considered a completer of this long-term trial if 
he/she is still continuing in the trial when the trial is stopped.
 
 
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A subject is considered to have discontinued after he/she has withdrawn consent or has been 
discontinued under the conditions specified in Section 7.1.4.1. Given the exploratory nature 
of the long-term trial, the retrieved dropout approach employed in the initial 104-week trial 
will be discontinued from this trial. All applicable activities scheduled for the final trial visit 
should be performed at the time of treatment discontinuation as defined in the long-term trial 
Flow Chart in Section 6.0.
A subject is considered to have been lost to follow-up if he/she is unable to be contacted by 
the investigator. The end of participation for a subject lost to follow-up is the last known 
contact (e.g., visit or telephone contact).
Clinical Criteria for Early Trial Termination
5.9
This trial may be terminated early by eDMC for safety concerns or based on the results of the 
interim efficacy analysis for futility of the initial 104-week trial (See section 8.1.4). 
The clinical trial may be terminated early if the extent (incidence and/or severity) of 
emerging effects/clinical endpoints is such that the risk/benefit ratio to the trial population as 
a whole is unacceptable.  In addition, further recruitment in the trial or at a particular trial 
site(s) may be stopped due to insufficient compliance with the protocol, GCP and/or other 
applicable regulatory requirements, procedure-related problems or the number of 
discontinuations for administrative reasons is too high.
 
 
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6.0 TRIAL FLOW CHART
NOTE: Subject participation in the long term trial (Part II) is optional and will only be conducted where approved by local authorities.
Extension Trial Period:
Treatment
Visit Number (counting from the initial 104-
week trial; Part  I)
12Bb
TCd
13
TCd
14
15
16
17
18
19
20
21
22
23
24
TCf
UV
ETV
Scheduled Week a (based on date of 
randomization in initial 104-week trial; Part I)
104
106
108
112
117
130 156 182
208
234
260
286 312 338
364
Visit Window (Weeks)
1
1
1
1
4
4
4
4
4
4
4
4
4
4
Administrative Procedures
Informed Consent
X
Collect Subject Identification Card
X
Inclusion/Exclusion Criteria
X
Record Concomitant Medication
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
Xe
X
Clinical Procedures/ Assessments
Vital Signsc
X
X
X
X
X
X
X
X
X
X
X
Xe
X
Body Weight
X
X
X
X
X
X
X
Xe
X
Directed Physical & Neurological Examinations
X
X
X
X
X
Xe
X
Directed Skin Examination by Site Physician 
X
X
X
X
X
X
Xe
X
12-Lead Electrocardiogram
X
Xe
CDR
X
X
X
X
X
X
X
ADAS-Cog (13-item)
X
X
X
X
X
X
X
X
Cognition Battery
COWAT
X
X
X
X
X
X
X
X
Trial Making Test (A & B)
X
X
X
X
X
X
X
X
CERAD Verbal Fluency
X
X
X
X
X
X
X
X
Digit Span Test
X
X
X
X
X
X
X
X
Digit Symbol-Coding (DSC)
X
X
X
X
X
X
X
X
ADCS-ADLMCI
X
X
X
X
X
X
X
X
MMSE
X
X
X
X
X
X
X
C-SSRS: Since Last Visit
X
X
X
X
X
X
X
X
X
X
X
X
Xe
X
NPI
X
X
X
X
X
X
X
 
 
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Extension Trial Period:
Treatment
Visit Number (counting from the initial 104-
week trial; Part  I)
12Bb
TCd
13
TCd
14
15
16
17
18
19
20
21
22
23
24
TCf
UV
ETV
Scheduled Week a (based on date of 
randomization in initial 104-week trial; Part I)
104
106
108
112
117
130 156 182
208
234
260
286 312 338
364
Visit Window (Weeks)
1
1
1
1
4
4
4
4
4
4
4
4
4
4
Modified RUD Lite: Follow-Up
X
X
X
X
X
X
X
HEA
X
X
X
X
X
X
X
EQ-5D
X
X
X
X
X
X
X
CAM
X------To be completed only for adverse events of delirium---------------------------------------------------------
Structural MRI
Xe
Monitor for Progression to Dementiah
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
Adverse Event Monitoring
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
Laboratory Procedures/ Assessments
Hematology and Chemistry Blood Samplesc
X
X
X
X
X
X
X
X
Xe
X
Urinalysisc
X
X
X
X
X
X
X
X
Xe
X
Trial Medication Procedures
Dispense Trial Medication
X
X
X
X
X
X
X
X
X
X
X
X
Xg
Medication Compliance
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
Drug Accountability Assessment
X
X
X
X
X
X
X
X
X
X
X
X
X
X
 
 
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Extension Trial Period:
Treatment
Visit Number (counting from the initial 104-
week trial; Part  I)
12Bb
TCd
13
TCd
14
15
16
17
18
19
20
21
22
23
24
TCf
UV
ETV
Scheduled Week a (based on date of 
randomization in initial 104-week trial; Part I)
104
106
108
112
117
130 156 182
208
234
260
286 312 338
364
Visit Window (Weeks)
1
1
1
1
4
4
4
4
4
4
4
4
4
4
ADAS-Cog = Alzheimer’s Disease Assessment Scale Cognitive subscale (modified: 13-item with delayed memory recall and number cancellation tasks); ADCS-
ADLMCI= Alzheimer’s Disease Cooperative Study Activities of Daily Living (MCI Version); AE = Adverse Event; CAM = Confusion Assessment Method; CDR =
Clinical Dementia Rating; COWAT = Controlled Oral Word Association Test; C-SSRS = Columbia Suicide Severity Rating Scale; DSC = Digit Symbol-Coding; 
EQ-5D = EuroQoL Five Dimension Questionnaire; ETV = Early Termination Visit; HEA = Health Economic Assessment; MCI = Mild Cognitive Impairment; 
MMSE = Mini-Mental State
Examination; MRI = magnetic resonance imaging; NPI = Neuropsychiatric Inventory; RUD Lite Resource Utilization in Dementia Lite Questionnaire; TC = 
telephone call; UV = Unscheduled Visit
a. Visits scheduled during the long term trial (Part II) will be based off of the date of randomization in the initial 104-week trial (Part I). The timing of each visit is relative to Study Day 
1 of that subject with Study Day 1 defined as the date of randomization into the initial 104-week trial (which should also be the date of the first administration of trial medication in the 
initial 104-week trial). However, if a subject enters the extension trial at a different time point than visit 12, i.e. V12 and V12B occur on different days, subsequent visits should be 
based on the date V12B actually occurred and not the date of randomization.  
b. Visit 12 from Part I and Visit 12B from Part II are considered a single visit and can be conducted on the same day. Subjects with a gap in therapy of > 4weeks may be allowed to 
continue if reason for the delay was due to, for example, HA/IRB approval, etc.  If there is a a gap in study therapy >3 months the sponsor should be consulted. It is recognized that lab 
results will not be available at Visit 12/12B if they occur on the same day. Therefore, such subjects may be enrolled prior to receiving these results; upon their receipt, if the PI feels 
they are clinically unacceptable the subject should be discontinued.
c. Vital Signs and laboratory samples should be collected for subjects with > 3 month gap in therapy between visit 12 and 12B.
d. Telephone contact with subject and trial partner/caregiver by site to assess safety, AEs, concomitant medications, medication compliance, and any other issues. Any telephone contact 
may be conducted as an in-person unscheduled visit if the subject or caregiver expresses a preference for this or of the site has significant safety/tolerability concerns.
e. Procedures may be performed if clinically indicated as determined by the investigator.
f. Telephone contact will be performed to assess for adverse events that may have occurred up to 14 days (+ 1-week) following cessation of study medication.
g. Drug dispensing may be performed at unscheduled visits at the discretion of the Investigator.
h. Progression to dementia should be evaluated at all visits during the long term trial until the investigator or qualified designee considers the subject as having progressed to dementia 
(AD or non-AD). Cases of progression in this trial will not be reviewed by an adjudication committee; therefore the final decision on progression will be the opinion of the investigator 
or qualified designee. Note: Subjects who were confirmed to have progressed to AD dementia by the adjudication committee in the initial 104-week trial may not continue in this trial. 
For those subjects for whom the adjudication committee rendered a decision of non-AD dementia, the subject may continue in this trial if in the investigator’s opinion the subject did 
not progress to AD or non-AD dementia during the initial 104-week trial.
 
 
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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.
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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Given the trial population and the duration of the study, it is possible that a subject’s 
cognition may decline to a point where they no longer have capacity to provide informed 
consent. If this occurs, the site should obtain consent to continue in the trial from the 
subject’s legally acceptable representative and in accordance with local standards and 
requirements. The subject’s assent to continue should also be obtained. In Germany only, 
due to more restrictive regulations, subjects who progress to the point where they are judged 
to be unable to give informed consent must be discontinued from the trial.
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
In the initial 104-week trial, all subjects were given a Subject Identification Card identifying 
them as participants in a research trial.  The card contains trial site contact information 
(including direct telephone numbers) to be utilized in the event of an emergency.
7.1.1.4
Concomitant Medications Review
7.1.1.4.1 Concomitant Medications
The investigator or qualified designee will record medication, if any, taken by the subject 
during the trial.
7.1.1.5
Trial Compliance (Medication/Diet/Activity/Other)
As part of the routine recording of the amount of trial treatment taken by each subject, the 
number of pills remaining in trial packaging will be counted and recorded at each regular 
visit. These results will be used to calculate subject compliance. Instances where the subject 
took more or less trial medication than prescribed will be recorded on the study medication 
eCRF. Events that meet criteria for overdose as defined in Section 7.2.1 will also be reported 
as an AE (ECI or SAE, as applicable). To monitor for potential misuse, the site will 
document significant discrepancies in drug returns where the subject or trial partner returns 
less trial medication than expected but denies taking extra trial medication (e.g., lost or 
missing medication equivalent to more than one pill per week).
Clinical Procedures/Assessments
7.1.2
7.1.2.1
Trial Partner Attendance at Trial Visits
The trial partner is expected to accompany the subject to all trial visits when feasible. At the 
discretion of the investigator, exceptions are acceptable, such as visits where no clinical 
measures are scheduled for administration to the trial partner. However, in these instances, 
the trial partner should be contacted by phone to complete AE, concomitant medication, and 
trial medication compliance review. For additional details, the Sponsor may be consulted.
 
 
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7.1.2.2
Physical Assessments/Examinations
7.1.2.2.1 Vital Signs
The following vital signs will be measured and recorded: pulse (beats/minute), blood 
pressure (mm Hg), temperature (ºC/ºF), and respiratory rate (breaths per minute). Blood 
pressure should be measured in the sitting position.
7.1.2.2.2 Body Weight (kg/lbs) 
Body weight data will be collected and recorded. Body weight data will be collected without 
shoes and with heavy clothing removed. Body weight should be performed on the same scale 
for the same individual. Measurements should be recorded to the nearest kilogram/pounds.
7.1.2.2.3 Directed Physical and Neurological Examinations
A routine physical and neurological examination with focus on subject-specific signs and 
symptoms should be performed. If the subject is discontinued for any reason during the 
treatment phase, every attempt should be made to perform a final physical examination. 
7.1.2.2.4 Skin Examinations
To monitor for hypopigmentation, skin examinations will be performed by a site physician at 
the visits specified in Section 6.0, Trial Flow Chart. At Weeks 130, 156, 208, 260, 312, and 
364, a site physician will perform a directed examination of the subject’s skin. In addition, 
sites will instruct subjects to perform a self-examination of their skin between clinic visits 
(with the assistance of their trial partner, if needed). Subjects should report any abnormal loss 
of skin pigment to the site. The site physician’s examination will focus on exposed skin and 
any areas of pigment loss noted by the subject or trial partner. If a clinically significant area 
of hypopigmentation is observed, the site should refer the subject to a dermatologist or 
medical expert for further follow-up. At each scheduled assessment, the following 
information should be recorded: whether significant sites of skin hypo- or depigmentation 
were observed, and any adverse events.
Based on the local standard of care, the investigator should refer subjects to a dermatologist 
or medical expert if: 1) a clinically significant area of skin develops hypopigmentation 
compared to baseline*; or 2) if needed based on their clinical judgment.  The following 
criteria are provided to guide the investigator but are not meant to be inclusive or to require 
referral in all cases. 
1) A clinically significant area of hypopigmentation may include: 
a) those greater than 3x3 cm  
b) a smaller area (e.g., 1x1 cm) on the face or hands 
c) a speckled pattern involving a larger amount of body surface area or  
d) a smaller area (e.g., 1x1 cm) of complete pigment loss.
 
 
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Hypopigmentation for criterion 1 is defined as a decrease in skin color relative to 
the surrounding skin and its prior baseline appearance.
2) Clinical judgment criteria include:
a) In the investigator’s judgment, the hypopigmentation requires evaluation by 
an expert (e.g., small lesions on the face), or 
b) The subject or caregiver is distressed by the appearance of the skin lesion 
or hypo/depigmentation.
Dermatologists will evaluate and treat any lesions based on local standard of care. No special 
procedures are required per protocol.
*In this trial baseline is considered the skin examination performed by a dermatologist in the 
initial 104-week trial at screening. For those subjects who did not have a skin examination 
performed by a dermatologist in the initial 104-week trial at screening, baseline should be 
considered either the full body skin examination performed by a dermatologist at 6 months, 
or, if that is unavailable, the directed skin examination performed by the site physician at the 
EOT visit in the initial 104-week trial.
7.1.2.2.5 12-Lead Electrocardiogram (ECG)
A 12-Lead Electrocardiogram will be performed according to the instructions in a separate 
ECG Instruction Manual. Note: Triplicate measurements of ECG will be required if there is 
an observation of QTc prolongation during this trial. Otherwise, single measurements should 
be done at specified time points indicated in Section 6.0, Trial Flow Chart.
7.1.2.2.6 Structural Magnetic Resonance Imaging (MRI)
Structural MRI for safety monitoring may be conducted at an unscheduled visit if the 
investigator considers that it is clinically indicated due to an adverse event. 
Amyloid-related imaging abnormalities that arise during the trial should be handled as 
follows:
1) Trial medication should be discontinued if an imaging abnormality consistent with 
intraparenchymal macrohemorrhage appears or a clinically symptomatic incident 
vasogenic edema, microhemorrhage, or superficial siderosis is seen.
2) If symptomatic cerebral vasogenic edema occurs, MRI scans should be repeated 
within three to four weeks to assess stability and then performed every four to six 
weeks (or as clinically indicated) until the vasogenic edema resolves.  Treatment 
with high dose dexamethasone can be considered, as suggested by the US FDA, if 
associated symptoms are severe.  
 
 
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3) For subjects who present with new clinically symptomatic microhemorrhages or 
superficial siderosis, an MRI re-scan at three to four weeks should be performed in 
order to evaluate their stability. 
4) Re-dosing can be considered with Sponsor approval based on investigators’ clinical 
judgment if clinical symptoms associated with symptomatic vasogenic edema, 
microhemorrhage, or superficial siderosis have resolved.
5) For intraparenchymal macrohemorrhage, subjects must be discontinued from study 
medication and cannot resume dosing. 
7.1.2.3
Cognitive and Clinical Assessments
Quality control is an essential part of all clinical trials.  For AD trials, it is particularly 
important to monitor clinical ratings.  This trial will include a review by outside expert(s) of 
the ratings administered as determined by the Sponsor. 
Raters of clinical assessments will undergo the applicable training prior to conducting 
assessments in the trial. Further, rater performance on these assessments will be carefully 
evaluated and monitored by central external experts to ensure and maintain adequate 
reliability throughout the trial.  Details will be specified in the Manual of Assessments and in 
training materials provided by the rater training vendor.  In order to qualify for the trial, 
raters must be approved by the Sponsor, which will require successful completion of a 
trial specific rater training program. To ensure the continued quality of the assessments, 
raters will be asked to audio record certain interviews and ratings through Week 130 (please 
see the MedAvante Manual for specific details regarding assessments to be audio recorded).  
Some or all of these recorded interviews will be reviewed by outside experts.  Raters may be 
provided feedback on the quality of their interviews and ratings reviewed by the outside 
experts via QCAT, e-mail, telephone or in face-to-face meetings in order to develop and 
maintain good rater reliability.  Based on this feedback, raters should consider changing their 
initially recorded scores if errors are identified.  Routine rater meetings may be conducted to 
assess and maintain reliability for the duration of the trial.  Raters who do not perform 
adequately may be required to undergo additional remediation or may be replaced. 
While concerns have been raised that audio recordings could theoretically compromise 
subjects' privacy, this issue must be balanced with the needs to conduct methodologically 
adequate and scientifically rigorous trials that are capable of testing the key hypotheses. 
Given that the key endpoints in this trial involve subjective judgments, monitoring the 
adequacy of subject interviews and ratings is essential and part of good research 
methodology. Prior studies have clearly demonstrated that the failure to adequately monitor 
such ratings can substantially increase the risks of failed trials [12; 13]. Recorded interviews 
will be secured using state of the art methods to ensure privacy. Recordings will only be 
reviewed by approved trial personnel for quality control purposes and will be destroyed 
within two years of the completion of the trial, unless local regulatory authorities or 
IRBs/ERCs have different requirements for storage.
 
 
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Subjects may participate in this protocol and also participate in certain observational studies 
(including studies with neuroimaging), if approved by the Sponsor. These studies must 
involve only limited cognitive testing.
7.1.2.3.1 Confirmation of Progression to Probable AD Dementia
The principal investigator or qualified designee* will assess whether or not the subject may 
have progressed to dementia at all visits during the long term trial until the investigator or 
qualified designee considers the subject as having progressed to dementia. Cases of 
progression in the long term trial will not be reviewed by an adjudication committee; 
therefore the final decision on progression will be the opinion of the investigator or qualified 
designee. 
Note: For subjects who were judged to have progressed to AD or non AD dementia by the 
adjudication committee in the initial 104-week trial, the investigator should document in their 
study records the reasons they judge that the subject had not progressed to dementia prior to 
the subject entering the extension trial.
* Note: Please refer to the Manual of Assessments for qualifications required of the Qualified 
Designee when the Qualified Designee completes the assessment of progression to probable 
AD dementia.
7.1.2.3.2 Clinical Dementia Rating (CDR)
The CDR [15] will be administered to both the subject and the subject’s trial 
partner/informant in paper form, and the CDR Sum of Boxes (CDR-SB) will be scored and 
recorded by a qualified, trained rater according to the instructions in the Manual of 
Assessments. When possible, the CDR should be administered as the first clinical rating 
during relevant visits. Additional detailed information concerning administration, scoring and 
documentation may also be provided by the rater training vendor.
7.1.2.3.3 Alzheimer’s Disease Assessment Scale Cognitive Subscale (ADAS-Cog)
The ADAS-Cog13 (including number cancellation and delayed recall) [16] will be 
administered to the subject in paper form and scored and recorded by a qualified, trained 
rater according to the instructions in the Manual of Assessments. When possible, the ADAS-
Cog should be administered to subjects after the CDR is administered. Additional detailed 
information concerning administration, scoring and documentation may also be provided by 
the rater training vendor.
7.1.2.3.4 Controlled Oral Word Association Test (COWAT)
The COWAT is a short, paper/pencil measure of phonemic fluency and executive 
functioning from the Multilingual Aphasia Examination [17].  The COWAT will be 
administered to the subject and scored by a qualified, trained rater according to the 
instructions in the Manual of Assessments. Additional detailed information concerning 
administration, scoring and documentation may also be provided by the rater training vendor.
 
 
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7.1.2.3.5 Trail Making Test (A&B)
The Trail Making Test [18; 19], a brief paper/pencil assessment of visual scanning (Part A) 
and visuomotor sequencing (Part B), will be administered to the subject and scored by a 
qualified, trained rater according to the instructions in the Manual of Assessments. 
Additional detailed information concerning administration, scoring and documentation may 
also be provided by the rater training vendor.
7.1.2.3.6 CERAD Verbal Fluency (CVF)
The CVF Test [20], a brief paper/pencil measure of semantic processing and executive 
functioning, will be administered to the subject and scored by a qualified, trained rater 
according to the instructions in the Manual of Assessments. Additional detailed information 
concerning administration, scoring and documentation may also be provided by the rater 
training vendor.
7.1.2.3.7 Digit Span Test
Digit Span, a brief paper/pencil measure from the Wechsler Adult Intelligence Scale-III [21], 
will be administered to the subject and scored by a qualified, trained rater according to the 
instructions in the Manual of Assessments. Digits Forward assesses attention, while Digits 
Backward also measures working memory and mental tracking.  Additional detailed 
information concerning administration, scoring and documentation may also be provided by 
the rater training vendor.
7.1.2.3.8 Digit Symbol-Coding (DSC) 
The DSC subtest of the Wechsler Adult Intelligence Scale-III [21] is a brief paper/pencil task 
assessing attention, psychomotor speed and visuomotor coordination.  The DSC will be 
administered to the subject and scored by a qualified, trained rater according to the 
instructions in the Manual of Assessments.  Additional detailed information concerning 
administration, scoring and documentation may also be provided by the rater training vendor.
7.1.2.3.9 Alzheimer’s Disease Cooperative Study Activities of Daily Living Inventory 
(ADCS-ADLMCI)
The ADCS-ADLMCI [22], a functional assessment adapted for MCI trials, will be 
administered to the subject’s trial partner/informant in paper form and scored and recorded 
by a qualified, trained rater according to the instructions in the Manual of Assessments.
Additional detailed information concerning administration, scoring and documentation may 
also be provided by the rater training vendor.
7.1.2.3.10
Mini-Mental State Examination (MMSE)
The paper version of the MMSE [23], a brief measure of cognition, will be administered to 
the subject and scored and recorded by a qualified, trained rater according to the instructions 
 
 
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in the Manual of Assessments. Additional detailed information concerning administration, 
scoring and documentation may also be provided by the rater training vendor.
7.1.2.3.11
Columbia Suicide Severity Rating Scale (C-SSRS)
Suicidal ideation and behavior will be prospectively assessed using the C-SSRS [24]. The 
paper version of the C-SSRS should be administered by trained raters at specified time 
points, as indicated in the Trial Flow Chart, as well as at unscheduled visits as clinically 
indicated. Site staff should review the contents of the C-SSRS for completeness and then 
transcribe the data to the eCRF. 
Subjects who at any time during this study report an AE of suicidal ideation or behavior, 
either between visits or during visit interviews, must be assessed by the investigator or 
qualified designee. Subjects who report suicidal ideation with intent, with or without a plan 
or method (i.e., a positive response to items 4 or 5 in the assessment of suicidal ideation on 
the C-SSRS) or suicidal behavior must be evaluated that day by a psychiatrist or other trained 
mental health professional who is a licensed psychologist, social worker or nurse practitioner 
(or comparable professional qualification in countries outside the United States). Only 
subjects whose suicidal ideation is passive, who expressly deny any intent to act, and who, 
after evaluation, are not judged to be at serious risk for self-harm during the course of the 
trial may continue with trial treatment; others must be discontinued from trial treatment and 
receive appropriate clinical follow-up care to assure their safety. After appropriate follow-up 
care, if the investigator judges that the subject can safely resume trial treatment, re-dosing 
can be considered with Sponsor approval.  
All reports of suicidal ideation or behavior must be recorded as an Event of Clinical Interest 
(ECI) (See Section 7.2.3.2). Sites are to indicate which health care professionals are to be 
responsible for acute care on-site and to specify referral center(s) to be used for further 
evaluation. 
The C-SSRS (Since Last Visit paper versions) will be administered to the subject and scored 
by a qualified trained rater as described in the Manual of Assessments.  Additional detailed 
information concerning administration, scoring, and documentation may also be provided by 
the rater training vendor. 
7.1.2.3.12 Neuropsychiatric Inventory (NPI)
The NPI [25] is an interview-based tool for assessing behavioral domains common in 
dementia (Hallucinations, Delusions, Agitation/aggression, Dysphoria/depression, Anxiety, 
Irritability, Disinhibition, Euphoria, Apathy, Aberrant motor behavior, Sleep and night-time 
behavior change, Appetite and eating change) in terms of frequency, severity and distress; it 
is widely used in clinical trials to assess behavior in AD and other dementias.  The NPI 
(paper version) will be administered to the subject’s trial partner/informant and scored by a 
qualified, trained rater according to the instructions in the Manual of Assessments. 
Additional detailed information concerning administration, scoring and documentation may 
also be provided by the rater training vendor.
 
 
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7.1.2.3.13
Modified Resource Utilization in Dementia (RUD) Lite Questionnaire
A modified RUD Lite Questionnaire will be administered to the subject’s trial 
partner/informant in paper form and documented by a qualified, trained rater according to the 
instructions in the Manual of Assessments.
7.1.2.3.14
Health Economic Assessment (HEA)
The HEA will be administered to the subject’s trial partner/informant in paper form and 
documented by a qualified, trained rater according to the instructions in the Manual of 
Assessments.
7.1.2.3.15
EuroQol Five Dimension Questionnaire (EQ-5D)
The EQ-5D will be completed by the subject’s trial partner/informant in paper form and 
reviewed by a qualified, trained rater according to the instructions in the Manual of 
Assessments.
7.1.2.3.16
Confusion Assessment Method (CAM)
The CAM is completed by the rater based on information provided by other sources (i.e. 
medical records, asking the subject questions). It should be completed only if and when an 
adverse event of delirium is suspected to ascertain the diagnosis of delirium.
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 12.2.
7.1.3.1
Laboratory Safety Evaluations (Hematology, Chemistry and Urinalysis)
Laboratory tests for hematology, chemistry and urinalysis are specified in Table 4.
 
 
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Table 4
Laboratory Tests
Hematology
Chemistry
Urinalysis
Basophils
Albumin
Blood
Eosinophils
Alkaline phosphatase
Glucose
Hematocrit
Alanine aminotransferase (ALT)
Ketones
Hemoglobin
Aspartate aminotransferase 
(AST)
Microscopic exam, if 
abnormal results are 
noted
Lymphocytes
Bicarbonate
pH
Monocytes
Blood Urea Nitrogen (BUN)
Protein
Neutrophils
Calcium
Specific gravity
Platelets
Chloride
RBC
Cholesterol
WBC
Creatinine
Glucose
Phosphorus
LDH
Potassium
Sodium
Total Bilirubin
Total protein
Other Procedures
7.1.4
7.1.4.1
Withdrawal/Discontinuation
When a subject discontinues/withdraws prior to trial completion, all applicable activities 
scheduled for the final trial visit should be performed at the time of discontinuation.  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. Subjects who permanently discontinue from treatment will be 
discontinued from the trial.
7.1.4.2
Blinding/Unblinding
TRIAL TREATMENT IDENTIFICATION INFORMATION IS TO BE UNMASKED 
ONLY IF NECESSARY FOR THE WELFARE OF THE SUBJECT. EVERY EFFORT 
SHOULD BE MADE NOT TO UNBLIND THE SUBJECT UNLESS NECESSARY.
For emergency situations where the investigator or sub-investigator needs to identify the drug 
used by a subject and/or the dosage administered, he/she will contact the emergency 
unblinding call center by telephone and make a request for emergency unblinding.  As 
requested by the investigator or sub-investigator the emergency unblinding call center will 
provide the information to him/her promptly and report unblinding to the sponsor.  The 
emergency unblinding call-center will make a record promptly however, the investigator or 
sub-investigator must enter the intensity of the adverse experiences observed, their relation to 
study drug, the reason thereof, etc., in the medical chart etc., before unblinding is performed.
 
 
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Additionally, the investigator must go into the IVRS system and perform the unblind in the 
IVRS system to update drug disposition.  In the event that the emergency unblinding call 
center is not available for a given site in this trial, IVRS/IWRS should be used for emergency 
unblinding in the event that this is required for subject safety.
In the event that unblinding has occurred, the circumstances around the unblinding (e.g., date 
and reason) must be documented promptly, and the Sponsor Clinical Director notified as 
soon as possible.  Once an emergency unblinding has taken place, the principal investigator, 
site personnel, and Sponsor personnel may be unblinded so that the appropriate follow-up 
medical care can be provided to the subject.
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.
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.  Progression of the condition under 
study (prodromal AD) is not considered an adverse event unless it is assessed as drug-related 
by the investigator, or is characterized by unusual or atypical decline for AD progression in 
the judgment of the investigator, or meets criteria for a serious adverse event (see Section 
7.2.3.1).
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.
Adverse events may occur during clinical trials, or as prescribed in clinical practice, from 
overdose (whether accidental or intentional), from abuse and from withdrawal.
All adverse events 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 
 
 
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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. 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 Electronic Data Capture (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
In this trial, an overdose is any dose higher than two times the daily dose of trial medication
in a calendar day specified in Section 5.2.2.
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.
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, 
 
 
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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 an other 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 5 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 
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 
 
 
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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 may 
require 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.
3. Certain adverse events associated with potential for abuse (euphoric mood, mania,
hypomania, or similar events); additional information may be requested for other 
adverse events associated with potential for abuse, but these AEs will not be 
considered ECIs;
4. ALT or AST ≥3 x ULN and a ≥20% increase from baseline;
 
 
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5. **Incident vasogenic edema in post-treatment brain MRI scans;
6. **Incident intraparenchymal macrohemorrhage in post-treatment brain MRI scans;
7. **Incident superficial siderosis in post-treatment brain MRI scans;
8. **Incident microhemorrhage in post-treatment brain MRI scans;
9. Suicidal ideation and/or suicidal behavior;
10. Delirium  that  is  ascertained  by  the  investigator  or  a  qualified  designee.  The 
Confusion Assessment Method (CAM) [26] should be used to verify delirium 
whenever feasible;
11. A clinically significant rash in the investigator's judgment (such as a duration >2 
weeks OR a rash that is >10% BSA, OR a rash causes significant discomfort not 
relieved by topical medication) OR a severe rash (as defined in Section 5.6);
12. Adverse events of clinically significant skin hypo- or depigmentation (see Section 
7.1.2.2.4 for details);
A separate guidance document will be provided to sites for follow-up care of elevated
LFT. Follow-up care for clinically significant rashes and severe rashes will also be 
detailed in another guidance document to sites, which includes evaluation by a 
dermatologist, photographs of skin lesions, and biopsy if indicated. For severe rashes, 
an adjudication committee will be adjudicating all cases of Stevens-Johnson 
Syndrome, erythroderma, toxic epidermal necrolysis, or DRESS syndrome based on 
photographs, biopsy results, and other available clinical data. Details will be 
described in the adjudication committee charter.
**Since routine MRI monitoring for safety has been discontinued, the central 
Reading Center is not automatically performing central reading for safety. Therefore, 
during the main study and the extension, the site investigator or radiologist should 
perform a local reading, as necessary. In some cases, central reads for safety may be 
performed. In the event that an Amyloid Related Imaging Abnormality (ARIA) is 
detected, then the Sponsor may request that the MRI be submitted for central reading.
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 5.  The investigator’s assessment of causality is required for 
each adverse event.  Refer to Table 5 for instructions in evaluating adverse events.
 
 
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Table 5
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 [including hospitalization for an elective procedure] for a preexisting 
condition which has not worsened does not constitute a serious adverse event.); 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 U.S. CLINICAL 
MONITOR AND THE INSTITUTIONAL REVIEW BOARD/INDEPENDENT ETHICS COMMITTEE AND APPROPRIATE RECONSENT 
OBTAINED.
WHERE RESTRICTED LOCALLY BY IRS (INCLUDING SITES IN FRANCE): FOR SAEs JUDGED TO BE RELATED TO TRIAL 
DRUG, SUBJECTS MUST BE DISCONTINUED FROM TRIAL DRUG.
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.
TRIAL GOVERNANCE AND OVERSIGHT
7.3
Executive Oversight Committee
7.3.1
The Executive Oversight Committee (EOC) comprises members of Sponsor Senior 
Management.  The EOC will receive and decide upon any recommendations made by the
external Data Monitoring Committee (eDMC) regarding the trial.
Data Monitoring Committee
7.3.2
To supplement the routine trial monitoring outlined in this protocol, an external Data 
Monitoring Committee (DMC) will monitor the safety data from this trial at the appropriate 
frequency and for the duration required per the DMC charter.  The voting members of the 
committee are external to the Sponsor.  The members of the DMC must not be involved with 
the trial in any other way (e.g., they cannot be trial investigators) and must have no 
competing interests that could affect their roles with respect to the trial. 
The DMC will make recommendations to the EOC regarding steps to ensure both subject 
safety and the continued ethical integrity of the trial.  Also, the DMC will review interim trial 
results, consider the overall risk and benefit to trial participants (see Section 8.2.13 - Interim 
Analyses) and recommend to the EOC if the trial should continue in accordance with the 
protocol.
Specific details regarding composition, responsibilities and governance, including the roles 
and responsibilities of the various members and the Sponsor protocol team; meeting 
facilitation; the trial governance structure; and requirements for and proper documentation of 
DMC reports, minutes, and recommendations will be described in a separate charter that is 
reviewed and approved by the DMC.  The DMC will monitor the trial at an appropriate 
frequency, as described in the detailed DMC charter.  The DMC will also make 
recommendations to the Sponsor protocol team regarding steps to ensure both subject safety 
and the continued ethical integrity of the trial.
Clinical Adjudication Committee
7.3.3
A Clinical Adjudication Committee (CAC) will evaluate the following events for the 
purposes of confirming them according to the criteria in Section 8.0 – Statistical Analysis 
Plan, as well as evaluating the presence of confounding factors.

For severe rashes, an external clinical adjudication committee will adjudicate all cases 
of Stevens-Johnson Syndrome, erythroderma, toxic epidermal necrolysis, or DRESS 
syndrome based on photographs, biopsy results, and other available clinical data. 
 
 
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All personnel involved in the adjudication process will remain blinded to treatment allocation 
throughout the trial.  Specific details regarding endpoint definitions can be found in the 
Adjudication Charter.
8.0 STATISTICAL ANALYSIS PLAN
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).
Efficacy Analyses
8.1.1
The primary and key secondary endpoints, primary analysis population, and statistical 
methods that will be employed for the efficacy analyses are presented in Table 6.
There are no formal hypotheses for this trial. All efficacy measurements analyzed during the 
initial 104-week trial will continue to be collected and analyzed in the long term trial. The 
primary endpoint is the 30-Month (6 months after the primary timepoint from the initial 104-
week trial) change-from-baseline treatment difference on CDR-SB.
Safety Analyses
8.1.2
The All-Subjects-as-Treated population will be employed for safety analyses.
The 
prespecified events of interest (Tier-1 events) are 1) Microhemorrhage, superficial siderosis 
or macrohemorrhage; 2) vasogenic edema; 3) delirium; and 4) rash ECI.  P-values and 95% 
confidence intervals for between-treatment differences in the percentage of subjects with 
events will be calculated using the Miettinen and Nurminen method [27]. 
Power and Sample Size
8.1.3
There are no sample size calculations for the long term trial, as there are no formal 
hypotheses. Subjects who complete the initial 104-week trial will be eligible for the long 
term trial. The number of individuals enrolled in the extension will not exceed the number 
enrolled in the base study.
Interim Analyses
8.1.4
The independent eDMC will routinely evaluate unblinded safety analyses of all trial subjects 
while the initial 104-week trial is blinded and as described in their charter. Additional safety 
analyses may be conducted throughout the trial as requested by the eDMC. The sponsor will 
be unblinded after completion of the initial 104-week trial.
 
 
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Statistical Analysis Plan
8.2
Responsibility for Analyses/In-House Blinding
8.2.1
The statistical analysis of the data obtained from this study will be the responsibility of the 
Clinical Biostatistics department of the SPONSOR.
The sponsor will be unblinded after completion of the initial 104-week trial. But prior to that, 
the extension trial will be conducted as a double-blind study under in-house blinding 
procedures. Planned interim analyses are described in Section 8.2.13. Blinding to treatment 
assignment will be maintained at all investigational sites. The results of interim analyses will 
not be shared with the investigators prior to unblinding of the trial. Subject-level unblinding 
will be restricted to an external unblinded group of statisticians.
Treatment-level results of the interim analysis will be provided by the external statisticians to 
the eDMC (and any necessary consultants thereto, e.g., ophthalmologists). Limited additional 
SPONSOR personnel may be unblinded to the treatment level results of the interim analysis 
(analyses), if required, in order to act on the recommendations of the eDMC.  The extent to 
which individuals are unblinded with respect to results of interim analyses will be 
documented by the external statisticians.
Prior to final study unblinding, the external statisticians will not be involved in any 
discussions regarding modifications to the protocol, statistical methods, identification of 
protocol violators, or data validation efforts.
Hypotheses/Estimation
8.2.2
Objectives and hypotheses of the study are stated in Section 3.0.
Analysis Endpoints
8.2.3
Efficacy and safety endpoints that will be evaluated for within- and/or between-treatment 
differences are listed below.
8.2.3.1
Efficacy Endpoints
It is noted that baseline refers to the baseline from the initial 104-week trial.
8.2.3.1.1 Primary Efficacy Endpoint
The primary efficacy endpoint is the change from Baseline in the CDR-SB score at Week 
130.
 
 
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8.2.3.1.2 Exploratory Efficacy Endpoints 
Exploratory endpoints include

the time to progression to probable AD dementia as determined by investigator-
diagnosis; and the following at all scheduled timepoints:

the change from Baseline score in the CDR-SB (with the exception of Week 130 which 
is designated as the primary endpoint);

the change from Baseline score in the CCS-3D;

the change from Baseline score for the composite cognition subscale (memory, 
orientation, judgment and problem solving) and composite functional subscale (home 
and hobbies, personal care and community affairs) of the CDR;

the change from
Baseline score for: ADCS-ADLMCI, ADAS-Cog13,
Number 
Cancellation, MMSE, CCS-2D, and NPI;

Modified RUD Lite, HEA, and EQ-5D;

the change from Baseline score for the three domain z-scores of the CCS-3D (episodic 
memory, executive function, and attention/processing speed);

the change from Baseline score for the domain-specific individual components of the 
CCS-3D: Immediate Word Recall (ADAS-Cog), Delayed Word Recall (ADAS-Cog), 
Word Recognition (ADAS-Cog), and Orientation (ADAS-Cog), Digit Span Test 
(Forwards), DSC, Digit Span Test (Backwards), Trails A Test, Trails B Test, COWAT, 
and CERAD Verbal Fluency Test.
8.2.3.2
Safety Endpoints
Refer to Section 8.2.8 for initial description of safety measures. It is noted that baseline refers 
to the baseline from the initial 104-week trial.
8.2.3.3
Derivations of Efficacy Endpoints
For the handling of missing data within an endpoint (i.e., if an individual subquestion needed 
for a total score is missing) see Section 8.2.7.5
The CCS-3D will be calculated as the mean of three domain z-scores (episodic memory, 
executive function, and attention processing). In a similar fashion, each of these three domain 
z-scores will be calculated as the mean of domain specific tests (after transformation to z-
scores), as follows:
Episodic Memory: Immediate Word Recall, Delayed Word Recall, Word 
Recognition, and Orientation (all from ADAS-Cog);
Executive Function: Digit Span Test (Backwards), Trails B Test, COWAT, CERAD 
Verbal Fluency Test;
Attention/Processing Speed: Trails A Test, Digit Span Test (Forwards), DSC
 
 
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The z-scores [(observed value - baseline mean)/ baseline standard deviation)] for each of the 
individual component tests will be calculated at each timepoint using the baseline mean and 
standard deviation of all treated subjects. Prior to taking the average of three domain scores 
for the computation of CCS-3D, each of the three domain scores will be normalized in a 
similar fashion.
The CCS-2D endpoint will be constructed by averaging the z-scores from five component 
tests: Immediate Word Recall (ADAS-Cog), Word Recognition (ADAS-Cog), Orientation 
(ADAS-Cog), COWAT, and CERAD Verbal Fluency. 
Analysis Populations
8.2.4
8.2.4.1
Efficacy Analysis Populations
The Full Analysis Set (FAS) population will serve as the primary population for the analysis 
of efficacy data in this study.  The FAS population for a given endpoint consists of all 
randomized subjects who:

receive at least one dose of study treatment,

have both 1) a baseline measurement for the analysis endpoint and 2) at least one 
within-analysis-window (± 6 weeks) post-dose, post-randomization observation for 
the analysis endpoint, and

are PET positive. 
All available observations from the initial 104-week trial will be included in the relevant 
model-based FAS analyses. Observations from the long term trial will be included according 
to the principles outlined above, with the following additional requirement: the subject must 
have taken at least one dose of study medication within  the 28 days preceding the 104-week 
visit and within the 28 days following the 104-week visit.
The Modified Full Analysis Set (MFAS) population will be utilized for sensitivity analyses 
and is defined identically to the FAS population with one exception: patients will only be 
required to have either 1) a baseline measurement for the analysis endpoint or 2) at least one 
within-analysis-window (± 6 weeks) post-dose, post-randomization observation for the 
analysis endpoint, but not necessarily both.
The MFAS population will be utilized to conduct sensitivity analyses in this study for the 
primary endpoint (CDR-SB 30-Month CFB).
Though no Per-Protocol analyses are planned, a list of protocol violations/violators will be 
maintained. The final determination on protocol violations will be made prior to the final
unblinding of the database and will be documented in a separate memo.   
Subjects will be included in the treatment group to which they are randomized for the 
analysis of efficacy data using the FAS population.  
 
 
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Safety Analysis Populations
8.2.5
The All Subjects as Treated (ASaT) population will be used for the analysis of safety data in 
this study.  The ASaT population consists of all randomized subjects who received at least 
one dose of study treatment. Subjects will be included in the treatment group corresponding 
to the study treatment they actually received for the analysis of safety data using the ASaT 
population.  For most subjects this will be the treatment group to which they are randomized.  
Subjects who take incorrect study treatment for the entire treatment period will be included in 
the treatment group corresponding to the study treatment actually received.
At least one laboratory or vital sign measurement obtained subsequent to at least one dose of 
study treatment is required for inclusion in the analysis of each specific parameter.  To assess 
change from baseline, a baseline measurement is also required.
Statistical Methods
8.2.6
Statistical testing and inference for safety analyses are described in Section 8.2.8. The final 
analysis is expected to be carried out using SAS v9.3.
Statistical Methods for Efficacy Analyses
8.2.7
8.2.7.1
Primary Efficacy Analysis
The primary efficacy endpoint is the change from Baseline (CFB) in CDR-SB score at Week 
130. Basic summary statistics (means and standard deviations, as observed), will be 
calculated. 
A delayed start design will be used to support the potential disease modifying effect of MK-
8931 by comparing the 40 mg/40 mg arm to the Pbo/40 mg arm. However, due to increased 
variance and anticipated dropout rate over time, the study is not powered to demonstrate 
significance on these endpoints, even if significance was demonstrated at 24 months in the 
initial study.
The 12 mg/12 mg arm will be compared to the Pbo/40 mg arm in a similar fashion.
All available data from the initial 104-week trial will be utilized in the analyses, even that 
from subjects who do not continue into long term trial. It is possible that the 40 mg dose may 
be dropped for reasons due to safety, in which case all subjects would receive 12 mg. The 
primary comparison in this case would be between the 12 mg / 12 mg arm and the Pbo / 12 
mg arm (with any subjects receiving 40 mg excluded from the analysis).
A longitudinal ANCOVA model will be used on the change scores, with time treated as a 
categorical variable so as not to impose any restriction on the trajectory of the means over 
time. The analysis model includes treatment, time, the time-by-treatment interaction, APOE4 
genotype (APOE4 positive, APOE4 negative), gender, geographic region, and the use of 
acetylcholinesterase inhibitors at screening (Use, Do Not Use) as categorical terms, with age 
and baseline MMSE score as continuous covariates. The baseline value of the dependent 
 
 
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variable, as well as the baseline-by-time interaction term will also be included. Model-based 
estimates of the mean change scores and the mean treatment difference on the change scores 
will be provided, along with the corresponding confidence intervals and p-values for the 
mean treatment differences. An unstructured covariance matrix will be used to model the 
correlation among repeated measurements. 
Three supportive analyses will be conducted on the primary efficacy endpoint. These 
analyses will be conducted to assess the effect of 1) missing data using a pattern-mixture 
model “tipping-point” approach, which is intended to provide a measure of robustness in the 
(unobservable) event that a larger-than-expected proportion of the missing data be missing-
not-at-random (MNAR) 2) the use of off-regimen data after the subject has permanently 
discontinued trial medication or after the subject has initiated AChEIs and 3) analysis using 
the cLDA model on the MFAS population.
For the first sensitivity analyses (tipping-point), the model-based estimates of the mean 
treatment difference on the change scores, along with the corresponding confidence intervals 
and p-values will be provided for a range of c values which have been subtracted from the 
values imputed for the active arms (see Section 8.2.7.5 for more details). Of specific interest 
is the smallest c value that, for a given endpoint, transforms a “statistically significant” result
to a “non-statistically significant” result (per the pre-defined α-level used in the initial 104-
week trial).
For the second sensitivity analysis (excluding observations obtained after study medication 
discontinuation or after the initiation of AChEIs), the model-based estimates of the mean 
treatment difference on the change scores, along with the corresponding confidence intervals 
and p-values will be provided. 
For the third sensitivity analysis (cLDA model on the MFAS population), the analysis of the 
primary efficacy endpoint will be conducted using a constrained longitudinal data analysis 
(cLDA) method proposed by Liang and Zeger [28]. This model assumes a common mean 
across treatment groups at baseline and a different mean for each treatment at each of the 
post-baseline time points. The response vector consists of baseline and the values observed at 
each post-baseline time point. The model-based estimates of the mean treatment difference 
on the change scores, along with the corresponding confidence intervals and p-values will be 
provided as obtained using the cLDA model, with all of the same covariates that were 
included in the primary model (now excluding the terms for baseline and baseline-by-time 
interaction). An unstructured covariance model will be used.
 
 
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Table 6
Analysis Strategy for Primary Endpoints
Endpoint/Variable
(Description, Time Point)
Primary 
vs. 
Supportive 
Approach
Statistical Method
Analysis 
Population
Missing Data 
Approach
Primary Endpoint
CFB
in CDR-SB scores at 
130 Weeks
P
Longitudinal 
ANCOVA
FAS
Model-based
S
Longitudinal 
ANCOVA
FAS
Pattern-Mixture 
Model 
(Tipping Point)
S
Longitudinal 
ANCOVA (Exclude 
data collected after the 
introduction of AChEIs 
and/or study 
medication 
discontinuation)
FAS
Model-based
S
cLDA
MFAS
Model-Based
AChEIs= acetylcholinesterase Inhibitors; CFB=Change from baseline.
8.2.7.2
Exploratory Efficacy Analyses 
One exploratory endpoint is the time to progression to probable AD dementia as determined 
by investigator-diagnosis (noting that the formal adjudication process utilized in the initial 
104-week study, will not be utilized in the long-term safety study). All available data from 
the initial 104-week trial will be utilized in the analysis. A Cox proportional hazard model 
adjusting for APOE4 genotype (APOE4 positive, APOE4 negative), gender, geographic 
region, and the use of acetylcholinesterase inhibitors at screening (Use, Do Not Use) as 
categorical terms, with age and baseline MMSE score as continuous covariates will be used 
to compare the hazard functions of the 40 mg/40 mg arm to the Pbo/40 mg arm, as well as to 
compute the hazard ratios and the corresponding confidence intervals (CIs). Subjects who 
reach the maximum treatment duration will be considered as completers and will be censored 
at that timepoint.  
The 12 mg/12 mg arm will be compared to the Pbo/40 mg arm in a similar fashion.
If the analysis model fails to converge due to the presence of too many factors in the model 
(i.e., empty cells), then factors will be removed one at a time until the model does converge. 
Factors will be removed in the following order: geographic region, gender, use of 
acetylcholinesterase inhibitors at screening, and APOE4 genotype.
For all other continuous exploratory endpoints, the same model that is used for the primary 
endpoint will be used as were specified in Section 8.2.3.1. 
No sensitivity analyses will be conducted on any of the exploratory endpoints.
 
 
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8.2.7.3
Health Economic Endpoints 
The Modified RUD Lite will be evaluated by tabulating the counts and percentages of each 
living-arrangement category across the treatment arms and visits.
For HEA, the counts and percentages of each category of non-trial medical visit will be 
tabulated by treatment group and visit.
The EuroQoL Five Dimension Questionnaire (EQ-5D) will be evaluated by tabulating the 
counts and percentages of each health dimension by treatment group and visit. Basic 
summary statistics will also be computed for the assessment of subject health state (0-100 
scale) by treatment and visit.
8.2.7.4
Pharmacogenetic Analyses
The relationship between APOE genotype and the following clinical outcomes: CDR-SB, 
ADAS-Cog and ADCS-ADLMCI will be evaluated as an exploratory analysis.    
Additional exploratory pharmacogenetics (PGt) studies may be performed if significant 
Pharmacokinetic/Pharmacodynamic (PK/PD) relationships are observed or for certain 
adverse events.  Genomic markers of disease may also be investigated. Pharmacogenetic 
studies may use PK/PD results or clinical outcomes.  Any nominally significant PGt 
relationships to outcome will require validation in future clinical trials.
8.2.7.5
Accounting for Missing Data 
It is expected that Missing at Random and Missing Completely at Random (MAR/MCAR) 
mechanisms will underlie most of the missingness.  Reasons for discontinuation from the 
study may include lack of efficacy, adverse experiences, relocation, withdrawal of consent, 
protocol violations, and/or data processing issues. Missing data caused by relocation and data 
processing issues are likely to be MCAR. On the other hand, missing data caused by 
discontinuation due to lack of efficacy may belong to MAR because the discontinuation may 
depend on the observed efficacy outcomes. The MAR or MNAR mechanisms might each 
underlie the other reasons to some extent. If treatment in large part determines the loss of 
data for these other reasons (such as clinical or laboratory adverse experiences), the 
mechanism may be close to MAR because treatment assignment is an observed variable and 
included in the analysis model. Based on results from similarly-designed, previously-
conducted trials, missing data due to other reasons is relatively infrequent.  Of note, in the 
event that there are no missing data, the estimated treatment difference from the above cLDA 
model will be identical to that from a traditional longitudinal ANCOVA model which uses 
the baseline value as a covariate. 
 
 
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A pattern-mixture model based on the tipping-point approach will be used to assess the 
robustness of the primary analysis approach. For a given constant, c, the tipping point 
analysis is conducted in a fashion similar to that used in standard multiple imputation [29; 
30; 31], whereby m complete datasets are randomly generated using the original observed 
dataset. These m complete datasets are subsequently analyzed using the primary model, and 
the results of those analyses are then combined. The construction and analysis of these m
(=50) datasets requires four primary steps:
a.
Using a Markov Chain Monte Carlo method [32], make the observed dataset 
monotone-missing. This will be accomplished for each treatment group using “PROC 
MI”
within 
SAS 
9.3 
by 
utilizing
the 
options 
“mcmc 
chain=multiple 
impute=monotone;”, in conjunction with all of the covariates (excluding treatment) 
included in the primary analysis model. The random seed will be set equal to 
8931019. This step will generate m monotone-missing datasets. 
b. Applying parametric regression to the monotone-missing datasets, impute the missing 
values in a stepwise fashion starting with the first postdose timepoint. This will be 
accomplished for each treatment group using “PROC MI” within SAS 9.3 utilizing 
the option “monotone reg”, in conjunction with all of the covariates (excluding 
treatment) included in the primary analysis model. The random seed will be set equal 
to 8931019. This step will generate m complete datasets. 
c.
To implement the tipping-point aspect of the procedure, subtract a constant c from 
each of the imputed values of the active arms (to the detriment of active).
d. Analyze each of the post-imputation complete datasets using the primary model, 
obtaining point estimates for the mean of interest (e.g., change-from-baseline 
treatment difference at 104 weeks) and the associated variance.
This procedure will be repeated (using the same m imputed datasets) until the smallest c is 
found such that the “significant” result turns “non-significant” (i.e., p ≥ 0.02495). This 
tipping point value c provides a measure of robustness of the primary result. A relatively 
large value of c implies better robustness of the primary analysis against the impact of 
missing data in the study.  It is noted that when c=0 the tipping point analysis described 
above corresponds to an analysis conducted under the assumption that the missing data are 
MAR. For values of c larger than 0, the tipping point analyses do not assume that the missing 
values follow a MAR mechanism. In fact, the analysis is based on a special MNAR 
mechanism in which all missing data in the active arm are assumed to have a worse response 
 
 
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by a constant amount of c than the values would have had under MAR, while the missing 
data in the control group are assumed to be the same as that obtained under MAR.  
It may be necessary to adjust c, in order to calibrate between the two analysis approaches 
(ANCOVA vs. MI), should a value of c=0 yield a different p-value than is produced from the 
primary ANCOVA analysis model. This will be accomplished by subtracting the calibration 
value cprim from c, where cprim is the offset to be applied to the active arm, per the above MI 
approach, that will yield the same p-value as produced by the primary ANCOVA analysis.
8.2.7.6
Handling of Missing Items Within a Clinical Assessment
The final scores of the ADAS-Cog, ADCS-ADLMCI, NPI, MMSE, CDR-SB, CCS-2D, and 
CCS-3D are all constructed from multiple subquestions/tests within each assessment. It is 
possible that one or more subquestions/tests may be missing within each overall assessment. 
In this event, the last recorded score for this subquestion(s) will be carried forward from the 
most recent postdose visit. (Last Observation Carried Forward approach). In a similar 
fashion, missing baseline values will be carried over from the most recent screening visit, if 
available. Baseline/screening values will never be carried forward to impute missing 
postdose values. Due to the degenerative properties of AD, with subjects expected to worsen 
over time, an individual subquestion will not be carried forward for more than one visit. If 
the same subquestion is missing two visits in a row, then LOCF will be applied to the first 
missing visit and the subquestion will remain as missing for the second visit (with the total 
score to then be computed as missing). Further, the total score will be computed as missing if 
too many subquestions, prior to applying the LOCF approach, are missing (see endpoint-
specific details below). This single imputation approach allows the total score to be 
calculated using the strength of the other subquestions collected at that time, for that subject. 
The Sponsor believes this approach to be more accurate than either setting the entire score to 
missing or to imputing the worst possible score. More complicated missing data approaches 
are not thought to be warranted, since the amount of missing data within an assessment is 
expected to be extremely low.  
For Baseline ADCS-ADLMCI only (from the initial 104-week trial): Past experience indicates 
that some subquestions on the ADCS-ADLMCI may mistakenly be omitted at the time of 
administration. Should this occur at baseline, there will be no opportunity to employ the 
stated LOCF approach. To avoid a missing total score on the ADCS-ADLMCI (and the 
subsequent removal of the subject from the primary ADCS-ADLMCI population), the worst 
possible score for that subquestion will be imputed. Note that this imputation approach will 
only be implemented for ADCS-ADLMCI (given the relatively small impact of the individual 
subquestions on the overall score) and only at baseline. A total score will only be computed 
if the number of missing subtotals is strictly less than three.
Endpoint specific details are as follows:
ADAS-Cog and MMSE: The site will be instructed to enter the worst possible score if the 
subject is unwilling or unable to answer a subquestion due to reasons related to the area the 
subquestion is trying to address. If the subject is unable to answer a subquestion for some 
 
 
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other reason, then the site will be instructed to leave the subquestion as missing. For both the 
ADAS-Cog and the MMSE, a total score will be calculated if the original number (prior to 
applying LOCF) of missing subtotals is strictly less than three.  
CCS-3D: If no more than one test is missing within a domain(s), LOCF will be applied to 
that individual test. Values will not be carried forward for more than one visit. If more than 
one test is missing within a domain (prior to applying LOCF), then the overall z-score for 
that domain will be computed as missing. The overall CCS-3D will be computed as missing
if any domain score is missing. Note that, in general and unless otherwise noted, the 
application of LOCF to these individual tests is solely for the computation of the domain z-
scores and ultimately the CCS-3D. LOCF will not be applied to these individual tests for the 
analyses of the individual tests themselves (e.g., LOCF may be applied to the Delayed Word 
Recall test for the computation of the Episodic Memory domain z-score and ultimately the 
CCS-3D, but would not be applied for the purposes of analyzing the Delayed Word Recall 
component individually).
CCS-2D: If no more than one of the five component tests is missing, then LOCF will be
applied to that individual test, solely for the purposes of computing the total score. If more 
than one of the component tests is missing, then the total score will be computed as missing.
CDR-SB, ADCS-ADLMCI, and NPI: The CDR-SB, ADCS-ADLMCI, and NPI are all 
administered to the trial partner, not the subject, so no within-assessment missing data are 
expected (though missing subquestion data is still possible due to data entry error or errors in 
test administration). For ADCS-ADLMCI and NPI, a total score will be calculated if the 
original number of missing subtotals is strictly less than three. For CDR-SB, a total score will 
be calculated if the original number of missing subtotals is strictly less than two.
Statistical Methods for Safety Analyses
8.2.8
Subjects from all three arms (40 mg / 40 mg, 12 mg / 12 mg, Pbo / 40 mg) will be included in 
the safety analyses. Where applicable, treatment comparisons will be conducted between the 
40 mg / 40 mg and Pbo / 40 mg arms, as well as between the 12 mg / 12 mg and Pbo / 40 mg 
arms.
Safety and tolerability will be assessed by clinical review of all relevant parameters including 
AEs, laboratory tests, vital signs, and ECG measurements. The primary approach for all 
safety analyses will be an On Drug approach, i.e., one that includes only those observations
obtained from the first dose through 14 days after the last dose of study medication. A 
supportive approach
will include all post-treatment
observations, including
those 
observations obtained more than 14 days after the last dose of study medication.
The analysis of safety results will follow a tiered approach (Table 7).  The tiers differ with 
respect to the analyses that will be performed.  Safety parameters or adverse experiences of 
special interest that are identified a priori constitute “Tier 1” safety endpoints that will be 
subject to inferential testing for statistical significance with p-values and 95% confidence 
intervals provided for between-group comparisons. Other safety parameters will be 
 
 
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considered Tier 2 or Tier 3.  Tier 2 parameters will be assessed via point estimates with 95% 
confidence intervals provided for between-group comparisons; only point estimates by 
treatment group are provided for Tier 3 safety parameters.
Adverse experiences (specific terms as well as system organ class terms) and predefined 
limits of change in laboratory, vital signs, and ECG parameters (see Section 12.3) that are not 
pre-specified as Tier-1 endpoints will be classified as belonging to "Tier 2" or "Tier 3", based 
on the number of events observed. Membership in Tier 2 requires that at least 1% of the 
subjects in any treatment group exhibit the event; all other adverse experiences and 
predefined limits of change will belong to Tier 3.
The threshold of "at least 1%" was chosen because the expected number of subjects in the 
ASaT population is expected to be greater than 400 per treatment group. Thus an incidence 
of at least 1% in a treatment group translates to at least four subjects experiencing that event 
in the treatment group, which is the minimum number needed to attain statistical significance 
at α=0.05.   Because many 95% CIs may be provided without adjustment for multiplicity, the 
CIs should be regarded as a helpful descriptive measure to be used in review, not a formal 
method for assessing the statistical significance of the between-group differences in AEs and 
PDLCs.
Continuous measures such as changes from baseline in laboratory, vital signs, and ECG
parameters that are not pre-specified as Tier-1 endpoints will be considered Tier 3 safety 
parameters.  Summary statistics for baseline, on-treatment, and change from baseline values 
will be provided by treatment group in table format.
For this protocol, 1) microhemorrhage, superficial siderosis or macrohemorrhage; 2) 
vasogenic edema; 3) delirium; and 4) rash ECI (see Section 7.2.3.2 for definition) are 
considered as Tier 1 events.  The broad clinical and laboratory AE categories consisting of 
the percentage of subjects with any AE, a drug related AE, a serious AE, an AE which is 
both drug-related and serious, and who discontinued due to an AE will be considered Tier 2 
endpoints. A composite endpoint of hypopigmentation adverse events is defined based on the 
following preferred AE terms or equivalent:
(noting that MedDRA terms are subject to 
change over time): skin hypopigmentation, skin depigmentation, vitiligo, leukoderma, 
hypopigmentation of eyelid, and idiopathic guttate hypomelanosis. This composite AE of 
hypopigmentation will be considered as either a Tier 2 or Tier 3 AE, per the criteria for Tier 
2 AEs defined above. P-values (Tier 1 only) and 95% confidence intervals (Tier 1 and Tier 2) 
will be provided for between-treatment differences in the percentage of subjects with events; 
these analyses will be performed using the Miettinen and Nurminen method [27], an 
unconditional, asymptotic method.
The prespecified categories of suicidal ideation and behavior will be analyzed per the tiered 
analysis strategy outlined above, and will be considered as either Tier 2 or Tier 3 AEs, 
depending on the percent of events observed within each treatment group. Counts for each 
category will be based upon events observed during the assessment period (without 
consideration of prior history). 
 
 
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Safety analyses will only be based on subjects who treated in the long term trial. Unless 
otherwise noted, postdose data from the initial 104-week trial will not be analyzed with data 
from the long term trial.
Table 7
Analysis Strategy for Safety Parameters
Safety Tier
Safety Endpoint†
p-Value
95% CI for 
Treatment 
Comparison
Descriptive 
Statistics
Tier 1
Incident Microhemorrhage, superficial 
siderosis or macrohemorrhage in brain MRI 
scans
X
X
X
Incident Vasogenic edema
X
X
X
Delirium
X
X
X
Rash  ECI
X
X
X
Tier 2
Any AE
X
X
Any Serious AE
X
X
Any Drug-Related AE
X
X
Any Serious and Drug-Related AE
X
X
Discontinuation due to AE
X
X
Specific AEs, SOCs, or PDLCs‡ (incidence 
≥1% of subjects in one of the treatment 
groups)
X
X
Tier 3
Specific AEs, SOCs or PDLCs‡ (incidence 
<1% of subjects in all of the treatment 
groups)
X
Change from Baseline Results (Labs, ECGs, 
Vital Signs)
X
†Adverse Experience references refer to both Clinical and Laboratory AEs.
‡Includes only those endpoints not pre-specified as Tier 1 or not already pre-specified as Tier-2 endpoints.
Note: SOC=System Organ Class; PDLC=Pre-Defined Limit of Change; X  = results will be provided.
Summaries of Baseline Characteristics, Demographics, and Other Analyses
8.2.9
8.2.9.1
Demographic and Baseline Characteristics
The comparability of the treatment groups for each relevant characteristic will be assessed by 
the use of tables and/or graphs. No statistical hypothesis tests will be performed on these 
characteristics. The number and percentage of subjects screened, randomized, the primary 
reasons for screening failure, and the primary reason for discontinuation will be displayed.  
Demographic variables baseline characteristics, primary and secondary diagnoses, and prior 
and concomitant therapies will be summarized by treatment either by descriptive statistics or 
categorical tables.
 
 
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Multiplicity
8.2.10
In the initial 104-week trial, strong Type I error control is achieved through the utilization of
a Bonferroni approach in conjunction with a closed testing sequential approach. Specifically, 
a separate hypothesis family is created for each of the two active doses, with each hypothesis 
within a family tested sequentially at the α=0.02495 level.
As there are no formal hypotheses for the long term trial, there is no need for a formal 
multiplicity strategy. However, 97.51% CIs will be produced for all endpoints with 
corresponding hypotheses conducted under strong control from the initial 104-week trial, 
even though formal hypotheses are not defined in this long-term safety trial, and it is 
acknowledged that strong control is not present.
Sample Size and Power Calculations
8.2.11
8.2.11.1 Sample Size and Power for Efficacy Analyses
8.2.11.1.1 Parameter Estimates
Parameter estimates for the primary endpoint were obtained from the Alzheimer's Disease 
Neuroimaging Initiative (ADNI). Extrapolations out to 30 months (Week 130) were 
performed on the 24-month (Week 104) parameter assumptions used in the initial 104-week 
trial and these extrapolations are presented below in Table 8.
Table 8
Parameter Assumptions for CDR-SB
Endpoint
Baseline  
SD
30m  SD
30m CFB 
Mean
(130-Week 
Placebo/ MK-
8931 40 mg 
Progression 
Rate)
Corr(Base, 30m)
CDR-SB
0.86
3.05
2.13
0.359
Based on N=151 subjects from ADNI, Late MCIs with either CSF+ (tau/ab142 >= 0.39) or 
PET+ (pib >1.6), and MMSE>=24.
 
 
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8.2.11.1.2
Power Calculations
Power calculations for the change-from-baseline treatment difference at 30 months (Week 
130) were performed (via simulation) for CDR-SB even though there are no formal 
hypotheses for the endpoint in the long term trial.  As shown in Table 9 the hypothesis is
underpowered at Week 130, both marginally and when applying an informal sequential 
testing approach. Specifically, it is possible that formal statistical significance may be 
observed in the initial 104 week trial (under the prespecified multiplicity approach), while 
nominal marginal significance (ie, p-value < 0.02495) fails to be observed at Week 130, even 
if the true underlying effect of MK-8931 continues to increase. This is due to the assumed 
increased variance and dropout rate over time, with 90% of subjects who complete the base 
study assumed to continue on into the extension.
Table 9
Power Calculations (MK-8931 40 mg / MK-8931 40 mg vs. Placebo / MK-
8931 40 mg)
Marginal Probability†
(%)
CDR-SB at Week 130
73.9 
Sequential Probability
Success‡ for CDR-SB at Week 104 and CDR-SB at Week 130
73.4
Conditional Probability
Success‡ for CDR-SB at Week 130 given success on CDR-SB 
at Week 104
76.1
† Marginal power calculations at Week 130 do not require success at Week 104.
‡ 40 mg dose only
Calculations are based on N=1350 randomized (450 subjects/arm) incorporating the assumed 
dropout rate of 25% at Week 104 and 37% at Week 130 ( α = 0.02495).
Subgroup Analyses and Effect of Baseline Factors
8.2.12
Subgroup analyses will be conducted on CDR-SB, CCS-3D, ADCS-ADLMCI at Week 130.  
The consistency of treatment effect across various subgroups will be assessed through the 
computation of within group summary statistics (model-based and as-observed), along with 
nominal 95% CIs. Further, model-based between-group treatment differences (or hazard 
ratios, as appropriate) and the corresponding 95% CIs will be constructed for those 
comparisons (active/active vs. placebo/active), for which both treatment groups within the 
subgroup level have at least 75 subjects (roughly 15% of subjects randomized).  No formal 
statistical testing of the treatment by subgroup interactions will be performed.  The following 
subgroups will be examined:

Gender (Male, Female);

Age (< 65, ≥ 65 years of age);

Race (white, black, Asian, other);

Ethnicity (Hispanic, Not Hispanic);
 
 
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
Geographic Region (US/Canada, Europe/Australia/New Zealand, Japan, Rest of 
World);

APOE Genotype (APOE 4 positive, APOE 4 negative);

Disease Severity via MMSE at Screening (24-26, 27-30)

PET/CSF status at Screening (PET+/CSF+, PET+/CSF-, PET+/CSF Unknown, PET-
/CSF+)

CSF evaluation at Screening (CSF evaluated, CSF not evaluated)

AD Treatment at Screening (use of AChEI or memantine, no use of AChEI or 
memantine)

Vitamin E use at Screening (0-400 IU/day, >400 IU/day)
Interim Analyses
8.2.13
The independent eDMC will routinely evaluate unblinded safety analyses of all trial subjects 
while the initial 104-week trial is blinded. Additional safety analyses may be conducted 
throughout the trial as requested by the eDMC. The sponsor will be unblinded after 
completion of the initial 104-week trial.
Compliance/Medication Adherence
8.2.14
In this study, as part of the routine recording of the amount of study treatment taken by each 
subject, the number of tablets remaining in study packaging will be counted, reviewed, and 
recorded at regular intervals.  These results will be used to calculate subject compliance. A 
day within the study will be considered an “On-Therapy” day if the subject takes one tablet. 
For a subject who is followed for the entire study period, the “Number of Days Should be on 
Therapy” is the total number of days from the subject’s first dose to the last scheduled day 
for treatment administration for that subject.  For a subject who discontinued from the study 
permanently, the “Number of Days Should be on Therapy” is the total number of days from 
the subject’s first dose to the date of the last dose of study medication.
For each subject, percent compliance will then be calculated using the following formula:
Therapy
on 
be
Should
Days
of
Number 
Therapy
on 
Days
of
Number 
Compliance
Percent 

x 100.
Summary statistics will be provided on percent compliance by treatment group for the FAS
population.
 
 
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Extent of Exposure
8.2.15
Basic summary statistics for the number of doses taken by timeframe (e.g., 0-3 months, 4-6 
months) as well as overall, will be provided by treatment group. Cumulative measures of 
exposure (e.g., Took at least 1 dose, Took at least 30 doses) will also be provided by 
treatment group.
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.
Clinical Supplies will be provided by the Sponsor as summarized in Table 10.
Table 10
Product Descriptions
Product Name 
& Potency
Dosage Form
MK-8931 12 mg
tablet
MK-8931 40 mg
tablet
Packaging and Labeling Information
9.2
Clinical supplies will be affixed with a clinical label in accordance with regulatory 
requirements.
Medication will be provided in bottles.
At the visits specified in the Trial Flow Chart (Section 6), the site will dispense medication 
using the IVRS/IWRS system. The site may provide a ‘calendar sleeve’ that wraps around 
itself and can slide up and down the bottle to expose the medication label as required. The 
pull off tab on the ‘calendar sleeve’ offers a visual reminder to help subjects/caregiver take 
their trial medication. The intention of the sleeves is to assist the subject/caregiver/trial
partner to remember when the subject missed a dose. The sponsor will provide the sleeve to 
the sites and site personnel will slide them onto each bottle. 
Additional instructions regarding the calendar sleeves will be provided to sites.  
When the subject/caregiver/trial partner returns to the clinical site, a physical pill count will 
be utilized for drug accountability and recorded in the eCRF.
 
 
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Clinical Supplies Disclosure
9.3
The emergency unblinding call center will use the randomization schedule for the trial to 
unblind subjects and to unmask treatment identity. The emergency unblinding call center 
should only be used in cases of emergency (see Section 7.1.4.2). In the event that the 
emergency unblinding call center is not available for a given site in this trial, the central 
electronic randomization system (IVRS/IWRS) should be used in order to unblind subjects 
and to unmask treatment/vaccine identity.
The Sponsor will not provide random 
code/disclosure envelopes or lists with the clinical supplies.
Treatment identification information is to be unmasked ONLY if necessary for the welfare of 
the subject.  Every effort should be made not to unblind the subject unless necessary. 
In the event that unblinding has occurred, the circumstances around the unblinding (e.g., date 
and reason) must be documented promptly, and the Sponsor Clinical Director notified as 
soon as possible.  Once an emergency unblinding has taken place, the principal investigator, 
site personnel, and Sponsor personnel may be unblinded so that the appropriate follow-up 
medical care can be provided to the subject.
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.
In order to align with regional standard medical practice, trial sites in Japan are allowed to 
dispense subjects’ treatment kits between drug dispensing visits identified in the protocol. 
Study medication will continue to be dispensed using the Interactive Voice Response 
System; however, study sites may increase the frequency with which study medication is 
dispensed to study participants in order to follow institutional regulations and/or local 
standard of care. All trial sites using partial dispensing options must follow the Merck 
guidance provided in the “Procedure for Investigational Medicinal Product (IMP) 
Management” document.
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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Standard Policies
9.6
Trial site personnel will have access to a central electronic randomization system 
(IVRS/IWRS system) to allocate subjects, to assign drug to subjects and to manage the 
distribution of clinical supplies. Each person accessing the IVRS system must be assigned an 
individual unique PIN.  They must use only their assigned PIN to access the system, and they 
must not share their assigned PIN with anyone.
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:

name, address, telephone number and e-mail address;

hospital or clinic address and telephone number;

curriculum vitae or other summary of qualifications and credentials; and
 
 
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
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.
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 or through a secure password-protected electronic portal 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 
 
 
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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.
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 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 
 
 
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investigator must consult with and obtain written approval by the Sponsor prior to discarding 
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.
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.    
 
 
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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 
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 by the Sponsor.
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 
 
 
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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, 
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. Dubois B, Feldman HH, Jacova C, Dekosky ST, Barberger-Gateau P, Cummings J, 
Delacourte A, Galasko D, Gauthier S, Jicha G, Meguro K, O'brien J, Pasquier F, Robert 
P, Rossor M, Salloway S, Stern Y, Visser PJ, Scheltens P. Research criteria for the 
diagnosis of Alzheimer's disease: revising the NINCDS-ADRDA criteria. Lancet Neurol. 
2007 Aug;6(8):734-46.
2. Dubois B, Feldman HH, Jacova C, Cummings JL, Dekosky ST, Barberger-Gateau P, 
Delacourte A, Frisoni G, Fox NC, Galasko D, Gauthier S, Hampel H, Jicha GA, Meguro 
K, O'Brien J, Pasquier F, Robert P, Rossor M, Salloway S, Sarazin M, de Souza LC, 
Stern Y, Visser PJ, Scheltens P. Revising the definition of Alzheimer's disease: a new 
lexicon. Lancet Neurol. 2010 Nov;9(11):1118-27.
 
 
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3. Forsberg A, Engler H, Almkvist O, Blomquist G, Hagman G, Wall A, Ringheim A, 
Långström B, Nordberg A. PET imaging of amyloid deposition in patients with mild 
cognitive impairment. Neurobiol Aging. 2008 Oct;29(10):1456-65.
4. Okello A, Koivunen J, Edison P, Archer HA, Turkheimer FE, Någren K, Bullock R, 
Walker Z, Kennedy A, Fox NC, Rossor MN, Rinne JO, Brooks DJ. Conversion of 
amyloid positive and negative MCI to AD over 3 years: an 11C-PIB PET study. 
Neurology. 2009 Sep 8;73(10):754-60.
5. Wolk DA, Price JC, Saxton JA, Snitz BE, James JA, Lopez OL, Aizenstein HJ, Cohen 
AD, Weissfeld LA, Mathis CA, Klunk WE, De-Kosky ST. Amyloid imaging in mild 
cognitive impairment subtypes. Ann Neurol. 2009 May;65(5):557-68.
6. Hansson O, Zetterberg H, Buchhave P, Londos E, Blennow K, Minthon L. Association 
between CSF biomarkers and incipient Alzheimer's disease in patients with mild 
cognitive impairment: a follow-up study. Lancet Neurol. 2006 Mar;5(3):228-34.
7. Mattsson N, Zetterberg H, Hansson O, Andreasen N, Parnetti L, Jonsson M, Herukka SK, 
van der Flier WM, Blankenstein MA, Ewers M, Rich K, Kaiser E, Verbeek M, Tsolaki 
M, Mulugeta E, Rosén E, Aarsland D, Visser PJ, Schröder J, Marcusson J, de Leon M, 
Hampel H, Scheltens P, Pirttilä T, Wallin A, Jönhagen ME, Minthon L, Winblad B, 
Blennow K. CSF biomarkers and incipient Alzheimer disease in patients with mild 
cognitive impairment. JAMA. 2009 Jul 22;302(4):385-93.
8. Vemuri P, Wiste HJ, Weigand SD, Shaw LM, Trojanowski JQ, Weiner MW, Knopman 
DS, Petersen RC, Jack CR Jr; Alzheimer's Disease Neuroimaging Initiative. MRI and 
CSF biomarkers in normal, MCI, and AD subjects: predicting future clinical change. 
Neurology. 2009 Jul 28;73(4):294-301.
9. Visser PJ, Verhey F, Knol DL, Scheltens P, Wahlund LO, Freund-Levi Y, Tsolaki M, 
Minthon L, Wallin AK, Hampel H, Bürger K, Pirttila T, Soininen H, Rikkert MO, 
Verbeek MM, Spiru L, Blennow K. Prevalence and prognostic value of CSF markers of 
Alzheimer's disease pathology in patients with subjective cognitive impairment or mild 
cognitive impairment in the DESCRIPA study: a prospective cohort study. Lancet 
Neurol. 2009 Jul;8(7):619-27.
10. Aisen PS, Andrieu S, Sampaio C, Carrillo M, Khachaturian ZS, Dubois B, Feldman HH, 
Petersen RC, Siemers E, Doody RS, Hendrix SB, Grundman M, Schneider LS, Schindler 
RJ, Salmon E, Potter WZ, Thomas RG, Salmon D, Donohue M, Bednar MM, Touchon J, 
Vellas B. Report of the task force on designing clinical trials in early (predementia) AD. 
Neurology. 2011;76:280–286.
11. Cedarbaum JM, Jaros M, Hernandez C, Coley N, Andrieu S, Grundman M, Vellas B; 
Alzheimer's Disease Neuroimaging Initiative. Rationale for use of the Clinical Dementia 
Rating Sum of Boxes as a primary outcome measure for Alzheimer's disease clinical 
trials. Alzheimers Dement. 2012 May 31. [Epub ahead of print]
 
 
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12. McKhann G, Drachman D, Folstein M, Katzman R, Price D, Stadlan EM. Clinical 
diagnosis of Alzheimer's disease: report of the NINCDS-ADRDA Work Group under the 
auspices of Department of Health and Human Services Task Force on Alzheimer's 
Disease. Neurology. 1984 Jul;34(7):939-44.
13. Becker RE, Greig NH. Alzheimer's disease drug development: old problems require new 
priorities. CNS Neurol Disord Drug Targets. 2008 Dec;7(6):499-511.
14. Becker RE, Greig NH.  Alzheimer's disease drug development in 2008 and beyond: 
problems and opportunities. Curr Alzheimer Res. 2008 Aug;5(4):346-57.
15. Hugues CP, Berg L, Danziger WL et al : A new clinical scale for the staging of dementia. 
British Journal of Psychiatry 1982;140:566-572.
16. Mohs R, Knopman D, Petersen R, Ferris S, Ernesto C, Grundman M, Sano M, 
Bieliauskas L, Geldmacher D, Clark C, Thal L and the ADCS. Development of Cognitive 
Instruments for Use in Clinical Trials of Antidementia Durgs: Additions to the 
Alzheimer’s Disease Assessment Scale That Broadens its Scope. Alzheimer’s Disease 
and Associated Disorders, 1997; 11(S2):S13-21.
17. Benton AL, Hamsher KdeS. Multilingual Aphasia Examination (2nd ed). AJA 
Associates, Inc., Iowa City, 1989.
18. Reitan RM. The relation of the Trail Making Test to organic brain damage.  Journal of 
Consulting Psychology, 1955; 19:393-394.
19. Reitan RM & Wolfson D. The Halstead-Reitan Neuropsychological Battery: Theory and 
clinical interpretation, Second Edition. Tucson, AZ: Neuropsychology Press, 1993.
20. Morris JC, Heyman A, Mohs RC, Hughes JP, van Belle G, Fillenbaum G, Mellits ED, 
Clark C. The Consortium to Establish a Registry for Alzheimer’s Disease (CERAD). Part 
I. Clinical and neuropsychological assessment of Alzheimer’s disease. Neurology, 1989; 
39:1159-65.
21. Wechsler D. Wechsler Adult Intelligence Scale, Third Edition. New York:  The 
Psychological Corporation, 1997.
22. Galasko, D.; Bennett, D.; Sano, M.; Ernesto, C.; Thomas, R.; Grundman, M.; Ferris, S.; 
and the ADCS.  An Inventory to Assess Activities of Daily Living for Clinical Trials in 
Alzheimer’s Disease.  Alzheimer’s Disease and Associated Disorders, 1997.  Volume 
11(2): S33-S39.
23. Folstein MF, Folstein SE, McHugh PR. “Mini-Mental State”. A practical method for 
grading the cognitive state of patients for the clinician. J Psychiatr Res, 1975; 12(3):189-
198.
 
 
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24. Posner, K.; Brent, D.; Lucas, C.; Gould, M.; Stanley, B.; Brown, G.; Fisher, P.; Zelazny, 
J.; Burke, A.; Oquendo, M.; Mann, J. “Columbia-Suicide Severity Rating Scale” January 
14, 2009
25. Cummings JL, Mega M, Gray K, Rosenberg-Thompson S, Carusi DA, Gornbein J. The 
Neuropsychiatric Inventory: comprehensive assessment of psychopathology in dementia. 
1994; 44(12):2308-14.
26. Inouye SK, van Dyck CH, Alessi CA, Balkin S, Siegal AP, Horwitz RI. Clarifying 
confusion: the confusion assessment method. A new method for detection of delirium. 
Ann Intern Med. 1990 Dec 15;113(12):941-8.
27. Miettinen O. and Nurminen M. Comparative Analysis of Two Rates. Statistics in 
Medicine, 1985; 4: 213-226.
28. Liang K, Zeger, S. Longitudinal data analysis of continuous and discrete responses for 
pre-post designs. Sankhyā: The Indian Journal of Statistics. 2000;62(Series B, Pt. 1):134-
148.
29. Rubin, D. B. (1987) Multiple Imputation for Nonresponse in Surveys. John Wiley: NY.
30. Ratitch B, O’Kelly, M, Tosiello, R. “Missing data in clinical trials: from clinical 
assumptions to statistical analysis using pattern mixture models.” Pharmaceutical 
Statistics, 2013; 12: 337–347.
31. SAS Institute Inc. 2011. SAS/STAT® 9.3 User’s Guide. Cary, NC: SAS Institute Inc. 
(Chapter 57).
32. Schafer, J.L. (1997) Analysis of Incomplete Multivariate Data. Chapman & Hall:London.
33. Barnard J, Rubin DB. Small-sample degrees of freedom with multiple imputation. 
Biometrika, 1999; 86: 948–55.
34. Haybittle JL. Repeated assessment of results in clinical trials of cancer treatment. Br J 
Radiol. 1971 Oct;44(526):793-7.
35. Peto R, Pike MC, Armitage P, Breslow NE, Cox DR, Howard SV, Mantel N, McPherson 
K, Peto J, Smith PG. Design and analysis of randomized clinical trials requiring 
prolonged observation of each patient. I. Introduction and design. Br J Cancer. 1976 
Dec;34(6):585-612.
36. Salloway S, Sperling R, Gilman S, Fox NC, Blennow K, Raskind M, Sabbagh M, Honig 
LS, Doody R, van Dyck CH, Mulnard R, Barakos J, Gregg KM, Liu E, Lieberburg I, 
Schenk D, Black R, Grundman M; Bapineuzumab 201 Clinical Trial Investigators. A 
phase 2 multiple ascending dose trial of bapineuzumab in mild to moderate Alzheimer 
disease. Neurology. 2009 Dec 15;73(24):2061-70.
 
 
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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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Approximate Blood/Tissue Volumes Drawn/Collected by Trial Visit and by Sample Types
12.2
Trial Visit (continuing 
from the initial 104-week 
trial; Part I)
Visit 13
Visit 14
Visit 15
Visit 16
Visit 18
Visit 20
Visit 22
Visit 24
Scheduled Week (based on 
date of randomization in 
initial 104-week trial; Part I)
108
117
130
156
208
260
312
364
Blood Parameter
Approximate Blood Volume (mL)
Hematology
2
2
2
2
2
2
2
2
Serum/Plasma Chemistry
5
5
5
5
5
5
5
5
Expected Total (mL)
7
7
7
7
7
7
7
7
 
 
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Predefined Limits of Change Criteria 
12.3
Table 1
Predefined Limits of Change Criteria for Laboratory Data
Laboratory Test
Criteria† as a % of a Limit of
Normal Range
Hematology
Hematocrit (M)
≤94.9% LLN
Hematocrit (F)
≤94.1% LLN
Hemoglobin (M)
≤90.5% LLN
Hemoglobin (F)
≤81.9% LLN
WBC
≤64.2% LLN
≥149.0% ULN
Neutrophils
≤37.0% LLN
Eosinophils
≥147.0% ULN
Platelets
≤57.7% LLN
≥177.7%ULN
Hepatic Function
Bilirubin
≥166.7% ULN
Alkaline Phosphatase
≥300% ULN
SGOT
≥300% ULN
SGPT
≥300% ULN
Renal Function
Creatinine
≥142.9% ULN
Clinical Chemistry
Sodium
≤94.7% LLN
≥105.4% ULN
Potassium
≤88.2% LLN
≥111.1% ULN
† A laboratory value must represent a worsening from baseline (i.e., 
be more abnormal in the direction of interest) to meet the definition.
LLN=Lower limit of normal.
ULN=Upper limit of normal.
 
 
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Table 2
Predefined Limits of Change Criteria for Vital Signs,
Weight, and Temperature
Measurement
Criteria
Systolic blood 
≥180 mm Hg and ≥20 mm Hg increase from baseline
  pressure
≤90 mm Hg and ≥20 mm Hg decrease from baseline
Diastolic blood 
≥105 mm Hg and ≥15 mm Hg increase from baseline
  pressure
≤50 mm Hg and ≥15 mm Hg decrease from baseline
Pulse
≥120 bpm and ≥15 bpm increase from baseline
≤50 bpm and ≥15 bpm decrease from baseline
Weight
≥7 % increase from baseline
≥7 % decrease from baseline
Temperature
≥101°F and ≥2°F increase from baseline (≥38.3°C and 
≥1°C increase from baseline)
Respiratory rate
> 25 or increase of  ≥10 (per minute) from baseline
< 5 or decrease of  ≥10 (per minute) from baseline
Table 3
Predefined Limits of Change Criteria for ECGs
Measurement
Criteria
QTc 
Interval
Fridericia
Prolongation compared to baseline ≥30 to ≤60 msec
Prolongation compared to baseline >60 msec
Value ≥500 msec
 
 
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List of Abbreviations 
12.4
Term
Definition
A
amyloid 
AChEI
Acetylcholinesterase Inhibitors
AD
Alzheimer’s Disease
ADAS-Cog
Alzheimer’s Disease Assessment Scale Cognitive Subscale
ADCS-ADLMCI
Alzheimer’s Disease Cooperative Study Activities of Daily Living 
Inventory (Mild Cognitive Impairment version)
ADL
Activities of Daily Living
ADNI
Alzheimer's Disease Neuroimaging Initiative
AE
Adverse Event
ALT
Alanine aminotransferase (SGPT)
aMCI
Amnestic Mild Cognitive Impairment
ANCOVA
Analysis of Covariance
APOE
Apolipoprotein E
APP
Amyloid Precursor Protein
ASaT
All Subjects as Treated
ARWMC
Age-related white matter changes
AST
Aspartate aminotransferase (SGOT)
BACE
-site APP cleaving enzyme
βhCG
β-Human Chorionic Gonadotropin
BMI
Body Mass Index
BSA
Body Surface Area
BUN
Blood Urea Nitrogen
CAC
Clinical Adjudication Committee
CAM
Confusion Assessment Method
CBC
Complete Blood Count
CCS-2D
Composite Cognition Score-2 Domain
CCS-3D
Composite Cognition Score-3 Domain
CDR
Clinical Dementia Rating
CDR-SB
Clinical Dementia Rating Sum of Boxes
CDx
Companion Diagnostic
CFB
Change from Baseline
CFR
Code of Federal Regulations
CI
Confidence Interval
cLDA
Constrained Longitudinal Data Analysis
COWAT
Controlled Oral Word Association Test;
CSF
Cerebrospinal Fluid
CSR
Clinical Study Report
C-SSRS
Columbia Suicide Severity Rating Scale
CVF
CERAD Verbal Fluency
CYP
Cytochrome P450
DNA
Deoxyribonucleic Acid
DMC
Data Monitoring Committee
DRESS
Drug Reaction with Eosinophilia and Systemic Symptoms
DSM-IV-TR
Diagnostic and Statistical Manual of Mental Disorders, 4th 
Edition, Text Revision
DSC
Digit Symbol-Coding Test
ECG
Electrocardiogram
ECI
Events of Clinical Interest
eCRF
Electronic Case Report Form
 
 
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Term
Definition
eDMC
External (to Sponsor) Data Monitoring Committee
EIA
Enzyme immunoassay
EQ-5D
EuroQol Five Dimension Questionnaire
EOC
Executive Oversight Committee
ETDRS
Early Treatment Diabetic Retinopathy Study
EU
European Union
FAS
Full Analysis Set
FBR
Future Biomedical Research
FDA
Food and Drug Administration, USA
FSH
Follicle Stimulating Hormone
GCP
Good Clinical Practice
HEA
Health Economic Assessment
HLA 
Human Leukocyte Antigen
IB
Investigator’s Brochure
ICF
Informed Consent Form
ICH
International 
Conference 
on 
Harmonisation 
of 
Technical 
Requirements for Registration of Pharmaceuticals for Human Use
ICMJE
International Committee of Medical Journal Editors
ID
Identification
IEC
Independent Ethics Committee
IMP
Investigational Medicinal Product
IND
Investigational New Drug Application; legal instrument in the 
USA that allows trial of unapproved, investigational new drugs in 
human subjects
Investigational 
Product
The drug, biologic, and/or device being investigated in the current 
trial
IRB
Institutional Review Board
IU
International Units
IVRS
Interactive Voice Response System
IWRS
Interactive Web Response System
LDH
Lactate Dehydrogenase
LFT
Liver Function Test
LOCF
Last Observation Carried Forward
MAO
Monoamine Oxidase
MAR
Missing at Random
MCAR
Missing Completely at Random
MCI
Mild Cognitive Impairment
MMSE
Mini-Mental State Examination
MNAR
Missing Not at Random
MRI
Magnetic Resonance Imaging
mSv
millisievert
NINCDS-ADRDA
National Institute of Neurological and Communicative Diseases 
and Stroke/Alzheimer's Disease and Related Disorders Association
NMDA
N-Methyl-D-Aspartate
NPI
Neuropsychiatric Inventory
PD
Pharmacodynamic
PDLC
Pre-Defined Limit of Change
PET
Positron Emission Tomography
PGt
Pharmacogenetic
PK
Pharmacokinetic
PK/PD
Pharmacokinetic/Pharmacodynamic 
 
 
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Term
Definition
PT
Prothrombin Time
p-tau
Phosphorylated Microtubule-Associated Protein Tau
RBC
Red Blood Cell
RNA
Ribonucleic Acid
RPE
Retinal Pigment Epithelium
RUD Lite
Resource Utilization in Dementia Lite Questionnaire
SAE
Serious Adverse Event
(S)AE
All adverse events, including serious adverse events
SAC
Scientific Advisory Committee
SAP
Statistical Analysis Plan
sAPP
N-terminal fragment secreted after -secretase cleavage of APP
SGOT
Serum Glutamic Oxaloacetic Transaminase (AST)
SGPT
Serum Glutamic Pyruvic Transaminase (ALT)
siDMC
Standing Internal (to Sponsor) Data Monitoring Committee
SOC
System Organ Class
T-BIL
Total Bilirubin
TC
Telephone Contact
Term
Termination
THV
Total hippocampal volume
TSH
Thyroid Stimulating Hormone
Tx
Treatment
UGT1A1
Uridine diphosphate glucuronosyltransferase 1A1
ULN
Upper Limit of Normal
UV
Unscheduled Visit
USA
United States of America
WBC
White Blood Cell
 
 
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13.0 SIGNATURES
Sponsor's Representative
13.1
TYPED NAME                                 SIGNATURE                                   DATE
_________________________      ____________________________     __________
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                                 SIGNATURE                                   DATE
_________________________      ____________________________     __________
 
 
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