A Randomized, Placebo Controlled, Parallel-Group, Double Blind Efficacy and Safety Trial of MK-8931 With a Long Term Double-Blind Extension in Subjects With Mild to Moderate Alzheimer's Disease (Protocol No. MK-8931-017-10)(Also Known as SCH 900931, P07738)
Phase: PHASE2
Conditions: Alzheimer's Disease
Sponsor: Merck Sharp & Dohme LLC

Official Protocol Title: 
NCT number: 
NCT01739348  
Document Date: 
01-AUG-2016
A Parallel-Group, Double Blind Long Term Safety Trial of MK-8931
in Subjects with Alzheimer’s Disease. (Protocol No. MK-8931-017-
21) (also known as SCH 900931, P07738)

SCH 900931 OR MK-8931
PAGE 1
PROTOCOL NO. P07738 OR 017-21
PROTOCOL
01 AUG 2016
1.0 TITLE PAGE
Abbreviated Title
A Long Term Safety Trial of MK-8931 in AD (EPOCH)
Title
A Parallel-Group, Double Blind Long Term Safety Trial of MK-8931 
in Subjects with Alzheimer’s Disease.  (Protocol No. MK-8931-017-
21) (also known as SCH 900931, P07738)
Sponsor
Merck Sharp & Dohme Corp., a subsidiary of Merck & Co., Inc.
Sponsor’s Address
One Merck Drive
P.O. Box 100
Whitehouse Station, NJ 08889-0100, U.S.A.
IND No.
110,186
EudraCT No.
2015-000616-18
Trial Physician/Director
Phase
2/3
Date of Finalization of This Current 
Version of the Protocol
01-AUG-2016 – Amendment 017-21  (France Specific )
Previous Versions of the Protocol
26-JUL-2016– Amendment No.20 (Country Specific)
22-JUL-2016– Amendment No.19 (France Specific)
21-JUL-2016– Amendment No.18 (Country Specific)
28-JUN-2016 – Amendment No.17
11-Sep-2015 – Amendment 017-16 (France Specific)
26 JUN 2015 – Amendment 017-15  France Specific
24 APR 2015 - Amendment 017-14 Country Specific
09 APR 2015 - Amendment 017-13
05 MAR 2015– Amendment 017-12 Country Specific
26 FEB 2015 - Amendment 017-11 Country Specific
18 DEC 2014 - Amendment 017-10
08 AUG 2014 - Amendment 017-09 Country Specific
11 FEB 2014 - Amendment #5 (017-08)
14 AUG 2013 - Amendment #4 (017-07)
08 NOV 2012 - Amendment #3 Brazil Version 1 (017-06)
26 SEP 2012 - Amendment #3 (017-05)
23 JUL 2012 - Amendment #2 Brazil Version 2 (017-04)
23 JUL 2012 - Amendment #2 Brazil Version 1 (017-03)
20 JUN 2012 - Amendment #2 (017-02)
31 MAY 2012 - Amendment #1 (017-01)
19 JAN 2012 - Initial Protocol (017-00)
Protocol Template Approval Date
28 MAR 2012
C O N F I D E N T I A L
TRIAL PROTOCOL
THIS CONFIDENTIAL INFORMATION ABOUT AN INVESTIGATIONAL DRUG OR PRODUCT IS PROVIDED 
FOR THE EXCLUSIVE USE OF INVESTIGATORS OF THIS DRUG OR PRODUCT AND IS SUBJECT TO 
RECALL AT ANY TIME. THE INFORMATION IN THIS DOCUMENT MAY NOT BE DISCLOSED UNLESS 
SUCH DISCLOSURE IS REQUIRED BY APPLICABLE LAW OR REGULATIONS.  SUBJECT TO THE 
FOREGOING, THIS INFORMATION MAY BE DISCLOSED ONLY TO THOSE PERSONS INVOLVED IN THE 
TRIAL WHO HAVE A NEED TO KNOW, WITH THE OBLIGATION NOT TO FURTHER DISSEMINATE THIS 
INFORMATION.  THESE RESTRICTIONS ON DISCLOSURE WILL APPLY EQUALLY TO ALL FUTURE 
ORAL OR WRITTEN INFORMATION SUPPLIED TO YOU BY THE SPONSOR OR ITS AFFILIATES OR 
REPRESENTATIVES THAT IS DESIGNATED AS “PRIVILEGED” OR “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.
PPD
 
 
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PROTOCOL
01 AUG 2016
SUMMARY OF CHANGES
PRIMARY REASON FOR THIS AMENDMENT:
This study (PN017-21) is a long term safety extension of the base protocol, PN017-19 for use in locations that require 
separate documents.  For locations that do not require separate documents, protocol PN017-17 is used, which includes 
the base protocol and the extension in one protocol.
Section 
Number(s)
Section Title(s)
Description of Change(s)
Rationale
2.2
7.1
7.6
Trial Flow Chart
Overall Trial Design
Trial Procedures
Added pharmacokinetic (PK) visits at 
weeks 4 and 13 of the extension (ie, 
weeks 82 and 91 from randomization 
visit in main study)
Added PK sample collection to trial 
procedures.
Added two PK collections to this 
extension protocol to facilitate robust PK 
and PK/PD modeling for the MK-8931 
program. In the base protocol, both 
plasma and dried blood spot (DBS)
samples were collected initially for 
assessment of PK, but plasma sampling 
was dropped when preliminary analyses 
indicated that DBS samples were 
sufficient.  However, due to quality 
issues identified with some DBS 
samples in the base protocol; dual 
sample collection (plasma and DBS) is 
being reinstated for the PN017 
protocols. These two additional PK time 
points are being added to offset some of 
the collected DBS samples with quality 
issues. 
2.0
Synopsis
Added note that Sponsor will be 
unblinded following the completion of the 
initial 78-week trial but some Sponsor 
Maintaining Sponsor blinding for efficacy 
data collected at 24 months in  the long-
term trial is needed to support the 
 
 
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PROTOCOL
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Section 
Number(s)
Section Title(s)
Description of Change(s)
Rationale
5.3
Trial Design 
Rationale
personnel will remain blinded during the 
long-term trial, as necessary, to support 
the conduct of the trial and the collection 
of efficacy data.
primary efficacy objective for the long-
term trial
 
 
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PROTOCOL
01 AUG 2016
ADDITIONAL CHANGE(S) FOR THIS AMENDMENT:
Section 
Number(s)
Section Title(s)
Description of Change(s)
Rationale
2.2
Trial Flow Chart for 
Long Term Safety 
Trial
Added the following to footnote ‘j’ for 
dermatology: “or who have >6 month 
gap in study therapy between Visit 10 
and 10B”.
Text in footnote was inadvertently 
missed out from previous amendment 
2.2
Trial Flow Chart for 
Long Term Safety 
Trial
Added the following text to footnote “b” 
in flowchart: “However, if waiting for test 
results from Visit 10B is necessary in 
the judgment of the investigator, Visit 
10B procedures can be performed over 
more than one visit but ideally should 
not exceed a 2-week timeframe. Trial 
medication is to be dispensed on the 
last day of Visit 10B.”
Added to ensure assessments are 
performed for subjects with extensive 
gap between end of main study and 
starting of extension
2.2
Trial Flow Chart for 
Long Term Safety 
Trial
Added the following text to footnote “c” 
in flowchart and added assessments to 
Visit 10B: C-SSRS, ECG, directed 
Physical Exam, Recording of 
Concomitant Medications should be 
performed and Vital Signs, Body Weight
and Laboratory samples (including 
urinalysis) should be collected for 
subjects with >3 month gap in therapy 
between Visit 10 and 10B. The timing of 
Visit 11 and all subsequent visits should 
be based on the trial dispensing date at 
Visit 10B
Added to ensure assessments are
performed for subjects with extensive 
gap between end of main study and 
starting of extension
 
 
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PROTOCOL
01 AUG 2016
Section 
Number(s)
Section Title(s)
Description of Change(s)
Rationale
2.2
Trial Flow Chart for 
Long Term Safety 
Trial
Added the following to Visit 10B: 
Issue/Collect Subject Identification Card
This is mandatory in France
7.1
Overall Trial Design
Removed statement about 
ophthalmology examination completed 
during the Week 182 visit as this will not 
be done.
Added reference to rater manual and 
deleted mention of specific scales in 
statement describing audio-recording 
procedures.
Clarification of previous clerical error 
and inconsistency with flow chart
Clarification to ensure consistency with 
rater manual.
7.2
Beginning and End of 
the Trial
Added the following statement: Given 
the exploratory nature of the extension 
trial endpoints, the retrieved dropout 
approach employed in the main 
cohort/safety cohort trial period (initial 
78 week treatment period), will not be 
applicable to this extension trial period. 
Thus, subjects who discontinue study 
medication during the extension trial 
period will be discontinued from the 
study.
Clarification
7.7.2.2.3
Events of Clinical 
Interest
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 
Clarification
 
 
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PROTOCOL
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Section 
Number(s)
Section Title(s)
Description of Change(s)
Rationale
radiologist should perform a local 
reading, as necessary. In some cases, 
central reads for safety may be 
performed. In the event that an ARIA is 
detected, then the Sponsor may 
request that the MRI be submitted for 
central reading.
8.2.7
Accounting for 
Missing Data
For the Tipping Point sensitivity 
analysis, stated intention to calibrate 
between the primary ANCOVA model 
and the multiple imputation model, if 
needed.
Also, removed an errant negative sign 
from the exponent in the tipping point 
test statistic.
The tipping point sensitivity analysis is 
intended to report the value c that 
would need to be applied to all multiply-
imputed values from the active arms, to 
turn a significant result, non-significant. 
However, it is possible that a slight 
difference may exist between the 
primary ANCOVA model and the 
multiple imputation (MI) model (absent 
any adjustment to the active arms) for 
the final observed dataset. Such a 
difference would bias the intended 
interpretation of c (i.e. some small 
fraction of c would represent the 
difference between the models, as 
opposed to the entirety of c
representing the detrimental effect 
needed to be applied to the active arms 
to tip the significant result to non-
significant.)
 
 
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01 AUG 2016
2.0 SYNOPSIS
TITLE OF TRIAL:  A, Parallel-Group, Double Blind Long Term Safety Trial of MK-8931 in Subjects with 
Alzheimer’s Disease.  (Protocol No. MK-8931-017-21) (also known as SCH 900931, P07738)
ABBREVIATED TITLE:  A Long Term Safety Trial of MK-8931 in AD (EPOCH)
OBJECTIVES:
.Primary Trial Objectives:
1. To evaluate the safety and tolerability of MK-8931 in the long term treatment of mild to moderate 
Alzheimer’s Disease
2. To compare the efficacy of MK-8931 on cognition and functional ability in activities of daily living in subjects 
with mild to moderate AD in subjects administered MK-8931 for 24 months to that of subjects administered 
placebo for 18 months followed by MK-8931 for 6 months.
Exploratory Trial Objective:
To compare the efficacy of MK-8931 administered to subjects for 18 months to that of subjects administered 
placebo for 18 months during the initial 78 week trial followed by long term treatment of MK-8931 during the 
long term safety trial on cognition, function, disease progression, and health economic burden at multiple time 
points.
Trial Design
Overview:  
This is a long-term safety study (up to approximately 260 weeks) which will be available to subjects who have 
completed the initial 78 week trial of MK-8931 Protocol 017. 
The initial 78 week trial is a double blind, placebo controlled trial to evaluate the efficacy of -site amyloid 
precursor protein (APP) cleaving enzyme (BACE) inhibitor MK-8931 as a potential disease-modifying therapy 
in subjects with mild to moderate AD.  The trial is powered to detect a clinically significant change in the two 
coprimary outcome measures (the Alzheimer’s Disease Assessment Scale Cognitive subscale [ADAS-Cog] 
and the Alzheimer’s Disease Cooperative Study Activities of Daily Living Inventory [ADCS-ADL] change-from-
baseline scores at Week 78).  
At the end of the initial 78-week trial, subjects who have completed treatment may choose to participate in this
long term safety trial, during which all subjects who received placebo during the initial 78 week trial will receive 
active drug. The long term safety trial will start with enrollment of the first subject who completes the initial 78 
week trial and chooses to participate in the long term safety trial.  The long term safety trial will end when the 
drug either becomes commercially available or when the MK-8931 program is terminated (or less, based on 
local regulation).  The long term safety trial is expected to have a duration of up to approximately 260 weeks (5 
years) for the first subject enrolled. 
Trial Governance: An independent eDMC will have the primary responsibility for monitoring safety throughout 
the trial.  
Treatment Arms: 
MK-8931 12 mg and 40 mg treatment assignments from the initial 78 week trial will be carried forward into the 
long term safety trial. Subjects originally on placebo will be assigned to the 40 mg dose.
The Sponsor will be unblinded following the completion of the initial 78 week trial. Sites and subjects will 
remain blinded during the long term safety trial. Some Sponsor personnel will remain blinded during the long-
term trial, as necessary, to support the conduct of the trial and the collection of efficacy data.
Sample Size:  
The enrollment target for the initial 78 week trial is 1960 subjects.  It is expected that 70% of subjects will 
complete the initial 78 week trial, and it is estimated that 90% of those will elect to enroll in the long term safety 
trial, with (1960* 0.70*0.90) 1235 subjects projected to enter the long term safety trial.
Number of Trial Centers:  Approximately 190-210.
Duration of Participation:  
Expected maximum duration of approximately 260 weeks (5 years), with the duration of individual subject 
participation dependent on the timing of enrollment.  Duration of participation may be limited based on local 
 
 
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PROTOCOL
01 AUG 2016
TITLE OF TRIAL:  A, Parallel-Group, Double Blind Long Term Safety Trial of MK-8931 in Subjects with 
Alzheimer’s Disease.  (Protocol No. MK-8931-017-21) (also known as SCH 900931, P07738)
regulations.  Subjects who do not complete initial 78 week trial of MK-8931 protocol 017 will not be permitted 
to continue in the long term safety trial.  
Duration of Trial:  
The duration of the long term safety trial is expected to be up to approximately 5 years or until MK-8931 
becomes commercially available or the MK-8931 program is terminated. Duration of the trial may be limited 
based on local regulations.
Key Inclusion Criteria:  
Each subject must have tolerated study medication and completed the initial 78-week trial. Subjects who did 
not complete the initial 78 weeks with study medication but did continue in the trial and completed the 
scheduled visits, may be permitted to enroll in the long term safety trial.
Each subject must 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/wk for a minimum of 6 waking hours/wk 
(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 (eg, dose, visit schedules, and evaluations).  It is recommended 
that the trial partner accompany the subject to all trial visits.  
Key Exclusion Criteria:
The subject is at 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 must be excluded if 
they report suicidal ideation with intent, with or without a plan (eg, suicidal ideation item 4 or 5 on the C-SSRS) 
in the past 1 month or suicidal behavior in the past 6 months.
The subject has developed a recent or ongoing, uncontrolled, clinically significant medical condition (such as, 
but not limited to, diabetes, hypertension, thyroid or endocrine disease, congestive heart failure, angina, 
cardiac or gastrointestinal disease, dialysis, or abnormal renal function with estimated creatinine clearance < 
30 mL/min ) other than Alzheimer’s disease such that, in the judgment of the investigator, participation in the 
trial would pose a significant medical risk to the subject.  Controlled co-morbid conditions (including diabetes, 
hypertension, heart disease, etc) are not exclusionary if stable.  All concomitant medications, supplements (eg 
Vitamin E), or other substances must be kept as stable as medically possible during the trial.
Note: urinary tract infections at screening are not exclusionary if adequately treated (as documented by repeat 
urinalysis).
The subject has a history of, or has developed during the initial 78 week trial evidence of long QT syndrome, 
QTC interval ≥470 milliseconds (for male subjects) or ≥480 milliseconds (for female subjects), or torsades de 
pointes.  Subjects with stable bundle branch block who exceed these limits for QTc interval are eligible for the 
trial if judged by the investigator not to be at increased risk for Torsades
The subject anticipates receiving any of the treatments listed in Table1.
The subject 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.
INVESTIGATIONAL PRODUCT, DOSE, MODE OF ADMINISTRATION
Investigational Product:
MK-8931 will be supplied as tablets of 12 mg and 40 mg . All active doses from the initial 78 week trial will be 
carried forward into the long term safety trial, with all subjects on active treatment continuing on their same 
treatment arm. Subjects originally on placebo will be assigned to 40 mg:
 
 
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PROTOCOL NO. P07738 OR 017-21
PROTOCOL
01 AUG 2016
TITLE OF TRIAL:  A, Parallel-Group, Double Blind Long Term Safety Trial of MK-8931 in Subjects with 
Alzheimer’s Disease.  (Protocol No. MK-8931-017-21) (also known as SCH 900931, P07738)
1.
MK-8931 12 mg orally once daily (QD) - 12/12 treatment group: 
2.
MK-8931 40 mg orally once daily (QD) - 40/40 and placebo/40 treatment groups: 
STATISTICAL METHODS:
Data Sets to be Analyzed:  

The Full Analysis Set (FAS) population will serve as the primary population for the analysis of efficacy 
data in this trial.  

The All-Patients-as-Treated (APaT) population will be used for the analysis of safety data in this trial.  
The APaT population consists of all randomized subjects who received at least one dose of trial 
treatment, with subjects included in the treatment group corresponding to the trial treatment they 
actually received.

It is noted that the first 200 subjects enrolled will be excluded from the primary efficacy and safety 
analyses, since the siDMC will have access to unblinded data from these subjects in advance of a 
dose decision.
Efficacy Analysis:  
There are no formal hypotheses for this trial. All efficacy measurements analyzed during the initial 78 week trial
will continue to be collected and analyzed in the long term safety trial. The primary endpoint is the 24-Month (6 
months after the primary timepoint from the initial 78 week trial) change-from-baseline treatment difference on 
ADAS-Cog and ADCS-ADL.
Safety Analysis:  Safety and tolerability will be assessed by a clinical review of all relevant parameters 
including adverse events (AEs), laboratory tests, vital signs, and ECG measurements.
Safety analyses will be conducted on the cumulative data from the initial 78-week trial pooled with the data 
from the long term safety trial; no analyses will be conducted on the long-term safety data alone.
The broad clinical and laboratory AE categories consisting of the percentage of subjects with any AE, with a 
drug related AE, with an SAE, with an AE which is both drug-related and serious, or who discontinued because 
of an AE are considered as Tier 2 endpoints and will be analyzed. Descriptive Safety Endpoints are considered 
as Tier 3 events and will also be analyzed.
Interim Analyses:  There are no planned interim analyses for this long-term safety trial. (The Sponsor will be 
unblinded following the completion of the initial 78 week trial. Some Sponsor personnel will remain blinded 
during the long-term trial, as necessary, to support the conduct of the trial and the collection of efficacy data.)
 
 
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2.1
Trial Design Diagram for Long Term Safety Trial
Double-Blind Treatment Period Long Term Safety Trial
(up to approximately 260 weeks)
Time (weeks from start of Initial 78 Week Trial)
Visit 13
Visit 14
Visit 15 Visit 16
104
130
156
182
91
208
234
Visit 18
Visit 17
Visit 12
82
78
MK-8931 12 mg Once Daily
MK-8931 40 mg Once Daily
80
Visit 11
12mg/12mg
40mg/40mg
Placebo/
40mg
Visit10B
First visit for Long Term 
Safety Trial will be same
day as final visit of Initial 
78 Week Trial
Placebo subjects from 
Initial 78 Week Trial will 
be assigned to the 40 
mg group in  Long Term
Safety Trial 
260
Visit 19
286
Visit 20
312
Visit 21
338
Visit 22
86
Tel Con
(2 weeks)
Tel Con
(4 weeks)
MK-8931 40 mg Once Daily
Treatment Arms
(Initial 78 Weeks / Long Term Safety)
 
 
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PROTOCOL
01 AUG 2016
2.2
Trial Flow Chart for Long Term Safety Trial
Extension Trial Period:
Treatment
Visit Number
(continuing from Initial 78 Week 
Trial)
10Bb
TC d
11
TC d
12
13 
14
15
16
17
18
19
20
21
22
TC d,f
UV
ETV
Scheduled Week a
(based on date of Randomization -
in Initial 78 Week Trial)
78
80
82
86
91
104
130
156
182
208
234
260
286
312
338
Extension Week (visual aid to show 
timing of visits in Long Term 
Safety Trial)
0
2
4
8
13
26
52
78
104
130
156
182
208
234
260
Visit Window (Weeks)
+/-1
+/-1
+/-1
+/-1
+/-4
+/-4
+/-4
+/-4
+/-4
+/-4
+/-4
+/-4
+/-4
+/-4
Informed Consent
X
Issue/Collect Subject Identification 
Card
X
X
Record Concomitant Medication 
X c
X
X
X
X
X
X
X
X
X
X e
X
Vital Signs
X c
X
X
X
X
X
X
X
X e
X
Body Weight
X c
X
X
X
X
X
X
X
X e
X
Directed Physical Exam
X c
X
X
X
X
X
X e
X
12-Lead Electrocardiogram
X c
X
X
X
X
X
X
X e
X
Skin Examination by Dermatologist
X e
Directed Skin Examination by Site 
Physician
X j
X
X
X
X
X
X e
Hematology and Chemistry 
Samples
X c
X
X
X
X
X
X
X
X
X e
X
PK/PD Blood Samplesk
X
X
Urinalysis
X c
X
X
X
X
X
X
X
X
X e
X
Inclusion/Exclusion Criteria
X
ADAS-Cog
X
X
X
X
X
X
X
X
ADCS-ADL
X
X
X
X
X
X
X
X
CDR-SB
X
X
X
X
X
X
X
Mini-Mental State Examination 
(MMSE)
X
X
X
X
X
X
X
 
 
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Extension Trial Period:
Treatment
Visit Number
(continuing from Initial 78 Week 
Trial)
10Bb
TC d
11
TC d
12
13 
14
15
16
17
18
19
20
21
22
TC d,f
UV
ETV
Scheduled Week a
(based on date of Randomization -
in Initial 78 Week Trial)
78
80
82
86
91
104
130
156
182
208
234
260
286
312
338
Extension Week (visual aid to show 
timing of visits in Long Term 
Safety Trial)
0
2
4
8
13
26
52
78
104
130
156
182
208
234
260
Visit Window (Weeks)
+/-1
+/-1
+/-1
+/-1
+/-4
+/-4
+/-4
+/-4
+/-4
+/-4
+/-4
+/-4
+/-4
+/-4
Neuropsychiatric Inventory (NPI)
X
X
X
X
X
X
X
Health Economic Assessment
(HEA)
X
X
X
X
X
X
X
Modified Resource Utilization in 
Dementia (RUD) Lite
X
X
X
X
X
X
X
EuroQol Five Dimension 
Questionnaire (EQ-5D)
X
X
X
X
X
X
X
Columbia Suicide Severity Rating 
Scale (C-SSRS)
X c
X
X
X
X
X
X
X
X
X
X
X
X
X e
X
Structural Magnetic Resonance 
Imaging (MRI)
X e
Record Adverse Events
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
Dispense Trial Medication
X
X
X
X
X
X
X
X
X
X
X
X
X g
Assess Medication Compliance
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
Ophthalmology Visit (details 
below)
Xi
X
X e
Visual Acuity
Xi
X
X e
Posterior Eye Exams
Xi
X
X e
Fundus Photography
Xi
X
X e
Fundus Autofluorescence h
Xi
X
X e
SD-OCT
Xi
X
X e
a
Visits scheduled during the Long Term Safety Trial will be based off of the date of randomization in the Initial 78 
Week Trial for subjects enrolling into the Long Term Safety Trial immediately following the completion of the Initial 
78-week Trial. Subjects with a gap in study therapy between Visit 10 and Visit 10B will begin trial assessments for 
Visit 10B as noted in the flowchart and continue with the visit schedule as noted in the flowchart.
 
 
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b
Visit 10 from the Initial 78 Week Trial and Visit 10B from the Long Term Safety Trial are considered a single visit 
and can be conducted on the same day. However, if waiting for test results from Visit 10B is necessary in the 
judgment of the investigator, Visit 10B procedures can be performed over more than one visit but ideally should not 
exceed a 2-week timeframe. Trial medication is to be dispensed on the last day of Visit 10B.
c
C-SSRS, ECG, directed Physical Exam, Recording of Concomitant Medications should be performed and Vital 
Signs, Body Weight and Laboratory samples (including urinalysis) should be collected for subjects with >3 month 
gap in therapy between Visit 10 and 10B. The timing of Visit 11 and all subsequent visits should be based on the trial 
dispensing date at Visit 10B.
d
Telephone contact with subject and trial partner/caregiver by site to assess safety, AEs, 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 if the site has significant safety/tolerability concerns.
e
Procedures should be performed if clinically indicated as determined by the investigator.
f
Telephone contact will be performed 14 to 21 days  after the final visit.
g
Drug dispensing may be performed at unscheduled visits at the discretion of the Investigator.
h
Best efforts will be made to accommodate the FAF assessment.  FAF images will be read by a central Reading Center 
designated by the Sponsor.
i
Subjects who did not have a baseline ophthalmology examination completed during the initial 78 week trial or who 
have >6 month gap in study therapy between Visit 10 and 10B must have an ophthalmology examination completed 
during the Week 78 visit (10B) prior to dispensing trial medication.
j
Subjects who did not have a baseline dermatology examination completed during the initial 78 week trial or who 
have >6 month gap in study therapy between Visit 10 and 10B must have a dermatology examination completed 
during the Week 78 visit (10B) prior to dispensing trial medication.
k
Both plasma and dried blood spot (DBS) PK samples will be taken at each time point. The site will record the date 
and time of each PK sample and the date and time of the last two doses of trial medication before each PK sample.  
PK samples can be taken at the same time when blood samples for hematology and chemistry are taken.
 
 
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3.0 TABLE OF CONTENTS
1.0 TITLE PAGE....................................................................................................... 1
SUMMARY OF CHANGES ....................................................................................... 2
2.0 SYNOPSIS ......................................................................................................... 7
2.1
Trial Design Diagram for Long Term Safety Trial ............................... 10
2.2
Trial Flow Chart for Long Term Safety Trial ........................................ 11
3.0 TABLE OF CONTENTS ................................................................................... 14
3.1
List of Tables.......................................................................................... 18
3.2
List of Appendices................................................................................. 19
4.0 LIST OF ABBREVIATIONS AND DEFINITIONS OF TERMS.......................... 20
5.0 INTRODUCTION .............................................................................................. 23
5.1
Therapeutic Rationale ........................................................................... 23
5.2
Subject Population Rationale ............................................................... 23
5.3
Trial Design Rationale ........................................................................... 24
5.4
Outcome Measures Rationale............................................................... 24
5.5
Dose and Administration Rationale ..................................................... 26
6.0 TRIAL OBJECTIVES ....................................................................................... 26
6.1
Primary Trial Objectives........................................................................ 26
6.2
Exploratory Trial Objective ................................................................... 27
7.0 INVESTIGATIONAL AND ANALYSIS PLAN................................................... 27
7.1
Overall Trial Design ............................................................................... 27
7.2
Beginning and End of the Trial............................................................. 31
7.3
Trial Population...................................................................................... 32
7.3.1
Subject Inclusion Criteria ................................................................ 32
7.3.2
Subject Exclusion Criteria............................................................... 32
7.3.3
Subject Discontinuation Criteria...................................................... 33
7.3.4
Replacement of Subjects................................................................ 35
7.4
Treatments ............................................................................................. 35
7.4.1
Trial Treatments.............................................................................. 35
7.4.1.1
Treatments Administered....................................................... 35
7.4.1.2
Method of Treatment Assignment, Randomization, and/or 
Stratification ........................................................................... 35
7.4.1.3
Selection and Timing of Dose for Each Subject..................... 36
7.4.1.3.1
Selecting the Dose for Each Subject............................. 36
7.4.1.3.2
Determining the Timing of Dose Administration for 
Each Subject................................................................. 36
7.4.1.4
Blinding Trial Treatments ....................................................... 36
7.4.1.5
Investigational Medicinal Products......................................... 36
 
 
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7.4.1.5.1
Identity of Investigational Medicinal Products ............... 37
7.4.1.5.2
Source........................................................................... 37
7.4.1.5.3
Labeling ........................................................................ 37
7.4.1.5.4
Packaging ..................................................................... 37
7.4.1.5.4.1
Calendar Sleeves for Study Medication Bottles ... 37
7.4.1.5.5
Storage ......................................................................... 38
7.4.1.5.6
Dispensing .................................................................... 38
7.4.1.5.7
Replacement of Investigational Product........................ 38
7.4.1.5.8
Investigational Medicinal Product Accountability........... 38
7.4.2
Non-Trial Treatments...................................................................... 39
7.4.2.1
Prior and Concomitant Medications ....................................... 39
7.4.2.1.1
Medications, Supplements, and Other Substances 
Prohibited During the Trial ............................................ 39
7.4.2.1.2
Concomitant Medications, Supplements, and Other
Substances Allowed During the Trial ............................ 39
7.4.3
Procedures for Monitoring Subject Compliance With 
Administration of Trial Treatments .................................................. 40
7.5
Trial Schedule ........................................................................................ 40
7.6
Trial Procedures .................................................................................... 41
7.7
Assessments.......................................................................................... 47
7.7.1
Efficacy Assessments..................................................................... 47
7.7.1.1
Primary Efficacy Endpoints .................................................... 47
7.7.1.2
Exploratory Efficacy Endpoints .............................................. 47
7.7.2
Safety Monitoring and Assessments............................................... 48
7.7.2.1
Safety Endpoints.................................................................... 48
7.7.2.2
Definition of Terms................................................................. 48
7.7.2.2.1
Adverse Event............................................................... 48
7.7.2.2.2
Serious Adverse Event.................................................. 49
7.7.2.2.3
Events of Clinical Interest.............................................. 50
7.7.2.2.4
Overdose ...................................................................... 51
7.7.2.2.5
Clinical Supply Complaint ............................................. 52
7.7.2.2.6
Planned Hospitalization................................................. 52
7.7.2.3
Monitoring .............................................................................. 52
7.7.2.3.1
Monitoring Adverse Events ........................................... 52
7.7.2.3.2
Monitoring Laboratory Assessments............................. 53
7.7.2.4
Assessment of Adverse Events ............................................. 53
7.7.2.4.1
Reference Safety Information (RSI) for the 
Assessment of Expectedness of Adverse Events......... 56
7.7.2.4.2
Potential Toxicities of Investigational Products ............. 56
 
 
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7.7.2.5
Reporting Safety Observations by the Investigator to the 
Sponsor.................................................................................. 56
7.7.2.5.1
Expedited Reporting...................................................... 56
7.7.2.5.2
Expedited Reporting by the Sponsor to a Regulatory 
Health Authority ............................................................ 57
7.7.2.5.3
Unblinding Treatment for a Subject During the Trial ..... 57
7.8
Criteria for Early Termination of the Trial............................................ 58
8.0 STATISTICAL AND ANALYTICAL PLAN ....................................................... 58
8.1
Subject Populations to be Analyzed .................................................... 59
8.2
Efficacy Analyses .................................................................................. 60
8.2.1
Primary Efficacy Analysis................................................................ 61
8.2.2
Multiplicity ....................................................................................... 62
8.2.3
Exploratory Analyses ...................................................................... 63
8.2.4
Subgroup Analyses......................................................................... 63
8.2.5
Parameter Estimates for Primary Endpoints................................... 64
8.2.5.1
Assumptions for the Effect of MK-8931.................................. 64
8.2.5.2
Power Calculations ................................................................ 64
8.2.6
Dropping Dose Arms....................................................................... 65
8.2.7
Accounting for Missing Data ........................................................... 66
8.2.8
Interim Analysis............................................................................... 68
8.3
Safety Analysis ...................................................................................... 69
8.3.1
Analysis of Prespecified Safety Endpoints...................................... 69
8.3.2
Analysis of Commonly Occurring Safety Endpoints........................ 70
8.3.3
Analysis of Descriptive Safety Endpoints........................................ 70
8.4
Trial Medication Compliance and Exposure........................................ 71
8.4.1
Compliance..................................................................................... 71
8.4.2
Exposure......................................................................................... 71
8.5
Demography........................................................................................... 71
9.0 ADHERENCE TO ETHICAL, REGULATORY, AND ADMINISTRATIVE 
CONSIDERATIONS ......................................................................................... 72
9.1
Ethical Conduct of the Trial .................................................................. 72
9.1.1
Independent Ethics Committee or Institutional Review Board ........ 72
9.1.2
Subject Information and Consent.................................................... 72
9.1.3
Subject Identification Card.............................................................. 73
9.1.4
Registration of the Trial................................................................... 74
9.2
Reporting Trial Data to the Sponsor .................................................... 74
9.2.1
Data Collection Forms .................................................................... 74
9.2.2
Preparing Case Report Forms for All Subjects ............................... 74
9.3
Publications and Other Rights ............................................................. 75
 
 
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9.3.1
Rights to Publish by the Investigator............................................... 75
9.3.2
Use of Proprietary or Confidential Information in a Publication....... 75
9.3.3
Use of Trial Information in a Publication ......................................... 76
9.3.4
Authorship of Publications .............................................................. 76
9.4
Trial Documents and Records Retention............................................. 76
10.0INVESTIGATORS AND TRIAL ADMINISTRATIVE STRUCTURE.................. 77
10.1
Sponsor .................................................................................................. 77
10.2
Investigators .......................................................................................... 77
10.2.1
Selecting Investigators.................................................................... 77
10.2.2
Financial Disclosure Requirement .................................................. 77
10.2.3
Clinical Study Report Coordinator Investigator ............................... 78
10.3
Central Organizations............................................................................ 78
10.3.1
Scientific Advisory Committee ........................................................ 78
10.3.2
Executive Oversight Committee...................................................... 78
10.3.3
Data Monitoring Committee ............................................................ 78
11.0REFERENCES ................................................................................................. 80
INVESTIGATOR SIGNATURE PAGE................................................................... 138
 
 
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3.1
List of Tables
Table 1 Prohibited Medications, Supplements, and Other Substances.............. 33
Table 2 Medications, Supplements, and Other Substances Allowed During 
the Trial
...................................................................................................... 40
Table 3 Laboratory Tests.................................................................................... 45
Table 4  Evaluating Adverse Events................................................................... 54
Table 5 Analysis Strategy for Primary Endpoints................................................ 60
Table 6 Parameter Assumptions for Progression Rate on Placebo, Standard 
Deviations, and Within Endpoint Correlations for ADAS-Cog, ADCS-ADL, 
and CDR-SB ................................................................................................. 64
Table 7 Power Calculations (MK-8931 40 mg / MK-8931 40 mg vs. Placebo / 
MK-8931 40 mg) ........................................................................................... 65
Table 8 Analysis Strategy for Safety Parameters ............................................... 70
 
 
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3.2
List of Appendices
Appendix 1
Code of Conduct for Clinical Trials................................................ 83
Appendix 2
DNA Sampling and Pharmacogenetic Analysis Procedures ......... 87
Appendix 3
The National Institute of Neurological and Communicative 
Diseases and Stroke/Alzheimer’s Disease and Related Disorders 
Association (NINCDS-ADRDA) Criteria for Probable AD18 ........................... 94
Appendix 4
Comparison of the Constrained Longitudinal Data Analysis 
Model and the Longitudinal ANCOVA Model and Guidance on 
Longitudinal Data Analysis: Efficient Use of Baseline Information in 
Longitudinal Data Analyses........................................................................... 97
Appendix 5
Predefined Limits of Change Criteria .......................................... 135
 
 
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4.0 LIST OF ABBREVIATIONS AND DEFINITIONS OF TERMS
Term
Definition
A
amyloid 
AChE
Acetylcholinesterase
AChEI
Acetylcholinesterase Inhibitor
AD
Alzheimer’s Disease
ADAS-Cog
Alzheimer’s Disease Assessment Scale Cognitive Subscale
ADCS-ADL
Alzheimer’s Disease Cooperative Study Activities of Daily Living Inventory
ADL
Activities of Daily Living
ADNI
Alzheimer's Disease Neuroimaging Initiative
AE
Adverse Event
ALT
Alanine aminotransferase (SGPT)
ANCOVA
Analysis of Covariance
APaT
All-Patients-as-Treated
APOE
Apolipoprotein E
APP
Amyloid Precursor Protein
AREDS
Age-Related Eye Disease Study
AST
Aspartate aminotransferase (SGOT)
BACE
-site APP cleaving enzyme
BP
Blood Pressure
βhCG
β-Human Chorionic Gonadotropin
BSA
Body Surface Area
BUN
Blood Urea Nitrogen
CAM
Confusion Assessment Method
CBC
Complete Blood Count
CDR-SB
Clinical Dementia Rating Sum of Boxes
CDT
Counterfeit, Diversion and Tampering
CFR
Code of Federal Regulations
CI
Confidence Interval
cLDA
Constrained Longitudinal Data Analysis
CMH
Cochran-Mantel-Haenzel
CMV
Cytomegaloviruse
CRF
Case Report Form
CRO
Clinical Research Organization
CSF
Cerebrospinal Fluid
CSR
Clinical Study Report
CTD
Clinical Trial Directive
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
EBV
Epstein-Barr Virus
ECG
Electrocardiogram
ECI
Events of Clinical Interest
 
 
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Term
Definition
eCRF
Electronic Case Report Form
EDC
Electronic Data Capture
eDMC
External (to Sponsor) Data Monitoring Committee
EDTA
Ethylenediamine Tetraacetic Acid
EIA
Enzyme immunoassay
EM
Exposure Multiples
EMA
European Medicines Agency
EQ-5D
EuroQol Five Dimension Questionnaire
EOC
Executive Oversight Committee
ETDRS
Early Treatment Diabetic Retinopathy Study
EU
European Union
FAF
Fundus Autofluorescence
FAS
Full Analysis Set
FDA
Food and Drug Administration, USA
FSH
Follicle Stimulating Hormone
FTA-ABS
Fluorescent treponemal antibody absorption
GCP
Good Clinical Practice
GMP
Good Manufacturing Practice
HEA
Health Economic Assessment
HLA
Human Leukocyte Antigen
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
IPR
Indirect Pharmacologic Response
IRB
Institutional Review Board
IU
International Units
IVRS
Interactive Voice Response System
Ki
Equilibrium Inhibition Constant
K-M
Kaplan-Meier
LDH
Lactate Dehydrogenase
LFT
Liver Function Test
LSM
Least Squares Mean
MAR
Missing at Random
MCAR
Missing Completely at Random
MFAS
Modified Full Analysis Set
MMSE
Mini-Mental State Examination
MNAR
Missing Not at Random
MRI
Magnetic Resonance Imaging
 
 
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Term
Definition
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
PiB
Pittsburgh compound B
P-gp
P-glycoprotein
PK
Pharmacokinetic
PK/PD
Pharmacokinetic/Pharmacodynamic 
p-tau
Phosphorylated Microtubule-Associated Protein Tau
RBC
Red Blood Cell
RNA
Ribonucleic Acid
RPE
Retinal Pigment Epithelium
RSD
Rising Single Dose
RSI
Reference Safety Information
RUD Lite
Resource Utilization in Dementia Lite Questionnaire
SAE
Serious Adverse Event
(S)AE
All adverse events, including serious adverse events
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
Unsched
Unscheduled
USA
United States of America
WBC
White Blood Cell
 
 
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5.0 INTRODUCTION
5.1
Therapeutic Rationale
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 cholinesterase inhibitors (eg, donepezil) and the low affinity 
NMDA receptor antagonist (memantine) which 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 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.
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 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 cerebrospinal fluid (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 Investigator’s Brochure).  
These results suggest that MK-8931 may reduce Aβ production in humans and 
could potentially slow progression in subjects with mild to moderate AD.  Detailed 
information about MK-8931 including preclinical studies, pharmacokinetics and other 
relevant information is provided in the Investigator’s Brochure.
5.2
Subject Population Rationale
This long term safety trial will start with enrollment of the first subject who completes 
the initial 78 week trial and will end when the drug either becomes commercially 
available or when the MK-8931 program is terminated.
 
 
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Subjects may start or switch to another cholinesterase inhibitor or memantine during 
this trial. Other additional treatments must not be initiated during the trial except as 
otherwise specified in this protocol.
Details about specific benefits and risks for subjects participating in this clinical trial 
can be found in the accompanying Investigator’s Brochure and Informed Consent 
documents.
5.3
Trial Design Rationale
This is a parallel group, multi-site, double-blind, long term safety 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 the extended treatment of mild to moderate AD.  MK-8931 is 
hypothesized to exert disease modifying effects in subjects with AD. A delayed-start 
design may provide supportive evidence of disease modification in 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 the start of active treatment. Results from the long term safety trial will also 
provide data regarding the sample sizes necessary for, and the feasibility of, delayed 
start studies with disease modifying therapeutics for AD.  In addition, this long term 
safety 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 78-week trial. Some Sponsor personnel will remain blinded during the long-
term trial, as necessary, for the conduct and collection of efficacy data, including the 
24-month timepoint to support the primary objective regarding efficacy. Details are 
included in the Sponsor’s blinding document.
Once a subject enters the long term safety trial, participation will continue until one 
of the following occurs: 1) MK-8931's development is terminated for mild to 
moderate AD (eg. due to a lack of efficacy), 2) MK-8931 is approved by regulatory 
agencies and becomes commercially available, 3) the subject voluntarily withdraws 
or 4) the subject is discontinued for safety reasons.  The long term safety trial is 
expected to continue up to five years after the first subject enters the trial.
5.4
Outcome Measures Rationale
The primary clinical measures in this trial are the Alzheimer’s Disease Assessment 
Scale Cognitive subscale (ADAS-Cog) and the Alzheimer’s Disease Cooperative 
Study Activities of Daily Living Inventory (ADCS-ADL). The ADAS-Cog is a measure 
of cognition while the ADCS-ADL is a measure of functional ability in activities of 
daily living. The measures are validated instruments that are acceptable to 
regulatory agencies, have been used previously in drug trials in this patient 
population, and can reliably detect clinically relevant changes in AD.
 
 
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After the initiation of P017, 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. There have been observations in the literature that mice 
lacking the gene for BACE2 have reduced pigment [30]. In recently completed 
studies of MK-8931 in two pigmented species (mouse and rabbit), reduced hair 
pigment was observed within four weeks of treatment in all animals, which was 
reversible with cessation of treatment. On microscopic examination, normal skin 
histology was observed except for loss of pigmentation in the hair follicle/shaft. 
There was no loss of melanocytes. All phases of the hair cycle were present, and no 
inflammatory or degenerative changes in hair follicles, sebaceous glands, epidermis, 
or dermis were observed.  In contrast to these observations in mouse and rabbit, no 
change in hair pigment or skin and retinal histology have been observed in monkeys 
treated for up to 9 months with MK-8931 at exposures 36-fold above those achieved 
at the highest dose of MK-8931 tested in P017 (60 mg).  Furthermore, no adverse 
events of skin hypo- or depigmentation have been reported thus far in prior human 
trials of MK-8931.
A review of preclinical data and the FDA request with a panel of expert 
dermatologists indicated the overall risk to patients is minimal.  The risk of vitiligo, 
with loss of dermal melanocytes, was seen as low.  If vitiligo were observed, medical 
management was recommended without discontinuation of study medication, given 
that 
vitiligo 
is 
not 
associated 
with 
significant 
morbidity 
or 
mortality.  
Hypopigmentation was viewed as being a more likely finding with BACE inhibitor 
treatment, rather than vitiligo.  Hypopigmentation by itself was also not seen as 
requiring discontinuation of study medication. Therefore, baseline and post-
treatment dermatology assessments were added to this protocol to document the
incidence of hypopigmentation, not to detect a significant safety risk. Patients will be 
informed of the risk of hypopigmentation and instructed to use sun screen in affected 
areas if exposed to sunlight.  A long-term risk may be increased skin cancer due to 
sun damage to the skin. Incident cases of hypopigmentation should be referred to a 
specialist for appropriate diagnosis and treatment, if clinically indicated.  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 in a future amendment. Sites would continue to collect 
skin-related adverse events and refer subjects for further dermatologic evaluation as 
needed.
 
 
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5.5
Dose and Administration Rationale
Subjects who tolerated study medication and completed the initial 78-week trial of 
Protocol 017 may enroll in this long term safety trial.  Those subjects who did not 
complete treatment in the initial 78-week trial, but did continue in the trial and 
completed the scheduled visits, may be permitted to enroll in this long term safety 
trial.  Subjects who received the 12 mg or 40 mg dose during the initial 78-week trial
will continue to receive the same dose in this long term safety trial. They will be 
referred to as the 12/12 and the 40/40 groups respectively. Subjects who received 
placebo during the initial 78 week trial will receive the 40 mg dose during this long 
term safety 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 78 week trial will be treated with the 40 mg 
dose in the long term safety trial to provide additional information about the long 
term safety of MK-8931 and to estimate the clinical effects of delayed start of this 
higher dose.
6.0 TRIAL OBJECTIVES
6.1
Primary Trial Objectives 
There are two primary objectives in which the subjects who received
40 mg / 40 
mg will be compared to those who received placebo / 40 mg. Similarly, subjects 
who received 12 mg / 12 mg will be compared to those who received placebo / 
40 mg. The two objectives are as follows:
1. To evaluate the safety and tolerability of MK-8931 in the long term treatment 
of mild to moderate Alzheimer’s Disease.
2. To compare the efficacy of MK-8931 administered to subjects for 24 months 
to that of subjects administered placebo for 18 months followed by MK-8931 
for 6 months using endpoints at follows.

the change-from-Baseline score in the ADAS-Cog at Week 104 (Visit 13).

the change-from-Baseline score in the ADCS-ADL at Week 104 (Visit 13).
 
 
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6.2
Exploratory Trial Objective 
To compare the efficacy of MK-8931 administered to subjects for 18 months 
to that of subjects administered placebo for 18 months during the initial 78 
week trial followed by long term treatment of MK-8931 in the long term safety 
trial on cognition, function, disease progression, and health economic burden 
at multiple time points.
7.0 INVESTIGATIONAL AND ANALYSIS PLAN
7.1
Overall Trial Design
Overview
This is a parallel group, multi-site, double-blind, long term safety trial of MK-8931 in 
subjects with mild to moderate AD.
Trial Governance Committees
An independent external Data Monitoring Committee (eDMC) will have the primary 
responsibility for monitoring safety throughout the trial.
In addition an internal 
Executive Oversight Committee (EOC) of the sponsor will receive recommendations 
throughout the trial from the eDMC and is responsible for acting upon the 
recommendations of the eDMC.  The composition, activities, and responsibilities of 
these trial governance committees will be described in the eDMC charter.
The eDMC will review data in a manner such that the trial team, investigators, 
subjects, and vendors will not have access to the unblinded data.  
The EOC will not have access to unblinded data or reports unless it is deemed 
necessary by the eDMC in order to act upon an eDMC recommendation.  The EOC 
will be completely independent of, and separate from, the trial team performing the 
medical monitoring and supervising the operational aspects of the protocol.
Summary
Subjects who have completed the initial 78 week trial and tolerated study medication 
may be eligible for enrollment into this long term safety trial, during which all subjects 
who received placebo during the initial 78 week trial will receive active drug.  
Subjects who did not complete the initial 78 week trial will not be permitted to 
continue into the long term safety trial.  
The two primary efficacy endpoints are the ADAS-Cog and ADCS-ADL scores.  
Additional Endpoints include the CDR-SB, the NPI and MMSE scores; and health 
economic and quality of life outcomes including a modified Resource Utilization in 
Dementia [RUD] Lite Questionnaire, the Health Economic Assessment [HEA]) and 
the EuroQol Five Dimension Questionnaire (EQ-5D).
 
 
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Safety and tolerability will be assessed by a clinical review of all relevant parameters 
including AEs, laboratory tests, vital signs, and ECG measurements.  The same 
safety parameters and AEs designated as being of special interest during the initial 
78 week trial will continue to be monitored in the long term safety trial, as follows:1) 
delirium; and 2) rash ECI (see Section 7.7.2.2.3). Some of these AEs are combined 
into composite endpoints for formal safety analyses (see Section 7.7.2.2.3.).
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 compounds that are intended to treat AD by reducing β-
amyloid in the brain. These imaging abnormalities, described by Salloway et al.(1), 
have, in the majority of instances, been asymptomatic and their presence has been 
detected by routine MRI scans. Symptoms, when present in association with such 
imaging abnormalities, have been reported to include headache, worsening 
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, with imaging abnormalities then resolving; 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, subsequently, routine MRI scans for 
safety monitoring. Following a comprehensive review of the existing data, the FDA 
has recently 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 drugs 
that may affect β-amyloid. Therefore, routine MRI safety monitoring is not included in
this long term safety trial. MRI scans are collected during the initial 78 week trial to 
assess eligibility and for brain structure volumetric outcome measures. MRIs may 
be performed at a post-treatment visit for safety monitoring if clinically indicated as 
determined by the investigator (e.g., in follow-up to an AE). If amyloid-related 
imaging abnormalities are identified during the trial they should be handled as 
follows.
1) Trial medication should be discontinued if an imaging abnormality consistent 
with 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. 
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.
 
 
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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 macrohemorrhage (symptomatic or asymptomatic), subjects must be 
discontinued from trial medication and cannot resume dosing. 
Ophthalmologic evaluation of subjects with AD can be challenging.  Experts have 
noted that assessment of visual acuity can be confounded by cognitive deficits20
which could limit its usefulness for assessing drug effects.  On the other hand, SD-
OCT is a sensitive method for evaluating retinal structure with micrometer resolution.  
 
  Additional 
ophthalmologic assessments included visual acuity test, SD-OCT measurements of 
other retinal layers, posterior eye exam including dilated funduscopy, and  fundus 
photography.  Fundus autofluorescence (FAF) was also included at centers with the 
appropriate capabilities.  During the initial 78-week trial ophthalmologic assessments 
were initially conducted at ophthalmology centers at Screening, Week 13, 26, 52 and 
78, and Early Termination Visit.  
Based on the recommendation of the eDMC in March 2015, after reviewing results 
from the initial 78-week trial and available data from an ongoing trial in prodromal AD 
patients (MK-8931-019) the frequency of ophthalmologic monitoring was modified.  
Within the long term safety trial, subjects who did not have a baseline ophthalmology 
examination during the initial 78 week trial or who have >6 month gap in study 
therapy between Visit 10 and 10B will have an ophthalmology examination 
completed at the Week 78 visit (visit 10B). In addition, subjects participating in the 
long term safety trial will have an ophthalmology examination completed at Week 
130.
Preclinical studies initially noted slight reduction of iris pigment in rabbits, as 
described in the IB.  More recent studies failed to replicate the effect on iris pigment 
(see IB). Iris pigment  monitoring is not included in this trial. 
CCI
CCI
 
 
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There is no randomization for this long-term safety trial, aside from that employed for
the initial 78 week trial.
Subjects will be asked to provide blood samples for pharmacokinetic (PK) analyses 
to determine plasma concentrations of MK-8931.  This information will be used to 
develop a population PK model and to explore the exposure-response relationship in 
the trial population.  Pharmacokinetic blood samples will be collected at the following 
visits:

Week 4 of extension (week 82 overall)

Week 13 of extension (week 91 overall)
Under Amendment 21, both plasma and dried blood spot (DBS) PK samples will be 
collected at each timepoint as noted in the Trial Flow Charts. Details regarding use 
of samples for PK and PK/PD modeling will be specified in the modeling analysis 
plan document.
For subjects who sign a separate consent form for pharmacogenetic analysis, blood 
samples for pharmacogenetic analysis will also be collected.
Quality control is an essential part of all clinical trials.  In an effort to maintain quality 
control of the clinical ratings, this trial will include a review of the ratings by outside 
expert(s).  This review may include all available medically relevant data, a narrative 
summary of the subject's history, and a review of video/audio recordings of key 
clinical interviews performed.
All sites must ensure raters are properly qualified and trained prior to the 
administration of any clinical assessments. 
Rater performance on these 
assessments will be carefully evaluated and monitored to ensure and maintain 
adequate reliability.  Details will be specified in the Manual of Assessments.  
Raters must be approved by the sponsor, which will typically 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 interviews and ratings
through Week 104, as directed in the manual from the rater training vendor.  Some 
or all of these recorded interviews will be reviewed by outside experts. Raters will be 
provided feedback on the quality of their interviews and ratings by the outside 
experts by e-mail, telephone or in meetings in order to develop and maintain good 
rater reliability.  Based on this feedback, raters may change their initially recorded 
scores if errors are identified.  Raters who do not perform adequately may be 
required to undergo additional remediation or may be replaced.
While concerns have been raised that video/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 
 
 
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demonstrated that the failure to adequately monitor such ratings can substantially 
increase the risks of failed trials(7,8). Recorded interviews will be encrypted 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 Institutional 
Review Boards or Independent Ethics Committees (IRBs/IECs) have different 
requirements for storage.  
Subjects may participate in this protocol and continue to participate in certain 
observational studies, if approved by the Sponsor. These studies must involve only 
limited cognitive testing (eg, annual) and subjects will not be permitted to undergo 
any non-protocol cognitive testing within the two months prior to Week 104.
7.2
Beginning and End of the Trial
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 safety trial will start with enrollment of the first subject who completes 
the initial 78 week trial and will end when the drug either becomes commercially 
available or when the MK-8931 program is terminated.  This long term safety trial
has an expected maximum duration of approximately 260 weeks, with the duration 
of individual subject participation dependent on the timing of enrollment.  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 (eg, visits or telephone contacts) or has 
prematurely discontinued from the trial.  A subject will be considered a completer of 
this long term safety trial if he/she is still continuing in the trial when the trial is 
stopped. 
A subject is considered to have discontinued after he/she has withdrawn consent or 
has been discontinued under the conditions specified in Section 7.3.3.  All 
applicable activities scheduled for the final trial visit should be performed at the time 
of treatment discontinuation as defined in the long term safety trial Flow Chart in
Section 2.2.
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 (eg, visit or telephone contact).
Each subject will be monitored for the occurrence of AEs beginning immediately 
after the subject has signed informed consent through 14 days after cessation of 
treatment.  Follow-up procedures related to pregnancy or existing SAEs may 
continue beyond the end of the clinical trial.
 
 
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Given the exploratory nature of the extension trial endpoints, the retrieved dropout 
approach employed in the main cohort/safety cohort trial period (initial 78 week 
treatment period), will not be applicable to this extension trial period. Thus, subjects 
who discontinue study medication during the extension trial period will be 
discontinued from the study.
7.3
Trial Population
The trial population is adult subjects with a diagnosis of AD who completed the initial 
78 week trial.
7.3.1
Subject Inclusion Criteria
A subject must meet all the criteria listed below to participate in the trial. Subjects 
must
1. have tolerated study medication and completed the initial 78 week trial.  
Subjects who did not complete the initial 78 weeks with study medication but 
did continue in the trial and completed the scheduled visits, may be permitted 
to enroll in the long term safety trial 
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/wk for a minimum of 6 waking hours/wk (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 (eg, dose, visit schedules, and evaluations).  It is recommended 
that the trial partner accompany the subject to all trial visits.  
3. sign (or legal representative sign) the informed consent form in accordance 
with local requirements, after the scope and nature of the investigation have 
been explained.
7.3.2
Subject Exclusion Criteria
A subject meeting any of the exclusion criteria listed below must be excluded from 
participating in the trial. Subject
1. is at 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 must be excluded if they report suicidal ideation with 
intent, with or without a plan (eg, suicidal ideation item 4 or 5 on the C-SSRS) in 
the past 1 month or suicidal behavior in the past 6 months.
2. has developed a recent or ongoing, uncontrolled, clinically significant medical 
condition (such as, but not limited to, diabetes, hypertension, thyroid or endocrine 
disease, congestive heart failure, angina, cardiac or gastrointestinal disease, 
 
 
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dialysis, or abnormal renal function with estimated creatinine clearance < 30 
mL/min) other than Alzheimer’s disease such that, in the judgment of the 
investigator, participation in the trial would pose a significant medical risk to the 
subject.  Controlled co-morbid conditions (including diabetes, hypertension, heart 
disease, etc) are not exclusionary if stable.  All concomitant medications, 
supplements, or other substances must be kept as stable as medically possible 
during the trial.
Note: urinary tract infections at Visit 10B are not exclusionary if adequately 
treated (as documented by repeat urinalysis).
3. has a history of, or has developed during the initial 78 week trial evidence of long 
QT syndrome, QTC interval ≥ 470 milliseconds (for male subjects) or ≥ 480 
milliseconds (for female subjects), or torsades de pointes.
4. anticipates receiving any of the treatments listed in Table 1 during the study.
Table 1 Prohibited Medications, Supplements, and Other Substances
Anti-amyloid agents (eg, tarenflurbil, tramiprosate)
Anti-amyloid antibodies (eg, bapineuzumab)
Anti-amyloid vaccine 
(Subjects who received placebo 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.
Drugs known to cause ocular changes or damage (eg, chloroquine, hydroxychloroquine
[sometimes used for arthritis],  many anti-malarial treatments, ethambutol for tuberculosis, 
amiodarone for ventricular arrhythmias, and tamoxifen for breast cancer)
NOTE: This is not a complete list of excluded medications.  Contact the Sponsor if there is a 
question about a specific medication.
5. 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.
7.3.3
Subject Discontinuation Criteria
A subject may discontinue from the clinical trial at any time for any reason. A subject 
must be discontinued from the trial if the subject or legal representative (such as a 
parent or legal guardian) withdraws consent.
The investigator should stop trial medication in any case in which emerging effects 
are of unacceptable risk to the individual subject, or if unmanageable factors arise 
 
 
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that may interfere significantly with the trial procedures and/or the interpretation of 
results.
A subject must discontinue trial medication for any of the following reasons:
1. The subject or legal representative withdraws consent;
2. Elevated ALT, AST, or T-BIL meeting any one of the following criteria:
A. ALT or AST 8 x ULN;
B. ALT or AST 5 x ULN for more than 2 weeks;
C. ALT or AST 3 x ULN and T-BIL 2 x ULN at the same visit;
D. ALT or AST 3 x ULN with the appearance of symptoms indicating 
hepatitis (eg, 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;
3. An imaging abnormality consistent with macrohemorrhage appears (see details 
in Section 7.1);
4. 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 > 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;
5. 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;
6. The subject develops a severe rash.  For the purpose of this program, a "severe 
rash" is defined as one of the following:
•
A vesicular rash (ie, 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
•
Stevens-Johnson 
Syndrome, 
erythroderma, 
or 
toxic 
epidermal 
necrolysis
•
DRESS syndrome
7. The subject develops an uncontrolled clinically significant rash defined as 
follows:
•
A clinically significant rash (see Section 7.7.2.2.3) that is not controlled 
by topical medications or oral medications such as antihistamines 
(detailed in the Rash Guidance Document), and
 
 
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•
A clinically significant rash that causes intolerable discomfort for the 
subject.
8. 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;
Subjects who are unwilling to continue should proceed to a termination visit. At a 
minimum, the following information should be collected when a subject discontinues:
1. The reason the subject discontinued;
2. The date of the last dose of test products from the trial;
3. The date of the last assessment and/or contact.  A follow-up contact (telephone 
or visit) will be arranged as appropriate;
4. (Serious) Adverse events;
5. Compliance with the test product administration as specified in this protocol;
6. Final Assessments:
7. Every effort should be made to ensure that all procedures and evaluations 
scheduled for the final trial visit are performed (Section 2.2, Trial Flow Chart)
8. Retrieve all investigative products and test articles from the subject.
7.3.4
Replacement of Subjects
A subject who discontinues from the trial will not be replaced.
7.4
Treatments
7.4.1
Trial Treatments
7.4.1.1
Treatments Administered
The rationale for selection of doses to be used in this trial is provided in Section 5.5
– Dose and Administration Rationale.  There are no specific calculations or 
evaluations required to be performed in order to administer the proper dose to each 
subject.
Subjects who received the 12 mg or 40 mg dose during the initial 78-week trial will 
continue to receive the same dose in this long term safety trial. They will be referred 
to as the 12/12 and the 40/40 groups respectively. Subjects who received placebo
during the initial 78 week trial will receive the 40 mg dose during this long term 
safety trial. They will be referred to as the placebo/40 group.
7.4.1.2
Method of Treatment Assignment, Randomization, and/or 
Stratification
During the initial 78-week trial, randomization was implemented through the use of a 
central interactive voice response system (IVRS).  The treatment arm to which 
 
 
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subjects were randomized during the initial 78 week trial will determine the treatment 
received during the long term safety trial – as described in Section 7.4.1.1.
Though not planned, it is possible that an active dose arm (eg, 40 mg) could be 
dropped depending on eDMC review.  In the event that only one active dose 
remains while enrollment is still ongoing, then subjects in the dropped dose arm will 
be re-assigned to receive the remaining active dose.
7.4.1.3
Selection and Timing of Dose for Each Subject
7.4.1.3.1
Selecting the Dose for Each Subject
The rationale for the selection of doses to be used in this trial is presented in 
Section 5.5.
7.4.1.3.2
Determining the Timing of Dose Administration for Each Subject
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 the same time 
every day. For each of the treatment groups, 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/caregiver and recorded by the site at the next visit. Subjects 
should not take more than one dose on the same calendar day. 
With the exception 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.
7.4.1.4
Blinding Trial Treatments
All doses of MK-8931 will be identical in appearance and will be packaged identically 
so that the treatment blind is maintained for the subject and investigator. The
sponsor will be unblinded at the completion of the initial 78-week trial.  
See Section 7.7.2.5.3 for a description of the method of unblinding a subject during 
the trial, should such action be warranted.
7.4.1.5
Investigational Medicinal Products
The investigator has the responsibility for taking all steps to maintain appropriate 
records and to ensure appropriate supply, handling, storage, distribution, and usage 
 
 
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of these materials in accordance with the protocol and any applicable laws and 
regulations.
7.4.1.5.1
Identity of Investigational Medicinal Products
The trial medication will be provided as a tablet formulation to support all subjects in 
the trial. Please see the Investigator's Brochure for a full description of the 
investigational medicinal product. 
7.4.1.5.2
Source
The sponsor will provide trial medication as follows: MK-8931 12 mg tablets; MK-
8931 40 mg tablets.
7.4.1.5.3
Labeling
MK-8931 bottle labels should include the following information and comply with the 
regulatory requirements appropriate for clinical site: Dosing directions will state, 
“Take 1 tablet once a day”.
7.4.1.5.4
Packaging
Trial medication will be provided in bottles.
At the visits specified in the Trial Flow Chart (Section 2.2), the site will dispense
medication using the IVRS system. The site will provide the medication to the 
caregiver/trial partner and may provide a ‘calendar sleeve’ to attach to the subject’s 
trial medication bottle. Additional instructions regarding the calendar sleeves will be 
provided to sites.
7.4.1.5.4.1
Calendar Sleeves for Study Medication Bottles
In addition to routine surveillance of subject trial medication compliance, subjects/ 
caregiver/trial partner may be given trial medication ‘calendar sleeves’ which affix to 
the exterior of trial medication bottles to help subjects remember when to take 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 sites personnel will slide them onto each bottle.  The site will 
then instruct the caregiver/trial partner on how to make sleeve subject specific (ie
document on the ‘calendar sleeve’ the date to start taking trial medication, bottle 
number). 
When the subject/caregiver/trial partner returns to the clinical site, the site will 
perform a pill count and also review the ‘calendar sleeves’(if they have utilized the 
sleeve), to verify pill count and any possible missed or extra doses taken.  If there is 
a discrepancy between the bottle and the ‘calendar sleeve’ then the physical pill 
count will be the final decision to be documented in the eCRF. Discrepancies should 
 
 
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be documented in the site’s source documents and the reasoning for what was 
ultimately recorded in the eCRF.
7.4.1.5.5
Storage
Trial treatment supplies must be stored in a secure, limited-access location under 
the storage conditions specified on the supply label.  Site storage conditions should 
be monitored by the site personnel for adherence to label specifications and 
reviewed during site visits.
7.4.1.5.6
Dispensing
The investigator or qualified designee(s) will dispense trial treatments at the 
designated site(s) to subjects who have provided written informed consent and have 
met the entry criteria.  Clinical supplies may not be used for any purpose other than 
that which is stated in this protocol.
See the Trial Flow Chart in Section 2.2 for a schedule of when clinical supplies are 
to be dispensed to the subjects.
7.4.1.5.7
Replacement of Investigational Product
Replacement of trial medication will be performed only in limited cases (eg, lost, 
broken, or spilled treatment bottles).  In the event that replacement units are needed, 
the IVRS help desk should be contacted.  The IVRS help desk will be responsible for 
obtaining permission to release replacement units from the sponsor.
7.4.1.5.8
Investigational Medicinal Product Accountability
Accurate and current accounting of the dispensing and return of investigational 
products will be maintained on an ongoing basis by a member of the trial site staff:
•
Investigational medicinal products dispensed to each subject will be recorded in 
the trial-specific Subject IMP Accountability Log (or equivalent document 
approved by the sponsor).
The Subject IMP Accountability Log will be verified by the sponsor's trial monitor.  
The original Subject IMP Accountability Log will be approved by the investigator and 
retained at the trial site and a copy supplied to the sponsor when the trial is 
complete.
Each subject will be instructed by the investigator or designee to return all unused 
and partially used test articles to the site at all protocol-specified visits.
The sponsor’s trial monitor will instruct the site on the return of all investigational 
products supplies.  Inventory records must be readily available for inspection by the 
trial monitor and/or auditor, and open to government inspection at any time.
 
 
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7.4.2
Non-Trial Treatments
Subjects who are provided non-trial 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. For example, a subject who attends day care the 
day prior to baseline testing should also attend day care on the day before all 
subsequent visits that include ADAS-Cog and ADCS-ADL testing.
7.4.2.1
Prior and Concomitant Medications
7.4.2.1.1
Medications, Supplements, and Other Substances Prohibited 
During the Trial
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 associated21,22
with substantial increased risk of Stevens-Johnson Syndrome and 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 (eg, celecoxib, valdecoxib, meloxicam) carbamazepine, 
phenytoin, valproic acid, nevirapine, lamotrigine, and chlormezanone
7.4.2.1.2
Concomitant Medications, Supplements, and Other Substances 
Allowed During the Trial
Medications, supplements, and other substances allowed during the trial include, but 
are not limited to, those listed in Table 2.  Note that the use of any concomitant 
medication must relate to the documented medical history, prophylaxis, or an 
adverse event of the subject.
 
 
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Table 2 Medications, Supplements, and Other Substances Allowed During the Trial
Acetylcholinesterase inhibitors (eg, donepezil, tacrine, rivastigmine, galantamine)
Memantine
Huperzine A
Vitamin E
Herbal supplements from Ginkgo biloba, ginseng, Huperzia serrata (Qian Ceng Ta)
Medical foods/supplement (eg, Axona®, Souvenaid® )
Estrogens and estrogen-like compounds 
Antihypertensives
Nonsteroidal anti-inflammatory drugs (NSAIDs)
Cycloxygenase 2 inhibitors
Neuroleptics: asenapine, aripiprazole, olanzapine, quetiapine, risperidone, ziprasidone
Analgesics/Narcotics: Use of ≤2 doses/week or short-term use (<1 month) of more than 2 doses/week for 
temporary conditions is acceptable (eg, codeine, morphine , hydromorphone, oxycodone, propoxyphene 
(Darvon) and its variations, & combination products that contain a narcotic).
Sedative/benzodiazepines: Use of the following medications is acceptable: trazodone, mirtazapine, zaleplon ≤ 
5 mg, zopiclone ≤ 7.5 mg, eszopiclone ≤ 3 mg, zolpidem ≤ 5 mg, or lorazepam ≤ 1.0 mg.  For other medications 
in this category not specified here, please contact the Sponsor for guidance.
Antidepressants:  bupropion, citalopram (40 mg or less), escitalopram, fluoxetine, mirtazapine, paroxetine, 
sertraline, venlafaxine. Use of 50mg or less at night of nortriptyline or desipramine during the trial is acceptable.
Pramipexole, ropinirole, and L-dopa (for sleep only):  Treatment for restless leg syndrome
Pregabalin and gabapentin: Treatment for neuropathic pain
Anticholinergic medications: Daily use of anticholinergic medications for incontinence (eg, oxybutynin, 
tolterodine, darifenacin, solifenacin, trospium, fesoterodine), nasal spray for rhinorrhea (ipratropium) or inhalants 
for pulmonary disorders (eg, tiotropium) is acceptable.
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  
Corticosteroids: Low dose oral treatment with the equivalent of 10 mg prednisone or less, short-term (<3 
weeks) oral treatment with the equivalent of 60 mg prednisone or less, if needed for management of rash, local 
injections into joints or bursae, topical use, inhaled or nasal use
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
7.4.3
Procedures for Monitoring Subject Compliance With Administration of 
Trial Treatments
At all protocol-specified visits, the investigator or qualified designee is to record 
whether treatment had been taken per protocol in the preceding interval.
7.5
Trial Schedule
The visit-by-visit schedule of trial activities is provided in the Trial Flow Chart in 
Section 2.2.
The timing of each subject visit is relative to Study Day 1 of that subject, with Study 
Day 1 defined as the date of randomization into the initial 78-week trial (which 
should also be the date of the first administration of trial medication in the initial 78 
week trial) (Section 7.4.1.1).
 
 
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All visits should be performed within the windows specified in Section 2.2, the Long 
Term Safety Trial Flow Chart.  Every attempt should be made to have each subject 
attend each visit as scheduled.  However, if a subject is unable to attend a visit 
within the specified windows, the visit should be scheduled as closely as possible to 
these windows.  A subject should not miss a protocol-specified visit due to 
scheduling difficulties.
The trial partner is expected to accompany the subject to all trial visits. 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. Other exceptions to 
trial partner attendance include visits scheduled to conduct procedures. For 
additional details, the Sponsor may be consulted.
7.6
Trial Procedures
The Trial Flow Chart in Section 2.2 summarizes the trial procedures to be 
performed at each visit.  Individual trial procedures are described below.
The order in which evaluations are completed is at the discretion of the investigator 
in order to best accommodate the needs of the subject/caregiver as well as the 
logistical considerations of the coordinator/staff.
In order to minimize variability of evaluations, it is preferred that the same individuals 
perform the same types of evaluations for all subjects at each trial site.  In addition, 
blood samples for a visit should NOT be collected prior to the testing of the clinical 
outcomes.
1. Explain Trial and Obtain Written Informed Consent
The investigator or qualified designee will explain the trial to the subject, answer 
all of his/her questions, and obtain written informed consent before performing 
any trial-related procedure.  A copy of the informed consent will be given to the 
subject (see Section 9.1.2 for further description of the Informed Consent).
Given the trial population and the duration of the trial, 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.
2. Issue or Collect Subject Identification Card
The investigator or qualified designee will provide the subject with a Subject 
Identification Card after the subject provides written informed consent.  The 
investigator or qualified designee will retrieve the card from the subject at the last 
contact (see Section 9.1.3 for further description of the Subject Identification 
Card).
 
 
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3. Record Concomitant Medications
A record of concomitant medication taken by the subject during the trial is to be 
obtained.
4. Record (Serious) Adverse Events
See Section 7.7.2.4, for instructions on the assessment and reporting of 
(Serious) Adverse Events and Section 7.7.2.5 for instructions on the reporting of 
(Serious) Adverse Events to the sponsor.
5. Vital Signs
The following vital signs will be measured and recorded:  pulse (beats/minute), 
BP (mm Hg), temperature (C/F), and respiratory rate (breaths per minute).  
Blood pressure should be measured in the sitting position.
6. 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. Physical & Neurological Examinations
A physical examination including a standard neurological examination will 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.
8. Mini-Mental State Examination (MMSE)
The MMSE will be administered to the subject in paper form and scored and 
recorded by the principal investigator or trained designee according to the 
instructions in the Manual of Assessments.    
9. Columbia Suicide Severity Rating Scale (C-SSRS)
The C-SSRS will be administered to the subject and scored and recorded by the 
principal investigator or trained designee according to the instructions in the 
Manual of Assessments. 
 
 
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The C-SSRS provides a detailed assessment of suicidal ideation and behaviors. 
The paper version of the C-SSRS will be completed at each visit as indicated in 
the Trial Flow Chart (and unscheduled visits as clinically indicated). 
Subjects 
who at any time during this study spontaneously report AEs of suicidal ideation or 
behavior with intent (with or without a plan), either as outpatient or during visit 
interviews, must be assessed by the Investigator and referred for further mental 
health evaluation as clinically indicated.  Subjects who report suicidal ideation 
with intent, with or without a plan or method (ie, 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.  As part of site validation, 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. All reports of suicidal 
ideation or behavior must be recorded as an Event of Clinical Interest (ECI).
10.Neuropsychiatric Inventory (NPI)
The NPI will be administered to the subject’s trial partner/caregiver in paper form 
and scored and recorded by the principal investigator or trained designee 
according to the instructions in the Manual of Assessments.
11.Review Inclusion/Exclusion Criteria
The inclusion and exclusion criteria will be reviewed by the investigator or 
qualified designee to ensure that the subject qualifies for the trial.
12.Alzheimer’s Disease Assessment Scale Cognitive Subscale (ADAS-Cog)
The ADAS-Cog will be administered to the subject in paper form and scored and 
recorded by the principal investigator or trained designee according to the 
instructions in the Manual of Assessments.  
13.Alzheimer’s Disease Cooperative Study Activities of Daily Living Inventory 
(ADCS-ADL)
The ADCS-ADL will be administered to the subject’s trial partner/caregiver in 
paper form and scored and recorded by the principal investigator or trained 
designee according to the instructions in the Manual of Assessments.
14.12-Lead Electrocardiogram (ECG)
A 12-Lead Electrocardiogram will be performed according to the instructions in a 
separate ECG Instruction Manual.
 
 
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15.Skin Examinations
To monitor for hypopigmentation, a skin examination will be performed at the visit
specified in Section 2.2, Trial Flow Chart. The 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 for further follow-up.
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) greater than 3x3 cm  
b) a smaller area (eg, 1x1 cm) on the face or hands 
c) a speckled pattern involving a larger amount of body surface area or  
d) a smaller area (eg, 1x1 cm) of complete pigment loss.
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 (eg, 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.
 
 
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16.Laboratory Tests
Laboratory tests for hematology, blood chemistry, and urinalysis are specified in
Table 3.  
Table 3 Laboratory Tests
Hematology
Chemistry
Urinalysis
Basophils
Albumin
Blood
Eosinophils
Alkaline phosphatase
Glucose
Hematocrit
ALT (SGPT)
Ketones
Hemoglobin
AST (SGOT)
Microscopic exam
Lymphocytes
Bicarbonate
pH
Monocytes
Blood urea nitrogen (BUN)
Protein
Neutrophils
Calcium
Specific gravity
Platelets
Chloride
RBC
Cholesterol
WBC
Creatinine
Glucose
Inorganic phosphorus
LDH
Potassium
Sodium
Total Bilirubin
Total protein
EIA=enzyme immunoassay; FTA-ABS=fluorescent treponemal antibody absorption
17.Pharmacokinetic/Pharmacodynamic Blood Samples
Blood samples for PK/PD analyses should be collected, processed, stored, and 
packaged according to the instructions in the Laboratory Manual.
Record the following information for each PK/PD blood sample collected:
•
Date and time of each PK/PD blood sample
•
Date and time of the last two doses of trial medication before each PK/PD 
blood sample
Careful attention to the collection, handling, and storage of the PK/PD blood 
samples is essential to reduce the risk of hemolysis and PK/PD variability. Any 
deviations from the PK/PD blood collection schedule, such as a missing or 
breaking a sample, should be documented
 
 
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18.Clinical Dementia Rating (CDR)
The CDR will be administered to both the subject and the subject’s trial 
partner/caregiver in paper form, and the CDR Sum of Boxes  (CDR-SB) will be 
scored and recorded by the principal investigator or trained designee according 
to the instructions in the Manual of Assessments.  
19.Modified Resource Utilization in Dementia (RUD) Lite Questionnaire
A modified RUD Lite Questionnaire will be administered to the subject’s trial 
partner/caregiver in paper form and recorded by the principal investigator or 
trained designee according to the instructions in the Manual of Assessments.
20.Health Economic Assessment (HEA)
The HEA will be administered to the subject’s trial partner/caregiver in paper 
form and recorded by the principal investigator or trained designee according to 
the instructions in the Manual of Assessments.
21.EuroQol Five Dimension Questionnaire (EQ-5D)
The EQ-5D will be completed by the subject’s trial partner/caregiver in paper 
form and reviewed by the principal investigator or trained designee according to 
the instructions in the Manual of Assessments.
22.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.  
Any unscheduled MRI’s collected during the long term safety trial should be read 
by the central reader.
23.Dispense Trial Medication
The investigator or qualified designee will dispense the subject's treatment kit 
(see 
Section 7.4.1.5.8) 
and 
instruct 
the 
subject 
and 
subject’s 
trial 
partner/caregiver regarding dosing with trial medication (see Section 7.4.1.3.2).
24.Medication Compliance/Drug Accountability Assessment
The investigator or qualified designee will account for trial medication as 
described in Section 7.4.1.5.8.
25.Visual Acuity Test
Visual acuity test will be attempted under standardized conditions according to 
the MK-8931 BACE Program Manual of Ophthalmic Procedures.  Use of the 
Early Treatment Diabetic Retinopathy Study (ETDRS) chart or equivalent (eg, 
Landolt ‘C’ ETDRS chart or Snellen chart) for the test should be attempted first.  
If cognitive impairment interferes with these tests, Teller Acuity Cards may be 
attempted to assess visual acuity during the trial.  For some subjects, dementia 
severity may prevent accurate assessment of visual acuity.
26.Posterior Eye Exams
Posterior eye exam with dilated funduscopy will be performed to assess retinal 
effects.  These procedures will be performed according to the MK-8931 BACE 
Program Manual of Ophthalmic Procedures.
 
 
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27.Fundus Photography
Fundus photography will be performed at the posterior pole of each eye 
according to the MK-8931 BACE Program Manual of Ophthalmic Procedures.  
Fundus photographs will be read by a central Reading Center designated by the 
Sponsor.
28.Fundus Autofluorescence
Fundus autofluorescence will be measured with a Sponsor-approved instrument 
according to the MK-8931 BACE Program Manual of Ophthalmic Procedures.  
Autofluorescence pattern changes with enlarged areas of hypo- and hyper-
fluorescence will be explored as detailed in the MK-8931 BACE Program Manual 
of Ophthalmic Procedures.
Best efforts will be made to accommodate the FAF assessment.  Where the FAF 
assessment is operationally infeasible sites can enroll subjects without the FAF 
assessment.  FAF images will be read by a central Reading Center designated 
by the Sponsor.
29.Spectral-domain Optical Coherence Tomography (SD-OCT)
SD-OCT images of the retina will be acquired according to the MK-8931 BACE 
Program Manual of Ophthalmic Procedures.  
 
 
 
7.7
Assessments
7.7.1
Efficacy Assessments
7.7.1.1
Primary Efficacy Endpoints
The primary efficacy endpoints are:
1. the change-from-Baseline score in the ADAS-Cog at Week 104 (Visit 13)
2. the change-from-Baseline score in the ADCS-ADL at Week 104 (Visit 13)
7.7.1.2
Exploratory Efficacy Endpoints
The exploratory efficacy endpoints are:
1. the change-from-Baseline score in the ADAS-Cog (at all scheduled timepoints 
with the exception of Week 104),
2. the change-from-Baseline score in the ADCS-ADL (all scheduled timepoints with 
the exception of Week 104)
3. the change-from-Baseline score in the CDR-SB (all scheduled timepoints).
4. the change-from-Baseline score in the MMSE (all scheduled timepoints)
5. the change-from-Baseline score in the NPI (all scheduled timepoints)
6. the Health Economics and Quality of Life Endpoints
CCI
 
 
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7. the Pharmacogenetic AnalysesSafety Monitoring and Assessments
7.7.2
Safety Monitoring and Assessments
7.7.2.1
Safety Endpoints
The same safety parameters and AEs designated as being of special interest in the 
initial 78-week trial will continue to be monitored during the long term safety triaI, as 
follows:1) delirium; and 2) rash ECI (see Section 7.7.2.2.3). Some of these AEs are 
combined into composite endpoints for formal safety analyses (see Table 8).
7.7.2.2
Definition of Terms
7.7.2.2.1
Adverse Event
Per the International Conference on Harmonization (ICH), an adverse event (AE) is 
defined as any untoward medical occurrence in a patient or clinical investigation 
subject administered a pharmaceutical product and which does not necessarily have 
to have a causal relationship with this treatment.  An AE can therefore be any 
unfavorable and unintended sign (including an abnormal laboratory finding, for 
example), symptom, or disease temporally associated with the use of a medicinal 
product, whether or not considered related to this medicinal product.  Any worsening 
(ie, any clinically significant adverse change in frequency and/or intensity) of a 
preexisting condition that is temporally associated with the use of the Sponsor’s 
product, is also an adverse event.
Changes resulting from normal growth and development that do not vary 
significantly in frequency or severity from expected levels are not to be considered 
adverse events.  Examples of this may include, but are not limited to, teething, 
typical crying in infants and children and onset of menses or menopause occurring 
at a physiologically appropriate time.
Progression of the condition under study 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 7.7.2.2.2).
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.
 
 
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7.7.2.2.2
Serious Adverse Event
Serious Adverse Event (SAE) is any untoward medical occurrence or effect that at 
any dose:
1. Results in death;
2. Is life-threatening; 
3. Requires hospitalization or prolongation of existing inpatients’ hospitalization;
4. Results in persistent or significant disability or incapacity; 
5. Is a congenital anomaly or birth defect;
6. 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.
7. Is a cancer;
8. Is associated with an overdose;
Refer to Table 4 for additional details regarding each of the above criteria.
Life-threatening in the definition of a serious adverse event refers to an event in 
which the subject was at risk of death at the time of event; it does not refer to an 
event which hypothetically might have caused death if it were more severe.
Medical judgment should be exercised in deciding whether an adverse 
event/reaction is serious in other situations.  Important adverse events/ reactions 
that are not immediately life-threatening or do not result in death or hospitalization, 
but may jeopardize the subject or may require intervention to prevent one of the 
other outcomes listed in the definition above, should also be considered serious.  
These are considered “Other Important Medical Events”.
For the time period beginning when the consent form is signed until 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 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).
 
 
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Additionally, any serious adverse event, considered by an investigator who is a 
qualified physician to be related to the Sponsor's product that is brought to the 
attention of the investigator at any time outside of the time period specified in the 
previous paragraph also must be reported immediately to the Sponsor. 
All subjects with serious adverse events must be followed up for outcome.
7.7.2.2.3
Events of Clinical Interest
An "Event of Clinical Interest" is a non-serious adverse event or occurrence that is 
designated to be of special interest and must be reported to the sponsor as though it 
were a serious adverse event – as described in Section 7.7.2.5.1.
For the time period beginning when the consent form is signed until 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 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).
The following events are considered events of clinical interest for this trial:
1. An overdose of Sponsor's product, as defined in Section 7.7.2.2.4, Overdose, 
that is not associated with clinical symptoms or abnormal laboratory results is to 
be reported as a non-serious ECI, using the terminology "accidental or intentional 
overdose without adverse effect.”
2. Adverse events associated with potential for abuse (euphoric mood, mania, 
hypomania, or similar events; see separate guidance document for details);
3. An elevated AST or ALT lab value that is 3 x the upper limit of normal (ULN) 
and an elevated total bilirubin lab value that is 2 x ULN and, at the same time, 
an alkaline phosphatase lab value that <2 x ULN, as determined by way of 
protocol-specified laboratory testing or unscheduled laboratory testing is to be 
reported as a non-serious ECI.
4. ALT or AST ≥3 x ULN and a ≥20% increase from baseline;
5. **Incident vasogenic edema in post-treatment MRI scans;
6. **Incident macrohemorrhage in post-treatment MRI scans;
7. **Incident superficial siderosis in post-treatment MRI scans;
8. **Incident microhemorrhage in post-treatment MRI scans;
9. Suicidal ideation or behavior (see separate guidance document for details);
 
 
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10.Delirium that is ascertained by the investigator or a qualified designee. The 
Confusion Assessment Method (CAM) should be used to verify delirium 
whenever feasible (10);
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 7.3.3);
12..Adverse events of clinically significant skin hypo- or depigmentation (see 
Section 5.4 for details);
 
 
 
 
* As determined by the central Reading Center designated by the Sponsor.
** 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.
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. 
7.7.2.2.4
Overdose
An overdose is a significant variation above the recommended/scheduled dosage for 
a product.  In this current trial an overdose of the investigational product MK-8931 is 
the administration of at least three times the daily dose of trial medication in a 
calendar day as specified in Section 7.4.1.3.2 of this protocol.
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. 
CCI
 
 
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Paper reporting procedures can be found in the Investigator Trial File Binder (or 
equivalent).
7.7.2.2.5
Clinical Supply Complaint
A clinical supply complaint is defined as any communication concerning 
manufacturing, packaging, labeling or distribution (including adverse storage at 
depots) of a clinical supply that describes a potential defect related to its identity, 
strength, quality or purity after it is released and left the control of a Merck-approved 
packaging facility for distribution.  A clinical supply GCP inquiry is defined as any 
communication of an event taking place at a trial site after the product was 
satisfactorily received at the trial site, which puts product disposition in question.  
Examples include adverse storage of product at the trial site and dosing past 
expiration.  Alleged Counterfeit, Diversion and Tampering (CDT), adverse events 
and trial site errors/issues which do not put product disposition in question should 
not be reported.
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.  This responsibility includes reporting of all clinical 
supply complaints and/or clinical supply GCP inquiries to the Sponsor.
Clinical supplies complaints and GCP inquiries, as defined above, must be reported 
to the Sponsor within 1 business day of first becoming aware of the issue.   Sponsor 
contact information and related reporting details can be found in the Investigator 
Trial File Binder.
7.7.2.2.6
Planned Hospitalization
A hospitalization planned by the subject prior to signing the ICF is considered a 
therapeutic intervention and not the result of a new SAE and should be recorded as 
medical history.  If the planned hospitalization or procedure is executed as planned, 
the record in the subject’s medical history is considered complete.  However, if the 
event/condition worsens during the trial, it must be reported as an AE.
7.7.2.3
Monitoring
7.7.2.3.1
Monitoring Adverse Events
All adverse events that occur after the consent form is signed but before 
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. From the time of 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 
 
 
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forms/worksheets.  The reporting timeframe for adverse events meeting any serious 
criteria is described in section 7.7.2.2.2. The investigator will make every attempt to 
follow all subjects with non-serious adverse events for outcome.  
Electronic reporting procedures can be found in the EDC data entry guidelines. 
Paper reporting procedures can be found in the Investigator Trial File Binder (or 
equivalent).
Subjects will be questioned and/or examined by the investigator or a qualified 
designee for evidence of AEs.  The questioning of subjects with regard to the 
possible occurrence of adverse events will be generalized such as, "How have you 
been feeling since your last visit?”  The presence or absence of specific AEs should 
not be elicited from subjects.  This does not preclude use of other sources of 
information that may suggest potential AE’s (eg. NPI, C-SSRS). 
Subjects having AEs will be monitored with relevant clinical assessments and 
laboratory tests, as determined by the investigator.
Adverse events, actions taken as a result of AEs, and follow-up results must be 
recorded in the electronic Case Report Forms (eCRF; Section 9.2), as well as in the 
subject's source documentation.  Follow-up laboratory results should be filed with 
the subject's source documentation.
For all AEs that require the subject to be discontinued from the trial and SAEs, 
relevant clinical assessments and laboratory tests will be repeated as clinically 
appropriate, until final resolution or stabilization of the event(s).
7.7.2.3.2
Monitoring Laboratory Assessments
All laboratory assessments will be performed centrally at a certified laboratory 
selected by the sponsor.  The clinical laboratory values will be reported to the 
investigator by the laboratory and he/she will review them for significance and 
consideration as an AE.
7.7.2.4
Assessment of Adverse Events
An investigator who is a qualified physician will evaluate all adverse events with 
respect to the elements outlined in Table 4.  The investigator’s assessment of 
causality is required for each adverse event.  Refer to Table 4 for instructions in 
evaluating adverse events.
 
 
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Table 4  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. 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.
WHERE RESTRICTED LOCALLY BY IRBS, (INCLUDING SITES IN FRANCE): FOR SAEs JUDGED TO BE RELATED TO TRIAL 
DRUG, SUBJECTS CANNOT BE RECHALLENGED WITH 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 there is another obvious cause of the AE.  (Also entered for a subject with overdose without an associated AE.)
 
 
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7.7.2.4.1
Reference Safety Information (RSI) for the Assessment of 
Expectedness of Adverse Events
The Reference Safety Information (RSI) for assessing the expectedness of an 
adverse event for the investigational product MK-8931 in this current trial is to be the 
most recent Investigator’s Brochure for MK-8931.
7.7.2.4.2
Potential Toxicities of Investigational Products
Refer to the Investigator’s Brochure for additional information on AEs related to 
toxicities observed to date.
7.7.2.5
Reporting Safety Observations by the Investigator to the Sponsor
7.7.2.5.1
Expedited Reporting 
Any occurrence of the following events or outcomes in a subject in the trial must be 
reported expeditiously by the investigator or qualified designee to the sponsor’s 
Global Safety representative or designee by entering all information relevant to the 
event in the appropriate eCRFs within 24 hours of learning of the event.  The 
Global Safety Intake Form – or a sponsor-approved equivalent form –  should be 
used in the event that the EDC system is not functioning.
1. SAE (including SAEs associated with overdose, pregnancy, exposure during 
pregnancy or lactation);
2. Death;
3. Planned hospitalizations (not previously reported in the medical history);
4. Events of Clinical Interest (ECI);
5. Cancer.
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 
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 
randomization through 14 days following cessation of Sponsor’s product must be 
reported by the investigator.  All reported pregnancies  must be followed to the 
completion/termination of the pregnancy. Pregnancy outcomes of spontaneous 
abortion, missed abortion, benign hydatidiform mole, blighted ovum, fetal death, 
intrauterine death, miscarriage and stillbirth must be reported as serious events 
(Important Medical Events). If the pregnancy continues to term, the outcome (health 
of infant) must also be reported.
 
 
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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).
If the investigator is unsure about when to report an observation from the lists above, 
the event or outcome should be reported to the sponsor or designee by entering all 
information relevant to the event in the appropriate eCRFs within 24 hours of 
learning of the event.  The Global Safety Intake Form – or a sponsor-approved 
equivalent form – should be used in the event that the EDC system is not 
functioning.
Any observation reported to the sponsor or designee that is also an AE, is to be 
recorded in the eCRF (Section 9.2), as well as in the subject's source 
documentation, along with any actions taken as a result of AE and follow-up results.
If an autopsy is performed, available results should be entered into the EDC
screens.
The investigator must assess causality of the event as relative to the investigational 
product administered in the trial as described in Section 7.7.2.4.2.
7.7.2.5.2
Expedited Reporting by the Sponsor to a Regulatory Health 
Authority
Global Safety will monitor data for safety.  The Sponsor will manage the expedited 
reporting of relevant safety information to concerned health authorities, competent 
authorities, and IRBs/IECs in accordance with local laws and regulations.
7.7.2.5.3
Unblinding Treatment for a Subject During the Trial
To assess an occurrence of a safety observation, Global Safety may unblind the 
treatment of any subject for whom a safety observation was reported by the 
investigator to the sponsor as described in Section 7.7.2.5.1.
When the investigator or sub-investigator needs to identify the drug used by a 
subject and the dosage administered in case of emergency eg, the occurrence of 
serious adverse experiences, 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 
(eg, date and reason) must be documented promptly, and the Sponsor Clinical 
Director notified as soon as possible.  Only the principal investigator or delegate and 
the respective subject’s code should be unblinded.  Trial site personnel and Sponsor 
personnel directly associated with the conduct of the trial should not be unblinded.
7.8
Criteria for Early Termination of the Trial
The trial may be terminated early by the eDMC for safety concerns or based on the 
results of the interim efficacy analysis for futility of the initial 78-week trial (see
Section 8.2.8).
8.0 STATISTICAL AND ANALYTICAL PLAN
This section outlines the statistical analysis strategy and procedures for the long 
term safety trial.  Changes to analysis plans made after the protocol has been 
finalized, along with an explanation as to when and why they occurred, will be listed 
in the Clinical Study Report (CSR) for the trial.  Post hoc exploratory analyses will be 
clearly identified in the CSR.  No separate Statistical Analysis Plan (SAP) will be 
issued for this trial.  The statistical analysis of the data obtained from this trial will be 
the responsibility of the designee from the Clinical Biostatistics Department of the 
sponsor.
References to either the Screening Visit or the Baseline Visit pertain to the initial 78-
week trial. The exact timing of the predose efficacy assessments (screening or 
baseline) is provided in the Trial Flowchart (Section 2.2). Without loss of generality, 
and within Section 8 only, a distinction will not be made between the Screening Visit 
and the Baseline Visit; all predose assessments will be referred to generally as 
"baseline" assessments. in the event that an assessment was taken at both the 
Screening Visit and at the Baseline Visit, the data from the Baseline Visit will be 
used in the analysis.
 
 
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8.1
Subject Populations to be Analyzed
The analysis populations are the Full Analysis Set population, the Modified Full 
Analysis Set population and the All-Patients-as-Treated population.
•
The Full Analysis Set (FAS) population will serve as the primary population 
for the analysis of efficacy data in this trial.  The FAS population consists of all 
randomized subjects who have a baseline observation and at least one 
within-analysis-window (± 6 weeks) post-Randomization observation for the 
analysis endpoint subsequent to at least one dose of trial treatment. Subjects
will be included in the treatment group to which they were randomized. Since 
the Sponsor’s standing internal DMC (siDMC) reviewed unblinded analyses 
(including the ADAS-Cog) from the first 200 subjects enrolled in the initial 78-
week trial, these subjects will be excluded from the FAS population, and 
hence all efficacy analyses.
All available observations from the initial 78-week trial will be included in the 
relevant model-based FAS analyses. Observations from the long term safety 
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 Visit 10B and within 
the 28 days following Visit 10B. 
•
The Modified Full Analysis Set (MFAS) population will be utilized for 
sensitivity analyses and is defined identically to the FAS population with one 
exception: subjects will 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 All-Patients-as-Treated (APaT) population will be used for the analysis of 
safety data in this trial.  The APaT population consists of all randomized 
subjects who received at least one dose of trial treatment, with subjects 
included in the treatment group corresponding to the trial treatment they 
actually received.  For most subjects this will be the treatment group to which 
they were randomized. Subjects who take incorrect trial treatment for the 
entire treatment period will be included in the treatment group corresponding 
to the trial treatment actually received. Since the siDMC reviewed unblinded 
analyses from the first 200 subjects enrolled in the initial 78-week trial, these 
subjects will be excluded from the primary safety analyses.
•
For laboratory, vital sign, and ECG endpoints, at least one postdose 
measurement is required for inclusion in the analysis of each specific 
parameter, 
and 
a 
Baseline 
measurement 
is 
required 
for 
change-from-Baseline analyses (safety only).
 
 
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8.2
Efficacy Analyses
Details pertaining to the analysis of all endpoints are discussed below. Table 5
provides a summary of the Primary Endpoints to be analyzed, as well as the 
analysis approaches that will be used.
The primary analysis approach will include all efficacy observations in the FAS 
population, including those obtained after the discontinuation of study medication.
Table 5 Analysis Strategy for Primary Endpoints
Endpoint/Variable
(Description, Time 
Point)
Primary vs.
Supportive
Approach
Statistical
Method†
Analysis
Population
Missing Data
Approach
Primary Endpoints
Primary Endpoints:
CFB at Week 104 (Visit 
13) in ADAS-Cog score
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
CFB at Week 104 (Visit 
13) in ADCS-ADL score
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
The primary model contains categorical terms for treatment, time, geographic region, gender, APOE genotype, 
study cohort (from initial 78-week trial), and the interaction of time-by-treatment, with the Baseline values of 
MMSE, and age included as continuous covariates. Terms for the baseline value and the baseline-by-time 
interaction of the dependent variable will also be included.
ADAS-Cog=Alzheimer’s Disease Assessment Scale Cognitive subscale; ADCS-ADL=Alzheimer’s Disease 
Cooperative Study Activities of Daily Living Inventory; CDR-SB=Clinical Dementia Rating Sum of Boxes; 
CFB=Change from Baseline; ANCOVA=Analysis of Covariance; cLDA=Constrained Longitudinal Data Analysis; 
FAS=Full Analysis Set; MMSE=Mini-Mental State Examination; NA=Not Applicable; NPI=Neuropsychiatric 
Inventory; P=Primary; S=Supportive.
 
 
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8.2.1
Primary Efficacy Analysis
The primary efficacy endpoints are the change from Baseline (CFB) in ADAS-cog 
score and the change from Baseline in ADCS-ADL score at Week 104 (Visit 13).
A delayed start design will be used to support the potential disease modifying effect 
of MK-8931 by comparing the 40mg/40mg arm to the Pbo/40mg 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 18 months.
All available data from the initial 78-week trial will be utilized in the analyses, even 
that from subjects who do not continue into long term safety 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 or 60 
mg excluded from the analysis).
The primary analysis approach will be conducted separately on each of the 
endpoints. 
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 will adjust for the categorical factors of 
geographic region (US/Canada, Europe/Australia/New Zealand, Japan, Rest of the 
World), treatment (one or two remaining dose[s] of MK-8931 or placebo), gender, 
APOE genotype (APOE 4 positive, APOE 4 negative), baseline use of Vitamin E (0-
400 IU/day, > 400 IU/day), baseline AD medication (use of AChEI or memantine, no 
use of AChEI or memantine), study cohort from the initial 78-week trial (Safety 
Cohort, Main Cohort) and the interaction of time-by-treatment, with the baseline 
values of MMSE and age included as continuous covariates. The baseline value of 
the dependent variable, as well as the baseline-by-time interaction term will also be 
included. The Week-78 change-from-Baseline mean treatment differences (MK-
8931 – placebo), corresponding confidence intervals (CIs), and P-values will be 
estimated from this model.  An unstructured covariance matrix will be used to model 
the correlation among repeated measurements. 
Three supportive analyses will be conducted on each of the Coprimary Endpoints. 
These analyses will be conducted to assess the effect of 1) missing data using a 
pattern-mixture model (“tipping-point” analysis), 2) the use of off-regimen data after 
the subject has permanently discontinued trial medication or after the subject has 
initiated AChEIs and 3) analyzing the data using the cLDA model on the MFAS 
population.
 
 
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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 8.2.10) 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.
For the second sensitivity analysis (excluding observations obtained after study 
medication discontinuation or after the initiation of AChEIs, memantine, or Vitamin 
E), 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 endpoints will be conducted using a constrained longitudinal 
data analysis (cLDA) method proposed by Liang and Zeger [11]. 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.
Additional details pertaining to the cLDA model are included in Section 12.5. 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.
Although the baseline measurement is included in the response vector, it is 
independent of treatment.  Hence, the Baseline means are constrained to be the 
same for different treatment groups.  Note that 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 analysis of covariance (ANCOVA) model that 
uses the Baseline value as a covariate.  However, unlike longitudinal ANCOVA, the 
cLDA model accounts for variability in the baseline values, thus providing more 
accurate standard errors and CIs for individual treatment effects.  Additional details 
pertaining to the use of the cLDA model in this trial are included in Appendix 4.
8.2.2
Multiplicity
As there are no formal hypotheses for the long term safety 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 78-
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.
 
 
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8.2.3
Exploratory Analyses
It is noted that no supportive analyses (eg, to account for the effect of missing data 
or protocol violations) will be conducted for any of the exploratory analyses. Basic 
summary statistics will be provided (mean, standard deviation, quartiles, counts and 
percentages, as appropriate) by treatment, timepoint, and baseline AD severity 
(MMSE >20,  MMSE 20) for all exploratory endpoints.
8.2.4
Subgroup Analyses
Subgroup analyses will be conducted on ADAS-Cog, ADCS-ADL, NPI, and MMSE 
at Week 104.  The consistency of treatment effect across various subgroups will be 
assessed through the computation of within-group summary statistics (model-based 
and as-observed)  Further, model-based between-group treatment differences 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 85 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 (< trial median age, trial median age);
•
Race (white, black, Asian, other);
•
Randomization Cohort (Safety Cohort, Main Cohort)
•
Ethnicity (Hispanic, Not Hispanic);
•
Geographic Region (US/Canada, Europe/Australia/New Zealand, Japan, Rest 
of the World);
•
APOE Genotype (APOE 4 positive, APOE 4 negative);
•
Disease Severity via MMSE (mild AD:  MMSE >20; moderate AD:  
MMSE 20);
•
Trial Completion Status (Completer, Non-completer);
•
AD Treatment at Screening (use of AChEI alone, use of memantine alone, 
use of AChEI and memantine, no use of AChEI or memantine);
•
Vitamin E use at Screening (0-400 IU/day, > 400 IU/day)
•
Behavioral Symptoms at Baseline (without symptoms NPI = 0, with symptoms 
NPI > 0);
•
Total Hippocampal Volume (AD profile positive, AD profile negative);
•
Evidence of Brain Amyloidosis in CSF and/or amyloid PET substudies 
(positive, negative);
•
Highest Education Level (No Undergraduate Degree, Undergraduate Degree 
or Higher)
 
 
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Regarding total hippocampal volume, an AD profile will be determined as described 
in the technical manual. The precise criteria to define an AD profile positive and AD 
profile negative subjects have not yet been determined but will be selected based on 
ongoing research at academic sites which is expected to be published before the 
end of this trial.  Similarly, cutoffs for evidence of brain amyloidosis, as measured by 
CSF and PET, will also be defined based on ongoing studies. All cutoffs will be 
prespecified prior to the final database lock and will be documented in a memo-to-
file. 
8.2.5
Parameter Estimates for Primary Endpoints
8.2.5.1
Assumptions for the Effect of MK-8931
Extrapolations out to 24 months (Week 104) were performed on the 18-month 
(Week 78) parameter assumptions used in the initial 78-week trial and these 
extrapolations are presented below in Table 6.
Table 6 Parameter Assumptions for Progression Rate on Placebo, Standard Deviations, and Within 
Endpoint Correlations for ADAS-Cog, ADCS-ADL, and CDR-SB
Endpoint
104-Week Placebo/ 
MK-8931 40 mg
Progression Rate
Baseline Standard
Deviation
104-Week 
Standard
Deviation
Correlation
(Baseline, Week 104)
ADAS-Cog
7.45
7.75
14.97
0.65
ADCS-ADL
-11.73
10.71
20.21
0.61
CDR-SB
2.91
2.28
4.65
0.56
ADAS-Cog=Alzheimer’s Disease Assessment Scale Cognitive subscale; ADCS-ADL=Alzheimer’s Disease 
Cooperative Study Activities of Daily Living Inventory; CDR-SB=Clinical Dementia Rating Sum of Boxes
8.2.5.2
Power Calculations
Power calculations for the change-from-baseline treatment difference at 24 months 
(Week 104) were performed (via simulation) for ADAS-Cog and ADCS-ADL, even 
though there are no formal hypotheses for these endpoints in the long term safety 
trial. As shown in Table 7 both of these hypotheses are underpowered at Week 
104, both marginally and when applying an informal sequential testing approach. 
Specifically, it is possible that formal statistical significance may be observed in the 
initial 78 week trial (under the prespecified multiplicity approach), while nominal 
marginal significance (ie, p-value < 0.02495) fails to be observed at Week 104, 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.
 
 
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Table 7 Power Calculations (MK-8931 40 mg / MK-8931 40 mg vs. Placebo / MK-8931 40 mg)
Marginal Probability†
(%)
ADAS-Cog at Week 104
62.3
ADCS-ADL at Week 104
74.1   
ADAS-Cog and ADCS-ADL at Week 104
48.0  
Sequential Probability
Success‡ for ADAS-Cog and ADCS-ADL at Week 78 and ADAS-Cog at Week 104
58.0    
Success‡ for ADAS- Cog and ADCS-ADL at Week 78  and ADCS-ADL at Week 
104
66.5     
Success‡ for ADAS-Cog  and ADCS-ADL at Week 78  and ADAS-Cog and ADCS-
ADL at Week 104
46.1    
Conditional Probability
Success‡ for ADAS-Cog at Week 104 given success on ADAS-Cog and ADCS-
ADL at Week 78
68.4      
Success‡ for ADCS-ADL at Week 104  given success on ADAS-Cog and ADCS-
ADL at Week 78
78.4     
Success‡ for ADAS-Cog  and ADCS-ADL at Week 104  given success on ADAS-
Cog and ADCS-ADL at Week 78
54.4      
† Marginal power calculations at Week 104 do not require success at Week 78.
‡ 40 mg dose only
Calculations are based on N=1710 randomized (570 subjects/arm) incorporating the assumed dropout 
rate of 30% at Week 78 and 45% at Week 104.( α = 0.0249).
8.2.6
Dropping Dose Arms
In the event of a dose being dropped, all subjects will receive the remaining active 
dose.
 
 
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8.2.7
Accounting for Missing Data
Common reasons for discontinuation from the trial may include lack of efficacy, 
clinical or laboratory 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 missing-completely-at-random 
(MCAR).  On the other hand, missing data caused by discontinuation due to lack of 
efficacy may be missing-at-random (MAR) because the discontinuation may depend 
on the observed efficacy outcomes.  The MAR or missing-not-at-random (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 prior trial results, missing data due to other reasons is relatively infrequent.
No explicit imputation of missing data (beyond the limited imputation performed 
within an assessment) will be done for the primary analysis approach.  
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(25,26,27), 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:
1) Using a Markov Chain Monte Carlo method(28), 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 8931017. This step will generate m monotone-missing datasets.
2) 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 8931017. This step will generate m complete 
datasets. 
3) 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).
 
 
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4) Analyze each of the post-imputation complete datasets using the primary 
model, obtaining point estimates for the mean of interest (eg, change-from-
baseline treatment difference at 104 weeks) and the associated variance.
Using “proc mianalyze” within SAS 9.3, the m=50 means and variances from the m
analyses will be combined to obtain the final test statistic and p-value(25). The final 
test statistic ܳത/ (T(1/2)) is approximately distributed as tν, where ܳതis the sample 
mean of the m mean estimates, T=ܷഥ+ (m+1) (B/m), ܷഥis the sample mean of the m
variance estimates, and B is the sample variance of the m mean estimates. The 
degrees of freedom, ν, will be computed as follows(29), ν = [(ν1)-1 + (ν2)-1]-1, where  ν1
= (m-1) [ 1 + (ܷഥ/(1+m-1) B)]2 and ν2 = (1-γ) ν0 (ν0 +1) / (ν0 +3), with γ = (1+m-1) B / T
and where ν0 represents the complete-data degrees of freedom .
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 (ie, 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 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.
Handling of Missing Items Within a Clinical Assessment
The final scores of the ADAS-Cog, ADCS-ADL, NPI, MMSE, and CDR-SB are all 
constructed from multiple subquestions within each assessment. It is possible that 
one or more subquestions may be missing within each assessment. In this event, 
the last recorded score for this subquestion(s) may be carried forward from the most 
recent postdose visit (Last Observation Carried Forward approach). In a similar 
fashion, missing baseline values may 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 
 
 
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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-ADL only (from the initial 78-week trial): Past experience 
indicates that some subquestions on the ADCS-ADL 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-
ADL (and the subsequent removal of the subject from the primary ADCS-ADL 
population), the worst possible score for that subquestion will be imputed. Note that 
this imputation approach will only be implemented for ADCS-ADL (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 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.  
CDR-SB, ADCS-ADL, and NPI: The CDR-SB, ADCS-ADL, and NPI are all 
administered to the caregiver, 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-ADL 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.
8.2.8
Interim Analysis
Access to Unblinded Reports
The independent eDMC will routinely evaluate unblinded safety analyses of all trial 
subjects while the initial 78 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 78-week trial.
 
 
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8.3
Safety Analysis
Subjects from all three arms (40 mg / 40 mg, 12 mg / 12 mg, Pbo / 40 mg) will be 
included in the safety analyses (with any subject treated with MK-8931 60 mg still 
excluded from the primary analysis). 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.
The broad clinical and laboratory AE categories consisting of the percentage of 
subjects with any AE, with a drug related AE, with an SAE, with an AE which is both 
drug-related and serious, or who discontinued because of an AE are considered as 
Tier 2 endpoints and will be analyzed. Descriptive Safety Endpoints are considered 
as Tier 3 events and will also be analyzed.
Analyses will be conducted both on the cumulative data including data from the 
initial 78-week trial as well as this long term safety trial, no analyses will be 
conducted on the long term safety trial alone.
8.3.1
Analysis of Prespecified Safety Endpoints
The Prespecified Safety Endpoints of 1) microhemorrhage, superficial siderosis or
macrohemorrhage in brain MRI scans, 2) vasogenic edema, 3) delirium, and 4) rash 
ECI are considered as Tier 1 events and will be analyzed as indicated in Table 8.
 
 
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Table 8 Analysis Strategy for Safety Parameters
8.3.2
Analysis of Commonly Occurring Safety Endpoints
The broad clinical and laboratory AE categories consisting of the percentage of 
subjects with any AE, with a drug-related AE, with an SAE, with an AE which is both 
drug-related and serious, or who discontinued because of an AE are considered as 
Tier 2 endpoints and will be analyzed as indicated in Table 8.
8.3.3
Analysis of Descriptive Safety Endpoints
Descriptive Safety Endpoints are considered as Tier 3 events and will be analyzed 
as indicated in Table 8.
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 AEa
X
X
Any Serious AE
X
X
Any Fatal 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 PDLC (incidence ≥1% in 
one of the treatment groups)
X
X
Tier 3
Specific AEs, SOCs or PDLC (incidence < 1% in 
all of the treatment groups)
X
Change from Baseline Results (Labs, ECGs, Vital 
Signs)
X
AE=adverse event; CI=confidence interval; ECG=electrocardiogram; PDLC=predefined limit of change; 
SOC=system organ class; X=results will be provided.
a    Adverse experience references refer to both clinical and laboratory AEs. Includes only those endpoints not 
prespecified as Tier 1 or not already prespecified as Tier 2 endpoints.
 
 
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8.4
Trial Medication Compliance and Exposure
8.4.1
Compliance
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 regular intervals.  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 7.7.2.2.4 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 (eg, lost or missing 
medication equivalent to more than one pill per week).
A day within the trial will be considered an “On-Therapy” day if the subject doses on 
that day. For a subject who is followed for the entire trial period, the “Number of 
Days Should be on Therapy” is the total number of days from the first dose to the 
last scheduled day for treatment administration for that subject.  For a subject who 
permanently discontinued trial medication, the “Number of Days Should be on 
Therapy” is the total number of days from the first dose to the last dose of trial
medication.
For each subject, percent compliance will be calculated as 100 times the number of 
days 'On Therapy" divided by the "Number of Days Should be on Therapy". The 
average compliance overall, and over each 3-month time frame, will be calculated by 
treatment group. The percent of subjects who meet various compliance thresholds 
(eg, 75%, 95% compliant) will also be calculated overall, and over each 3-month 
time frame, by treatment group. The FAS population will be used for all trial
medication compliance calculations.
8.4.2
Exposure
Basic summary statistics for the number of doses of trial medication taken will be 
calculated overall, and as well as over each 3-month time frame by treatment group. 
The cumulative percent of subjects taking various numbers of doses of trial
medication (eg, one dose, 30 doses) will be calculated by treatment group. The 
APaT population will be used for all trial medication exposure calculations.
8.5
Demography
Basic summary statistics (means, standard deviations, counts, percentages) will be 
provided, as applicable, by treatment group, for subject baseline characteristics, 
subject disposition, and prior and concomitant medication usage.
 
 
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9.0 ADHERENCE TO ETHICAL, REGULATORY, AND ADMINISTRATIVE 
CONSIDERATIONS
The trial must be conducted in accordance with Good Clinical Practice (GCP) as 
outlined in the International Conference on Harmonisation of Technical 
Requirements for Registration of Pharmaceuticals for Human Use (ICH) Guidelines, 
E6 Good Clinical Practice:  Consolidated Guidance and other applicable laws and 
regulations.  In addition, the trial must be conducted in accordance with:  (i) the USA 
Code of Federal Regulations (CFR) if the trial is conducted under a USA IND, 
regardless of the country involved; (ii) the European Union (EU) Clinical Trial 
Directive (CTD) and local regulations if the trial is conducted in the EU; and (iii) any 
specific local regulations if the trial is conducted elsewhere.
9.1
Ethical Conduct of the Trial
9.1.1
Independent Ethics Committee or Institutional Review Board
Prior to initiation of the trial at any site, the trial, including the protocol, informed 
consent, and other trial documents must be approved by an appropriate Institutional 
Review Board (IRB) or Independent Ethics Committee (IEC).  The IRB/IEC must be 
constituted according to applicable regulatory requirements.  As appropriate, 
amendments to the protocol must also be approved by the IRBs/IECs before 
implementation at the sites, unless warranted to eliminate an immediate hazard.  
The IRB/IEC approval should be obtained in writing, clearly identifying the trial, the 
documents reviewed (including informed consent), and the date of the review.  The 
trial as described in the protocol (or amendment), informed consent, and other trial 
documentation may be implemented only after all the necessary approvals have 
been obtained and the sponsor has confirmed that it is acceptable for the 
investigator to do so.
In the event that the IRB/IEC requires changes in the protocol, the sponsor shall be 
advised and must approve the changes prior to implementation.  The investigator 
shall not modify the trial described in the protocol once finalized and after approval 
by the IRB/IEC without the prior written approval of sponsor.
In countries where the investigator submits the trial protocol and statement of 
informed consent to the IRB/IEC, the investigator or qualified designee will forward 
the approvals to the sponsor.
9.1.2
Subject Information and Consent
The details of the protocol must be provided in written format and discussed with 
each potential subject, and written informed consent must be obtained for all 
subjects before any trial-related procedure is performed. Informed consent will be 
obtained for this trial. NOTE subject participation in this long term safety trial is 
optional and will only be conducted where approved by local authorities. 
In 
obtaining informed consent, the information must be provided in language and terms 
 
 
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understandable to the subject. The subject, or the subject's legal representative, 
must give their written consent to participate in the trial.  The signed and dated 
consent form itself must be retained by the investigator as part of the trial records.  A 
copy of the signed and dated consent forms must be given to the subject.  The 
consent forms must include all of the required elements of informed consent in 
accordance with ICH Guidelines E6 and local laws.  In addition, the sponsor 
specifically requests that the consent forms identify it as the sponsor and state that 
use of the investigational product(s) is experimental and the side effects of the 
investigational product(s) are not completely known.  The consent forms must be 
approved by the appropriate IRB/IEC and sponsor before trial initiation at a trial site.  
Any subsequent changes to the approved informed consent forms must be reviewed 
and approved by the appropriate IRB/IEC and sponsor before implementation.
9.1.3
Subject Identification Card
All subjects will be given a Subject Identification Card identifying them as 
participants in a research trial.  The card will contain trial site contact information 
(including direct telephone numbers) to be utilized in the event of an emergency.  
The investigator or qualified designee will provide the subject with a Subject 
Identification Card after the subject provides written informed consent. The card is to 
be shown to caregivers in the event of an emergency.
At a minimum, the card must contain the following information:
1. Protocol number;
2. The subject’s protocol identification number;
3. A statement identifying the card-carrier as a participant in a clinical trial (eg, “This 
person is participating in a clinical research trial.”);
4. A statement indicating the person might be taking an investigational drug 
(eg, “This person is taking an experimental drug which could have interactions 
with other medications, or placebo”); and
5. Contact information in the event of an emergency or hospitalization.  The contact 
information on the card is to be the investigator or a designated site contact, 
rather than contact from within the sponsor;
The cards may also include other trial-specific information to assist with treatment 
decisions in the event of an emergency, such as types of concomitant therapies that 
may, or may not be, permitted as part of emergency treatment.  As with any other 
information provided to subjects, the Subject Identification Card must be approved 
by the IRB/IEC.  Monitors will request that Investigators provide Subject 
Identification Cards to each subject.  Investigators will be asked to request that 
subjects carry the cards with them while they are participating in the trial.
 
 
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9.1.4
Registration of the Trial
The trial will be registered by the sponsor on a publicly accessible database.  The 
results will be disclosed by the sponsor on a publicly accessible database.
9.2
Reporting Trial Data to the Sponsor
9.2.1
Data Collection Forms
The Sponsor will provide the site with data collection forms, be they Case Report 
Forms (CRF), either in paper format or electronic Case Report Forms (eCRF); 
diaries; Electronic Data Capture (EDC) screens; or other appropriate data collection 
forms as the trial requires.  The investigator is to provide subject data according to 
the Sponsor’s instructions, in the designated data collection form, compliant with 
GCP practices.  The Sponsor will also provide the site with instructions for assisting 
other parties - such as a central laboratory - to collect data.  As instructed by the 
Sponsor, a designated central laboratory may collect data in a database and provide 
the completed database to sponsor.  All data collection forms and the databases 
from the trial are the exclusive property of sponsor.
The investigator must maintain records and data during the trial in compliance with 
all applicable legal and regulatory requirements.  Each data point must be supported 
by a source document at the trial site.  Any records or documents used as the 
source of information (called the “subject source data”) are to be retained for review 
by authorized representatives of the sponsor or a regulatory agency.  
The investigator will ensure that there are sufficient time, staff, and facilities available 
for the duration of the trial to conduct and record the trial as described in the protocol 
and according to all applicable guidances, laws, and regulations.
All data collection forms (eg, CRFs, diaries; EDC screens), electronic database 
entries, etc, should be completed as soon as possible after the evaluation has 
occurred.  All dates appearing on the sponsor's subject data collection forms for 
laboratory tests, cultures, and other data collected, must be the dates on which the 
specimens were obtained, or the procedures performed.
9.2.2
Preparing Case Report Forms for All Subjects
A CRF must be completed for all subjects who have given informed consent.  The 
Sponsor must not collect subject names, initials, or other personal information that is 
beyond the scope of the trial from any subject.  Subjects are not to be identified by 
name or initials on the CRF or any trial documents.  The only acceptable 
identification for a subject who may appear on a CRF or trial document is the unique 
subject identification number.  The investigator must maintain contact information for 
each participant so that all can be quickly contacted by the investigator, if necessary.
All entries into CRFs are the responsibility of the investigator and must be completed 
by the investigator or a qualified designee.  Through signing the Investigator 
 
 
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Signature Page of the 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.
9.3
Publications and Other Rights
9.3.1
Rights to Publish by the Investigator
The investigator has the right to publish or publicly present the results of the trial in 
accordance with this Section 9.3 of the protocol.  In the event that the protocol is a 
part of a multi-site trial, it is understood that it is the intent of the sponsor and the 
investigator to initially only publish or present the trial results together with the other 
sites, unless specific written permission is obtained in advance from the sponsor to 
publish separate results.  The sponsor shall advise as to the implications of timing of 
any publication in the event clinical trials are still in progress at sites other than the 
investigator's site.
The investigator agrees not to publish or publicly present any interim results of the 
trial without the prior written consent of the sponsor.  The investigator further agrees 
to provide to the sponsor 45 days prior to submission for publication or presentation, 
review copies of abstracts or manuscripts for publication (including, without 
limitation, slides and texts of oral or other public presentations and texts of any 
transmission through any electronic media, eg, any computer access system such 
as the Internet, World Wide Web, etc) that report any results of the trial.  The 
sponsor shall have the right to review and comment with respect to publications, 
abstracts, slides, and manuscripts and the right to review and comment on the data 
analysis and presentation with regard to the following concerns:
1. Proprietary information that is protected by the provisions contained in 
Section 9.3.2;
2. The accuracy of the information contained in the publication; and
3. To ensure that the presentation is fairly balanced and in compliance with US FDA 
regulations.
If the parties disagree concerning the appropriateness of the data analysis and 
presentation, and/or confidentiality of the sponsor's confidential information, 
investigator agrees to meet with the sponsor's representatives at the clinical trial site 
or as otherwise agreed, prior to submission for publication, for the purpose of 
making good faith efforts to discuss and resolve any such issues or disagreement.
9.3.2
Use of Proprietary or Confidential Information in a Publication
No publication or manuscript shall contain any trade secret information of the 
sponsor or any proprietary or confidential information of the sponsor and shall be 
confined to new discoveries and interpretations of scientific fact.  If the sponsor 
believes there is patentable subject matter contained in any publication or 
 
 
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manuscript submitted for review, the sponsor shall promptly identify such subject 
matter to investigator.  If sponsor requests and at sponsor’s expense, investigator 
shall use its best efforts to assist sponsor to file a patent application covering such 
subject matter with the USA Patent and Trademark Office or through the Patent 
Cooperation Treaty prior to any publication.
9.3.3
Use of Trial Information in a Publication
Investigator is granted the right subject to the provisions of this protocol to use the 
results of all work provided by investigator under this protocol, including but not 
limited to, the results of tests and any raw data and statistical data generated for 
investigator's 
own 
teaching, 
research, 
and 
publication 
purposes 
only.  
Investigator/Institution agrees, on behalf of itself and its employees, officers, 
trustees, and agents, not to cause said results to be knowingly used for any 
commercial purpose whatsoever except as authorized by the sponsor in writing.
9.3.4
Authorship of Publications
Authors of publications must meet the International Committee of Medical Journal 
Editors (ICMJE) guidelines for authorship and must satisfy the 3 criteria that follow:
1. Authors must make substantial contributions to the conception and design of the 
trial, acquisition of data, or analysis of data and interpretation of results;
2. Authors must draft the publication or, during draft review, provide contributions 
(data analysis, interpretation, or other important intellectual content) leading to 
significant revision of the manuscript with agreement by the other authors;
3. Authors must provide written approval of the final draft version of the publication 
prior to submission.
All contributors who do not meet the 3 criteria for authorship should be listed in an 
acknowledgments section within the publication, if allowed by the journal, per the 
ICMJE guidelines for acknowledgment.
9.4
Trial Documents and Records Retention
During the trial and after termination of the trial – including after early termination of 
the trial – the investigator must maintain copies of all documents and records 
relating to the conduct of the trial.  This documentation includes, but is not limited to, 
protocols, CRFs and other data collection forms, advertising for subject participation, 
adverse event reports, subject source data, correspondence with health authorities 
and IRBs/IECs, consent forms, investigator’s curricula vitae/biosketch, monitor visit 
logs, laboratory reference ranges, and laboratory certification or quality control 
procedures and laboratory director curriculum vitae.  Subject files and other source 
data must be kept for the maximum period of time permitted by the hospital, 
institution or private practice, or as specified below.  The sponsor must be consulted 
if the investigator wishes to assign the files to someone else, remove them to 
another location, or is unable to retain them for the specified period.
 
 
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The investigator must retain trial records for the amount of time specified by 
applicable laws and regulations.  At a minimum, trial records must be retained for the 
amount of time specified by ICH Guidelines, the EU Good Clinical Practices 
Directive, or applicable local laws, whichever is longer:
1. The ICH Guidelines specify that records must be retained for a minimum of 
2 years after a marketing application for the indication is approved (or not 
approved) or 2 years after notifying the appropriate regulatory agency that an 
investigation is discontinued.
2. The European Union (EU) Commission Directive 2003/63/EC which requires that 
Essential Documents (including Case Report Forms) other than subjects’
medical files, are retained for at least fifteen (15) years after completion or 
discontinuation of the trial, as defined in the protocol.
All trial documents shall be made available if required by relevant health authorities.  
The investigator should consult with the sponsor prior to discarding trial and/or 
subject files.
Sponsor will retain all sponsor-required documentation pertaining to the trial for the 
lifetime of the investigational product.  Archived data may be held on microfiche or 
electronic record, provided that a back-up exists and that a paper copy can be 
obtained from it, if required.
10.0
INVESTIGATORS AND TRIAL ADMINISTRATIVE STRUCTURE
10.1
Sponsor
The sponsor of this trial is indicated in Section 1, Title Page.
10.2
Investigators
10.2.1
Selecting Investigators
Only investigators qualified by training and experience to perform a clinical 
investigation with MK-8931 are selected.  The sponsor will contact and select all 
investigators (ie, the legally responsible party[ies] at each trial site), who, in turn, will 
select their staff.
10.2.2
Financial Disclosure Requirement
In connection with the clinical trial described in the protocol, the investigator certifies 
that, if asked, the investigator will read and answer the Certification/Disclosure Form 
or equivalent document truthfully and to the best of investigator's ability.  Investigator 
also certifies that, if asked, the investigator will have any other applicable party(s) 
(eg, subinvestigators) read and answer the Certification/Disclosure Form as a
condition of their participation in the trial.
 
 
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If the financial interests reported on the Certification/Disclosure Form change during 
the course of the trial or within 1 year after the last subject has completed the trial as
specified in the protocol, the investigator and the other applicable party(s) are 
obligated to inform the sponsor of such financial change.
10.2.3
Clinical Study Report Coordinator Investigator
A Clinical Study Report (CSR) will be prepared by the sponsor or its qualified 
designee to describe the results of the trial.  One of the investigators shall be 
selected by the sponsor to review the CSR and provide approval of the final CSR in 
writing.  The investigator chosen to review and approve the CSR is to be called the 
CSR Coordinating Investigator.  A second investigator shall be selected as the 
Alternate CSR Coordinating Investigator.  The Alternate CSR Coordinating 
Investigator is to review and approve the CSR should the first CSR Coordinating 
Investigator be unable to do so.  The sponsor is to select the CSR Coordinating 
Investigator and Alternate CSR Coordinating Investigator from the investigators 
using the following criteria:
1. Must be the Principal Investigator at a trial site actively enrolling subjects and 
participating in the trial;
2. Must be willing and capable of completing the necessary reviews and providing 
approval of the CSR in writing;
10.3
Central Organizations
Central organizations to be used in the conduct, monitoring and/or evaluation of this 
trial are provided on the Contact List.
10.3.1
Scientific Advisory Committee
This trial was developed in collaboration with a Scientific Advisory Committee (SAC).  
The SAC comprises both Sponsor and non-Sponsor scientific experts who provide 
input with respect to trial design, interpretation of trial results and subsequent peer-
reviewed scientific publications.
10.3.2
Executive Oversight Committee
The EOC is comprised of members of Sponsor Senior Management. The EOC will 
receive and decide upon any recommendations made by the eDMC and siDMC 
regarding the trial.
10.3.3
Data Monitoring Committee
To supplement the routine trial monitoring outlined in this protocol, an eDMC will 
monitor the interim data from this trial.  The voting members of the committee are 
external to the Sponsor.  The members of the eDMC must not be involved with the 
 
 
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trial in any other way (eg, they cannot be trial investigators) and must have no 
competing interests that could affect their roles with respect to the trial. 
The eDMC will make recommendations to the EOC regarding steps to ensure both 
subject safety and the continued ethical integrity of the trial.  Also, the eDMC will 
review interim trial results, consider the overall risk and benefit to trial participants 
(see Section 8.2.8 - Interim Analyses) and recommend to the EOC if the trial should 
continue in accordance with the protocol.
Specific details regarding 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 eDMC reports, minutes, and recommendations will be described in 
a separate charter that is reviewed and approved by the eDMC.  The eDMC will 
monitor the trial at an appropriate frequency, as described in the detailed eDMC 
charter. 
To supplement the routine monitoring outlined in this protocol, the siDMC of the 
Sponsor will receive unblinded analyses for the first 200 subjects of the 78 week trial
only.  The siDMC is comprised of members of Sponsor Senior Management, none of 
whom are directly associated with the conduct of this trial.  Specific details regarding 
responsibilities of the siDMC will be described in a separate charter that is reviewed 
and approved by the siDMC.
 
 
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11.0 REFERENCES
1. 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.
2. Sevigny JJ, Ryan JM, van Dyck CH, Peng Y, Lines CR, Nessly ML; MK-677 
Protocol 30 Study Group. Growth hormone secretagogue MK-677: no clinical 
effect on AD progression in a randomized trial. Neurology. 2008 Nov 
18;71(21):1702-8.
3. Fleisher AS, Raman R, Siemers ER, Becerra L, Clark CM, Dean RA, Farlow MR, 
Galvin JE, Peskind ER, Quinn JF, Sherzai A, Sowell BB, Aisen PS, Thal LJ. 
Phase 2 safety trial targeting amyloid beta production with a gamma-secretase 
inhibitor in Alzheimer disease. Arch Neurol. 2008 Aug;65(8):1031-8.
4. Wilcock GK, Black SE, Hendrix SB, Zavitz KH, Swabb EA, Laughlin MA; 
Tarenflurbil Phase II Study investigators. Efficacy and safety of tarenflurbil in mild 
to moderate Alzheimer's disease: a randomised phase II trial. Lancet Neurol. 
2008 Jun;7(6):483-93.
5. http://newsroom.lilly.com/releasedetail.cfm?releaseid=499794
6. Buchhave P, Blennow K, Zetterberg H, Stomrud E, Londos E, Andreasen N, 
Minthon L, Hansson O. Longitudinal study of CSF biomarkers in patients with 
Alzheimer's disease. PLoS One. 2009 Jul 17;4(7):e6294.
7. 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.
8. 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.
9. Rosen WG, Terry RD, Fuld PA, Katzman R, Peck A.  Pathological Verification of 
Ischemic Score in Differentiation of Dementias.  Ann Neurol. 1980 May; 
7(5):486-488.
10.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.
11.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.
 
 
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12.Schneider LS, Sano M. Current Alzheimer's disease clinical trials: methods and 
placebo outcomes. Alzheimers Dement. 2009 Sep;5(5):388-97.
13.Aisen PS, Schneider LS, Sano M, Diaz-Arrastia R, van Dyck CH, Weiner MF, 
Bottiglieri T, Jin S, Stokes KT, Thomas RG, Thal LJ; Alzheimer Disease 
Cooperative Study. High-dose B vitamin supplementation and cognitive decline 
in Alzheimer disease: a randomized controlled trial. JAMA. 2008 Oct 
15;300(15):1774-83.
14.Saumier D, Aisen PS, Gauthier S, Vellas B, Ferris SH, Duong A, Suhy J, Oh J, 
Lau W, Garceau D, Haine D, Sampalis J. Lessons learned in the use of 
volumetric MRI in therapeutic trials in Alzheimer's disease: the ALZHEMED 
(Tramiprosate) experience. J Nutr Health Aging. 2009 Apr;13(4):370-2.
15.Feldman HH, Doody RS, Kivipelto M, Sparks DL, Waters DD, Jones RW, 
Schwam E, Schindler R, Hey-Hadavi J, DeMicco DA, Breazna A; LEADe 
Investigators. Randomized controlled trial of atorvastatin in mild to moderate 
Alzheimer disease: LEADe. Neurology. 2010 Mar 23;74(12):956-64.
16.Vellas B, Andrieu S, Sampaio C, Coley N, Wilcock G; European Task Force 
Group. Endpoints for trials in Alzheimer's disease: a European task force 
consensus. Lancet Neurol. 2008 May;7(5):436-50.
17.Vellas B, Andrieu S, Cantet C, Dartigues JF, Gauthier S. Long-term changes in 
ADAS-cog: what is clinically relevant for disease modifying trials in Alzheimer? J 
Nutr Health Aging. 2007 Jul-Aug;11(4):338-41.
18.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.
19.Doc ID 5706793.  Investigator’s Brochure of MK-8931 (Formerly SCH 900931)
20.Morse AR, Teresi J, Rosenthal B, Holmes D, Yatzkan ES. J. Vis. Impair. Blind. 
Visual acuity assessment in persons with dementia. 2004 Sep;98(9) 560-566.
21.Roujeau JC, Kelly JP, Naldi L, Rzany B, Stern RS, Anderson T, Auquier A, 
Bastuji-Garin S, Correia O, Locati F, et al. Medication use and the risk of 
Stevens-Johnson syndrome or toxic epidermal necrolysis. N Engl J Med. 1995 
Dec 14;333(24):1600-7.
22.Mockenhaupt M, Viboud C, Dunant A, Naldi L, Halevy S, Bouwes Bavinck JN, 
Sidoroff A, Schneck J, Roujeau JC, Flahault A. Stevens-Johnson syndrome and 
toxic epidermal necrolysis: assessment of medication risks with emphasis on 
recently marketed drugs. The EuroSCAR-study. J Invest Dermatol. 2008 
Jan;128(1):35-44.
 
 
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23.Haybittle JL. Repeated assessment of results in clinical trials of cancer treatment. 
Br J Radiol. 1971 Oct;44(526):793-7.
24.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.
25.Rubin, D. B. (1987) Multiple Imputation for Nonresponse in Surveys. John 
Wiley:NY.
26.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
27.SAS Institute Inc. 2011. SAS/STAT® 9.3 User’s Guide. Cary, NC: SAS Institute 
Inc. (Chapter 57).
28.Schafer, J.L. (1997) Analysis of Incomplete Multivariate Data. Chapman & 
Hall:London.
29.Barnard J, Rubin DB. Small-sample degrees of freedom with multiple imputation. 
Biometrika, 1999; 86: 948–55.
30.Rochin L, Hurbain I, Serneels L, Fort C, Watt B, Leblanc P, Marks MS, De 
Strooper B, Raposo G, van Niel G. BACE2 processes PMEL to form the 
melanosome amyloid matrix in pigment cells. Proc Natl Acad Sci U S A. Jun 
25;110(26):10658-63.  2013.
 
 
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Appendix 1
Code of Conduct for Clinical Trials
 
 
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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 studies 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 studies 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 (eg, contract research organizations, collaborative research 
efforts).  This Code is not intended to apply to studies which are observational 
in nature, or which are retrospective.  Further, this Code does not apply to 
investigator-initiated studies (eg, Medical School Grant Program), which are 
not under the control of Merck.
II. Scientific Issues
A. Trial Conduct
1. Trial Design
Except for pilot or estimation studies, 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, studies to assess or validate 
various endpoint measures, or studies to determine patient preferences, 
etc.
The design (ie, 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 
patients, 
adequacy
of 
facilities 
and 
staff, 
previous 
performance in Merck studies, as well as budgetary considerations.  Prior 
to trial initiation, sites are evaluated by Merck personnel to assess the 
ability to successfully conduct the trial.
 
 
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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.
D. Publication and Authorship
To the extent scientifically appropriate, Merck seeks to publish the results of 
studies it conducts.  Some early phase or pilot studies 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.
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’s Consent Form Review department (U.S. studies) or Clinical 
Research Director (non-U.S. studies) 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 study at any time, without any influence on their access to, or 
receipt of, medical care that may otherwise be available to them.
 
 
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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. DNA Research
DNA sequence analyses, including use of archival specimens collected as 
part of a clinical trial, will only be performed with the specific informed consent 
of the subject.  With IRB approval, an exception to this restriction on use of 
archival specimens may be possible (for instance, if specimens are de-
identified and are not referable to a specific subject).
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 studies will 
indicate Merck as a source of funding.
C. Funding for Travel and Other Requests
Funding of travel by investigators and support staff (eg, 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 
attachment 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., 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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Appendix 2
DNA Sampling and Pharmacogenetic Analysis Procedures
 
 
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1. Definitions
a. Pharmacogenomics:  The investigation of variations of DNA and RNA 
characteristics as related to drug response.
b. Pharmacogenetics:  A subset of pharmacogenomics, pharmacogenetics is 
the influence of variations in DNA sequence on drug response.
c. Genomic Biomarkers:  A measurable DNA and/or RNA characteristic that is 
an indicator of normal biologic processes, pathogenic processes, and/or 
response to therapeutic or other interventions.
d. DNA:  Deoxyribonucleic acid.
e. RNA:  Ribonucleic acid.
2. Summary of Procedures for Pharmacogenetics
a. Subjects for Enrollment:  All subjects enrolled in the current clinical trials will 
be considered for enrollment.
b. Consent
Informed consent for biosamples (ie, DNA, RNA, protein, etc) will be obtained 
during screening for protocol enrollment from all subjects or legal guardians, 
at an outpatient visit, or during an inpatient stay by the investigator or his or 
her designate.
Subjects are not required to participate in the pharmacogenetic sub-study in 
order to participate in the main trial.
3. Scope of Pharmacogenetic Study
The DNA sample collected in the current trial will be used to study various 
genetic causes for how subjects may respond to a drug.  The DNA sample will be 
stored to provide a resource for future studies conducted by Merck focused on 
the study of genes responsible for how a drug enters and is removed by the 
body, how a drug works, other pathways a drug may interact with, or other 
aspects of disease.  All samples will be used by Merck or designees and 
research will be monitored and reviewed by a committee of our scientists and 
clinicians.
4. Techniques to Collect Samples
Blood samples will generally be obtained for all trial participants.  Blood samples 
for both DNA and RNA isolation will usually be obtained at a time when the 
subject is having blood drawn for other trial purposes.
 
 
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5. Confidential Subject Information for Pharmacogenetic Analysis
Samples will be collected and sent to the laboratory designated for the trial where 
they will be processed (ie, DNA or RNA extraction, etc) following the Merck 
approved policies and procedures for sample handling and preparation.
When samples are collected for a specific genotype or expression analysis, this
analysis will be detailed in the main body of the clinical protocol 
(Section 7.7.3.1).  These samples will be processed, analyzed, and the 
remainder of the sample will be destroyed.  The results of these analyses will be 
reported along with the other trial results.  A separate sample will be obtained 
from subjects in these protocols for storage in the biorepository for future 
analyses.
To maintain privacy of information collected from samples obtained for storage 
and future analysis, Merck has developed secure policies and procedures to 
maintain subject privacy.  At the clinical site, a unique Code will be placed on the 
blood sample for transfer to the storage facility.  The Code is a random number 
used only to identify the biosample of each subject.  No other personal identifiers 
will appear on the sample tube.  The first Code will be replaced with a Sample 
Code (eg, Genetic Sample Code for DNA sample, Serum Sample code for serum 
sample) at the Central Laboratory or at the Merck designated facility.  This 
sample is now a single coded sample.  The Sample Code is stored separately 
from all previous sample identifiers.  A secure code, hereinafter referred to as a 
“first coding key”, will be utilized to match the Sample Code to the original blood 
code and subject number to allow clinical information collected during the course 
of the study to be associated with the biosample.  This “first coding key” will be 
transferred by the central laboratory or Merck designated facility under secure 
procedures to the Merck group designated as the entrusted keyholder to 
maintain confidentiality of the biosamples.  The Sample Code will be logged into 
the primary biorepository database, and in this database this identifier will not 
have identifying demographic data or identifying clinical information (ie, race, sex, 
age, diagnosis, lab values) associated with it.  The sample will be stored in a 
designated repository site with secure policies and procedures for sample 
storage and usage.
 
 
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For DNA samples, a Storage Code will replace the Sample Code at the Merck 
designated facility.  The DNA sample is now a double coded sample.  This 
storage code will be stored separately from all previous sample identifiers.  The 
second secure key referred to as a “second coding key” file will be transferred by 
the Merck designated facility under secure procedures to the Merck entrusted 
keyholder.  Samples with the second code are sometimes referred to as de-
identified samples. The use of the second code provides additional confidentiality 
and privacy protection for subjects over the use of a single code.  Access to both 
coding keys is needed to link any data or samples back to a subject identifier.
The “keys” could be utilized to reconstruct the link between genetic information 
and identifiable clinical information, at the time of analysis.  This linkage would 
not be possible for the investigator conducting the analysis, but may only be 
done by the Merck entrusted keyholder under strict security policies and 
procedures.  The Merck entrusted keyholder will link the information, conduct the 
analysis, then issue an anonymized data summary on the initially single or 
double coded samples to the investigator conducting the genetic analysis.  The 
only circumstance by which genetic information would be linked to clinical 
information would be those situations mandated by health authorities (eg, EMEA, 
FDA), whereby this information would be directly transferred to the health 
authority.  Once the link between subject’s identifiers and the unique codes is 
deleted, it is no longer possible to trace the data and samples back to individual 
subjects through the coding keys.  Anonymization is intended to prevent subject 
re-identification.
6. Biorepository Sample Usage
Samples obtained for the Merck biorepository will be used for analyses using 
good scientific practices.  Exploratory analyses will not be conducted under 
highly validated conditions.  The scope of research performed on these samples 
is limited to the investigation of the variability in inherited biomarkers that may 
correlate with a clinical phenotype in subjects.
Genetic analysis utilizing the DNA samples may be performed by the sponsor, or 
an additional third party (eg, a university investigator) designated by the sponsor.  
The investigator conducting the analysis will be provided with a double (single) 
coded sample.  Reassociation of analysis results with corresponding clinical data 
will only be conducted by the Merck entrusted keyholder.  Any contracted third 
party genetic analysis will conform to the specific genetic analysis outlined in the 
clinical protocol.  DNA sample remaining with the third party vendor after genetic 
analysis will be returned to the sponsor or destroyed and documentation of 
destruction will be reported to Merck.
 
 
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Consent form signed by the subject will be kept under secure storage for 
regulatory reasons.  Information contained on the consent form alone cannot be 
traced to any samples, test results, or medical information once the specimens 
have been rendered de-identified.  Laboratory personnel performing the genetic 
testing will not have access to the informed consent document, nor will they be 
able to identify subjects from the double (single) coded specimens.  Specimens 
will be identified to the laboratory only by the Sample double (single) code.  
Subjects who decline to sign the informed consent document for the sub-study 
will not have the sample collected or stored, nor will they be discontinued from 
the main trial unless the pharmacogenetics sample is specifically required for trial 
enrollment.
A template of each site’s informed consent will be stored in the Sponsor’s clinical 
document repository.  Each consent will be assessed for appropriate sample 
permissions.  The tracking number on this document will be used to assign 
sample permissions for each sample in the entrusted keyholder’s Sample 
Database.
7. Withdrawal From the Biorepository and Pharmacogenetic Database
Subjects may withdraw their consent to store the blood sample or the DNA or 
RNA derived from it.  Subjects can also request that their sample be destroyed at 
any time.  If samples can be identified in any way (ie, are not anonymized 
samples), subjects may withdraw consent for banking samples at any time by 
contacting the investigator responsible for administering their initial informed 
consent.  At that time, subject samples will be removed from the biorepository.  
Any DNA, RNA, or other biologic samples will be destroyed, destruction will be 
documented, and sample database information deleted.  However, any analyses 
performed or data obtained from the samples prior to the subject withdrawing 
consent will not be deleted.
8. Retention of Data and Biosamples
It is anticipated that data generated from processed samples collected during the 
course this trial will be retained for an indefinite period. DNA specimens will be 
maintained for potential analysis for 20 years from the acquisition.  Samples will 
be destroyed according to Merck policies and procedures and this destruction will 
be documented in the repository database.
9. Data Security
Pharmacogenetic
and other research databases are accessible only to 
authorized sponsor and trial administrator research personnel and/or designated 
collaborators and are only stored and accessible as anonymized data.  Database 
user authentication is highly secure, and is accomplished using network security 
policies and practices based in international standards (eg, ISO17799) to protect 
against unauthorized access.  The Merck entrusted key holder maintains control 
over access to all sample data.  These data are collected for pharmacogenetic
research purposes only as specified in the clinical protocol and will not be used 
for any other purpose without explicit consent from the research subject.
 
 
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10.Reporting of Data to Subjects
There is no definitive requirement in either authoritative ethical guidelines or in 
relevant laws/regulations globally that research results have to be, in all 
circumstances, returned to trial participant.  Some guidelines advocate a 
proactive return of data in certain instances.
No information obtained from exploratory laboratory studies will be reported to 
the subject or family, and this information will not be entered into the clinical 
database maintained by Merck on subjects.  Principle reasons not to inform or 
return results to the subject include: lack of relevance of data, limitations of 
predictive capability of research data, concerns of misinterpretation of data, 
absence of good clinical practices standards in exploratory research.
If any exploratory results are definitively associated with clinical significance for 
subjects while the Merck clinical trial is still ongoing, investigators will be 
contacted with information as to how to offer genetic testing (paid for by Merck) 
to subjects enrolled and will be advised that genetic counseling should be made 
available for all who choose to participate.
If any exploratory results are definitively associated with clinical significance after 
completion of a clinical trial, Merck will publish the results without revealing 
specific subject information, inform all sites who participated in the Merck clinical 
trial, and post the anonymized results on our website or other accredited 
website(s) that allow for public access (eg, Disease-societies who have primary 
interest in the results) in order that physicians and subjects may pursue genetic
testing if they wish to do so.
 
 
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11.Gender, Ethnicity, and Minorities
Although many diagnoses differ in terms of frequency by ethnic population and 
gender, every effort will be made to recruit all subjects diagnosed and treated on 
Merck clinical trials for pharmacogenetic sampling.  When studies with samples 
are conducted and subjects identified to serve as controls, every effort will be 
made to group samples from subjects and controls to represent the ethnic and 
gender population representative of the disease under current investigation.
12.Risks Versus Benefits of Pharmacogenetic Testing
For pharmacogenetic testing, risks to the subject have been minimized.  Risks 
include those associated with venipuncture to obtain the whole blood sample.  
This sample will be obtained at the time of routine blood samples drawn for 
clinical reasons. 
Data privacy concerns of the subject have been strictly protected against with 
Merck security, policies and procedures.  Data privacy risks are largely limited to 
rare situations involving possible breach of confidentiality.  In this highly unlikely 
situation there is risk that the information, like all medical information, may be 
misused.
It is necessary for subject-related data (ie, ethnicity, diagnosis, drug therapy and 
dosage, age, toxicities, etc) to be reassociated to double (single) coded samples 
at the time of data analysis.  These subject data will be kept in a separate, 
secure Merck database, and all samples will be stripped of subject identifiers.  
No information concerning results obtained from genotyping or biomarker studies 
conducted with samples from the biorepository will be entered into clinical 
records, nor will it be released to outside persons or agencies, in any way that 
could be tied to an individual subject.
13.Self-Reported Ethnicity
Subjects who participate in pharmacogenetic study will be asked to provide self-
reported ethnicity.  Subjects who do not wish to provide this data may still 
participate in the pharmacogenetic study.
14.Questions
Any questions related to the genetic informed consent, genetic sampling, genetic 
sample handling, or genetic sample storage should be e-mailed directly to 
PPD
 
 
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Appendix 3
The National Institute of Neurological and Communicative 
Diseases and Stroke/Alzheimer’s Disease and Related 
Disorders Association (NINCDS-ADRDA) Criteria for 
Probable AD18
 
 
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I. The criteria for the clinical diagnosis of PROBABLE Alzheimer's disease 
include:
• dementia established by clinical examination and documented by the 
Mini-Mental Test; Blessed Dementia Scale, or some similar examination, 
and confirmed by neuropsychological tests;
• deficits in two or more areas of cognition;
• progressive worsening of memory and other cognitive functions;
• no disturbance of consciousness;
• onset between ages 40 and 90, most often after age 65; and
• absence of systemic disorders or other brain diseases that in and of 
themselves could account for the progressive deficits in memory and 
cognition.
II. The diagnosis of PROBABLE Alzheimer‘s disease is supported by:
• progressive deterioration of specific cognitive functions such as language 
(aphasia), motor skills (apraxia), and perceptions (agnosia);
• impaired activities of daily living and altered patterns of behavior;
• family history of similar disorders, particularly if confirmed neuropathologically; 
and
• laboratory results of:
• normal lumbar puncture as evaluated by standard techniques,
• normal pattern or non-specific changes in EEG, such as increased slow-
wave activity, and
• evidence of cerebral atrophy on CT with progression documented by serial 
observation.
III. Other clinical features consistent with the diagnosis of PROBABLE Alzheimer‘s 
disease, after exclusion of causes of dementia other than Alzheimer‘s disease, 
include:
• plateaus in the course of progression of the illness;
•
associated symptoms of depression, insomnia, incontinence, delusions, 
illusions, hallucinations, catastrophic verbal, emotional, or physical outbursts, 
sexual disorders, and weight loss;
 
 
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• other neurologic abnormalities in some patients, especially with more advanced 
disease and including motor signs such as increased muscle tone, myoclonus, or 
gait disorder;
• seizures in advanced disease; and
• CT normal for age.
IV. Features that make the diagnosis of PROBABLE Alzheimer‘s disease uncertain 
or unlikely include:
• sudden, apoplectic onset;
• focal neurologic findings such as hemiparesis, sensory loss, visual field deficits, 
and incoordination early in the course of the illness; and
• seizures or gait disturbances at the onset or very early in the course of the 
illness.
 
 
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Appendix 4
Comparison of the Constrained Longitudinal Data Analysis 
Model and the Longitudinal ANCOVA Model and Guidance 
on Longitudinal Data Analysis: Efficient Use of Baseline 
Information in Longitudinal Data Analyses
 
 
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Comparison of the Constrained Longitudinal Data Analysis Model and the 
Longitudinal ANCOVA Model
The Constrained Longitudinal Data Analysis (cLDA) model will be used as the primary analysis 
model in the BACE Phase 2/3 program. This one-page document highlights the relevant differences 
and similarities between the cLDA model and the traditional longitudinal ANCOVA model. These 
two models are fully defined and characterized in the attached Merck & Co., Inc. internal technical 
document "Guidance on Longitudinal Data Analysis: Efficient Use of Baseline Information in 
Longitudinal Data Analyses". This attached guidance document also provides a fuller explanation of 
the cLDA model, including additional advantages held by the cLDA model, not listed below, which 
are not applicable to the BACE program (but nevertheless, provide evidence that the cLDA model is 
preferred in general over the longitudinal ANCOVA model). 
o
Both models provide unbiased estimates for their model parameters, resulting in estimates of 
the treatment difference that are unbiased; this is true for the case of no missing data as well 
as when the data are missing-at-random (MAR).
o
The estimated variance for the treatment difference is unbiased for the cLDA model. On 
average, the variance for the estimated treatment difference is also unbiased for the 
longitudinal ANCOVA model.
o
The variance of the estimated treatment difference from the cLDA model will not be larger 
than the average variance from the longitudinal ANCOVA model. However, in most cases 
the variances from the two models are similar (as confirmed via simulation, see Appendix of 
the attached).
o
The cLDA model provides unbiased standard errors for within-group treatment effects and 
provides coverage at the appropriate 100(1-α)% level, whereas the longitudinal ANCOVA 
does not.
o
The cLDA model assumes that the underlying population means of all treatments are equal at 
baseline. It is noted that this assumption need not be verified as it is theoretically known to be 
true; the only way in which this assumption can be violated is if there is a problem with the 
blinded randomization to treatment group (a problem which is more severe than unequal 
baseline means).
 
 
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Guidance on Longitudinal Data Analysis:
Efficient Use of Baseline Information in Longitudinal Data Analyses
1. Introduction
Measurements are often collected prior to treatment randomization in longitudinal 
clinical trials.  This information can potentially be used for several purposes, 
including subject selection in studies targeting a study population with a certain 
disease condition, and as a starting point for measuring the treatment effect in a 
change from baseline analysis.  Comparing treatments in terms of mean change from 
baseline is common in many longitudinal clinical trials.  When there is only one post-
randomization measure, treatment effects on mean change from baseline are often 
assessed using an analysis of covariance (ANCOVA) model with the baseline value 
as a covariate and either the post-baseline value or the calculated change from 
baseline value as the dependent variable; throughout this document, without loss of 
generality, we assume that the dependent variable is the change from baseline for 
ANCOVA-based analyses.  Estimates and statistical tests from an ANCOVA model 
conditional on baseline values are unbiased under an assumption of normality [1].  
When the baseline measurement is correlated with the post-baseline measurement, 
adjusting for baseline using ANCOVA has been shown to remove conditional bias in 
treatment group comparisons due to chance imbalances [2], and to improve efficiency 
over unadjusted comparisons [3].  
With several post-randomization measurements (repeated measures over time), a 
longitudinal data analysis (LDA) model can be used, in which the change from 
baseline is calculated at each post-randomization time point and the baseline 
measurement is included as a covariate in the model.  This model will hereafter be 
referred to as the Longitudinal ANCOVA model.  Alternatively, a full likelihood 
approach can be used.  First proposed by Liang and Zeger [4], in the full likelihood 
LDA model the baseline value is included as a dependent variable in the response 
vector, along with the post-baseline values.  Of note, in the Longitudinal ANCOVA 
model, the baseline mean responses for each treatment group are implicitly assumed 
equal, which is reasonable due to randomization.  A similar "constraint" can also be 
imposed in the full likelihood LDA model; the constrained full likelihood LDA model 
will hereafter be referred to interchangeably simply as the LDA model.  
While both the Longitudinal ANCOVA and LDA models produce identical point 
estimates for the treatment effect in simple models that adjust for [categorical] time 
when no data are missing, estimates of standard errors for within-group mean changes 
from baseline from the LDA (but not the Longitudinal ANCOVA) model account for 
the variability of the baseline measurements.  In addition, the LDA model does not 
exclude from the analysis post-randomization values for subjects with missing 
baseline values, leading to more efficient use of all the data.
 
 
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A comprehensive review of late-stage clinical trials at Merck revealed inconsistencies 
and inefficiencies in methods being used for the analysis of longitudinal data among 
various therapeutic areas.  This guidance document, produced by the Longitudinal 
Data Analysis Working Group of the Early/Late-stage Statistical Technical Issues 
Committee (ELSTIC), is intended to remove unnecessary disparities across BARDS 
sites for addressing analyses of mean change from baseline by recommending an 
efficient and statistically sound default strategy with supporting rationale.
The recommendation is to use the full likelihood LDA model proposed by Liang 
and Zeger [4] as the default strategy for comparing treatments in terms of mean 
change from baseline in longitudinal clinical trials [5]. This LDA model will 
include baseline as one of the repeated measures with a constraint of equal mean 
across randomized groups at baseline, and use Kenward-Roger adjustment [6] 
with REML approach and an unstructured covariance [7].  
Table 1 provides a summary of the reasons for recommending the LDA over the 
Longitudinal ANCOVA model.  When there are no missing data, the Longitudinal 
ANCOVA and the LDA models are generally comparable with respect to treatment 
group comparisons.  However, in the presence of missing baseline data, the LDA 
model has superior power to detect treatment differences.  Moreover, in both cases 
(missing or no missing data), confidence intervals for the least square means 
(LSMEANS) of the individual treatment groups are not covered at the appropriate 
100(1-α)% level in the Longitudinal ANCOVA model, or in any model that uses 
baseline as a covariate.  Note that this limitation also exists in the special case where 
there is only 1 post-baseline time point.  As such, the recommendation is to use the 
LDA model in lieu of the standard ANCOVA model even when there is only one 
post-baseline time point.  This recommendation also holds whether or not 
stratification factors are being adjusted for in the model.
 
 
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Table 1
Advantages of the full likelihood LDA versus Longitudinal ANCOVA
Issue
Advantage of the LDA model
1)  Missing baseline data.
The LDA model provides more efficient 
between-group comparisons because, unlike the 
Longitudinal ANCOVA model, it includes 
subjects who are missing a baseline measurement 
but have at least one post-baseline measurement.
2)  Variability estimate for designing 
future trials.
The LDA model provides unbiased standard 
errors for within-group treatment effects, 
whereas the longitudinal ANCOVA model
underestimates the variance. 
3)  Coverage of within-group 
confidence intervals for mean 
change from baseline.
The LDA model provides coverage at the 
appropriate 100(1-α)% level (under normality), 
whereas the Longitudinal ANCOVA model does 
not.
4)  Subjects missing all post-baseline 
measurements.
The LDA model includes baseline measurements 
of such subjects in the analysis, whereas the 
Longitudinal ANCOVA model does not.  If the 
probability of missing a post-baseline 
measurement depends on the magnitude of the 
baseline measurement (missing at random), then 
the LDA model will yield unbiased result but the 
Longitudinal ANCOVA model will not.
5)  Implicit modeling assumptions 
regarding baseline means in models 
that adjust for stratification and 
stratification by time interaction.
The LDA model provides more flexibility and is 
less restrictive than the Longitudinal ANCOVA 
model.  For example, a standard implementation 
of the latter implicitly (and often, erroneously) 
assumes that the baseline mean is the same for 
all strata.  Moreover, the LDA model can more 
easily accommodate user-specified weights for 
the different strata for estimating and testing 
treatment effects.
6)  Implicit modeling assumptions 
regarding correlation between 
baseline and post-baseline 
measurements in models that adjust 
for stratification and stratification by 
time interaction.
The Longitudinal ANCOVA model implicitly 
(and often, erroneously) assumes that the 
correlation between baseline and each post-
baseline measurement is the same for all levels 
of the stratification factor. The LDA model does 
not make this restrictive assumption. 
If the parameter of interest is the mean percent change from baseline rather than the 
mean change from baseline, then the following two options may be considered: (1) 
Use the LDA model in which the longitudinal response vector includes the baseline 
measurement and the calculated post-baseline percent change from baseline 
measurements; (2) Use the LDA model in which the longitudinal response vector 
includes the log-transformed baseline and post-baseline measurements, and then use 
the delta method, or any other appropriate method (eg, see [8]), to get point estimates 
and standard errors on the original measurement scale.
 
 
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Of note, ignoring baseline values in the analysis is not recommended in general, 
unless baseline values are non-informative or confounded with covariates included in 
the analysis (eg, a categorical baseline severity variable).
A detailed description of the rationale for recommending use of the LDA model, 
along with suggestions on appropriate implementation and template language for the 
Data Analysis Section (DAS) of a clinical protocol, is provided in the sections that 
follow.
2. Longitudinal data analysis methods for comparing treatments in terms of mean 
change from baseline
Sections 2 through 5 consider models to compare treatments in terms of mean change 
from baseline while adjusting for time as a categorical factor in the model.  Adjusting 
for additional variables (eg, stratification factors) is considered in Section 6. 
2.1 Longitudinal ANCOVA model
Suppose responses are measured at baseline (
0

T
) and at  T post-baseline time 
points in a clinical trial. Let 
ijt
Y
be the response for subject i, with treatment 
assignment j , at time t.  The marginal mean of the change from baseline, 
conditional on baseline 
0
ij
Y
, at time t can be modeled as:
T
t
t
time
I
j
treatment
I
Y
Y
Y
E
jt
ij
t
ij
ijt
,
,2
,1
),
(
)
(
)
|
*
(
0
0








,
where 
0
*
ij
ijt
ijt
Y
Y
Y


is the change from baseline value at time t.  The slope, 
t
, 
can be different for each time t and 
jt

is the effect for treatment j at time t
after adjusting for the baseline effect.  The standard analysis using this model 
assumes that post-baseline values are multivariate normally distributed.  The 
model conditions on a subject's baseline value.  As such, the baseline is treated as 
fixed (rather than as a random variable) in the analysis, and subjects with missing 
baseline values are excluded.  This model corresponds to the commonly used 
ANCOVA model for a pre-post study design when 
1

T
.
With repeated measures (ie, 
1

T
), a covariance matrix can be specified in the 
mixed model to account for within subject correlation at times 
0

t
.  A separate 
covariance matrix can be specified for each treatment group; however, because 
the baseline value is not part of the response vector, the correlation between 
baseline and each post-baseline measurement in the ANCOVA model is implicitly 
assumed to be the same for each treatment group.  For convenience, we focus on 
 
 
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the last time point (
T
t 
) and assume the study has two arms, a test drug (
1

j
) 
and a control (
0

j
).  The comparison of interest is the treatment effect on the 
change from baseline at the last time point:
T
T
T
0
1





.
The change from baseline LSMEANS for test drug and control are estimated as:
T
T
T
Y
1
0
1
ˆ
~
ˆ
ˆ







and 
T
T
T
Y
0
0
0
ˆ
~
ˆ
ˆ







,
respectively, where 
0
~

Y
is the overall mean at baseline of all subjects included in 
the analysis.
2.2 LDA model
Utilizing the same notation, the LDA model includes the baseline value as part of 
the response vector.  The marginal mean responses can be modeled as:
T
t
t
and
t
time
I
j
treatment
I
Y
E
jt
ijt
,
,2
,1,0
),
0
(
)
(
)
(
0









,
where 
0

is the mean response at 
0

t
, which is constrained to be the same for 
both treatment groups due to randomization, 
jt

is the effect for treatment j at 
time t.  The LDA model assumes that baseline and post-baseline values are 
jointly multivariate normally distributed.  A covariance matrix can be specified in 
the mixed model to account for within subject correlation at times 
0

t
(including baseline).  Unlike the ANCOVA model, when a separate covariance 
matrix is specified for each treatment group the correlation between baseline and 
each post-baseline measurement is not assumed to be the same for each treatment 
group.
The treatment effect on the change from baseline at the last time point is 
estimated from this model as:
T
T
T
0
1





.
The change from baseline LSMEANS for test drug and control are estimated as:
T
1ˆ
and 
T
0ˆ
, respectively.
 
 
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3. Comparing the Longitudinal ANCOVA and LDA models
3.1 Treatment difference estimates
Under the Longitudinal ANCOVA model, the treatment difference is the 
conditional mean difference between treatment groups:
)
|
(
)
|
*
*
(
0
0
1
0
0
1
0
1
Y
Y
Y
E
Y
Y
Y
E
T
i
T
i
T
i
T
i
T
T
T









.
Using conditional expectation, it can be seen that
T
T
i
T
i
T
T
T
Y
Y
E









)
(
0
1
0
1
.
Both models provide unbiased estimates for their parameters, resulting in 
estimates of the treatment difference that are unbiased; this is true for the case of 
no missing data, and when data are missing at random (MAR).  Furthermore, 
baseline means are assumed equal for the test drug and control groups in both 
models.  Therefore, the resulting treatment difference estimate for both models is 
the expectation of the response difference between groups under the constraint of 
common baseline mean.
The overall variance of the estimated treatment difference, 
)
ˆ
(
T
Var 
, can be 
determined using the conditional variance formula:
))
|
ˆ
(
(
))
|
ˆ
(
(
)
ˆ
(
0
0
Y
E
Var
Y
Var
E
Var
T
T
T





where 
)
|
ˆ
(
0
Y
Var
T

is the variance estimated from the Longitudinal ANCOVA 
model.  The second term on the right hand side of the equation is zero since 
T
T
T
T
T
Y
E
Y
E
Y
E
0
1
0
0
0
1
0
)
|
ˆ
(
)
|
ˆ
(
)
|
ˆ
(









is constant.  Therefore, 
))
|
ˆ
(
(
)
ˆ
(
0
Y
Var
E
Var
T
T



.
As such, on average, the variance for the estimated treatment difference is 
unbiased from the longitudinal ANCOVA model.  This was confirmed 
empirically through simulations (see Appendix).
Under the LDA model, the estimated variance for the treatment difference 
estimate is unconditional. The variance estimate is based on REML and unbiased 
under the model assumption.  It can be shown that 
).
ˆ
(
))
|
ˆ
(
(
))
ˆ
(
(
)
ˆ
(
0
0
0
T
T
Y
T
Y
T
Var
Y
Var
E
E
Var
Var







 
 
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Therefore, the variance of the estimated treatment difference from the LDA model 
will not be larger than the average variance from the longitudinal ANCOVA. 
When there are no missing data, the point estimate of the treatment difference is 
identical. This implies that the LDA model will be at least powerful as the 
longitudinal ANCOVA for the treatment comparisons. In most of the cases, the 
variances from these two models are fairly similar though. This was also 
confirmed through simulations (see Appendix).
3.2 LSMEAN estimates
Under the Longitudinal ANCOVA model, the LSMEAN for individual treatment 
groups is defined as:
jT
T
jT
Y



ˆ
ˆ
ˆ
0 



.
When there are no missing data, the baseline slope coefficient can be estimated 
as:
1
)
(
)
)(
(
ˆ
2
0
0
0
0










i
j
j
ij
i
j
j
ij
jT
ijT
T
y
y
y
y
y
y

and
1
)
/
(
)
ˆ
(
0 





T
T
E
where 
T

and 
0

are the standard deviations of the responses at time T
and 
baseline, respectively.  In general, the parameter estimates for 
T
, 
T
1

and 
T
0

are asymptotically unbiased under MAR.  In fact, the change from baseline 
LSMEAN for each treatment group estimates the expected difference between 
response at time T and baseline for that group:
)
(
]
~
[
)]
|
ˆ
~
ˆ
(
[
)
ˆ
(
0
0
0
0
ij
ijT
jT
T
jT
T
jT
Y
Y
E
Y
E
Y
Y
E
E
E















.
The last equality uses that the expected baseline means are the same across the 
subjects due to randomization. 
 
 
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However, the conditional variance estimate of 
jT
ˆ
, 
)
|
ˆ
(
0
Y
Var
jT

, obtained from 
the Longitudinal ANCOVA model may incorrectly estimate the overall variance 
of 
jT
ˆ
.  Using the conditional variance formula, we have:
]
)1
/
[(
)]
|
ˆ
(
[
)
ˆ
(
0
0
0
jT
T
jT
jT
Y
Var
Y
Var
E
Var











N
Y
Var
E
T
jT
/
)
1
/
(
)]
|
ˆ
(
[
2
0
2
0
0







where N is the total sample size used in calculating the baseline mean.  To 
illustrate the issue, assume equal allocation between treatment groups, no missing 
data and the same measurement variances over time (ie, 
2
0
2



T
).  Under these 
assumptions, the residual variance for the Longitudinal ANCOVA model 
conditional 
on 
the 
baseline 
is 
))
1(
(
2
2
0



, 
resulting 
in 
N
c
Y
Var
E
jT
/)
1(
(
)]
|
ˆ
(
[
2
2
0
0





, where c is a constant independent of 
2
0

and 
N .  This reduces 
)
ˆ
(
jT
Var 
to:
N
Y
Var
E
Var
jT
jT
/
)
1
(
)]
|
ˆ
(
[
)
ˆ
(
2
0
2
0







)}]
1(
/{
)
1
(
1
)][
|
ˆ
(
[
2
2
0







c
Y
Var
E
jT
)}]
1(
/{
)
1(
1
)][
|
ˆ
(
[
0







c
Y
Var
E
jT
Therefore, the estimated variance of the change from baseline LSMEAN obtained 
from the Longitudinal ANCOVA approach (
)
|
ˆ
(
0
Y
Var
jT

) underestimates the 
overall variance of 
jT
ˆ
.  The relative amount of underestimation is proportional 
to 
)
1
/((
)
1(




.  It is more extreme when the correlation between baseline 
and the response at time T
is small or negative, and less extreme when the 
correlation is close to 1.  The relative underestimation does not decrease with 
increasing sample size, as confirmed through simulation (see Appendix).
Note that the above derivation holds asymptotically when there are missing data 
because the restricted maximum likelihood (REML) estimates are asymptotically 
unbiased for all parameters, as long as the data are missing at random.  If there are 
subjects who have an observed baseline value but all post-baseline values are 
missing, and the missing data depends on the baseline value, then the MAR 
condition is no longer satisfied when these subjects are excluded from the analysis 
model.  As such, the Longitudinal ANCOVA model may produce biased 
LSMEAN estimates.
 
 
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For the full likelihood LDA model, the parameter estimates are unconditional.  
All subjects with available data either at baseline or post-baseline are included in 
the analysis.  Inference based on maximum likelihood is valid, as long as the data 
are missing at random.  Therefore, there are no bias or variance underestimation 
issues for the LDA model.
3.3 Normality assumption
The Longitudinal ANCOVA model assumes that the post-baseline measurements 
are multivariate normally distributed, while the LDA model assumes that the 
baseline and post-baseline measurements are jointly multivariate normally 
distributed.  The robustness of both models to deviations from normality was 
assessed via simulation (see Appendix).  Both models were robust to mild 
departures from normality, but were generally inefficient under more severe 
departures from normality.  As such, robust parametric or non-parametric 
alternatives to the REML-based analysis of the LDA model may be more 
appropriate if a considerable departure from normality is suspected; users should 
refer to the Guidance for Analysis of Continuous Non-normal Longitudinal Data 
for further details.
4. Longitudinal data analysis methods for an endpoint calculated from baseline in 
a non-linear form
When baseline is used to calculate a dependent variable of a non-linear form, the 
LDA model can still be used.  For example, if the parameter of interest is the mean 
percent change from baseline rather than the mean change from baseline, then the 
following two options may be considered: (1) Use the LDA model in which the 
longitudinal response vector includes the baseline measurement and the calculated 
post-baseline percent change from baseline measurements; (2) Use the LDA model in 
which the longitudinal response vector includes the log-transformed baseline and 
post-baseline measurements, and then use the delta method, or any other appropriate 
method (eg, see [8]), to get point estimates and standard errors on the original 
measurement scale.
 
 
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5. Issues with SAS MIXED procedure for LSMEAN estimates
When the SAS MIXED procedure is used to fit a longitudinal ANCOVA model with 
repeated measures and missing data, the default LSMEAN estimates may not be 
appropriate.  For a given treatment group, the individual treatment group LSMEANS 
should be:
jT
T
jT
Y



ˆ
~
ˆ
ˆ
0 



where 
0

Y
is the mean response at baseline of all subjects in the analysis population.  
The default in the SAS MIXED procedure is to calculate the baseline mean from the 
analysis dataset.  When data are missing, some subjects have fewer observations in 
the analysis dataset.  As a result, the default baseline mean is a weighted average of 
baseline values across subjects, where the weight is proportional to the number of 
observations in the analysis dataset for a given subject.  Under MAR, the weighted 
baseline mean may be biased.
To fix this problem, the baseline mean should be calculated outside of the SAS 
MIXED procedure, using one baseline observation per subject.  This calculated mean 
can be used in the LSMEAN statement with the AT =option or in the ESTIMATE
statement.
When the model is more complicated (adjustment for other factors), the ESTIMATE 
statement provides more flexibility.
6. Stratification
Adjustments for stratification factors (such as study center, gender, etc.) do not pose 
any additional theoretical difficulties, although assumptions between models that 
appear similar can be different.  For example, adding a stratification and stratification 
by time interaction to the Longitudinal ANCOVA model defined in Section 2.1 
implicitly makes several assumptions, including that (1) the correlation between 
baseline and post-baseline measurements is the same for each level of the 
stratification variable; and (2) the baseline means are the same for each level of the 
stratification factor.  The LSMEAN estimates are calculated in SAS using this 
common mean.  In contrast, an LDA model with the additional stratification and 
stratification by time factors does not impose the same implicit assumptions.  As a 
result, estimates from the two models will not be the same, even when there are no 
missing data.  An LDA model can be constructed that imposes the same implicit 
assumptions as the Longitudinal ANCOVA model when adjusting for additional 
stratification factors, although in most situations the less restrictive assumptions of 
the LDA model may make more sense. 
 
 
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7. REML and Kenward-Roger adjustment 
Restricted (or residual) maximum likelihood (REML) is the default estimation 
method for the covariance parameters in SAS PROC MIXED. It is a particular form 
of the maximum likelihood applied to linear functions of Y, say KY, for which K is 
specifically designed so that KY contains none of the fixed effects which are part of 
the model for Y. Let Y = X+ . Then K is any matrix with row rank n – rank(X) 
satisfying KX = 0. As a result, variance components are estimated without being 
affected by the fixed effects, , and, in estimating variance components, degrees of 
freedom for the fixed effects are taken into account implicitly [9]. In contrast, the 
conventional maximum likelihood based on the full set of observations generally 
underestimates the variance components. Therefore, REML is the recommended 
estimation method for the covariance parameters. 
By default, the variance for the fixed effects estimate, 
1
1
)
(
)ˆ
var(




X
V
X

, is 
estimated by plugging in the REML estimates of the covariance parameters, 
1
1
)
ˆ
(
)ˆ
r(
aˆ
v




X
V
X

. This underestimates the true variability of ˆ as the uncertainty 
associated with the estimation of the covariance parameters is not taken into account. 
In addition, statistical inference for a linear combination of the fixed effects, H: L= 
0, is often based on the general t-statistic, 
L
X
V
X
L
L
t





1
1
)
ˆ
(
/
ˆ
, which, in 
general, is only approximately t-distributed, and its degrees of freedom must be 
estimated. The default method for degrees of freedom in SAS PROC MIXED 
procedure is the "between-within" approach [??], which does not have good statistical 
properties when there are missing data. It is recommended to use DDFM=KR option 
in the MODEL statement of SAS PROC MIXED, which first adjusts the estimated 
variance for ˆ and then computes Satterthwaite-type degrees of freedom [6]. It is 
shown that the adjusted variance estimate and corresponding degrees-of-freedom 
provide better statistical properties, especially for studies with small sample sizes.
8. Assessing the Recommendation Using Simulations
Results from an extensive simulation study (see Appendix) empirically confirm the 
more desirable properties of the LDA model presented in this guidance.  The 
simulation study compared the LDA model to the Longitudinal ANCOVA model 
under a variety of scenarios when considering treatment and time factors in the 
model.  As noted in Section 6, adjustments for additional stratification factors do not 
pose any additional theoretical difficulties, although consideration for the 
assumptions in Longitudinal ANCOVA model versus the LDA model may warrant 
some attention.  When both models contain the same constraints for the stratification 
factor(s) and baseline means, the more desirable properties of the LDA model hold.
 
 
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It is worth noting that the constraint (mean baseline responses are the same for both 
treatment groups) implicitly assumed in the Longitudinal ANCOVA model does not 
have to be assumed in the LDA model, but it makes sense in the context of 
randomized clinical trials where proper randomization ensures that the assumption is 
true.  When the assumption is true, the LDA model with the constraint will adjust for 
observed chance imbalances in baseline measurements between treatment groups and 
increase efficiency of treatment group comparisons [2, 3].
Results from a separate simulation study also empirically confirm the more desirable 
properties of the Kenward-Roger adjustment. The simulation study compared three 
methods for computing the denominator degrees of freedom for the tests of fixed 
effects: the between-within method, the Satterthwaite approximation, and the 
Kenward-Roger adjustment.
 
 
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9. Implementing the Recommendation using SAS
The SAS code required to fit the LDA model for analyses in terms of change from 
baseline is provided in this section.  For illustration, assume that there is 1 baseline 
and 3 post-baseline measurements for each subject, and a stratification variable that 
has 3 levels.  The data take the form:
Subj
Strata
Trt
time
Y
cy
Bl
1
1
0
5.25664
0.00000
5.25664
1
1
1
4.65575
-0.60089
5.25664
1
1
2
2.58320
-2.67344
5.25664
1
1
3
1.16863
-4.08801
5.25664
2
1
0
4.27706
0.00000
4.27706
2
1
1
2.79553
-1.48153
4.27706
2
1
2
1.85245
-2.42461
4.27706
2
1
3
0.69176
-3.58530
4.27706
3
1
0
4.59872
0.00000
4.59872
3
1
1
3.69201
-0.90671
4.59872
3
1
2
2.71452
-1.88420
4.59872
3
1
3
1.52998
-3.06874
4.59872






1
2
0
5.69308
0.00000
5.69308
1
2
1
3.44989
-2.24319
5.69308
1
2
2
5.40212
-0.29096
5.69308
1
2
3
3.12272
-2.57036
5.69308
2
2
0
4.30366
0.00000
4.30366
2
2
1
3.12098
-1.18268
4.30366
2
2
2
3.16588
-1.13778
4.30366
2
2
3
2.79032
-1.51334
4.30366
3
2
0
4.48876
0.00000
4.48876
3
2
1
3.14964
-1.33912
4.48876
3
2
2
2.71894
-1.76982
4.48876
3
2
3
2.37974
-2.10902
4.48876






PPD
 
 
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9.1 Fitting the LDA model in SAS without adjusting for stratification variables
The LDA model described in Section 2.2 of the guidance document can be fit 
within SAS using the following code:
******************************************************************
**;
** data step necessary prior to running SAS PROC MIXED;
******************************************************************
**;
DATA long; SET long;
ARRAY T{4} t0-t3; * time indicator variables;
ARRAY TT{4} tt0-tt3; * time by treatment 1 (vaccine) indicator variables;
** define week times treatment 1 indicator variables;
DO i = 1 TO 4;
t{i} = (time=(i-1));
tt{i} = t{i}*(trt=1);
END;
DROP i;
RUN;
******************************************************************
**;
** LDA model fit in SAS PROC MIXED;
******************************************************************
**;
PROC MIXED DATA=long;
CLASS subj time;
MODEL y=time tt1 tt2 tt3/ddfm=KR;
REPEATED time / SUBJECT=subj TYPE=UN;
ESTIMATE 'T1 Diff (V-P)' tt1 1;
ESTIMATE 'T2 Diff (V-P)' tt2 1;
ESTIMATE 'T3 Diff (V-P)' tt3 1;
ESTIMATE 'T1 Placebo LSM' time -1 1 0 0;
ESTIMATE 'T2 Placebo LSM' time -1 0 1 0;
ESTIMATE 'T3 Placebo LSM' time -1 0 0 1;
ESTIMATE 'T1 Vaccine LSM' time -1 1 0 0 tt1 1;
ESTIMATE 'T2 Vaccine LSM' time -1 0 1 0 tt2 1;
ESTIMATE 'T3 Vaccine LSM' time -1 0 0 1 tt3 1;
ODS OUTPUT Estimates=outm1;
RUN;
 
 
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The corresponding Longitudinal ANCOVA model can be fit within SAS using the 
following code:
******************************************************************
**;
** Longitudinal ANCOVA model fit in SAS PROC MIXED;
******************************************************************
**;
PROC SQL NOPRINT;
SELECT mean(y) INTO: bb
FROM long WHERE time=0;
QUIT;
PROC MIXED DATA=long;
WHERE time>0;
CLASS subj time trt;
MODEL cy = bl trt time trt*time bl*time/ddfm=KR;
REPEATED time / SUBJECT=subj TYPE=UN;
LSMEANS trt trt*time / pdiff at bl=&bb;
ODS OUTPUT LSMeans=outm2a Diffs=outm2b;
RUN;
Of note, the baseline by time interaction term is included in the Longitudinal 
ANCOVA model for consistency in the modeling assumptions.  If this interaction 
term is removed in the Longitudinal ANCOVA model, the correlation of the 
baseline measurement to each post-baseline measurement is assumed constant 
(even when specifying an unstructured correlation matrix).  The LDA model does 
not make this assumption.  If in reality there is no baseline by time interaction, 
enforcing the assumption of different correlations between the baseline 
measurement and each post-baseline measurement may result in a minor 
efficiency loss.  Given the sample sizes of most clinical trials, there is no material 
effect on the efficiency of the analysis.  However, if there really is such an 
interaction, leaving it out could potentially lead to more bias.
Also of note, a typical exploratory analysis in the analyses of longitudinal data is 
to refit the Longitudinal ANCOVA model defined in Section 2.1 with a baseline 
by treatment interaction, in order to assess whether the treatment effect is 
consistent across varying baseline values.  A similar test cannot be performed 
using the LDA model since the baseline measurement is part of the response 
vector.  As an exploratory analysis, the need for a formal test (and p-value) is 
open to discussion.  If required, a baseline by treatment interaction can be 
explored using the LDA model after creating a categorical baseline variable and 
adjusting for it in the model.  Alternatively, graphical displays can be used to 
assess the consistency of the treatment effect for varying levels of baseline.
 
 
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9.2 Adjusting for stratification variables when fitting the LDA model in SAS
An LDA model that adjusts for stratification variables can be fit within SAS using 
the following code (assuming equal weights for combining estimates across 
strata):
******************************************************************
**;
** data step necessary prior to running SAS PROC MIXED;
******************************************************************
**;
DATA long; SET long;
ARRAY T{4} t0-t3; * time indicator variables;
ARRAY TT{4} tt0-tt3; * time by treatment 1 (vaccine) indicator variables;
** define week times treatment 1 indicator variables;
DO i = 1 TO 4;
t{i} = (time=(i-1));
tt{i} = t{i}*(trt=1);
END;
DROP i;
RUN;
******************************************************************
**;
** LDA model fit in SAS PROC MIXED;
******************************************************************
**;
PROC MIXED DATA=long;
CLASS subj time strata;
MODEL y=strata time strata*time tt1 tt2 tt3/ddfm=KR;
REPEATED time / SUBJECT=subj TYPE=UN;
ESTIMATE 'T1 Diff (V-P)' tt1 1;
ESTIMATE 'T2 Diff (V-P)' tt2 1;
ESTIMATE 'T3 Diff (V-P)' tt3 1;
ESTIMATE 'T1 Placebo LSM' time -3 3 0 0 
  strata*time -1 -1 -1 1 1 1 0 0 0 0 0 0 / divisor = 3;
ESTIMATE 'T2 Placebo LSM' time -3 0 3 0
  strata*time -1 -1 -1 0 0 0 1 1 1 0 0 0 / divisor = 3;
ESTIMATE 'T3 Placebo LSM' time -3 0 0 3
  strata*time -1 -1 -1 0 0 0 0 0 0 1 1 1 / divisor = 3;
ESTIMATE 'T1 Vaccine LSM' time -3 3 0 0 tt1 3
  strata*time -1 -1 -1 1 1 1 0 0 0 0 0 0 / divisor = 3;
ESTIMATE 'T2 Vaccine LSM' time -3 0 3 0 tt2 3
  strata*time -1 -1 -1 0 0 0 1 1 1 0 0 0 / divisor = 3;
ESTIMATE 'T3 Vaccine LSM' time -3 0 0 3 tt3 3
  strata*time -1 -1 -1 0 0 0 0 0 0 1 1 1 / divisor = 3;
ODS OUTPUT Estimates=outm1;
RUN;
 
 
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Note that this model does not implicitly assume that the baseline means or the 
correlation between the baseline and post-baseline measurements are the same for 
each stratum.  The typical Longitudinal ANCOVA model that does make this 
implicit assumption is fit within SAS using the following code:
******************************************************************
**;
** Longitudinal ANCOVA model fit in SAS PROC MIXED;
******************************************************************
**;
PROC SQL NOPRINT;
SELECT mean(y) INTO: bb
FROM long WHERE time=0;
QUIT;
PROC MIXED DATA=long;
WHERE time>0;
CLASS subj time trt strata;
MODEL cy = bl trt time trt*time bl*time strata strata*time/ddfm=KR;
REPEATED time / SUBJECT=subj TYPE=UN;
LSMEANS trt trt*time / pdiff at bl=&bb;
ODS OUTPUT LSMeans=outm2a Diffs=outm2b;
RUN;
Note that for a stratification factor included in the analysis model the SAS default 
LSMEANS will apply equal weight over the levels of the stratification factor. In 
order to use different weights, such as a weight proportional to number of subjects 
in each level of the stratification factor in the analysis dataset, the OM option may 
be used in the LSMEANS statement. If the ESTIMATE statement is used, a two-
step approach may be considered to incorporate a different weighting scheme for 
the stratification factor [10]. 
   
 
 
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10. Standard template language for DAS/SAP
Recommended template language on the use of the cLDA model for analyzing 
longitudinal clinical trials with adjustment for baseline is provided below. This 
template language is also applicable in the special case where T=1. For completeness, 
the template is also given for the regular LDA model without adjustment for baseline, 
which may be used for studies without baseline or when baseline is not informative 
for the analysis.  
For cLDA Model (with adjustment for baseline)
In the primary analysis, a constrained longitudinal data analysis (cLDA) method 
proposed by Liang and Zeger [4] will be used. 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. In this model, the response vector consists of 
baseline and the values observed at each post-baseline time point.  Time is treated as 
a categorical variable so that no restriction is imposed on the trajectory of the means 
over time. The analysis model will also adjust for factor1, factor2, … (add other 
adjustment factors here, if applicable, and consider the time by factor interaction 
terms, as appropriate). The treatment difference in terms of mean change from 
baseline to a given time point will be estimated and tested from this model. An 
unstructured covariance matrix will be used to model the correlation among repeated 
measurements. The Kenward-Roger adjustment will be used with restricted (or 
residual) maximum likelihood (REML) to make proper statistical inference.
Although the baseline measurement is included in the response vector, it is 
independent of treatment, and hence, the baseline means are constrained to be the 
same for different treatment groups. 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. However, unlike longitudinal ANCOVA, the cLDA model accounts for 
variability in the baseline values, thus providing more accurate standard errors and 
confidence intervals for individual treatment effects.  Moreover, this model allows the 
inclusion of patients who are missing either the baseline or post-baseline 
measurements, thereby increasing efficiency. Details of the model specification, 
assumptions, and SAS implementation codes are given in Appendix II.    
The above REML-based analysis assumes that the vector of model-based residuals 
follows a multivariate normal distribution.  Under severe departures from normality, 
the REML-based analysis can be inefficient or potentially misleading.  Accordingly, 
the residuals from the REML-based analysis, scaled by the inverse Cholesky root of 
the marginal variance-covariance matrix, will be subjected to a test for normality.  If 
normality is not rejected at the α=0.001 level, then the above REML-based analysis 
will serve as the primary analysis.  However, if normality is rejected, then the 
primary analysis will be conducted using multiple imputation (MI) of missing values 
(if any) in conjunction with a robust regression (RREG) approach that uses M-
 
 
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estimation.  Details of the normality test and the MIRREG method, along with 
sample SAS code, are provided in Appendix xx.  Of note, the 0.001 level for the 
normality test was chosen so that the default REML-based analysis is abandoned only 
under a clear departure from normality; moreover, this choice guarantees that there 
is no material inflation in the type I error rate for the treatment effect comparison due 
to a potential correlation between the test statistics for the treatment effect and the 
normality test.          
For LDA Model (without adjustment for baseline)
In the primary analysis, a longitudinal data analysis (LDA) method will be used. This 
model assumes a different mean for each treatment at each of the repeated time 
points in the analysis. In this model, time is treated as a categorical variable so that 
no restriction is imposed on the trajectory of the means over time. The analysis model 
will also adjust for factor1, factor 2… (add other adjustment factors here, if 
applicable, and also consider the time by factor interaction terms, as appropriate). 
The treatment difference at a given time point will be estimated and tested from this 
model. An unstructured covariance matrix will be used to model the correlation 
among repeated measurements. The Kenward-Roger adjustment will be used with 
restricted (or residual) maximum likelihood (REML) to make proper statistical 
inference.
Of note, in the event that there are no missing data, the estimated treatment difference 
from the above LDA model will be identical to that from a corresponding traditional 
ANOVA model at a given time point. However, the LDA model allows the inclusion of
patients who have missing data at certain time points, thereby increasing efficiency. 
Details of the model specification, assumptions, and SAS implementation code are 
given in Appendix 2.    
The above REML-based analysis assumes that the vector of model-based residuals 
follows a multivariate normal distribution.  Under severe departures from normality, 
the REML-based analysis can be inefficient or potentially misleading.  Accordingly, 
the residuals from the REML-based analysis, scaled by the inverse Cholesky root of 
the marginal variance-covariance matrix, will be subjected to a test for normality.  If 
normality is not rejected at the α=0.001 level, then the above REML-based analysis 
will serve as the primary analysis.  However, if normality is rejected, then the 
primary analysis will be conducted using multiple imputation (MI) of missing values 
(if any) in conjunction with a robust regression (RREG) approach that uses M-
estimation.  Details of the normality test and the MIRREG method, along with 
sample SAS code, are provided in Appendix xx.  Of note, the 0.001 level for the 
normality test was chosen so that the default REML-based analysis is abandoned only 
under a clear departure from normality; moreover, this choice guarantees that there 
is no material inflation in the type I error rate for the treatment effect comparison due 
to a potential correlation between the test statistics for the treatment effect and the 
normality test.          
 
 
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Note: sample SAS codes for the normality test and the MIRREG method are 
provided in Section 4 of the ELSTIC document: Analysis of Continuous but 
Potentially Non-Normal Longitudinal Data   
Prepared by the ELSTIC Longitudinal Data Analysis Working Group:
 
References
1. Crager RM (1987).  Analysis of covariance in parallel-group clinical trials with 
pretreatment baselines.  Biometrics, 43, 895-901.
2. Senn SJ (1989).  Covariate imbalance and random allocation in clinical trials.  Statistics 
in Medicine, 8, 467-475.
3. Frison L, Pocock SJ (1992).  Repeated measures in clinical trials: analysis using mean 
summary statistics and its implications for design.  Statistics in Medicine, 11, 1685-1704.   
4. Liang K, Zeger, S (2000).  Longitudinal data analysis of continuous and discrete 
responses for pre-post designs.  Sankhyā:  The Indian Journal of Statistics, 62 (Series B), 
134-148.
5. Liu G, Lu K, Mogg R, Mallick M, Mehrotra DV (2009). Should baseline be a covariate 
or dependent variable in analyses of change from baseline in clinical trials? Statistics in 
Medicine, 28, 2509-1530.
6. Kenward MG, Roger JH (1997). Small sample inference for fixed effects from restricted 
maximum likelihood. Biometrics, 53, 983-997.
7. Lu K, Mehrotra DV (2009). Specification of covariance structure in longitudinal data 
analysis for randomized clinical trials. Statistics in Medicine, DOI: 10.1002/sim.3820
8. Wong P, Mukhopadhyay S, Quan H, Larson P (1997).  Confidence intervals for between-
treatment mean difference when analysis is on the log percent scale.  Proceedings of the 
Biopharmaceutical Section of American Statistical Association, 111-116.
9. McCulloch CE, Searle SR (2001). Generalized, Linear, and Mixed Models. Wiley: New 
York.
10. Qi E, Liu G (2002). Two step approach to automatically generate ESTIMATE statements 
for pair-wise treatment comparisons.  SAS Conference Proceedings: PharmaSUG, Salt 
Lake City, Utah.
PPD
 
 
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Appendix I:  Simulation Study
An extensive simulation study was undertaken to assess the performance of the Longitudinal 
ANCOVA and the LDA models under a variety of scenarios.  Treatment difference 
LSMEAN and individual treatment group LSMEAN estimates were compared with respect 
to bias, coverage, MSE, Type I error and Power.
We simulated data from two treatment groups (placebo and treatment) and four repeated 
measures per subject (including baseline).  Four scenarios were considered:  (a)  50 subjects 
per treatment group, 
1
2 

at each time point; (b)  50 subjects per treatment group, 
4
2 

at each time point; (c)  30 subjects per treatment group, 
4
2 

at each time point; and (d)  
80 subjects per treatment group, 
4
2 

at each time point.  Data were generated under (i)  
multivariate normal (Case 0); (ii) a truncated normal distribution at baseline and multivariate 
normal post-baseline (Case 1); and (iii) a truncated t-distribution with 3 degrees of freedom 
at baseline and multivariate t distribution with 3 degrees of freedom post-baseline (Case 2).  
The following correlation structure used was used when generating the data:












1
7.0
4.0
2.0
7.0
1
7.0
4.0
4.0
7.0
1
7.0
2.0
4.0
7.0
1
For all cases, data were generated with a mean vector for the placebo group of 
)
0.
2
3.
2
5.
2
0.
3
(


.  For Cases 1 and 2, the baseline distribution was left-truncated at 2.  
The post-baseline means under the alternative were chosen to target ~80% power under each 
scenario when no data were missing.  In the analysis, an unstructured covariance matrix was 
assumed.  Two missing data scenarios were considered:  (i)  no missing data; and (ii) 10% of 
baseline measurements missing completely at random and a monotone MAR missing data 
mechanism post-baseline.  The probability a post-baseline measurement was missing 
depended on the measurement at the previous time point, with higher values resulting in a 
higher probability of drop-out.  The percent of data missing by study week is shown in Table 
2 for each scenario.
 
 
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Table 2
Summary of Percent of Data Missing in Simulation Study
Baseline
Time 1
Time 2
Time 3
CASE 0
Placebo/Treatment (under null)
~10%
~13%
~22%
~30%
Placebo (under alt)
~10%
~13%
~22%
~30%
Treatment (under alt)
~10%
~19%
~31%
~40%
CASE 1
Placebo/Treatment (under null)
~10%
~18%
~29%
~37%
Placebo (under alt)
~10%
~18%
~29%
~37%
Treatment (under alt)
~10%
~25%
~40%
~49%
CASE 2
Placebo/Treatment (under null)
~10%
~22%
~34%
~42%
Placebo (under alt)
~10%
~22%
~34%
~42%
Treatment (under alt)
~10%
~29%
~44%
~53%
Results under the null hypothesis are provided in Tables 3 and 4 for the treatment difference 
LSMEAN estimate and individual LSMEAN estimates, respectively.  Similar results are 
provided in Tables 5 and 6 under the alternative.  The results indicate the following:

When there are no missing data, the Longitudinal ANCOVA and the LDA models are 
generally comparable with respect to treatment group comparisons.

In the presence of missing baseline data, the LDA model has superior power to detect 
treatment differences.

In both cases (missing or no missing data), confidence intervals for the least square 
means (LSMEANS) of the individual treatment groups are not covered at the
appropriate 100(1-α)% level in the Longitudinal ANCOVA model.

Both models were robust to mild departures from normality and quite inefficient 
under more severe departures from normality.  As such, other non-parametric 
methods may be considered if a considerable departure from normality is suspected.

In the presence of missing data, the LDA model also resulted in treatment group 
estimates that did not always cover at the appropriate 100(1-α)% level when the data 
were not multivariate normal.  However, this may be explained by the small effective 
sample sizes, as the appropriate coverage was attained in the LDA model when no 
data were missing.
An additional scenario was considered to assess the coverage of the confidence intervals for 
the LSMEANS of the individual treatment groups with "large" sample sizes in the optimal 
situation where the data are multivariate normal (Case 0) and no data are missing:  (e)  250 
 
 
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subjects per treatment group, 
4
2 

at each time point.  Results are provided in Table 7, 
and clearly demonstrate that the confidence intervals for the LSMEANS of the individual 
treatment groups are not covered at the appropriate 100(1-α)% level in the Longitudinal 
ANCOVA model regardless of sample size.
A separate set of simulation studies were conducted to compare the following three methods 
for computing the denominator degrees of freedom for the tests of fixed effects in the context 
of small samples: (1) the between-within method (SAS default), DDFM=BETWITHIN (or 
DDFM=BW); (2) a general Satterthwaite approximation, DDFM=SATTERTH (or 
DDFM=SAT); and (3) the Kenward-Roger adjustment, DDFM=KENWARDROGER (or 
DDFM=KR). We simulated data from two treatment groups (placebo and treatment) and 
three repeated measures per subject (including baseline). Under the null hypothesis H0, the 
mean vector was (3.0, 2.5, 2.0) for both groups; under the alternative hypothesis H1, the 
mean vector was (3.0, 2.5, 2.0) for the placebo group, and (3.0, 2.0, 1.0) for the treatment 
group. The variance-covariance matrix for the repeated measures was 










1
8.0
6.0
8.0
1
8.0
6.0
8.0
1
4
The endpoint was change from baseline at the last time point (t=2). Each simulated data set 
consisted of 20 subjects with 12 on placebo and 8 on treatment (unbalanced allocation). 
Twenty thousand (20,000) simulated data sets were generated for each case. Three degrees of 
missing data were considered under both H0 and H1: (1) no missing data; (2) low amount of 
missing data (~8% at t=1, ~13% at t=2); and (3) moderate amount of missing data (~15% at 
t=1, ~23% at t=2). The three DDFM methods have no impact on the point estimate of fixed 
effects, hence the comparison was based on the variance estimates, type I error/power and 
coverage of 95% CIs.  Results are provided in Table 8 for the between-group LSMEAN 
difference at time 2 and in Table 9 for the LSMEAN change from baseline at time 2 for the 
treatment group, respectively. The results indicate the following:

The default variance estimate (as used by DDFM=BW and DDFM=SAT) 
underestimated the true variability of the fixed effects estimate. 

Although the variance estimates were identical for the DDFM=SAT and DDFM=BW 
options, the former produced smaller denominator degrees of freedom and resulted in 
better coverage and less inflated Type I error.

The DDFM=KR option appropriately adjusted the estimated variance and the 
denominator degrees of freedom, and produced proper coverage and controlled the 
Type I error. 
 
 
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Table 3
Simulation Results Comparing the LDA and Longitudinal ANCOVA Models under H0
LSMEAN Treatment Difference in Change from Baseline at Time 3
LSMEAN OF TREATMENT DIFFERENCE IN CHANGE FROM BASELINE AT TIME 3
Bias
Coverage (%)
MSE
Type I Error (%)
Simulation 
Scenario
Case
LDA
Longitudinal
ANCOVA
LDA
Longitudinal
ANCOVA
LDA
Longitudinal
ANCOVA
LDA
Longitudinal
ANCOVA
No Missing Data under H0 (5000 simulations)
(a) 
n = 50/group, 
= 1
Case 0
0.000
0.000
95.2
95.4
0.038
0.038
2.3
2.2
Case 1
-0.000
-0.000
94.8
95.2
0.038
0.038
2.4
2.3
Case 2
-0.001
-0.001
95.2
95.6
0.087
0.087
2.6
2.4
(b) 
n = 50/group, 
= 4
Case 0
-0.002
-0.002
94.9
95.3
0.156
0.156
2.6
2.5
Case 1
-0.000
-0.000
95.4
95.5
0.150
0.150
2.3
2.2
Case 2
-0.001
-0.001
95.2
95.4
0.373
0.373
2.3
2.2
(c) 
n = 30/group, 
= 4
Case 0
0.002
0.002
94.6
95.0
0.262
0.262
3.0
2.8
Case 1
-0.000
-0.000
94.5
94.9
0.261
0.261
2.7
2.5
Case 2
0.001
0.001
94.8
95.2
0.625
0.625
2.6
2.3
(d) 
n = 80/group, 
= 4
Case 0
-0.000
-0.000
94.9
95.1
0.095
0.095
2.6
2.5
Case 1
0.000
0.000
95.1
95.2
0.096
0.096
2.7
2.5
Case 2
0.002
0.002
95.2
95.3
0.228
0.228
2.3
2.3
Missing Data under H0 (5000 simulations)
(a) 
n = 50/group, 
= 1
Case 0
0.002
0.002
95.0
95.4
0.048
0.048
2.4
2.3
Case 1
-0.001
-0.001
95.5
95.8
0.050
0.050
2.2
2.0
Case 2
-0.003
-0.003
94.6
95.1
0.098
0.098
2.7
2.5
(b) 
n = 50/group, 
= 4
Case 0
-0.003
-0.003
94.8
95.1
0.213
0.213
2.6
2.6
Case 1
-0.003
-0.003
95.1
95.3
0.225
0.225
2.5
2.3
Case 2
0.003
0.002
95.1
95.4
0.428
0.428
2.3
2.2
(c) 
n = 30/group, 
= 4
Case 0
-0.000
-0.000
94.6
95.1
0.358
0.358
2.9
2.7
Case 1
0.002
0.002
94.5
95.2
0.397
0.397
2.6
2.3
Case 2
-0.013
-0.013
94.0
94.6
0.744
0.744
3.0
2.7
(d) 
n = 80/group, 
= 4
Case 0
0.002
0.002
94.9
95.1
0.130
0.130
2.9
2.8
Case 1
0.000
0.000
94.4
94.5
0.145
0.145
2.8
2.7
Case 2
-0.002
-0.002
94.4
94.6
0.257
0.257
3.0
3.0
 
 
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Table 4
Simulation Results Comparing the LDA and Longitudinal ANCOVA Models under H0
LSMEAN of Change from Baseline at Time 3 for Placebo and Treatment Groups
LSMEAN of change from baseline at Time 3
for Placebo
LSMEAN of change from baseline at Time 3
for Treatment
% Bias
Coverage (%)
% Bias
Coverage
Simulation 
Scenario
Case
LDA
Longitudinal
ANCOVA
LDA
Longitudinal
ANCOVA
LDA
Longitudinal
ANCOVA
LDA
Longitudinal
ANCOVA
No Missing Data under H0 (5000 simulations)
(a) 
n = 50/group, 
= 1
Case 0
0.01%
0.01%
95.2
91.5
-0.01%
-0.01%
95.2
91.1
Case 1
-0.02%
-0.02%
94.6
92.2
0.02%
0.02%
95.3
93.1
Case 2
-0.03%
-0.03%
95.4
92.8
0.03%
0.03%
94.4
91.1
(b) 
n = 50/group, 
= 4
Case 0
-0.10%
-0.10%
95.3
91.5
0.10%
0.10%
95.4
91.4
Case 1
0.00%
0.00%
95.5
93.7
0.00%
0.00%
95.5
94.1
Case 2
-0.03%
-0.03%
94.5
91.2
0.03%
0.03%
95.1
92.1
(c) 
n = 30/group, 
= 4
Case 0
0.08%
0.08%
95.0
90.9
-0.08%
-0.08%
94.9
90.9
Case 1
-0.01%
-0.01%
94.7
92.9
0.01%
0.01%
94.5
93.1
Case 2
0.03%
0.03%
94.8
91.8
-0.03%
-0.03%
94.8
91.9
(d) 
n = 80/group, 
= 4
Case 0
0.00%
0.00%
94.9
91.2
0.00%
0.00%
95.2
91.2
Case 1
0.01%
0.01%
95.1
93.3
-0.01%
-0.01%
94.6
92.8
Case 2
0.05%
0.05%
95.4
92.4
-0.05%
-0.05%
94.9
92.3
Missing Data under H0 (5000 simulations)
(a) 
n = 50/group, 
= 1
Case 0
0.04%
0.04%
95.1
92.3
-0.11%
-0.11%
95.1
92.0
Case 1
0.09%
0.09%
94.9
92.8
0.18%
0.18%
95.2
93.7
Case 2
-0.20%
-0.20%
94.4
91.6
0.00%
0.00%
93.6
90.7
(b) 
n = 50/group, 
= 4
Case 0
-0.54%
-0.54%
94.6
92.0
-0.29%
-0.29%
94.6
92.1
Case 1
-0.22%
-0.22%
94.4
93.7
-0.04%
-0.04%
94.7
94.2
Case 2
0.14%
0.18%
91.9
91.1
0.02%
0.06%
91.5
91.0
(c) 
n = 30/group, 
= 4
Case 0
-0.05%
-0.05%
94.6
92.4
-0.04%
-0.04%
94.2
91.9
Case 1
0.03%
0.03%
93.5
93.2
-0.10%
-0.10%
94.5
94.0
Case 2
-0.82%
-0.82%
91.3
91.2
-0.22%
-0.22%
92.0
91.6
 
 
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LSMEAN of change from baseline at Time 3
for Placebo
LSMEAN of change from baseline at Time 3
for Treatment
% Bias
Coverage (%)
% Bias
Coverage
Simulation 
Scenario
Case
LDA
Longitudinal
ANCOVA
LDA
Longitudinal
ANCOVA
LDA
Longitudinal
ANCOVA
LDA
Longitudinal
ANCOVA
(d) 
n = 80/group, 
= 4
Case 0
0.10%
0.10%
94.7
91.9
-0.08%
-0.09%
94.9
92.5
Case 1
0.02%
0.02%
94.6
94.0
0.01%
0.01%
94.0
93.3
Case 2
-0.18%
-0.17%
91.2
90.4
-0.07%
-0.06%
90.9
90.1
 
 
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Table 5
Simulation Results Comparing the LDA and Longitudinal ANCOVA Models under H1
LSMEAN Treatment Difference in Change from Baseline at Time 3
LSMEAN OF TREATMENT DIFFERENCE IN CHANGE FROM BASELINE AT TIME 3
% Bias
Coverage (%)
MSE
Power
Simulation 
Scenario
Case
LDA
Longitudinal
ANCOVA
LDA
Longitudinal
ANCOVA
LDA
Longitudinal
ANCOVA
LDA
Longitudinal
ANCOVA
No Missing Data under H1 (2000 simulations)
(a) 
n = 50/group, 
= 1
Case 0
-0.19%
-0.19%
94.3
94.5
0.040
0.040
85.8
85.4
Case 1
0.11%
0.11%
94.6
95.0
0.039
0.039
86.0
85.5
Case 2
-0.18%
-0.18%
94.3
94.5
0.093
0.093
55.1
54.4
(b) 
n = 50/group, 
= 4
Case 0
0.13%
0.13%
94.7
94.9
0.156
0.156
83.9
83.2
Case 1
0.15%
0.15%
95.1
95.3
0.158
0.158
82.8
82.1
Case 2
-0.17%
-0.17%
95.1
95.3
0.377
0.377
48.3
47.5
(c) 
n = 30/group, 
= 4
Case 0
0.19%
0.19%
94.7
95.3
0.265
0.265
82.2
81.3
Case 1
-0.25%
-0.25%
94.2
95.0
0.268
0.268
82.7
81.8
Case 2
0.23%
0.23%
94.8
95.3
0.598
0.598
51.9
50.4
(d) 
n = 80/group, 
= 4
Case 0
-0.19%
-0.19%
94.8
94.9
0.098
0.098
82.2
81.9
Case 1
-0.13%
-0.13%
95.1
95.3
0.095
0.095
83.0
82.3
Case 2
0.14%
0.14%
96.2
96.2
0.229
0.229
49.1
48.6
Missing Data under H1 (2000 simulations)
(a) 
n = 50/group, 
= 1
Case 0
-0.63%
-0.62%
94.5
94.8
0.054
0.054
75.1
73.9
Case 1
0.35%
0.40%
94.7
95.2
0.053
0.053
74.7
73.7
Case 2
-0.72%
-0.71%
94.7
95.1
0.105
0.105
49.6
48.6
(b) 
n = 50/group, 
= 4
Case 0
-0.38%
-0.38%
94.0
94.3
0.237
0.237
69.3
67.8
Case 1
0.38%
0.38%
95.0
95.2
0.258
0.258
62.0
61.0
Case 2
-0.47%
-0.47%
95.0
95.3
0.464
0.464
40.5
39.4
(c) 
n = 30/group, 
= 4
Case 0
1.11%
1.11%
94.3
94.8
0.382
0.382
68.9
67.3
Case 1
-0.98%
-0.98%
93.6
94.3
0.455
0.455
61.7
60.1
Case 2
2.01%
2.01%
94.1
95.2
0.733
0.733
42.9
40.8
 
 
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LSMEAN OF TREATMENT DIFFERENCE IN CHANGE FROM BASELINE AT TIME 3
% Bias
Coverage (%)
MSE
Power
Simulation 
Scenario
Case
LDA
Longitudinal
ANCOVA
LDA
Longitudinal
ANCOVA
LDA
Longitudinal
ANCOVA
LDA
Longitudinal
ANCOVA
(d) 
n = 80/group, 
= 4
Case 0
-0.87%
-0.87%
95.3
95.7
0.139
0.139
67.9
67.5
Case 1
-0.83%
-0.83%
94.2
94.4
0.165
0.165
62.2
61.0
Case 2
1.01%
1.01%
95.0
95.5
0.277
0.277
42.6
41.4
Table 6
Simulation Results Comparing the LDA and Longitudinal ANCOVA Models under H1
LSMEAN of Change from Baseline at Time 3 for Placebo and Treatment Groups
LSMEAN of change from baseline at Time 3
for Placebo
LSMEAN of change from baseline at Time 3
for Treatment
% Bias
Coverage (%)
% Bias
Coverage
Simulation 
Scenario
Case
LDA
Longitudinal
ANCOVA
LDA
Longitudinal
ANCOVA
LDA
Longitudinal
ANCOVA
LDA
Longitudinal
ANCOVA
No Missing Data under H1 (2000 simulations)
(a) 
n = 50/group, 
= 1
Case 0
0.06%
0.06%
95.2
91.6
-0.04%
-0.04%
94.9
91.6
Case 1
-0.03%
-0.03%
94.9
92.1
0.02%
0.02%
95.2
92.6
Case 2
0.04%
0.04%
93.9
90.4
-0.03%
-0.03%
94.5
91.9
(b) 
n = 50/group, 
= 4
Case 0
-0.08%
-0.08%
95.2
91.8
0.04%
0.04%
94.6
90.5
Case 1
-0.05%
-0.05%
94.7
92.9
0.03%
0.03%
95.6
93.4
Case 2
0.04%
0.04%
94.6
91.3
-0.03%
-0.03%
94.6
91.3
(c) 
n = 30/group, 
= 4
Case 0
-0.14%
-0.14%
94.6
90.0
0.06%
0.06%
95.4
92.1
Case 1
0.10%
0.10%
95.4
93.6
-0.06%
-0.06%
94.2
92.4
Case 2
-0.08%
-0.08%
95.3
92.2
0.05%
0.05%
95.1
92.3
(d) 
n = 80/group, 
= 4
Case 0
0.09%
0.09%
94.6
91.3
-0.05%
-0.05%
95.7
91.5
Case 1
0.03%
0.03%
95.5
93.9
-0.02%
-0.02%
94.6
92.8
Case 2
-0.03%
-0.03%
94.8
92.3
0.02%
0.02%
95.3
91.9
 
 
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LSMEAN of change from baseline at Time 3
for Placebo
LSMEAN of change from baseline at Time 3
for Treatment
% Bias
Coverage (%)
% Bias
Coverage
Simulation 
Scenario
Case
LDA
Longitudinal
ANCOVA
LDA
Longitudinal
ANCOVA
LDA
Longitudinal
ANCOVA
LDA
Longitudinal
ANCOVA
Missing Data under H1 (2000 simulations)
(a) 
n = 50/group, 
= 1
Case 0
0.37%
0.37%
94.6
92.1
-0.01%
-0.01%
95.1
92.0
Case 1
-0.11%
-0.11%
94.8
93.0
0.04%
0.04%
94.7
93.4
Case 2
0.15%
0.29%
93.2
90.3
-0.11%
-0.01%
94.6
91.9
(b) 
n = 50/group, 
= 4
Case 0
0.03%
0.02%
93.6
92.2
-0.19%
-0.19%
93.9
91.8
Case 1
-0.20%
-0.20%
93.7
93.4
0.03%
0.02%
94.7
93.9
Case 2
0.69%
0.69%
91.2
90.9
0.30%
0.30%
90.4
89.4
(c) 
n = 30/group, 
= 4
Case 0
-1.82%
-1.82%
93.4
91.6
-0.08%
-0.08%
94.4
92.5
Case 1
0.65%
0.65%
94.2
94.4
-0.09%
-0.09%
93.6
93.2
Case 2
-0.52%
-0.52%
90.3
90.4
0.48%
0.48%
91.4
90.8
(d) 
n = 80/group, 
= 4
Case 0
0.54%
0.54%
94.7
92.8
-0.13%
-0.13%
95.2
93.0
Case 1
0.08%
0.08%
94.4
94.1
-0.22%
-0.22%
94.0
93.2
Case 2
-0.15%
-0.15%
91.0
91.3
0.19%
0.19%
91.2
89.9
 
 
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Table 7
Simulation Results Comparing the LDA and Longitudinal ANCOVA Models under H1
LSMEAN of Change from Baseline at Time 3 for Placebo and Treatment Groups
LSMEAN of change from baseline at Time 3
for Placebo
LSMEAN of change from baseline at Time 3
for Treatment
% Bias
Coverage (%)
% Bias
Coverage
Simulation 
Scenario
Case
LDA
Longitudinal
ANCOVA
LDA
Longitudinal
ANCOVA
LDA
Longitudinal
ANCOVA
LDA
Longitudinal
ANCOVA
No Missing Data under H1 (2000 simulations)
(c) 
n = 30/group, 
= 4
Case 0
-0.14%
-0.14%
94.6
90.0
0.06%
0.06%
95.4
92.1
(b) 
n = 50/group, 
= 4
Case 0
-0.08%
-0.08%
95.2
91.8
0.04%
0.04%
94.6
90.5
(d) 
n = 80/group, 
= 4
Case 0
0.09%
0.09%
94.6
91.3
-0.05%
-0.05%
95.7
91.5
(d) 
n = 250/group, 
= 4
Case 0
0.03%
0.03%
94.3
90.2
0.02%
0.02%
95.5
91.6
 
 
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Table 8
Simulation Results Comparing Three DDFM Methods
LSMEAN Treatment Difference in Change from Baseline at Time 2
Avg. of Estimated Variance
Type I Error/Power (%)
Empirical Coverage (%)
Simulation 
Scenario
Monte 
Carlo 
Variance
BW
SAT
KR
BW
SAT
KR
BW
SAT
KR
Under H0 (20,000 simulations) 
No missing
0.567
0.504
0.504
0.560
6.4
6.3
5.2
93.6
93.7
94.8
Low 
missing
0.660
0.568
0.568
0.656
7.1
6.7
5.1
92.9
93.3
94.9
Moderate 
missing
0.758
0.639
0.639
0.777
7.5
6.7
4.8
92.5
93.3
95.2
Under H1 (20,000 simulations)
No missing
0.567
0.504
0.504
0.560
27.9
27.7
24.6
93.6
93.7
94.8
Low 
missing
0.656
0.565
0.565
0.651
26.5
25.7
22.0
93.0
93.4
95.0
Moderate 
missing
0.749
0.632
0.632
0.765
25.2
23.8
19.3
92.6
93.3
95.3
 
 
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Table 9
Simulation Results Comparing Three DDFM Methods
LSMEAN Change from Baseline at Time 2 for the Treatment Group
Avg. of Estimated Variance
Empirical Coverage (%)
Simulation 
Scenario
Monte Carlo 
Variance
BW
SAT
KR
BW
SAT
KR
Under H1 (20,000 simulations)
No missing
0.368
0.342
0.342
0.362
94.2
94.1
94.7
Low missing
0.422
0.380
0.380
0.414
93.7
93.8
94.8
Moderate 
missing
0.493
0.423
0.423
0.479
93.1
93.4
94.8
 
 
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Appendix II: Sample Protocol Appendix for Model Details and 
SAS Implementation
Appendix for cLDA Model (with adjustment for baseline)
Let Yijt be the response for subject i, with treatment assignment j, at time t. The marginal 
mean responses of the cLDA model can be formulated as 
,0
    
,
)
(
0
0


t
Y
E
ij

and 
.
,...,
2,1
      
,1,0
     
,
)
(
0
T
t
j
Y
E
jt
ijt






The mean response γ0 at t =0 is constrained to be the same for both treatment groups due to 
randomization. The effect γ jt denotes the change from baseline for treatment j at time t. The 
cLDA model assumes that baseline and post-baseline values have a joint multivariate normal 
distribution. An unstructured covariance matrix can be specified in the mixed model to 
account for within subject correlation at times t ≥0 (including baseline). 
The treatment difference for the mean change from baseline at time point t, 
T
t
,...,
2
,1

is 
defined as:
t
t
t
0
1





.
At each time point t, 
T
t
,...,
2
,1

, the mean change from baseline (LSMEANS) for test drug 
and control are 
t1
and 
t0, respectively, as defined in the cLDA model above.
This longitudinal model provides valid statistical inference in the presence of possible 
missing data if the missing data mechanism is ignorable (or more specifically, missing at 
random [MAR] or missing completely at random [MCAR]). This missing data mechanism 
requires that the probability of a data point being missing does not depend on the missing 
data after adjusting for the observed data. Some justification may be provided here, for 
example: 
In this study, we expect that MAR/MCAR mechanisms will underlie most of the missingness 
and the proportion of data missing not at random [MNAR], driven solely by unobserved 
values of the study endpoints, will be small. Specifically, discontinuation reasons may 
include lack of efficacy, clinical or laboratory AEs, relocation, withdrawal of consent, 
protocol violations, and/or data processing issues. Reasons such as relocation and data 
processing issues are likely to be MCAR. On the other hand, 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 
 
 
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AEs), the mechanism may be close to MAR because treatment assignment is an observed 
variable and included in the analysis model. Based on prior study results, missing data due to 
other reasons is relatively infrequent.  
Sample SAS code is provided below to fit the full likelihood cLDA model. (project teams 
are responsible to modify the following code according to their requirements)
For example, assume that there is a baseline and three post-baseline measurements from a 
vaccine trial. The primary interest here is to compare the treatments (vaccine vs. placebo) in 
terms of mean change from baseline in longitudinal clinical trial. The full likelihood LDA 
method models the response as a function of treatment, time and the interaction of time by 
treatment.
********************************************************************;
** data step necessary prior to running SAS PROC MIXED;
********************************************************************;
DATA long; SET long;
ARRAY T{4} t0-t3; * time indicator variables;
ARRAY TT{4} tt0-tt3; * time by treatment 1 (vaccine) indicator variables;
** define week times treatment 1 indicator variables;
DO i = 1 TO 4;
t{i} = (time=(i-1));
tt{i} = t{i}*(trt=1);
END;
DROP i;
RUN;
********************************************************************;
** LDA model fit in SAS PROC MIXED;
********************************************************************;
PROC MIXED DATA=long;
CLASS subj time;  ** subj is the patient id number **; 
MODEL y=time tt1 tt2 tt3/ddfm=KR;
REPEATED time / SUBJECT=subj TYPE=UN;
ESTIMATE 'T1 Diff (V-P)' tt1 1;
ESTIMATE 'T2 Diff (V-P)' tt2 1;
ESTIMATE 'T3 Diff (V-P)' tt3 1;
ESTIMATE 'T1 Placebo LSM' time -1 1 0 0;
ESTIMATE 'T2 Placebo LSM' time -1 0 1 0;
ESTIMATE 'T3 Placebo LSM' time -1 0 0 1;
ESTIMATE 'T1 Vaccine LSM' time -1 1 0 0 tt1 1;
ESTIMATE 'T2 Vaccine LSM' time -1 0 1 0 tt2 1;
ESTIMATE 'T3 Vaccine LSM' time -1 0 0 1 tt3 1;
ODS OUTPUT Estimates=outm1;
RUN;
 
 
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Appendix for LDA Model (without adjustment for baseline)
Let Y ijt be the response for subject i, with treatment assignment j, at time t. The marginal 
mean responses of the full likelihood LDA model is modeled as 
,
,......,
2,1
      
,1,0
     
,
)
(
T
t
j
Y
E
jt
ijt



The LDA model assumes that repeated measurements follow a multivariate normal 
distribution. An unstructured covariance matrix can be specified in the mixed model to 
account for within subject correlation. 
The treatment difference at time point t, 
T
t
,...,
2
,1

is defined as:
t
t
t
0
1





.
For 
T
t
,...,
2
,1

, the mean response (LSMEANS) for test drug and control are 
t1
and 
t0, 
respectively, as defined in the LDA model above.
This longitudinal model provides valid statistical inference in the presence of possible 
missing data if the missing data mechanism is ignorable (or more specifically, missing at 
random [MAR] or missing completely at random [MCAR]). This missing data mechanism 
requires that the probability of a data point being missing does not depend the missing data 
after adjusting for the observed data. Some justification may be provided here, for example: 
In this study, we expect that MAR/MCAR mechanisms will underlie most of the missingness 
and the proportion of data missing not at random [MNAR], driven solely by unobserved 
values of the study endpoints, will be small. Specifically, the discontinuation reasons may 
include lack of efficacy, clinical or laboratory AEs, relocation, withdrawal of consent, 
protocol violations, and/or data processing issues. Reasons such as relocation and data 
processing issues, are likely to be MCAR. On the other hand, 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 
AEes), the mechanism may be close to MAR since treatment assignment is an observed 
variable and included in the analysis model. Based on the prior study results, missing data 
due to other reasons is relatively infrequent.  
Sample SAS code is provided below to fit the full likelihood LDA model. (project teams are 
responsible to modify the following code according to their requirements)
For example, assume that there are three repeated measurements from a vaccine trial. The 
primary interest here is to compare the treatments (vaccine vs. placebo) at last time point in 
this longitudinal clinical trial. The full likelihood LDA method models the response as a 
function of treatment, time and the interaction of time by treatment.
 
 
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********************************************************************;
** LDA model fit in SAS PROC MIXED;
********************************************************************;
PROC MIXED DATA=long;
CLASS subj trt time;  ** subj is the patient id number, trt is the treatment variable, time is 
the time points for repeated measures **; 
MODEL y=trt time trt*time / noint ddfm=KR;
REPEATED time / SUBJECT=subj TYPE=UN;
ESTIMATE 'T1 Diff (V-P)' trt -1 1 trt*time -1 0 0  1 0 0 ;
ESTIMATE 'T2 Diff (V-P)' trt -1 1 trt*time  0 -1 0  0 1 0 ;
ESTIMATE 'T3 Diff (V-P)' trt -1 1 trt*time  0 0 -1  0 0 1 ;
ESTIMATE 'T1 Placebo LSM' trt 1 0 time 1 0 0 trt*time 1 0 0  0 0 0;
ESTIMATE 'T2 Placebo LSM' trt 1 0 time 0 1 0 trt*time 0 1 0  0 0 0;
ESTIMATE 'T3 Placebo LSM' trt 1 0 time 0 0 1 trt*time 0 0 1  0 0 0;
ESTIMATE 'T1 Vaccine LSM' trt 0 1 time 1 0 0 trt*time 0 0 0  1 0 0;
ESTIMATE 'T2 Vaccine LSM' trt 0 1 time 0 1 0 trt*time 0 0 0  0 1 0;
ESTIMATE 'T3 Vaccine LSM' trt 0 1 time 0 0 1 trt*time 0 0 0  0 0 1;
ODS OUTPUT Estimates=outm1;
RUN;
 
 
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Appendix 5
Predefined Limits of Change Criteria
 
 
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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 (ie, be 
more abnormal in the direction of interest) to meet the definition.
LLN=Lower limit of normal.
ULN=Upper limit of normal.
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
 
 
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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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INVESTIGATOR SIGNATURE PAGE
Abbreviated Title
A Long Term Safety Trial of MK-8931 in AD (EPOCH)
Title
A Parallel-Group, Double Blind Long Term Safety Trial of MK-8931 in 
Subjects with Alzheimer’s Disease.  (Phase 2/3; Protocol No. MK-8931-
017-21) (also known as SCH 900931, P07738)
Sponsor
One Merck Drive
P.O. Box 100
Whitehouse Station, NJ 08889-0100, U.S.A.
Trial Physician/Director
Date of Finalization of This Current 
Version of the Protocol
01-AUG-2016 – Amendment 017-21( France Specific)
Previous Versions of the Protocol
26-JUL-2016– Amendment No.20 (Country Specific)
22-JUL-2016– Amendment No.19 (France Specific)
21-JUL-2016– Amendment No.18 (Country Specific)
28-JUN-2016 – Amendment No.17
11-Sep-2015 – Amendment 017-16 (France Specific)
26 JUN 2015 – Amendment 017-15 France Specific
24 APR 2015 - Amendment 017-14 Country Specific
09 APR 2015 - Amendment 017-13
05 MAR 2015 – Amendment 017-12 Country Specific
26 FEB 2015 – Amendment 017-11 Country Specific
18-DEC-2014– Amendment 017-10
08 AUG 2014 - Amendment 017-09 Country Specific
11 FEB 2014 – Amendment #5 (017-08)
14 AUG 2013 – Amendment #4 (017-07)
08 NOV 2012 – Amendment #3 Brazil Version 1 (017-06)
26 SEP 2012 – Amendment #3 (017-05)
23 JUL 2012 – Amendment #2 Brazil Version 2 (017-04)
23 JUL 2012 – Amendment #2 Brazil Version 1 (017-03)
20 JUN 2012 -  Amendment #2 (017-02)
31 MAY 2012 -  Amendment #1 (017-01)
19 JAN 2012 - Initial Protocol (017-00)
THIS CONFIDENTIAL INFORMATION ABOUT AN INVESTIGATIONAL DRUG OR PRODUCT IS PROVIDED 
FOR THE EXCLUSIVE USE OF INVESTIGATORS OF THIS DRUG OR PRODUCT AND IS SUBJECT TO
RECALL AT ANY TIME. THE INFORMATION IN THIS DOCUMENT MAY NOT BE DISCLOSED UNLESS 
SUCH DISCLOSURE IS REQUIRED BY APPLICABLE LAWS OR REGULATIONS.  SUBJECT TO THE 
FOREGOING, THIS INFORMATION MAY BE DISCLOSED ONLY TO THOSE PERSONS INVOLVED IN THE 
TRIAL WHO HAVE A NEED TO KNOW, WITH THE OBLIGATION NOT TO FURTHER DISSEMINATE THIS 
INFORMATION.  THESE RESTRICTIONS ON DISCLOSURE WILL APPLY EQUALLY TO ALL FUTURE 
ORAL OR WRITTEN INFORMATION, SUPPLIED TO YOU BY THE SPONSOR OR ITS AFFILIATES OR 
REPRESENTATIVES THAT IS DESIGNATED AS "PRIVILEGED" OR "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.
PPD
 
 
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Name and Degree of Sponsor Representative
dd MMM yyyy
Department of Sponsor Representative
I have read Protocol No. MK-8931-017-21 (also known as P07738) dated 01 AUG
2016, including all appendices, and agree to conduct the trial in accordance with the 
protocol.  The protocol and trial documents must also be approved by the IRBs/IECs 
and regulatory authorities as appropriate, before implementation at the site.  I agree 
to implement the protocol and trial documents only after all necessary approvals 
have been obtained and the sponsor has confirmed that it is acceptable to do so.
Name, Degree, full mailing address of Investigator
Site Number
dd MMM yyyy
 
 
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