An Efficacy and Safety Trial of Verubecestat (MK-8931) in Mild to Moderate Alzheimer's Disease (P07738)

Two substudies are included in Part I of the study: 1) a medical imaging substudy to
evaluate changes in brain amyloid protein load using positron emission tomography (PET) and
an amyloid tracer ([18F]flutemetamol); and 2) a cerebrospinal fluid (CSF) biomarker substudy
to evaluate changes in CSF concentrations of amyloid-β related peptides, total tau, and
phosphorylated tau (p-tau). The substudies will be conducted only at designated
investigational sites. Participants are not required to take part in a substudy in order to
take part in the larger trial.

Inclusion Criteria:

- Diagnosis of probable AD based on both a) the National Institute of Neurological and
Communicative Diseases and Stroke/Alzheimer's Disease and Related Disorders
Association (NINCDS-ADRDA) criteria and b) the Diagnostic and Statistical Manual of
Mental Disorders, 4th Edition, Text Revision (DSM-IV-TR) criteria for AD

- AD is of mild to moderate severity

- Clear history of cognitive and functional decline over at least one year that is
either a) documented in medical records or b) documented by history from an informant
who knows the subject well

- Able to read at a 6th grade level or equivalent, and must have a history of academic
achievement and/or employment sufficient to exclude mental retardation

- If a participant is receiving an acetylcholinesterase inhibitor, memantine, medical
food/supplement (e.g., vitamin E) and/or herbal medications for AD, the dose must
have been stable for at least three months before Screening, and the participant must
be willing to remain on the same dose for the duration of the trial. Participants may
need to be on AD treatments in accordance with local requirements

- Participant must have a reliable and competent trial partner/caregiver who must have
a close relationship with the subject

Inclusion Criteria for Extension Period (Part II):

- Tolerated study drug and completed the initial 78-week period of the trial (Part I)

- Participant must have a reliable and competent trial partner who must have a close
relationship with the subject

Exclusion Criteria:

- History of stroke

- Evidence of a neurological disorder other than the disease being studied (i.e.,
probable AD)

- History of seizures or epilepsy within the last 5 years before Screening

- Evidence of a clinically relevant or unstable psychiatric disorder, excluding major
depression in remission

- Participant is at imminent risk of self-harm or of harm to others

- History of alcoholism or drug dependency/abuse within the last 5 years before
Screening

- Participant does not have a magnetic resonance imaging (MRI) scan obtained within 12
months of Screening and is unwilling or not eligible to undergo an MRI scan at the
Screening Visit. With Sponsor approval, a head computed tomography (CT) scan may be
substituted for MRI scan to evaluate eligibility

- History of hepatitis or liver disease that has been active within the six months
prior to Screening Visit

- Recent or ongoing, uncontrolled, clinically significant medical condition within 3
months of the Screening Visit (e.g., diabetes, hypertension, thyroid or endocrine
disease, congestive heart failure, angina, cardiac or gastrointestinal disease,
dialysis, or abnormal renal function) other than the condition being studied such
that participation in the trial would pose a significant medical risk to the subject.
Controlled co-morbid conditions are not exclusionary if stable within three months of
the Screening Visit

- History or current evidence of long QT syndrome, corrected QT (QTc) interval ≥470
milliseconds (for male subjects) or ≥480 milliseconds (for female subjects), or
torsades de pointes

- History of malignancy occurring within the five years before Screening, except for
adequately treated basal cell or squamous cell skin cancer, in situ cervical cancer,
or localized prostate carcinoma; or malignancy which has been treated with
potentially curative therapy with no evidence of recurrence for ≥3 year post-therapy

- Clinically significant vitamin B12 or folate deficiency in the six months before
Screening Visit

- Use of any investigational drugs within 30 days (or longer depending on drug) before
Screening or participation in studies involving repeated cognitive testing within 30
days before Screening. Participation in an observational study, such as those
involving annual cognitive assessments and/or neuroimaging, may be allowed if
approved by Sponsor

- History of a hypersensitivity reaction to more than three drugs

- Has tested positive for human immunodeficiency virus (HIV)

- Close family member (including the caregiver, the spouse or any children) who is
among the personnel of the investigational or sponsor staff directly involved with
this trial

Additional Exclusion Criteria for Safety Cohort:

- History of an ongoing medical condition that has been poorly controlled within 6
months of the Screening Visit (e.g., hypotension, diabetes, hypertension,
cerebrovascular disease, thyroid disease, endocrine disturbance, congestive heart
failure, cardiac or gastrointestinal disease, dialysis, or abnormal renal function)
other than the condition being studied such that a subject's participation in the
trial would pose a significant medical risk

- History of congestive heart failure (moderate or greater severity), myocardial
infarction, heart surgery, syncope, bradycardia, or clinically significant
hypotension within one year before Screening

Exclusion Criteria for Extension Period (Part II):

- Participant is at imminent risk of self-harm or of harm to others

- Has developed a recent or ongoing, uncontrolled, clinically significant medical
condition other than AD

- Has history of or has developed during Part I evidence of long QT syndrome, QTc
interval ≥470 milliseconds (for male subjects) or ≥480 milliseconds (for female
subjects), or torsades de pointes

- Has developed a form of dementia that is not AD