Efficacy and Safety Trial of Verubecestat (MK-8931) in Participants With Prodromal Alzheimer's Disease (MK-8931-019)

Two substudies are included in the study protocol: 1) a PET medical imaging substudy using
an amyloid tracer ([18F]flutemetamol) to evaluate changes in brain composite cortical
amyloid standard uptake value ratio; and 2) a companion diagnostic substudy using Luminex
investigational xMAP™ Tau/Amyloid Assay to evaluate response to treatment in CSF positive
participants (i.e., those with defined tau:amyloid-β42 ratio in CSF) and changes in CSF
concentrations of amyloid-β related peptides, total tau and phosphorylated tau (Substudy
Title: A Companion Diagnostic Clinical Study of Luminex xMAP™ Tau/Amyloid Assay in Subjects
with Amnestic Mild Cognitive Impairment due to Alzheimer's Disease [Prodromal AD] who are
Enrolled into Merck MK-8931 Pivotal Phase III Clinical Trial [Study No. MK-8931-019]). 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:

1. Diagnosis of prodromal AD, including the following:

1. History of subjective memory decline with gradual onset and slow progression for
at least one year corroborated by an informant,

2. Objective impairment in episodic memory by memory test performed at Screening,

3. Does not meet criteria for dementia, AND

4. Positive Screening amyloid imaging PET scan using [18F]flutametamol tracer or
positive Screening CSF tau:amyloid-β42 (Aβ42) ratio

2. Able to read at a 6th grade level or equivalent

3. If participant is receiving an acetylcholinesterase inhibitor or memantine, the dose
must have been stable for at least three months before Screening

4. Must have a reliable and competent trial partner/informant who has a close
relationship with the participant and is willing to accompany the participant to all
required trial visits, and to monitor compliance of the administration of the trial
medication

5. Agree to inform their general practitioner of their participation in this study

Inclusion Criteria for Extension Period (Part II):

1. Tolerated study drug and completed the initial 104-week period of the trial (Part I)

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

Exclusion Criteria:

1. History of stroke

2. Evidence of a clinically relevant neurological disorder other than the disease being
studied (i.e., prodromal AD)

3. History of seizures or epilepsy within the last 5 years

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

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

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

7. 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

8. History of hepatitis or liver disease that has been active within the 6 months prior
to Screening

9. Recent or ongoing, uncontrolled, clinically significant medical condition within 3
months of Screening

10. History of malignancy occurring within the 5 years before Screening, except for
adequately treated basal cell or squamous cell skin cancer, in situ cervical cancer,
or localized prostate carcinoma

11. Clinically significant vitamin B12 or folate deficiency in the 6 months before
Screening

12. Use of any investigational drugs or participation in clinical trials within the 30
days before Screening

13. History of a hypersensitivity reaction to more than three drugs

14. Has human immunodeficiency virus (HIV) by medical history

15. Participant is unwilling or has a contraindication to undergo PET scanning including
but not limited to claustrophobia, excessive weight or girth

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

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

Exclusion Criteria for Extension Period (Part II):

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

2. Has developed a recent or ongoing, uncontrolled, clinically significant medical or
psychiatric condition

3. Results of safety assessments (e.g., laboratory tests) performed in participant at
end of Part I that are clinically unacceptable to the Investigator

4. Has developed a form of dementia that is not AD