Efficacy and Safety Trial of Verubecestat (MK-8931) in Participants With Prodromal Alzheimer's Disease (MK-8931-019)
Condition: Amnestic Mild Cognitive Impairment; Alzheimer's Disease; Prodromal Alzheimer's Disease
MeSH terms: Alzheimer Disease; Cognitive Dysfunction
Intervention: Verubecestat 12 mg (Parts 1 and 2); Verubecestat 40 mg (Parts 1 and 2); Placebo (Part 1)
Intervention description: Verubecestat 12 mg oral tablet, given once daily.; Verubecestat 40 mg oral tablet, given once daily. Verubecestat 40 mg given to participants in Arm C continuing to study Part 2.; Placebo matching verubecestat, given once daily as an oral tablet.
Phase: Phase 3
Study type: Interventional
Primary purpose: Treatment
Allocation: Randomized
Intervention model: Parallel Assignment
Masking: Triple (Participant, Investigator, Outcomes Assessor)
Enrollment: 1454.0
Sex: All
Minimum age: 50 Years
Maximum age: 85 Years
Healthy volunteers: No

Summary:

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

Eligibility criteria:

        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 (Participants with a prior
                  positive amyloid imaging PET scan or a Screening PET scan with florbetaben or
                  florbetapir may be enrolled without a Screening flutemetamol scan with Sponsor
                  approval)

          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

        Inclusion Criteria for Extension Period (Part 2):

          1. Tolerated study drug and completed the initial 104-week period of the trial (Part 1)

          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 2):

          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 1 that are clinically unacceptable to the Investigator

          4. Has developed a form of dementia that is not AD

          5. Has progressed to dementia due to AD per investigator diagnosis in the initial
             104-week study (Part 1).

        Exclusion Criteria for NFT PET Substudy (Part 2):

        1. Had one or two PET scans with MK-6240 in the initial 104-week study.