Dose-Finding Study To Evaluate Safety, Tolerability, and Efficacy of E2609 in Participants With Mild Cognitive Impairment Due to Alzheimer's Disease (Prodromal Alzheimer's Disease) and Mild to Moderate Dementia Due to Alzheimer's Disease
Condition: Alzheimer Disease; Dementia, Alzheimer Type
MeSH terms: Alzheimer Disease; Dementia; Cognitive Dysfunction
Intervention: E2609; Placebo
Intervention description: Each participant will receive 2 tablets, which when combined will make up the required doses of E2609 or placebo, to be administered orally once per day (QD) with food.; Each participant will receive 2 tablets, which when combined will make up the required doses of E2609 or placebo, to be administered orally once per day (QD) with food.
Phase: Phase 2
Study type: Interventional
Primary purpose: Treatment
Allocation: Randomized
Intervention model: Parallel Assignment
Masking: Triple (Participant, Care Provider, Investigator)
Enrollment: 70.0
Sex: All
Minimum age: 50 Years
Maximum age: 85 Years
Healthy volunteers: No
Keywords: E2609; Mild Cognitive Impairment; Mild to Moderate Dementia; Alzheimer's Disease; Prodromal Alzheimer's Disease

Summary:

      This is a Phase 2 study to evaluate safety and efficacy in participants with Mild Cognitive
      Impairment due to Alzheimer's Disease/Prodromal Alzheimer's Disease (referred to as
      MCI/Prodromal) and mild to moderate dementia due to Alzheimer's Disease (referred to as mild
      to moderate AD). This study will have a Core Phase and an Extension Phase.
    

Eligibility criteria:

        Inclusion criteria:

        Participants must meet all of the following criteria to be included in this study:

          1. Meets the core clinical research criteria of the National Institute on
             Aging-Alzheimer's Association (NIA-AA) for MCI due to AD (which is consistent with
             Prodromal AD) or AD dementia and is 'staged' or classified as either MCI or mild to
             moderate dementia.

          2. Amyloid positive Positron Emission Tomography (PET) image based on centralized PET
             scan reading.

          3. Male or female, age 50 to 85 years, inclusive at time of consent.

          4. Must have an identified caregiver or informant who is willing and able to provide
             follow-up information on the participant throughout the course of the study.

          5. If receiving an Acetylcholinesterase Inhibitor (AChEI) or memantine, must have been on
             a stable dose for at least 12 weeks before the Baseline cognitive assessments, with no
             plans for dose adjustment in the foreseeable future. Treatment-naive participants can
             be entered into the study but there should be no plans to initiate treatment with
             AChEIs or memantine at the time of entry into the study.

          6. Must have been on stable doses of all other permitted chronically used concomitant
             medications (that is, not related to their cognitive decline) for at least 4 weeks
             before randomization.

        Exclusion criteria:

        Participants who meet any of the following criteria will be excluded from this study:

          1. Any neurological condition that may be contributing to cognitive impairment above and
             beyond that caused by the participant's AD pathology, including any co-morbidities
             such as cerebrovascular disease, detected by medical history, neurological
             examination, or magnetic resonance imaging (MRI).

          2. History of transient ischemic attacks or stroke within 12 months of Screening.

          3. History of epilepsy.

          4. Evidence of depression on a rating scale at Screening or any psychiatric diagnosis or
             symptoms, (example, hallucinations, major depression, etc.) that could confound the
             diagnosis or could interfere with study assessments or procedures. This includes
             suicidal ideation or suicidal behavior within 6 months prior to Screening, or
             hospitalization or treatment for suicidal behavior in the past 5 years.

          5. Abnormally low serum vitamin B12.

          6. Thyroid stimulating hormone above the normal range. This applies to all participants
             regardless of whether or not they are taking thyroid supplements.

          7. Participants with liver disease (hepatic impairment), at Screening or Baseline.
             Participant with Gilbert's syndrome need not be excluded.

          8. Not able to have a MRI, PET scanning, or cerebrospinal fluid (CSF) collection by
             Lumbar Puncture (LP).

          9. Severe visual or hearing impairment that would prevent the participant from performing
             psychometric tests accurately.

         10. History of immunodeficiency disorders.

         11. Participants with chronic viral hepatitis.

         12. History of Tuberculosis (TB). Participants with no history of TB will be tested for
             previous TB exposure and a positive test will be exclusionary.

         13. History of ophthalmic shingles or ocular Herpes Simplex Virus (HSV) infection.

         14. Any live vaccine in the 3 months or any active infection within the last 4 weeks
             before study drug administration (that is, randomization).

         15. Any chronic inflammatory disease that is not adequately controlled or requires
             immunosuppressive or immunomodulatory therapy.

         16. T helper cell, cytotoxic T cell, or B cell absolute counts below normal.

         17. Immunoglobulin (Ig) IgG, IgA, or IgM levels below normal at Screening or Baseline,
             unless both the Investigator and the Medical Monitor agree that the finding is not
             clinically significant.

         18. Clinically significant deviation from normal in physical examination, vital signs, or
             clinical laboratory tests at Screening or Baseline.

         19. Exclusionary cardiac factors include: prolonged QT interval greater than 450
             millisecond from Electrocardiograms (ECGs); history of risk factors for torsade de
             pointes or the use of concomitant medications that prolong the QT/corrected QT
             interval (QTc); left bundle branch block; persistent low or high heart rate;
             persistent low or high blood pressure; history of cardiac arrhythmias; other
             clinically significant ECG abnormalities.

         20. Type 1 or Type 2 diabetes mellitus that is not well controlled.

         21. Malignant neoplasms within 5 years before Screening (except for basal or squamous cell
             carcinoma in situ of the skin, or localized prostate cancer that did not require
             systemic therapy; these do not exclude the participant).

         22. Medical conditions (example, cardiac, respiratory, gastrointestinal, renal disease)
             that are not stably controlled, or which, in the opinion of the investigator(s), could
             affect the participant's safety or interfere with the study assessments.

         23. Hypopigmentation conditions (example, albinism and vitiligo).

         24. Known or suspected history of drug or alcohol dependency or abuse within 2 years,
             current use of recreational drugs or a positive urine drug test.

         25. Planned surgery that requires general, spinal, or epidural anesthesia that would take
             place during the study.

         26. Participation in any other interventional clinical study related to cognitive
             impairment within 6 months before Screening unless it can be documented that the
             participant was in a placebo treatment arm.

         27. Currently enrolled in another clinical study or used any investigational drug or
             device within 60 days or 5 half-lives of the investigational medication (whichever is
             longer) proceeding informed consent.

         28. Hypersensitivity to the study drug or any of the excipients or to other Beta Secretase
             Cleaving Enzyme (BACE) inhibitors, or to the PET tracer, or components of its
             formulation.

         29. Females who are lactating or pregnant. Females of childbearing potential who do not
             agree to adhere to the protocol specified methods for avoiding pregnancy.

         30. Males who do not meet the protocol requirements for avoiding their partners becoming
             pregnant. Sperm donation is not permitted.