[11C]MK-6884 Positron Emission Tomography (PET) Tracer Validation Trial (MK-6884-001)
Condition: Alzheimer's Disease
MeSH terms: Alzheimer Disease
Intervention: [11C]MK-6884
Intervention description: IV bolus dose of ~370 MBq [11C]MK-6884
Phase: Phase 1
Study type: Interventional
Primary purpose: Other
Allocation: Non-Randomized
Intervention model: Parallel Assignment
Masking: None (Open Label)
Enrollment: 20.0
Sex: All
Minimum age: 18 Years
Maximum age: 85 Years
Healthy volunteers: Accepts Healthy Volunteers

Summary:

      The purpose of this open-label, 3-part study is to investigate the safety and efficacy of
      [11C]MK-6884 as a positron emission tomography (PET) imaging agent for quantifying muscarinic
      4 (M4) positive allosteric modulator (PAM) receptor density in brain regions of interest. The
      study will enroll healthy participants (Parts 1 and 2) and participants with Alzheimer's
      Disease (AD) (Part 3). The primary efficacy hypothesis is that the average intra-subject
      test-retest (T-RT) variability of tracer uptake in brain regions of interest is ≤20%.
    

Eligibility criteria:

        Inclusion Criteria:

        Part 1, 2 and 3:

          -  Male, or non-pregnant and non-breast feeding female of 18 to 55 years of age (Part 1)
             or 55 to 85 years of age (Parts 2 and 3); in addition:

               -  Male participant who is sexually active with females of childbearing potential
                  must be willing to use a condom from the first dose of study drug until 3 months
                  post the last dose of study drug

               -  Female participant with reproductive potential must have serum β-human chorionic
                  gonadotropin (β-hCG) test result consistent with non-pregnant state at screening
                  and agree to use two acceptable methods of birth control beginning at screening
                  visit, during study and until 2 weeks after the last dose of study drug

               -  Female participant of non-childbearing potential must be post-menopausal female
                  (participant has been without menses for at least 1 year and has a follicle
                  stimulating hormone [FSH] level in the postmenopausal range at screening), or
                  surgically sterile female (status post hysterectomy, oophorectomy, or tubal
                  ligation)

          -  Body Mass Index (BMI) ≤35 kg/m^2, with height ≤195 cm and weight ≤136 kg

          -  In good health (Part 1) or generally healthy (Parts 2 and 3) based on medical history,
             physical examination, vital sign measurements and electrocardiogram (ECG)

          -  Nonsmoker and/or has not used nicotine or nicotine-containing products for at least
             approximately 3 months

        Part 2 Only:

          -  Willing to allow placement of an arterial catheter in the radial artery

          -  Mini Mental Status Examination (MMSE) score ≥27

          -  No history of subjective memory or other cognitive complaints

          -  No objective evidence of memory or cognitive impairment

        Part 3 Only:

          -  Moderate to severe AD as defined by:

               -  MMSE score ≤20

               -  Meets National Institute of Neurological and Communicative Diseases and
                  Stroke/Alzheimer's Disease and Related Disorders Association (NINCDS-ADRDA)
                  criteria for probable AD

               -  Meets Diagnostic and Statistical Manual of Mental Disorders, 5th Edition (DSM-V)
                  criteria for AD

               -  Rosen-Modified Hachinski score ≤4

               -  Screening magnetic resonance imaging (MRI) scan consistent with a diagnosis of AD

          -  Clear history of cognitive and functional decline over ≥1 year

          -  On a stable dose of one of protocol-defined acetylcholinesterase inhibitors (AChEIs)
             (i.e., donepezil and rivastigmine) for symptomatic treatment of AD. Dose must be
             stable for at least the last 4 weeks before screening

          -  Has a reliable trial partner/caregiver who is able to accompany the participant to all
             clinic visits, if needed, and able to provide information to study investigator/staff
             via telephone contact

        Exclusion Criteria:

        Part 1, 2, and 3:

          -  Mentally or legally incapacitated, has significant emotional problems at the time of
             screening visit or expected during the conduct of the trial or has a history of
             clinically significant psychiatric disorder of the last 5 years, except (for Part 3
             only) for psychiatric disorders associated with AD

          -  History of clinically significant endocrine, gastrointestinal, cardiovascular,
             hematological, hepatic, immunological, renal, respiratory, genitourinary or major
             neurological abnormalities or diseases, unless (for Part 2 and 3 only) adequately
             controlled through a stable medication regimen

          -  History of cancer

          -  History of significant multiple and/or severe allergies or has had an anaphylactic
             reaction or significant intolerability to prescription or non-prescription drugs or
             food. For Part 2, this includes any known allergy to lidocaine which may be used as an
             anesthetic for the placement of the arterial catheter

          -  Has positive test result for hepatitis B surface antigen, hepatitis C antibodies or
             human immunodeficiency virus (HIV)

          -  Has had major surgery or donated or lost 1 unit of blood (approximately 500 mL) within
             4 weeks prior to screening

          -  Has participated in another investigational trial within 4 weeks of screening

          -  Corrected QT (QTc) interval ≥470 msec (for males) or ≥480 msec (for females)

          -  Is unable to refrain from or anticipates the use of any medication, including
             prescription and non-prescription drugs or herbal remedies, beginning approximately 2
             weeks prior to administration of the initial dose of study drug and throughout the
             study.

          -  Consumes >3 servings of alcohol a day

          -  Consumes >6 caffeine servings a day

          -  Is currently a regular or recreational user of cannabis, any illicit drugs or has a
             history of drug (including alcohol) abuse within approximately 3 months

          -  Has participated in a PET research study or other study involving administration of a
             radioactive substance or ionizing radiation within 12 months prior to screening or has
             undergone an extensive radiological examination within this period

          -  Suffers from claustrophobia or an inability to tolerate confinement in small places
             and would be unable to undergo MRI or PET scanning

        Part 2 Only:

        - Has been administered an AChEI within the prior 3 months or will require administration
        of an AChEI during study

        Part 3 Only:

          -  Has been administered galantamine within the prior 7 days or will require
             administration of galantamine during study

          -  History within 2 years prior to screening, or current evidence of any neurological or
             neurodegenerative disorder other than AD that is associated with transient or
             sustained alterations in cognition

          -  History within 2 years prior to screening, or current evidence of a psychotic disorder
             or a major depressive disorder

        Part 2 and 3 Only:

        - Has or is suspected to have implanted or embedded metal objects, or fragments in the head
        or body that would present a risk during the MRI scanning procedure