[18F]MK-6240 Positron Emission Tomography (PET) Tracer First-in-Human Validation Study (MK-6240-001)
Condition: Alzheimer's Disease; Amnestic Mild Cognitive Impairment
MeSH terms: Alzheimer Disease; Cognitive Dysfunction
Intervention: [18F]MK-6240, ~185 MBq; [18F]MK-6240, ~160 MBq
Intervention description: IV dose of ~185 MBq [18F]MK-6240; IV dose of ~160 MBq [18F]MK-6240
Phase: Phase 1
Study type: Interventional
Primary purpose: Diagnostic
Allocation: Non-Randomized
Intervention model: Parallel Assignment
Masking: None (Open Label)
Enrollment: 13.0
Sex: All
Minimum age: 18 Years
Maximum age: 85 Years
Healthy volunteers: Accepts Healthy Volunteers

Summary:

      This 2-part, open-label study was designed to investigate the safety, tolerability, and
      efficacy of [18F]MK-6240, a Positron Emission Tomography (PET) imaging agent, for the
      quantification of neurofibrillary tangle (NFT) deposition in the brain. Brain NFT deposition
      is a pathologic finding in Alzheimer's Disease (AD), with brain NFT density shown to
      correlate with the severity of cognitive impairment in AD. The objectives of the study
      include performing the following with respect to [18F]MK-6240 administered as a PET imaging
      agent: 1) assess safety and tolerability; 2) determine radiation safety profile; 3) determine
      optimal imaging protocol parameters for quantification of brain NFTs in AD; 4) compare tracer
      binding in brain PET scans from participants with AD, participants with amnestic mild
      cognitive impairment (MCI) and healthy elderly participants; and 5) evaluate intra-subject
      test-retest (T-RT) variability of tracer uptake in brain regions of interest.
    

Eligibility criteria:

        Inclusion Criteria:

        Part 1 and Part 2:

          -  Male, or non-pregnant and non-breast feeding female; 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

               -  Post-menopausal female participant has been without menses for at least 1 year
                  and has a documented follicle stimulating hormone (FSH) level in the
                  postmenopausal range at screening

               -  Surgically sterile female participant may enroll in study if procedure
                  (hysterectomy, oophorectomy, or tubal ligation) is documented/confirmed by
                  medical records or protocol-defined examination/tests

          -  Nonsmoker and/or has not used nicotine or nicotine-containing products for at least
             approximately 3 months

        Part 1 only:

          -  18 to 55 years of age

          -  Body Mass Index (BMI) between 18-32 kg/m^2

          -  In good health based on medical history, physical examination, vital sign
             measurements, electrocardiogram (ECG) and laboratory safety tests

        Part 2 only:

          -  56 to 85 years of age

          -  Body weight <136 kg

          -  In stable medical condition based on medical history, physical examination, vital sign
             measurements and ECG

          -  In good health based on laboratory safety tests

          -  For some participants, willing to allow placement of an arterial catheter in the
             radial artery

          -  For AD participants:

               -  Mini-Mental State Examination (MMSE) score ≤28

               -  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, 4th Edition, Text
                  Revision (DSM-IV-TR) criteria for AD

               -  Modified Hachinski score ≤4

               -  Screening magnetic resonance imaging (MRI) scan consistent with a diagnosis of AD

               -  Able to read at a 6th grade level or equivalent and has a history of academic
                  achievement and/or employment sufficient to exclude mental retardation

               -  Has a reliable informant/caregiver who is able to accompany the participant to
                  all clinic visits and provide information to study investigator/staff via
                  telephone contact

               -  If taking symptomatic treatment for AD, be on a stable dose for at least 4 weeks
                  prior to study

          -  For amnestic MCI participants:

               -  MMSE score ≥26

               -  A history of subjective memory decline before screening

               -  Objective impairment in verbal memory based on investigator's clinical assessment

               -  General cognitive function and activities of daily living sufficiently intact, so
                  as not to meet criteria for mild AD dementia

               -  Modified Hachinski score ≤4

               -  MRI scan obtained at the screening visit is either normal or consistent with a
                  diagnosis of AD

               -  Able to read at a 6th grade level or equivalent and has a history of academic
                  achievement and/or employment sufficient to exclude mental retardation

          -  For non-AD/non-MCI healthy elderly participants:

               -  MMSE score ≥27

               -  No history of subjective memory or other cognitive complaints

               -  No objective evidence of memory or cognitive impairment

        Exclusion Criteria:

        Part 1 and Part 2:

          -  Subject has participated in another investigational trial within 4 weeks of screening

          -  Subject 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

          -  History within 2 years prior to screening, or current evidence of a psychotic disorder
             or a major depressive disorder

          -  History of alcoholism or drug dependency/abuse within the last 2 years before
             screening

          -  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

          -  Has positive test result for hepatitis B surface antigen, hepatitis C antibodies or
             human immunodeficiency virus (HIV)

          -  Participant has had major surgery or donated or lost 1 unit of blood (approximately
             500 mL) within 4 weeks prior to screening

          -  QTc interval ≥470 msec (for males) or ≥480 msec (for females)

          -  Participant consumes >3 servings of alcohol a day

          -  Participant consumes >6 caffeine servings a day

          -  Participant 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

          -  Suffers from claustrophobia or an inability to tolerate confinement in small places
             and would be unable to undergo PET or (for Part 2 only) MRI scanning

        Part 1 Only:

          -  Evidence of a clinically relevant neurological disorder at screening

          -  History of clinically significant endocrine, gastrointestinal, cardiovascular,
             hematological, hepatic, immunological, renal, respiratory, genitourinary or major
             neurological abnormality or disease

          -  Participant 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

        Part 2 Only:

          -  Evidence of a clinically relevant neurological disorder other than AD at screening

          -  History or current evidence of clinically significant endocrine, gastrointestinal,
             cardiovascular, hematological, hepatic, immunological, renal, respiratory,
             genitourinary or major neurological abnormality or disease, which is not adequately
             controlled through a stable medication regimen

          -  Participant 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

          -  For participants undergoing arterial catheter placement only:

               -  Allergy to lidocaine which may be locally injected as an anesthetic

               -  Currently uses aspirin or aspirin-containing medications at doses exceeding 100
                  mg daily, or nonsteroidal anti-inflammatory drugs (NSAIDs), which cannot be
                  discontinued 2 weeks prior to dosing and throughout the course of the study