Comparison of PET Amyloid Imaging in Japanese and Western Subjects
Condition: Mild Cognitive Impairment; Alzheimer's Disease; Healthy
MeSH terms: Alzheimer Disease; Cognitive Dysfunction
Intervention: [18F] Flutemetamol
Intervention description: PET brain imaging and Magnetic resonance brain imaging
Intervention MeSH terms: Flutemetamol
Phase: Phase 2
Study type: Interventional
Primary purpose: Diagnostic
Allocation: Non-Randomized
Intervention model: Parallel Assignment
Masking: None (Open Label)
Enrollment: 70.0
Sex: All
Minimum age: 25 Years
Healthy volunteers: Accepts Healthy Volunteers

Summary:

      This was a Phase 2, multicenter study to assess the extent and patterns of [18F] flutemetamol
      uptake in the brains of 3 groups of Japanese subjects: healthy volunteers (HV), amnestic mild
      cognitive impairment (aMCI), and probable Alzheimer's disease (pAD), and to assess the
      reproducibility of brain uptake and of image interpretation. Subjects underwent open-label
      intravenous (i.v.) administration of Flutemetamol F 18 Injection and Positron emission
      tomography (PET) imaging of the brain. Blinded visual image reads were performed by 10
      independent board-certified readers (5 Japanese and 5 non-Japanese) with nuclear medicine
      image interpretation experience. The blinded visual assessments were compared with the
      subject's clinical diagnoses, and the agreement between the image interpretations made by the
      2 groups of readers (Japanese and non-Japanese) was determined.
    

Eligibility criteria:

        Inclusion Criteria:

        General inclusion criteria for all subjects:

          1. The subject had at least 6 years of education.

          2. The subject was of first-order Japanese descent.

          3. The subject exhibited adequate visual, auditory and communication capabilities, and
             was willing and able to complete standard tests of cognitive function.

          4. The subject's general health was adequate to comply with all study procedures, as
             ascertained by review of their medical history, and laboratory and physical
             examinations, which was performed within 45 days before the first administration of
             Flutemetamol F 18 Injection.

          5. The subject (and the caregiver, if relevant) was/were compliant and had a high
             probability of completing the study in the opinion of the investigator.

          6. Women were either surgically sterile (had a documented bilateral oophorectomy and/or
             documented hysterectomy) or were postmenopausal (cessation of menses for more than 2
             years).

          7. Informed consent was signed and dated by the subject and/or subject's legally
             acceptable representative, if applicable, in accordance with local regulations.

        Inclusion criteria specific for HV:

          1. The subject was 25 years or older at the time of obtaining informed consent.

          2. The subject had no evidence of cognitive impairment by medical history.

          3. The subject had a Mini-Mental State Examination (MMSE) score of =< 27.

          4. The subject had a Clinical Dementia Rating (CDR) of 0.

          5. The subject had an MRI image as part of the screening visit of sufficient diagnostic
             quality and consistent with normal brain function (details provided in the associated
             Imaging Manual) for volume of interest (VOI) definition and partial volume correction.

        Inclusion criteria specific for subjects with pAD:

          1. The subject was 55 years or older at the time of obtaining informed consent.

          2. The subject met National Institute of Neurological and Communicative Disorders and
             Stroke; Alzheimer's Disease and Related Disorders Association (NINCDS-ADRDA) criteria
             for clinical pAD and Diagnostic and Statistical Manual of Mental Disorders (DSM-IV]),
             4th Edition, criteria for AD (DSM-IV criteria, American Psychiatric Association 1994).

          3. The subject had an MMSE score of 15 to 26 (inclusive) and a CDR of 0.5, 1 or 2.

          4. The subject had a score of =< 4 on the Modified Hachinski Ischemic scale.

          5. The subject had an appropriate caregiver capable of accompanying the subject on all
             study visits.

          6. The subject had an MRI image as part of the screening visit consistent with the
             diagnosis of pAD and of sufficient diagnostic quality (details provided in the
             associated Imaging Manual) for VOI definition and partial volume correction.

        Inclusion criteria specific for subjects with aMCI:

          1. The subject was 55 years or older at the time of obtaining informed consent.

          2. The subject met Petersen criteria for aMCI.

          3. The subject had an MMSE score of 27 to 30 (inclusive) and a CDR of 0 to 0.5.

          4. The subject had a score of =< 4 on the Modified Hachinski Ischemic Scale.

          5. The subject had an appropriate caregiver/companion capable of accompanying the subject
             on all study visits if necessary and applicable according to local regulations.

          6. The subject had an MRI image as part of the screening visit consistent with the
             diagnosis of aMCI and of sufficient diagnostic quality (details provided in Imaging
             Manual) for VOI definition and partial volume correction.

        Exclusion Criteria:

          1. The subject was not able to complete the study procedures as judged by the
             investigator.

          2. The subject had received ionizing radiation exposure of more than 1 mSv (except
             arising from head computed tomography [CT]) in the last 12 months or was determined
             unsuitable by the investigator as a result of radiation exposure in the past.

          3. The subject had a known or suspected hypersensitivity/allergy to [18F] flutemetamol or
             to any of its excipients.

          4. Female subjects who were of childbearing potential, pregnant, or nursing.

          5. The subject had a history of alcohol and/or drug abuse within the last 2 years based
             upon a review of medical records or reported medical history.

          6. The subject had a contraindication for MRI or PET (including, but not limited to,
             claustrophobia, pacemaker, the presence of metallic fragments, or cochlear implant).

          7. The subject had participated in a clinical trial using an investigational medicinal
             product (IMP) within 30 days of dosing.

          8. The subject had positive serology for HBs antigen, HCV antibody, HIV antibody or
             serologic test for syphilis.

          9. The subject regularly took medication with a known anticholinergic effect (which could
             have impaired memory) within the prior 3 months.

         10. The subject had a history of head injury associated with significant loss of
             consciousness that, in the opinion of the investigator, would have interfered with the
             interpretation of PET images.

        Exclusion criteria specific for HV:

          1. The subject had any clinically significant medical or neurological condition or any
             clinically significant abnormality on physical, neurological or laboratory
             examination.

          2. The subject had a family history of pAD (more than 1 first degree relative with the
             diagnosis of pAD).

        Exclusion criteria specific for subjects with pAD and aMCI:

          1. The subject had a significant neurological or psychiatric disorder (including, but not
             limited to, major depression, schizophrenia, mania, etc.) other than pAD that may have
             affected cognition.

          2. The subject had a previous history of clinically evident stroke or significant
             cerebrovascular disease on brain imaging.