Comparison of PET Amyloid Imaging in Japanese and Western Subjects

Study Overview
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Brief Summary
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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.

Detailed Description
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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: HV, aMCI, and pAD, and to assess the reproducibility of brain uptake and of image interpretation. The 3 comparison groups (HV, aMCI, and pAD) were defined by the subjects' main clinical diagnoses at study entry. Subjects underwent diagnostic quality anatomic brain magnetic resonance imaging (MRI), followed by open-label intravenous (i.v) administration of Flutemetamol F 18 Injection and 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. Blinded visual assessments were also compared to quantitative image assessments (standardized uptake value ratio [SUVRs]). Inter-reader and intra-reader agreement was also assessed. Test-retest variability was evaluated following a second administration of Flutemetamol F 18 Injection given to a subset (N=5) of pAD subjects between 1 and 4 weeks after their first administration of Flutemetamol F 18 Injection.

Official Title
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An Open-label Study to Assess Brain Uptake and Safety of Flutemetamol F 18 Injection in Japanese Subjects With Probable Alzheimer's Disease, Subjects With Amnestic Mild Cognitive Impairment and Healthy Volunteers

Conditions
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Mild Cognitive Impairment, Alzheimer's Disease, Healthy

Intervention / Treatment
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* Drug: [18F] Flutemetamol


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: General inclusion criteria for all subjects: The subject had at least 6 years of education. The subject was of first-order Japanese descent. The subject exhibited adequate visual, auditory and communication capabilities, and was willing and able to complete standard tests of cognitive function. 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. 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. 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). 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: The subject was 25 years or older at the time of obtaining informed consent. The subject had no evidence of cognitive impairment by medical history. The subject had a Mini-Mental State Examination (MMSE) score of =< 27. The subject had a Clinical Dementia Rating (CDR) of 0. 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: The subject was 55 years or older at the time of obtaining informed consent. 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). The subject had an MMSE score of 15 to 26 (inclusive) and a CDR of 0.5, 1 or 2. The subject had a score of =< 4 on the Modified Hachinski Ischemic scale. The subject had an appropriate caregiver capable of accompanying the subject on all study visits. 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: The subject was 55 years or older at the time of obtaining informed consent. The subject met Petersen criteria for aMCI. The subject had an MMSE score of 27 to 30 (inclusive) and a CDR of 0 to 0.5. The subject had a score of =< 4 on the Modified Hachinski Ischemic Scale. The subject had an appropriate caregiver/companion capable of accompanying the subject on all study visits if necessary and applicable according to local regulations. 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: The subject was not able to complete the study procedures as judged by the investigator. 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. The subject had a known or suspected hypersensitivity/allergy to [18F] flutemetamol or to any of its excipients. Female subjects who were of childbearing potential, pregnant, or nursing. 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. The subject had a contraindication for MRI or PET (including, but not limited to, claustrophobia, pacemaker, the presence of metallic fragments, or cochlear implant). The subject had participated in a clinical trial using an investigational medicinal product (IMP) within 30 days of dosing. The subject had positive serology for HBs antigen, HCV antibody, HIV antibody or serologic test for syphilis. The subject regularly took medication with a known anticholinergic effect (which could have impaired memory) within the prior 3 months. 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: The subject had any clinically significant medical or neurological condition or any clinically significant abnormality on physical, neurological or laboratory examination. 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: 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. The subject had a previous history of clinically evident stroke or significant cerebrovascular disease on brain imaging.

Ages Eligible for Study
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Minimum Age: 25 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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Accepts Healthy Volunteers

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Diagnostic
Allocation: Non-Randomized
Intervention Model: Parallel Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Healthy volunteers<br>185 MBq [18F] Flutemetamol | Drug: [18F] Flutemetamol<br>* PET brain imaging and Magnetic resonance brain imaging<br>* Other names: GE067;|
| Experimental: Mild cognitive impairment<br>185 MBq [18F] Flutemetamol | Drug: [18F] Flutemetamol<br>* PET brain imaging and Magnetic resonance brain imaging<br>* Other names: GE067;|
| Experimental: Alzheimer's Disease<br>185 MBq [18F] Flutemetamol | Drug: [18F] Flutemetamol<br>* PET brain imaging and Magnetic resonance brain imaging<br>* Other names: GE067;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Blinded Visual Assessment of Positron Emission Tomography (PET) Imaging and Clinical Diagnosis by Non-Japanese Readers | The performance of Flutemetanol F 18 injection in participants was determined by evaluation of the level of association between the blinded visual assessment of a participant's brain image and the participant's clinical diagnosis by 5 non-Japanese readers, who classified each participant's images as either normal or abnormal (raised) Flutemetanol F 18 uptake. | Up to 90 minutes after investigational medicinal product (IMP) administration | 
| Blinded Visual Assessment of Positron Emission Tomography (PET) Imaging and Clinical Diagnosis by Japanese Readers | The performance of Flutemetanol F 18 injection in participants was determined by evaluation of the level of association between the blinded visual assessment of a participant's brain image and the participant's clinical diagnosis by 5 Japanese readers, who classified each participant's images as either normal or abnormal (raised) Flutemetanol F 18 uptake. | Up to 90 minutes after IMP administration |