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.
OBJECTIVE
This Phase 2 study assessed the performance of positron emission tomography (PET) brain images made with Flutemetamol F 18 Injection in detecting β-amyloid neuritic plaques in Japanese subjects.


METHODS
Seventy subjects (25 with probable Alzheimer's disease (pAD), 20 with amnestic mild cognitive impairment (aMCI), and 25 cognitively normal healthy volunteers[HVs]) underwent PET brain imaging after intravenous Flutemetamol F 18 Injection (185 MBq). Images were interpreted as normal or abnormal for neuritic plaque density by each of five non-Japanese and five Japanese readers who were blinded to clinical data. The primary efficacy analysis (based on HV and pAD data) was the agreement of the non-Japanese readers' image interpretations with the clinical diagnosis, resulting in estimates of positive percent agreement (PPA; based on AD subjects; similar to sensitivity) and negative percent agreement (NPA; based on HVs; similar to specificity). Secondary analyses included PPA and NPA for the Japanese readers; inter-reader agreement (IRA); intra-reader reproducibility (IRR); quantitative image interpretations (standardized uptake value ratios [SUVRs]) by diagnostic subgroup; test-retest variability in five pAD subjects; and safety.


RESULTS
PPA was 92% for all non-Japanese readers and ranged from 88 to 92% for the Japanese readers. NPA ranged from 96 to 100% for both the non-Japanese readers and the Japanese readers. The majority image interpretations (the interpretations made independently by ≥3 of 5 readers) resulted in PPA values of 92 and 92% and NPA values of 100 and 96% for the non-Japanese and Japanese readers, respectively. IRA and IRR were strong. Composite SUVR values (mean of multiple regional values) allowed clear differentiation between pAD subjects and HVs. Test-retest variability ranged from 1.14 to 2.27%, and test-retest agreement of the blinded visual interpretations was 100% for all readers. Flutemetamol F 18 Injection was generally well tolerated.


CONCLUSIONS
The detection of brain neuritic plaques in Japanese subjects using [18F]Flutemetamol PET images gave results highly consistent with clinical diagnosis, with non-Japanese and Japanese readers giving similar results. Inter-reader agreement and intra-reader reproducibility were high for both sets of readers. Visual delineation of abnormal and normal scans was corroborated by quantitative assessment, with low test-retest variability.


BACKGROUND
Clinicaltrials.gov registration number NCT02813070.
Department of Geriatrics, Osaka City University Hospital, 5-7, Asahi-machi 1-chome, Abeno-ku, Osaka City, Japan. m1359432@med.osaka-cu.ac.jp.|Izumiotsu Municipal Hospital, Shimojyo-chou 16-1, Izumiotsu, Osaka, 595-0027, Japan. m1359432@med.osaka-cu.ac.jp.
Takami
T
Miki
Department of Geriatrics, Osaka City University Hospital, 5-7, Asahi-machi 1-chome, Abeno-ku, Osaka City, Japan.
Hiroyuki
H
Shimada
Nuclear Medicine Department, Asan Medical Center, 388-1 Pungnap-2 Dong, Songpa-Gu, Seoul, South Korea.
Jae-Seung
JS
Kim
Neuropsychiatry Department, Kobe University Hospital, 5-2, Kusunoki-cho 7-chome, Chuo-ku, Kobe City, Hyogo Prefecture, Japan.
Yasuji
Y
Yamamoto
Aino Hospital, Center of Geriatric Somato-Psychological Care, 11-18, Takada-cho, Ibaraki City, Osaka, Japan.
Masakazu
M
Sugino
Neurology Department, Kobe University Hospital, 5-2, Kusunoki-cho 7-chome, Chuo-ku, Kobe City, Hyogo Prefecture, Japan.
Hisatomo
H
Kowa
GE Healthcare, Uppsala, Sweden.|Nuclear Medicine and PET, Uppsala University, Uppsala, Sweden.
Kerstin
K
Heurling
GE Healthcare, Marlborough, MA, USA.
Michelle
M
Zanette
GE Healthcare, Marlborough, MA, USA.
Paul F
PF
Sherwin
Positron Medical Department, Institute of Biomedical Research and Innovation Hospital, 2, Minatojima Minami-machi 2-chome, Chuo-ku, Kobe City, Hyogo Prefecture, Japan.
Michio
M
Senda
D000368:Aged; D000369:Aged, 80 and over; D000544:Alzheimer Disease / Q000000981:diagnostic imaging*; D000647:Amnesia / Q000000981:diagnostic imaging; D000814:Aniline Compounds / Q000737:chemistry*; D052160:Benzothiazoles / Q000737:chemistry*; D001921:Brain / Q000187:drug effects* / Q000378:metabolism; D060825:Cognitive Dysfunction / Q000000981:diagnostic imaging*; D005260:Female; D064368:Healthy Volunteers; D006801:Humans; D007564:Japan; D008297:Male; D008875:Middle Aged; D049268:Positron-Emission Tomography; D011237:Predictive Value of Tests; D015203:Reproducibility of Results
D000814:Aniline Compounds; D052160:Benzothiazoles; C581552:flutemetamol
Alzheimer’s disease; Radiotracer; [18F]Flutemetamol; β-Amyloid