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

Abstract

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.

Trial registration: Clinicaltrials.gov registration number NCT02813070.

Keywords: Alzheimer’s disease; Radiotracer; [18F]Flutemetamol; β-Amyloid.

Fig. 1

Blinded Visual Interpretations for Non-Japanese and Japanese Readers—efficacy population. a positive percent agreement. b Negative percent agreement. The analyses are based on blinded visual interpretations of the images collected after the first dose of Flutemetamol F 18 Injection. Error bars represent 95% exact binomial confidence interval. *Majority interpretation by non-Japanese readers (Readers A, B, C, D and E). ^Majority interpretation by Japanese readers (Readers F, G, H, I and J)

Fig. 2

Composite SUVR Values and Age for HV subjects (efficacy population) [Clinical diagnosis at screening as HV (N = 25)] Using a cerebellum reference region (SUVR-CER), and b Pons Reference Region (SUVR-PONS). For the cerebellum reference region, the regression line was plotted based on SUVR = 0.8931 + 0.0053 *AGE with R ² = 0.3055. For the pons reference region, the regression line was plotted based on SUVR = 0.4013 + 0.0019 *AGE with R ² = 0.1392. HV, healthy volunteer; SUVR, standardized uptake value ratio.

Fig. 3

Example negative images

Fig. 4

Example positive images