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J Alzheimers Dis. 2017;57(2):557-573. doi: 10.3233/JAD-160216.

Central Review of Amyloid-Related Imaging Abnormalities in Two Phase III Clinical Trials of Bapineuzumab in Mild-To-Moderate Alzheimer's Disease Patients.

Author information

1
Janssen Alzheimer Immunotherapy Research and Development, LLC, South San Francisco, CA, USA.
2
Janssen Research and Development, LLC, Raritan, NJ, USA.
3
BioClinica Inc. (formerly Synarc), Newtown, PA, USA.
4
Department of Radiology, VU University Medical Center, Amsterdam, Netherlands.

Abstract

BACKGROUND:

Amyloid-related imaging abnormalities (ARIA) consist of ARIA-E (with effusion or edema) and ARIA-H (hemosiderin deposits [HDs]).

OBJECTIVES:

To address accurate ascertainment of ARIA identification, a final magnetic resonance imaging (MRI) reading was performed on patients with mild-to-moderate Alzheimer's disease randomized to bapineuzumab IV or placebo during two Phase III trials (APOE ɛ4 allele carriers or noncarriers).

METHODS:

Final MRI central review consisted of a systematic sequential locked, adjudicated read in 1,331 APOE ɛ4 noncarriers and 1,121 carriers by independent neuroradiologists. Assessment of ARIA-E, ARIA-H, intracerebral hemorrhages, and age-related white matter changes is described.

RESULTS:

In the Final Read, treatment-emergent ARIA-E were identified in 242 patients including 76 additional cases not noted previously in real time. Overall, incidence proportion of ARIA-E was higher in carriers (active 21.2%; placebo 1.1%) than in noncarriers (pooled active 11.3%; placebo 0.6%), and was more often identified in homozygote APOE ɛ4 carriers than heterozygotes (34.5% versus 16.9%). Incidence rate of ARIA-E increased with increased dose in noncarriers. Frequency of ARIA-E first episodes was highest after the first and second bapineuzumab infusion and declined after repeated infusions. Incidence of total HDs <10 mm (cerebral microhemorrhages) was higher in active groups versus placebo.

CONCLUSION:

ARIA was detected more often on MRI scans when every scan was reviewed by trained neuroradiologists and results adjudicated. There was increased incidence of ARIA-E in bapineuzumab-treated carriers who had a microhemorrhage at baseline. ARIA-E was a risk factor for incident ARIA-H and late onset ARIA-E was milder radiologically. Age-related white matter changes did not progress during the study.

TRIAL REGISTRATION:

ClinicalTrials.gov NCT00574132 NCT00575055.

KEYWORDS:

Alzheimer’s disease; NCT00575055 (Bapineuzumab-302); bapineuzumab; brain amyloid-related imaging abnormality; magnetic resonance imaging Registration: NCT00574132 (Bapineuzumab-301)

PMID:
28269765
DOI:
10.3233/JAD-160216
[Indexed for MEDLINE]

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