THE A4 TRIAL: ANTI‐AMYLOID TREATMENT OF ASYMPTOMATIC ALZHEIMER'S DISEASE

Abstract

Converging evidence suggests that approximately one-third of clinically normal older individuals demonstrate amyloid-b accumulation, associated with functional and structural imaging abnormalities, elevated CSF phospho-tau, and increased rate of cognitive decline, consistent with the preclinical stages of AD. The A4 study is a secondary prevention trial that will test the hypothesis that an anti-amyloid treatment can slow cognitive decline in amyloid-positive older individuals at high risk for progression to the symptomatic phases of AD. The Alzheimer's Disease Cooperative Study (ADCS) is partnering with Eli Lilly and Company to conduct a Phase 3, double-blind, placebo-controlled, 168–week trial of solanezumab in over 1000 clinically normal older individuals with evidence of amyloid-positivity on PET amyloid imaging with florbetapir. Eligible subjects will be ages 65-85 years, CDR 0, and MMSE 27-30, but may have subjective cognitive concerns. The primary outcome is a cognitive composite of episodic memory and executive function measures (ADCS-PACC). Exploratory outcomes include iPAD testing in collaboration with CogState, participant–reported outcomes, longitudinal amyloid PET imaging, functional connectivity and volumetric MRI, and CSF biomarkers in a subset. The A4 study also imbeds an ethics component to study the process of safely disclosing PET amyloid imaging results, and a natural history cohort called LEARN (Longitudinal Evaluation of Amyloid Risk and Neurodegeneration) to elucidate the risk of decline in “amyloid-negative” individuals compared with “amyloid-positive” individuals randomized to the A4 placebo arm. The A4 study will be conducted at 60 ADCS sites in the U.S., Canada, and Australia, and is funded by a public-private-philanthropic partnership. The A4 trial started enrollment in early 2014, and we will present an update on study progress. Based on power analyses from ongoing large biomarker cohorts, we should have adequate power with n=500 subjects per arm to detect a 30% treatment-related decrease in the rate of cognitive decline. The A4 trial will provide complementary information to the prevention studies being conducted in genetic-risk cohorts. The A4 study design may prove to be a valuable platform to test other anti-amyloid agents during the preclinical stages of AD, and ultimately combination therapies, to prevent progression to AD dementia.