Randomized, Double-Blind, Placebo-Controlled Studies to Evaluate Treatment with Aducanumab (BIIB037) in Patients with Early Alzheimer’s Disease: Phase 3 Study Design (S1.003)

Abstract

OBJECTIVE: To describe the design of two Phase 3 studies evaluating efficacy and safety of aducanumab (BIIB037) in patients with Early Alzheimer’s disease (AD). BACKGROUND: Aducanumab is a human monoclonal antibody against aggregated amyloid beta (Aβ) being investigated as a disease-modifying treatment for AD. Interim results from an ongoing Phase 1b study in prodromal/mild AD demonstrated target engagement, pharmacodynamic effect of Aβ reduction, and a clinical effect on exploratory outcomes; the main safety/tolerability findings were amyloid-related imaging abnormalities (ARIA). DESIGN/METHODS: Two randomized, placebo-controlled, Phase 3 studies (ENGAGE; EMERGE), identical in design, are enrolling patients (N≍1350, ≍150 sites per study) aged 50-85 years, with Early AD, Clinical Dementia Rating (CDR) Global Score 0.5, Repeatable Battery for Assessment of Neuropsychological Status score ≤85, Mini-Mental State Examination (MMSE) score 24-30, and presence of brain amyloid (measured by PET). For the 18-month placebo-controlled period, patients will be randomized 1:1:1 to monthly IV low- (3 or 6 mg/kg) or high-dose (6 or 10 mg/kg) aducanumab (based on ApoE4 carrier status; dose titration to limit ARIA), or placebo. The primary endpoint is change from baseline in CDR-Sum of Boxes score (Week 78). Secondary endpoints are change from baseline in MMSE, AD Assessment Scale-Cognitive Subscale, and AD Cooperative Study-Activities of Daily Living Inventory (MCI version) scores (Week 78). Tertiary endpoints include safety, pharmacokinetics, and clinical, radiologic, and patient/informant-reported outcomes. Following the placebo-controlled period, individuals may enter the 24-month dose-blind extension in which those randomized to placebo in placebo-controlled period will be re-randomized 1:1 (based on ApoE ε4 carrier status) to low- or high-dose aducanumab, to evaluate long-term safety, tolerability and efficacy of aducanumab. RESULTS: N/A. CONCLUSION: ENGAGE and EMERGE are Phase 3 clinical trials designed to confirm the clinical efficacy and safety profile of aducanumab in individuals with Early AD. Study support: funded by Biogen