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AHEAD 3–45

The AHEAD 3-45 Study: Design of a Prevention Trial for Alzheimer's Disease (BAN2401-G000-303)

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Year of Publication: 2023

Authors: Michael S. Rafii, Reisa A. Sperling, Michael C. Donohue, ..., Paul S. Aisen

Journal: Alzheimer's & Dementia

Citation: Alzheimers Dement. 2023 April; 19(4): 1227-1233

Link: https://doi.org/10.1002/alz.12748

PDF: https://onlinelibrary.wiley.com/doi/pdfd....1002/alz.12748

Clinical Question

Can intervention with lecanemab (BAN2401), initiated during the asymptomatic/preclinical stage of AD, slow biomarker changes (amyloid/tau accumulation) and/or cognitive decline in cognitively unimpaired individuals?

Bottom Line

Design paper for ongoing trial - no results available. The AHEAD 3-45 Study is testing whether early intervention with lecanemab can prevent or slow AD progression in two populations: early preclinical AD (intermediate amyloid) and preclinical AD (elevated amyloid).

        Major Points
        Launched July 14, 2020 as a public-private partnership between ACTC, NIA/NIH, and Eisai Inc.
Two sister trials under single protocol: A3 (intermediate amyloid, Phase 2) and A45 (elevated amyloid, Phase 3)
A45 Trial: ~1000 participants with elevated amyloid (>40 Centiloids), cognitive primary endpoint (PACC5)
A3 Trial: ~400 participants with intermediate amyloid (20-40 Centiloids), PET imaging primary endpoint
Treatment duration 216 weeks (4+ years) with 12-week follow-up after last infusion
Innovative plasma biomarker screening using C2N mass spectrometry Aβ42/40 ratio to reduce unnecessary PET scans
Recruitment enriched via TRC-PAD, ADNeT Registry, and J-TRC trial-ready cohorts
Uses NAV4694 (amyloid) and MK6240 (tau) PET tracers for optimal sensitivity

      

Design

Study Type: Phase 2 (A3) and Phase 3 (A45) randomized controlled trials under single master protocol

Randomization: 1

Blinding: Double-blind; all participants, investigators, site personnel, ACTC coordinating center, and sponsor staff masked; unblinded pharmacist prepares infusions; two medical monitoring teams (blinded and unblinded) for safety oversight

Enrollment Period: Launched July 14, 2020; ongoing

Follow-up Duration: 216 weeks treatment + 12 weeks follow-up

Countries: United States, Australia, Japan

Sample Size: 1400

Analysis: MMRM for primary analysis; includes baseline value, age, treatment arm, APOE ε4 status, sex, education, geographical region, visit, baseline-by-visit interaction, and treatment arm-by-visit interaction as fixed effects; A3 and A45 data analyzed separately

Inclusion Criteria

Age 55-80 years
Cognitively unimpaired
A3 Trial: Intermediate brain amyloid (≈20-40 Centiloids) on screening amyloid PET
A45 Trial: Elevated brain amyloid (>40 Centiloids) on screening amyloid PET
On the 'Alzheimer's continuum' per NIA-AA Research Framework

Exclusion Criteria

Not explicitly listed in design paper

Baseline Characteristics

Characteristic	Control	Active
Note	Design paper - no baseline data available yet	Design paper - no baseline data available yet

Arms

Field	A45 Lecanemab	Control	A3 Lecanemab	Control
Intervention	Lecanemab 5 mg/kg IV Q2W for 6 weeks (titration), then 10 mg/kg IV Q2W for 86 weeks (induction), then 10 mg/kg IV Q4W for 120 weeks (maintenance)	Placebo IV Q2W for 94 weeks, then Q4W for 120 weeks	Lecanemab 5 mg/kg IV Q4W for 4 weeks (titration), then 10 mg/kg IV Q4W for 208 weeks	Placebo IV Q4W for 216 weeks
Duration	216 weeks	216 weeks	216 weeks	216 weeks

Outcomes

Outcome	Type	Control	Intervention
A45 Trial: Change from baseline in PACC5 at 216 weeks; A3 Trial: Change from baseline in amyloid PET SUVr at 216 weeks	Primary	Design paper - no results	Design paper - no results
A3 Trial key secondary: Tau PET (neocortical composite)	Secondary	Design paper - no results	Design paper - no results
Amyloid PET (A45 Trial secondary)	Secondary	Design paper - no results	Design paper - no results
Tau PET (A45 Trial secondary)	Secondary	Design paper - no results	Design paper - no results
Plasma biomarkers (Aβ42, Aβ40, Aβ42/40 ratio) - exploratory	Secondary	Design paper - no results	Design paper - no results
CSF biomarkers (p-tau-217, p-tau-181, total tau, Aβ42, Aβ40) - exploratory	Secondary	Design paper - no results	Design paper - no results
Neurodegeneration markers (CSF NFL, neurogranin) - exploratory	Secondary	Design paper - no results	Design paper - no results
Note	Adverse	Design paper - no safety data available	Design paper - no safety data available

Subgroup Analysis

Design paper - subgroup analyses planned but not yet performed. Randomization stratified by APOE ε4 status and geographical region.

Criticisms

Design paper only - efficacy and safety results not yet available
Recruitment challenges anticipated, particularly identifying young asymptomatic individuals (age 55+) with elevated amyloid
COVID-19 pandemic expected to impact recruitment
Under-representation of diverse populations was an issue in prior A4 study and may be challenging to address
Long duration (216 weeks) may increase dropout rates

Funding

Public-Private Partnership: National Institute on Aging (National Institutes of Health) and Eisai Inc.; conducted through the Alzheimer's Clinical Trial Consortium (ACTC)

Based on: AHEAD 3–45 (Alzheimer's & Dementia, 2023)