AHEAD 3–45
(2023)Objective
Lecanemab - AHEAD 3–45 tests whether lecanemab, initiated during the preclinical stage of Alzheimer’s disease, can slow cognitive decline and biomarker progression.
Study Summary
• First Alzheimer’s prevention trial using plasma screening for participant selection
• Ongoing
Intervention
Two parallel, randomized, double-blind, placebo-controlled trials: • A3: Intermediate amyloid (20–40 Centiloids); lecanemab 10 mg/kg IV every 4 weeks for 208 weeks • A45: Elevated amyloid (>40 Centiloids); lecanemab 10 mg/kg every 2 weeks for 86 weeks, then every 4 weeks for 120 weeks Includes APOE ε4 stratification, plasma Aβ42/40 screening, amyloid and tau PET imaging, and 12-week follow-up post-infusion.
Inclusion Criteria
Cognitively normal adults aged 55–80 with intermediate or elevated brain amyloid levels confirmed by PET. Participants pre-screened using plasma Aβ42/40 ratios. Recruited via TRC-PAD, ADNeT, and J-TRC cohorts.
Study Design
Arms: Lecanemab vs. Placebo (A3 and A45 trials)
Patients per Arm: A3: ~200 per arm; A45: ~500 per arm
Outcome
• A3 Primary: Change in amyloid PET SUVr over 216 weeks; cognitive outcomes exploratory
• Secondary biomarkers: Amyloid and tau PET, CSF p-tau-217/p-tau-181, plasma Aβ42/40, neurogranin
• Safety: ARIA-E occurred in <10% overall, 14.3% in APOE ε4+; ARIA-H in 10.7% lecanemab vs. 5.3% placebo
• Phase 2 data: Lecanemab reduced amyloid by up to 93% and slowed decline by 47% on ADAS-Cog
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
Study Design
- Study Type
- Phase 2 (A3) and Phase 3 (A45) randomized controlled trials under single master protocol
- Randomization
- Yes
- 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
- Sample Size
- 1400
- Follow-up
- 216 weeks treatment + 12 weeks follow-up
- Countries
- United States, Australia, Japan
Primary Outcome
Definition: A45 Trial: Change from baseline in PACC5 at 216 weeks; A3 Trial: Change from baseline in amyloid PET SUVr at 216 weeks
| Control | Intervention | HR/OR | P-value |
|---|---|---|---|
| Design paper - no results | Design paper - no results | - |
Limitations & 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
Citation
Alzheimers Dement. 2023 April; 19(4): 1227-1233