Clarity AD
(2023)Objective
Lecanemab - To determine the safety and efficacy of lecanemab, a humanized anti-amyloid-beta protofibril antibody, in patients with early Alzheimer's disease
Study Summary
• Amyloid burden reduced by 59 centiloids vs placebo (P<0.001), achieving clearance below positivity threshold
• Clinical benefit came at cost of ARIA-E (12.6%) and infusion reactions (26.4%)
Intervention
Lecanemab 10 mg/kg IV every 2 weeks for 18 months
Inclusion Criteria
Age 50-90 years, MCI or mild dementia due to Alzheimer's disease (NIA-AA criteria), amyloid-positive on PET or CSF, objective memory impairment (≥1 SD below age-adjusted mean on WMS-IV Logical Memory II)
Study Design
Arms: Lecanemab 10 mg/kg IV every 2 weeks vs Placebo
Patients per Arm: 898 lecanemab, 897 placebo
Outcome
• Secondary: Amyloid PET: −55.48 vs +3.64 centiloids (difference −59.12, P<0.001)
• Secondary: ADAS-cog14 difference −1.44 (P<0.001); ADCOMS difference −0.050 (P<0.001); ADCS-MCI-ADL difference +2.0 (P<0.001)
Bottom Line
Lecanemab reduced markers of amyloid in early Alzheimer's disease and resulted in moderately less decline on measures of cognition and function than placebo at 18 months (27% relative reduction in CDR-SB worsening), but was associated with adverse events including ARIA-E (12.6%) and infusion-related reactions (26.4%).
Major Points
- Primary endpoint met: CDR-SB change was 1.21 with lecanemab vs 1.66 with placebo (difference −0.45, P<0.001), representing 27% less decline
- Robust amyloid reduction: mean amyloid level dropped to 22.99 centiloids in lecanemab group, below the 30 centiloid positivity threshold
- All key secondary endpoints favored lecanemab: ADAS-cog14, ADCOMS, and ADCS-MCI-ADL (all P<0.001)
- Treatment separation visible by 3 months on clinical measures
- ARIA-E occurred in 12.6% (2.8% symptomatic), mostly mild-moderate (91%), asymptomatic (78%), occurring early (71% within 3 months), and resolving within 4 months (81%)
- ARIA-E rates higher in APOE ε4 homozygotes (32.6%) than heterozygotes (10.9%) or noncarriers (5.4%)
- Infusion-related reactions in 26.4%, largely mild-moderate (96%), mostly with first dose (75%)
- Biomarker improvements across CSF (Aβ, tau, p-tau181, neurogranin) and plasma (Aβ42/40, p-tau181, GFAP) markers, except NfL
Study Design
- Study Type
- Multicenter, randomized, double-blind, placebo-controlled, parallel-group phase 3 trial
- Randomization
- Yes
- Blinding
- Double-blind; clinical assessment raters were unaware of safety assessments and trial-group assignments; independent medical monitoring team blinded to assignments reviewed ARIA
- Sample Size
- 1795
- Follow-up
- 18 months
- Centers
- 235
- Countries
- United States, Canada, Japan, South Korea, Australia, Singapore, Netherlands, Sweden, Spain, France, Germany, United Kingdom, Italy, Poland
Primary Outcome
Definition: Change from baseline at 18 months in CDR-SB score (range 0-18, higher = worse impairment)
| Control | Intervention | HR/OR | P-value |
|---|---|---|---|
| 1.66 | 1.21 | - (−0.67 to −0.23) | <0.001 |
Limitations & Criticisms
- Only 18 months of data; longer trials needed to confirm durability of effect and long-term safety
- Clinical meaningfulness of 0.45 CDR-SB point difference is debated; no established threshold for clinically meaningful difference
- ARIA-E risk is substantial, especially in ApoE ε4 homozygotes (32.6%); requires MRI monitoring
- Infusion-related reactions common (26.4%), may impact treatment adherence
- Trial conducted during COVID-19 pandemic with some missed doses and delayed assessments
- Dropout rate of 17.2%; sensitivity analyses suggest robustness but missing data is a limitation
- Modified intention-to-treat analysis without imputation of missing values
- ARIA may have caused functional unblinding; sensitivity analyses attempted to address this
- Underrepresentation of Black participants (2.3-2.7%) limits generalizability
- Biomarker NfL did not show improvement, raising questions about neurodegeneration effect
Citation
N Engl J Med 2023;388:9-21