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Clarity AD

Q: What were the key findings of the Clarity AD trial?

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% less decline on CDR-SB; adjusted mean difference −0.45 points), but was associated with adverse events including ARIA-E (12.6%) and infusion-related reactions (26.4%).

Lecanemab in Early Alzheimer's Disease

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Year of Publication: 2023

Authors: Christopher H. van Dyck, Chad J. Swanson, Paul Aisen, ..., Takeshi Iwatsubo

Journal: New England Journal of Medicine

Citation: N Engl J Med 2023;388:9-21

Link: https://www.nejm.org/doi/full/10.1056/NEJMoa2212948

PDF: https://www.nejm.org/doi/pdf/10.1056/NEJ...ticleTools=true

Clinical Question

Does lecanemab slow cognitive and functional decline compared with placebo in patients with early Alzheimer's disease?

Study Overview

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

Lecanemab reduced cognitive and functional decline in early Alzheimer's disease with 27% less decline on CDR-SB at 18 months (adjusted mean difference −0.45 points, 95% CI −0.67 to −0.23, P<0.001)
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

Patients per Arm

898 lecanemab, 897 placebo

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% less decline on CDR-SB; adjusted mean difference −0.45 points), 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 (adjusted mean difference −0.45, 95% CI −0.67 to −0.23, 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 CSF NfL

      

Design

Study Type: Multicenter, randomized, double-blind, placebo-controlled, parallel-group phase 3 trial

Randomization: 1

Blinding: Double-blind; clinical assessment raters were unaware of safety assessments and trial-group assignments; independent medical monitoring team blinded to assignments reviewed ARIA

Enrollment Period: March 2019 through March 2021

Follow-up Duration: 18 months

Centers: 235

Countries: United States, Canada, Japan, South Korea, Australia, Singapore, Netherlands, Sweden, Spain, France, Germany, United Kingdom, Italy, Poland

Sample Size: 1795

Analysis: Modified intention-to-treat analysis using mixed model for repeated measures (MMRM); model included baseline CDR-SB score as covariate, with trial group, visit, stratification variables (clinical subgroup, AD medication use, ApoE ε4 status, geographic region), baseline-by-visit interaction, and trial group-by-visit interaction as fixed effects

Inclusion Criteria

Age 50 to 90 years
Mild cognitive impairment due to Alzheimer's disease or mild Alzheimer's disease dementia (NIA-AA criteria)
Amyloid positivity confirmed by PET or CSF Aβ1-42 measurement
Objective memory impairment (≥1 SD below age-adjusted mean on Wechsler Memory Scale IV–Logical Memory II)
Global CDR score of 0.5 to 1.0

Exclusion Criteria

Not explicitly detailed in the publication

Baseline Characteristics

Characteristic	Lecanemab (N=859)	Placebo (N=875)
Age - years	71.4 ± 7.9	71.0 ± 7.8
Female sex - %	51.6	53.0
White race - %	76.3	77.4
Black race - %	2.3	2.7
Asian race - %	17.1	16.9
Hispanic ethnic group - %	12.5	12.3
Time since diagnosis - years	1.41 ± 1.51	1.34 ± 1.54
Time since symptom onset - years	4.13 ± 2.35	4.15 ± 2.53
Global CDR 0.5 - %	80.8	80.7
Global CDR 1.0 - %	19.2	19.3
MCI due to AD - %	61.5	62.2
Mild AD dementia - %	38.5	37.8
ApoE ε4 noncarrier - %	31.1	31.4
ApoE ε4 heterozygote - %	53.1	53.5
ApoE ε4 homozygote - %	15.8	15.1
Current AD medication use - %	52.0	53.5
CDR-SB score	3.17 ± 1.34	3.22 ± 1.34
Amyloid burden on PET - centiloids (PET substudy, n=354)	77.92 ± 44.84
ADAS-cog14 score	24.45 ± 7.08	24.37 ± 7.56
ADCOMS	0.398 ± 0.147	0.400 ± 0.147
ADCS-MCI-ADL score	41.2 ± 6.6	40.9 ± 6.9
MMSE score	25.5 ± 2.2	25.6 ± 2.2
Amyloid burden on PET - centiloids (PET substudy, n=344)		75.03 ± 41.82

Arms

Field	Control	Lecanemab 10 mg/kg
Intervention	Placebo intravenous infusion every 2 weeks	Lecanemab 10 mg/kg intravenous infusion every 2 weeks
Duration	18 months	18 months

Outcomes

Outcome	Type	Control	Intervention	P-value
Change from baseline at 18 months in CDR-SB score (range 0-18, higher = worse impairment) — continuous outcome; NNT/ARR/RRR not applicable	Primary	1.66	1.21	<0.001
Amyloid burden on PET (centiloids) - change at 18 months (PET substudy: n=354 lecanemab, n=344 placebo)	Secondary	+3.64	−55.48	<0.001
ADAS-cog14 score change at 18 months	Secondary	5.58	4.14	<0.001
ADCOMS change at 18 months	Secondary	0.214	0.164	<0.001
ADCS-MCI-ADL score change at 18 months	Secondary	−5.5	−3.5	<0.001
Any adverse event	Adverse	735 (81.9%)	798 (88.9%)
Serious adverse event	Adverse	101 (11.3%)	126 (14.0%)
Death	Adverse	7 (0.8%)	6 (0.7%)
Discontinuation due to AE	Adverse	26 (2.9%)	62 (6.9%)
Infusion-related reaction	Adverse	66 (7.4%)	237 (26.4%)
ARIA-E	Adverse	15 (1.7%)	113 (12.6%)
Symptomatic ARIA-E	Adverse	0	25 (2.8%)
ARIA-E - ApoE ε4 noncarrier	Adverse	1/286 (0.3%)	15/278 (5.4%)
ARIA-E - ApoE ε4 heterozygote	Adverse	9/478 (1.9%)	52/479 (10.9%)
ARIA-E - ApoE ε4 homozygote	Adverse	5/133 (3.8%)	46/141 (32.6%)
ARIA-H (microhemorrhages or hemosiderin deposits)	Adverse	81 (9.0%)	155 (17.3%)
Macrohemorrhage	Adverse	1 (0.1%)	5 (0.6%)
Headache	Adverse	73 (8.1%)	100 (11.1%)
Fall	Adverse	86 (9.6%)	93 (10.4%)

Subgroup Analysis

Results were consistent across key randomization strata (clinical subgroup, AD medication use, ApoE ε4 status, region). Exploratory analysis in ApoE ε4 homozygotes (15% of population) numerically favored lecanemab for ADAS-cog14 and ADCS-MCI-ADL but not for CDR-SB or ADCOMS. Prespecified exploratory analysis of time to worsening of global CDR score showed HR 0.69 favoring lecanemab (multiplicity-unadjusted).

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 CSF NfL did not show improvement, raising questions about neurodegeneration effect

Funding

Eisai (regulatory sponsor), with partial funding by Biogen

Based on: Clarity AD (New England Journal of Medicine, 2023)