CoChat
Sign Up
Cited by 847Alzheimer's disease research and treatmentsDementia and Cognitive Impairment ResearchNeuroinflammation and Neurodegeneration Mechanisms

The DOI matches its Crossref record; 34 of the 34 references it cites were found in a registry or an index.

A randomized, double-blind, phase 2b proof-of-concept clinical trial in early Alzheimer’s disease with lecanemab, an anti-Aβ protofibril antibody

Open access
Swanson, Chad J., Zhang, Yong, Dhadda, Shobha, Wang, Jinping, Kaplow, June, Lai, Robert Y. K., Lannfelt, Lars, Bradley, Heather, Rabe, Martin, Koyama, Akihiko, Reyderman, Larisa, Berry, Donald A., Berry, Scott, Gordon, Robert, Kramer, Lynn D., Cummings, Jeffrey L.·2021·Alzheimer's Research & Therapy
DOI 10.1186/s13195-021-00813-8PMC PMC8053280
Open this paper in CoChat — free accountOpen PDF

Abstract

BACKGROUND: Lecanemab (BAN2401), an IgG1 monoclonal antibody, preferentially targets soluble aggregated amyloid beta (Aβ), with activity across oligomers, protofibrils, and insoluble fibrils. BAN2401-G000-201, a randomized double-blind clinical trial, utilized a Bayesian design with response-adaptive randomization to assess 3 doses across 2 regimens of lecanemab versus placebo in early Alzheimer's disease, mild cognitive impairment due to Alzheimer's disease (AD) and mild AD dementia. METHODS: BAN2401-G000-201 aimed to establish the effective dose 90% (ED90), defined as the simplest dose that achieves ≥90% of the maximum treatment effect. The primary endpoint was Bayesian analysis of 12-month clinical change on the Alzheimer's Disease Composite Score (ADCOMS) for the ED90 dose, which required an 80% probability of ≥25% clinical reduction in decline versus placebo. Key secondary endpoints included 18-month Bayesian and frequentist analyses of brain amyloid reduction using positron emission tomography; clinical decline on ADCOMS, Clinical Dementia Rating-Sum-of-Boxes (CDR-SB), and Alzheimer's Disease Assessment Scale-Cognitive Subscale (ADAS-Cog14); changes in CSF core biomarkers; and total hippocampal volume (HV) using volumetric magnetic resonance imaging. RESULTS: A total of 854 randomized subjects were treated (lecanemab, 609; placebo, 245). At 12 months, the 10-mg/kg biweekly ED90 dose showed a 64% probability to be better than placebo by 25% on ADCOMS, which missed the 80% threshold for the primary outcome. At 18 months, 10-mg/kg biweekly lecanemab reduced brain amyloid (-0.306 SUVr units) while showing a drug-placebo difference in favor of active treatment by 27% and 30% on ADCOMS, 56% and 47% on ADAS-Cog14, and 33% and 26% on CDR-SB versus placebo according to Bayesian and frequentist analyses, respectively. CSF biomarkers were supportive of a treatment effect. Lecanemab was well-tolerated with 9.9% incidence of amyloid-related imaging abnormalities-edema/effusion at 10 mg/kg biweekly. CONCLUSIONS: BAN2401-G000-201 did not meet the 12-month primary endpoint. However, prespecified 18-month Bayesian and frequentist analyses demonstrated reduction in brain amyloid accompanied by a consistent reduction of clinical decline across several clinical and biomarker endpoints. A phase 3 study (Clarity AD) in early Alzheimer's disease is underway. TRIAL REGISTRATION: Clinical Trials.gov NCT01767311 .

Overview

The claims and statistics of this paper haven’t been checked yet.

Run the check — free, no account needed. It reads the open-access text and checks the sources it cites.

A few free checks a day · papers already verified open instantly · results are public

Integrity signals

Registry

Crossref · 10.1186/s13195-021-00813-8

Cites

34 of 34 references verified0 citation errors · 0 not checkable

Statistics

Figures

Fig. 1 Lecanemab Study 201 study design. Study 201 (NCT01767311) was an 18-month, multicenter, double-blind, placebo-controlled Bayesian design clinical trial employing response adaptive randomization across placebo and five lecanemab arms (2.5 mg/kg biweekly, 5 mg/kg monthly, 5 mg/kg biweekly, 10 mg/kg monthly, 10 mg/kg biweekly) to assess safety and efficacy in subjects with early Alzheimer's disease. At the first three interim analyses, if there is a .5% posterior probability that the most likely ED90 is superior to placebo by the (clinically significant difference; 25%), the trial will stop early for futility. Beginning at the 350-subject IA, and continuing to completion of the trial, the futility criterion is increased to 7.5%. Interim monitoring for early success occurs at each IA beginning when 350 subjects have been enrolled. At this point, if enrollment were to stop for early success, enough subjects would be available to complete the trial so that the full dose response could be modeled. If there is a .95% posterior probability that the most likely ED90 is better than placebo by the CSD, then early success is declared. Enrollment is stopped, but all randomized subjects continue for the full 18-month duration of the study. If the trial is not stopped early for futility or success, then trial success is evaluated at the completion of the trial when both accrual and follow-up for the primary endpoint are complete. At that time, if there is a .80% probability that the most likely ED90 is better than placebo by the CSD, the trial will be considered a success. R, randomization
Fig. 1 Lecanemab Study 201 study design. Study 201 (NCT01767311) was an 18-month, multicenter, double-blind, placebo-controlled Bayesian design clinical trial employing response adaptive randomization across placebo and five lecanemab arms (2.5 mg/kg biweekly, 5 mg/kg monthly, 5 mg/kg biweekly, 10 mg/kg monthly, 10 mg/kg biweekly) to assess safety and efficacy in subjects with early Alzheimer's disease. At the first three interim analyses, if there is a .5% posterior probability that the most likely ED90 is superior to placebo by the (clinically significant difference; 25%), the trial will stop early for futility. Beginning at the 350-subject IA, and continuing to completion of the trial, the futility criterion is increased to 7.5%. Interim monitoring for early success occurs at each IA beginning when 350 subjects have been enrolled. At this point, if enrollment were to stop for early success, enough subjects would be available to complete the trial so that the full dose response could be modeled. If there is a .95% posterior probability that the most likely ED90 is better than placebo by the CSD, then early success is declared. Enrollment is stopped, but all randomized subjects continue for the full 18-month duration of the study. If the trial is not stopped early for futility or success, then trial success is evaluated at the completion of the trial when both accrual and follow-up for the primary endpoint are complete. At that time, if there is a .80% probability that the most likely ED90 is better than placebo by the CSD, the trial will be considered a success. R, randomizationCC BY · PubMed Central
Fig. 2 Randomization allocations by treatment group per protocol-defined interim analyses. The response adaptive randomization correctly allocated subjects into the dose groups likely to be ED90 doses (10 mg/kg monthly and biweekly) as early as the first interim analysis at 197 subjects, with both emerging by the 300th subject randomized, and these doses remained the most likely doses to demonstrate efficacy throughout the remainder of the study. However, before the interim analysis of 350 subjects, Health Authorities restricted randomization around ApoE4 carrier status, whereby ApoE4 carriers (hetero- or homozygous) were not to be randomized to the 10 mg/kg biweekly dose going forward. As a consequence, the response adaptive randomization algorithm was revised. After each subsequent interim analysis (starting with 350 subjects randomized), the randomization probability vector was split between ApoE4 carrier and non-carrier strata to ensure no ApoE4 carriers were enrolled on the 10 mg/kg biweekly dose (more details in Appendix C). At the same time, the revised response adaptive randomization preserved the overall randomization probabilities
Fig. 2 Randomization allocations by treatment group per protocol-defined interim analyses. The response adaptive randomization correctly allocated subjects into the dose groups likely to be ED90 doses (10 mg/kg monthly and biweekly) as early as the first interim analysis at 197 subjects, with both emerging by the 300th subject randomized, and these doses remained the most likely doses to demonstrate efficacy throughout the remainder of the study. However, before the interim analysis of 350 subjects, Health Authorities restricted randomization around ApoE4 carrier status, whereby ApoE4 carriers (hetero- or homozygous) were not to be randomized to the 10 mg/kg biweekly dose going forward. As a consequence, the response adaptive randomization algorithm was revised. After each subsequent interim analysis (starting with 350 subjects randomized), the randomization probability vector was split between ApoE4 carrier and non-carrier strata to ensure no ApoE4 carriers were enrolled on the 10 mg/kg biweekly dose (more details in Appendix C). At the same time, the revised response adaptive randomization preserved the overall randomization probabilitiesCC BY · PubMed Central
Fig. 3 Change from baseline in brain amyloid pathophysiology. Results as measured by amyloid PET SUVr are shown in a. Outcomes from the qualitative (binary) visual read of the PET scans for conversion of brain amyloid pathology from positive to negative are depicted in b. *P < 0.05, **P < 0.01, ***P < 0.001, ****P < 0.0001 (all nominal). For PET analysis, N = 306 at 12 months and N = 288 at 18 months. The PET substudy was optional, so only a portion of the total enrolled subject population opted to participate
Fig. 3 Change from baseline in brain amyloid pathophysiology. Results as measured by amyloid PET SUVr are shown in a. Outcomes from the qualitative (binary) visual read of the PET scans for conversion of brain amyloid pathology from positive to negative are depicted in b. *P < 0.05, **P < 0.01, ***P < 0.001, ****P < 0.0001 (all nominal). For PET analysis, N = 306 at 12 months and N = 288 at 18 months. The PET substudy was optional, so only a portion of the total enrolled subject population opted to participateCC BY · PubMed Central
Fig. 4 Efficacy assessments. a Change from baseline for 10 mg/kg biweekly and monthly doses in the Alzheimer’s Disease Composite Score (ADCOMS). The MMRM used treatment group, visit, clinical subgroup (MCI due to AD, Mild AD), the presence or absence of ongoing AD treatment at baseline, ApoE4 status (positive, negative), region, treatment group-by-visit interaction as factors, and baseline value as covariate. *P < 0.05 (nominal). The primary analysis conducted at month 12 of treatment for all subjects indicated that the 10 mg/kg biweekly dose had a 64% probability to be better than placebo by 25% on ADCOMS at 12 months, missing the pre-specified 80% probability threshold for success. Bayesian analysis at 18 months determined that the lecanemab 10 mg/kg biweekly dose had a 76% probability of being better than placebo by 25% on ADCOMS. In addition, Bayesian analyses indicated a 98% probability of being superior to placebo by any magnitude at both 12 and 18 months, respectively, which is consistent with subsequent conventional analysis results. b Results for 10 mg/kg biweekly and monthly doses on CDR-SB. The number of subjects that were assessed at each time point are indicated in the table. The MMRM used treatment group, visit, clinical subgroup (MCI due to AD, Mild AD), the presence or absence of ongoing AD treatment at baseline, ApoE4 status (positive, negative), region, treatment group-by-visit interaction as factors, and baseline value as covariate. *P < 0.05 (nominal). c Results for 10 mg/kg biweekly and monthly doses on ADAS-Cog14. The number of subjects that were assessed at each time point are indicated in the table. The MMRM used treatment group, visit, clinical subgroup (MCI due to AD, Mild AD), the presence or absence of ongoing AD treatment at baseline, ApoE4 status (positive, negative), region, treatment group-by-visit interaction as factors, and baseline value as covariate. *P < 0.05 (nominal)
Fig. 4 Efficacy assessments. a Change from baseline for 10 mg/kg biweekly and monthly doses in the Alzheimer’s Disease Composite Score (ADCOMS). The MMRM used treatment group, visit, clinical subgroup (MCI due to AD, Mild AD), the presence or absence of ongoing AD treatment at baseline, ApoE4 status (positive, negative), region, treatment group-by-visit interaction as factors, and baseline value as covariate. *P < 0.05 (nominal). The primary analysis conducted at month 12 of treatment for all subjects indicated that the 10 mg/kg biweekly dose had a 64% probability to be better than placebo by 25% on ADCOMS at 12 months, missing the pre-specified 80% probability threshold for success. Bayesian analysis at 18 months determined that the lecanemab 10 mg/kg biweekly dose had a 76% probability of being better than placebo by 25% on ADCOMS. In addition, Bayesian analyses indicated a 98% probability of being superior to placebo by any magnitude at both 12 and 18 months, respectively, which is consistent with subsequent conventional analysis results. b Results for 10 mg/kg biweekly and monthly doses on CDR-SB. The number of subjects that were assessed at each time point are indicated in the table. The MMRM used treatment group, visit, clinical subgroup (MCI due to AD, Mild AD), the presence or absence of ongoing AD treatment at baseline, ApoE4 status (positive, negative), region, treatment group-by-visit interaction as factors, and baseline value as covariate. *P < 0.05 (nominal). c Results for 10 mg/kg biweekly and monthly doses on ADAS-Cog14. The number of subjects that were assessed at each time point are indicated in the table. The MMRM used treatment group, visit, clinical subgroup (MCI due to AD, Mild AD), the presence or absence of ongoing AD treatment at baseline, ApoE4 status (positive, negative), region, treatment group-by-visit interaction as factors, and baseline value as covariate. *P < 0.05 (nominal)CC BY · PubMed Central
Fig. 5 Change from baseline in CSF biomarker measures. a Change from baseline in CSF Aβ1–42 measures. The combined 10 mg/kg monthly and 10 mg/kg biweekly group is compared versus placebo. The number of subjects that were assessed at each time point are indicated in the table. The MMRM used treatment group, visit, clinical subgroup (MCI due to AD, Mild AD), the presence or absence of ongoing AD treatment at baseline, ApoE4 status (positive, negative), region, treatment group-by-visit interaction as factors, and baseline value as covariate. *P < 0.001. b Change from baseline in p-tau measures. The combined 10 mg/kg monthly and 10 mg/kg biweekly group is compared versus placebo. The number of subjects that were assessed at each time point are indicated in the table. The MMRM used treatment group, visit, clinical subgroup (MCI due to AD, Mild AD), the presence or absence of ongoing AD treatment at baseline, ApoE4 status (positive, negative), region, treatment group-by-visit interaction as factors, and baseline value as covariate. *P < 0.001, **P = 0.005. c Change from baseline in t-tau measures. The combined 10 mg/kg monthly and 10 mg/kg biweekly group is compared versus placebo. The number of subjects that were assessed at each time point are indicated in the table. The MMRM used treatment group, visit, clinical subgroup (MCI due to AD, Mild AD), the presence or absence of ongoing AD treatment at baseline, ApoE4 status (positive, negative), region, treatment group-by-visit interaction as factors, and baseline value as covariate. *P = 0.029
Fig. 5 Change from baseline in CSF biomarker measures. a Change from baseline in CSF Aβ1–42 measures. The combined 10 mg/kg monthly and 10 mg/kg biweekly group is compared versus placebo. The number of subjects that were assessed at each time point are indicated in the table. The MMRM used treatment group, visit, clinical subgroup (MCI due to AD, Mild AD), the presence or absence of ongoing AD treatment at baseline, ApoE4 status (positive, negative), region, treatment group-by-visit interaction as factors, and baseline value as covariate. *P < 0.001. b Change from baseline in p-tau measures. The combined 10 mg/kg monthly and 10 mg/kg biweekly group is compared versus placebo. The number of subjects that were assessed at each time point are indicated in the table. The MMRM used treatment group, visit, clinical subgroup (MCI due to AD, Mild AD), the presence or absence of ongoing AD treatment at baseline, ApoE4 status (positive, negative), region, treatment group-by-visit interaction as factors, and baseline value as covariate. *P < 0.001, **P = 0.005. c Change from baseline in t-tau measures. The combined 10 mg/kg monthly and 10 mg/kg biweekly group is compared versus placebo. The number of subjects that were assessed at each time point are indicated in the table. The MMRM used treatment group, visit, clinical subgroup (MCI due to AD, Mild AD), the presence or absence of ongoing AD treatment at baseline, ApoE4 status (positive, negative), region, treatment group-by-visit interaction as factors, and baseline value as covariate. *P = 0.029CC BY · PubMed Central

Verification

Claims the paper makes

The claims and statistics of this paper haven’t been checked yet.

Run the check — free, no account needed. It reads the open-access text and checks the sources it cites.

A few free checks a day · papers already verified open instantly · results are public

Claims other papers make about this one

Each is checked against this paper’s own text: does it say what the citing paper says it does?

Self-check

Percentages, sums and reported differences re-computed from the paper’s own numbers.

The self-check needs the paper’s full text.

Citations

Cites

Show all 34 references

Cited by

Sorted by citations

Items 301–400 of 846

Related

See all

Metadata

Authors
Swanson, C. J., Zhang, Y., Dhadda, S., Wang, J., Kaplow, J., Lai, R. Y. K., Lannfelt, L., Bradley, H., Rabe, M., Koyama, A., Reyderman, L., Berry, D. A., Berry, S., Gordon, R., Kramer, L. D., & Cummings, J. L.
Affiliations
  • Eisai (United States) (US)
  • Eisai (United Kingdom) (GB)
  • Uppsala University (SE)
  • Berry Consultants, LLC (United States) (US)
  • University of Nevada, Las Vegas (US)
Corresponding author
Cummings, Jeffrey L.
ORCID
Venue
Alzheimer's Research & Therapy
Publisher
Springer Science and Business Media LLC
Published
2021-04-17
Volume
13
Issue
1
Pages
80-80
ISSN
1758-9193 (ISSN-L)
DOI
10.1186/s13195-021-00813-8
PMC
PMC8053280
OpenAlex
W3152692563
Cited by
847
References
34
Citations by year
2026: 123 · 2025: 158 · 2024: 194 · 2023: 196 · 2022: 132 · 2021: 42
FWCI
88.37
Type
journal article
Language
en
Update notices
correction (2022-05-21)
Open access
Licence
Locations
  • Alzheimer s Research & Therapy (publishedVersion, cc-by)
  • PubMed Central (publishedVersion, cc-by)
  • PubMed (publishedVersion)
  • Digital Scholarship - UNLV (University of Nevada Reno) (submittedVersion, cc-by)
  • KTH Publication Database DiVA (KTH Royal Institute of Technology) (submittedVersion, other-oa)
  • DOAJ (DOAJ: Directory of Open Access Journals) (submittedVersion, cc-by-sa)
Funders
  • National Institute of General Medical Sciences (P20GM109025)
  • National Institute of Neurological Disorders and Stroke (U01NS093334)
  • National Institute on Aging (R01AG053798, P20AG068053)
Topics
  • Life Sciences › Neuroscience › Cellular and Molecular Neuroscience › Alzheimer's disease research and treatments
  • Health Sciences › Medicine › Psychiatry and Mental health › Dementia and Cognitive Impairment Research
  • Life Sciences › Neuroscience › Neurology › Neuroinflammation and Neurodegeneration Mechanisms
Keywords
lecanemab, anti-amyloid monoclonal antibodies, early Alzheimer's disease, amyloid protofibrils, amyloid oligomers, cerebrospinal fluid biomarkers, hippocampal volume, cognitive decline, mild cognitive impairment, mild dementia, treatment safety, dose escalation
MeSH terms
Alzheimer Disease, Bayes Theorem, Brain, Double-Blind Method, Humans, Amyloid beta-Peptides

About these checks

Registry, retraction, Cites and statistics results are computed, not judged, with one exception: a printed reference that no index lists is read once by a model before it counts as a citation error. Claims are extracted by a model and kept only when their quote appears verbatim in the text; each cited source is then checked, with a model’s help, for whether it says what the claim relies on. Those verdicts can be wrong — read the claim’s quote and the cited source before relying on one.

Statistics and arithmetic are recomputed, not judged.

Confidence bands are shown only for fields calibrated on our annotated test set. None is calibrated yet, so no band is shown.

What counts as a claim ›How we measure confidence ›How we check this ›

Are you an author, or do you see a problem with this page? Request a review