Consistency of efficacy results across various clinical measures and statistical methods in the lecanemab phase 2 trial of early Alzheimer's disease.
Journal
Alzheimer's research & therapy
ISSN: 1758-9193
Titre abrégé: Alzheimers Res Ther
Pays: England
ID NLM: 101511643
Informations de publication
Date de publication:
09 12 2022
09 12 2022
Historique:
received:
17
10
2022
accepted:
21
11
2022
entrez:
9
12
2022
pubmed:
10
12
2022
medline:
15
12
2022
Statut:
epublish
Résumé
Lecanemab (BAN2401) is a humanized IgG1 monoclonal antibody that preferentially targets soluble aggregated Aβ species (protofibrils) with activity at insoluble fibrils and slowed clinical decline in an 18-month phase 2 proof-of-concept study (Study 201; ClinicalTrials.gov NCT01767311) in 856 subjects with early Alzheimer's disease (AD). In this trial, subjects were randomized to five lecanemab dose regimens or placebo. The primary efficacy endpoint was change from baseline in the Alzheimer's Disease Composite Score (ADCOMS) at 12 months with Bayesian analyses. The key secondary endpoints were ADCOMS at 18 months and Clinical Dementia Rating-Sum-of-Boxes (CDR-SB) and Alzheimer's Disease Assessment Scale-Cognitive Subscale (ADAS-Cog14) at 18 months. The results have been published previously. Herein, we describe the results of sensitivity analyses evaluating the consistency of the lecanemab efficacy results in Study 201 at the identified dose, the ED90, across multiple statistical methods and multiple endpoints over the duration of the study. The protocol-specified analysis model was a mixed model for repeated measures (MMRM). Sensitivity analyses address the consistency of the conclusions using multiple statistical methods. These include a disease progression model (DPM), a natural cubic spline (NCS) model, a quadratic mixed model (QMM), and 2 MMRMs with additional covariates. The sensitivity analyses showed positive lecanemab treatment effects for all endpoints and all statistical models considered. The protocol-specified ADCOMS analysis showed a 29.7% slower decline than placebo for ADCOMS at 18 months. The various other analyses of 3 key endpoints showed declines ranging from 26.5 to 55.9%. The results at 12 months are also consistent with those at 18 months. The conclusion of the primary analysis of the lecanemab Study 201 is strengthened by the consistently positive conclusions across multiple statistical models, across efficacy endpoints, and over time, despite missing data. The 18-month data from this trial was utilized in the design of the confirmatory phase 3 trial (Clarity AD) and allowed for proper powering for multiple, robust outcomes.
Sections du résumé
BACKGROUND
Lecanemab (BAN2401) is a humanized IgG1 monoclonal antibody that preferentially targets soluble aggregated Aβ species (protofibrils) with activity at insoluble fibrils and slowed clinical decline in an 18-month phase 2 proof-of-concept study (Study 201; ClinicalTrials.gov NCT01767311) in 856 subjects with early Alzheimer's disease (AD). In this trial, subjects were randomized to five lecanemab dose regimens or placebo. The primary efficacy endpoint was change from baseline in the Alzheimer's Disease Composite Score (ADCOMS) at 12 months with Bayesian analyses. The key secondary endpoints were ADCOMS at 18 months and Clinical Dementia Rating-Sum-of-Boxes (CDR-SB) and Alzheimer's Disease Assessment Scale-Cognitive Subscale (ADAS-Cog14) at 18 months. The results have been published previously. Herein, we describe the results of sensitivity analyses evaluating the consistency of the lecanemab efficacy results in Study 201 at the identified dose, the ED90, across multiple statistical methods and multiple endpoints over the duration of the study.
METHODS
The protocol-specified analysis model was a mixed model for repeated measures (MMRM). Sensitivity analyses address the consistency of the conclusions using multiple statistical methods. These include a disease progression model (DPM), a natural cubic spline (NCS) model, a quadratic mixed model (QMM), and 2 MMRMs with additional covariates.
RESULTS
The sensitivity analyses showed positive lecanemab treatment effects for all endpoints and all statistical models considered. The protocol-specified ADCOMS analysis showed a 29.7% slower decline than placebo for ADCOMS at 18 months. The various other analyses of 3 key endpoints showed declines ranging from 26.5 to 55.9%. The results at 12 months are also consistent with those at 18 months.
CONCLUSIONS
The conclusion of the primary analysis of the lecanemab Study 201 is strengthened by the consistently positive conclusions across multiple statistical models, across efficacy endpoints, and over time, despite missing data. The 18-month data from this trial was utilized in the design of the confirmatory phase 3 trial (Clarity AD) and allowed for proper powering for multiple, robust outcomes.
Identifiants
pubmed: 36482412
doi: 10.1186/s13195-022-01129-x
pii: 10.1186/s13195-022-01129-x
pmc: PMC9733166
doi:
Banques de données
ClinicalTrials.gov
['NCT01767311']
Types de publication
Randomized Controlled Trial
Clinical Trial, Phase II
Journal Article
Research Support, Non-U.S. Gov't
Langues
eng
Sous-ensembles de citation
IM
Pagination
182Informations de copyright
© 2022. The Author(s).
Références
Alzheimers Res Ther. 2016 Apr 06;8(1):14
pubmed: 27048170
PLoS One. 2012;7(2):e32014
pubmed: 22355408
Alzheimers Res Ther. 2021 Apr 17;13(1):80
pubmed: 33865446
J Prev Alzheimers Dis. 2022;9(2):197-210
pubmed: 35542991
Nature. 2022 Oct;610(7930):15-16
pubmed: 36175566
J Alzheimers Dis. 2013;37(1):29-40
pubmed: 23780660
Stat Med. 2018 Sep 20;37(21):3047-3055
pubmed: 29761523
J Neurochem. 2007 Oct;103(1):334-45
pubmed: 17623042
N Engl J Med. 2021 May 6;384(18):1691-1704
pubmed: 33720637
J Alzheimers Dis. 2015;43(2):575-88
pubmed: 25096615
Neurodegener Dis. 2011;8(3):117-23
pubmed: 20714111
Neurobiol Dis. 2009 Dec;36(3):425-34
pubmed: 19703562