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.govNCT01767311.

BackgroundDevelopment of new therapies for Alzheimer's disease (AD) is increasingly focused on more mildly affected populations, and requires new assessment and outcome strategies. Patients in early stages of AD have mild cognitive decline and no, or limited, functional impairment. To respond to these assessment challenges, we developed a measurement approach based on established scale items that exhibited change in previous amnestic Mild Cognitive Impairment (aMCI) trials.MethodsPartial least squares regression with a longitudinal clinical decline model identified items from commonly used clinical scales with the highest combined sensitivity to change over time in aMCI and weighted these items according to their relative contribution to detecting clinical progression in patients’ early stages of AD. The resultant AD Composite Score (ADCOMS) was assessed for its ability to detect treatment effect in aMCI/prodromal AD (pAD) clinical trial populations.ResultsADCOMS consists of 4 Alzheimer's Disease Assessment Scale–cognitive subscale items, 2 Mini-Mental State Examination items, and all 6 Clinical Dementia Rating—Sum of Boxes items. ADCOMS demonstrated improved sensitivity to clinical decline over individual scales in pAD, aMCI and in mild AD dementia. ADCOMS also detected treatment effects associated with the use of cholinesterase inhibitors in these populations. Improved sensitivity predicts smaller sample size requirements when ADCOMS is used in early AD trials.ConclusionsADCOMS is proposed as new standard outcome for pAD and mild AD dementia trials, and is progressing in a CAMD-sponsored qualification process for use in registration trials of pAD.

Background Aβ pathologies occur years prior to cortical tauopathy, neurodegeneration, and clinical symptoms. BAN2401 is a humanized immunoglobulin G1 monoclonal antibody that selectively binds to soluble Aβ aggregated species (oligomers, protofibrils). BAN2401 reduced amyloid on PET and slowed cognitive decline in a Phase 2 study in early symptomatic AD. The AHEAD 3‐45 study will test the safety and efficacy of BAN2401 even earlier in the AD continuum. Method AHEAD 3‐45 consists of two trials (A3 Trial and A45 Trial) under a single protocol and screening process, common schedule of assessments, and distinct dosing regimens tailored to the baseline amyloid level. The study is a Public‐Private Partnership of the Alzheimer’s Clinical Trial Consortium (ACTC), National Institutes of Health (NIH), and Eisai, Inc. The A3 Trial will enroll cognitively normal individuals (CN) with intermediate amyloid (approximately 20‐40 centiloids), at risk for further amyloid accumulation and development of neurofibrillary tangles on tau PET over four years. Approximately 400 participants will be randomized 1:1 to placebo or BAN2401 infusion—8 weeks of titration followed by 10 mg/kg every four weeks for 216 weeks. The A45 Trial will enroll CN individuals with elevated amyloid, defined as amyloid PET approximately >40 centiloids, at risk for cognitive decline over four years. Approximately 1000 participants will be randomized 1:1 to placebo or BAN2401 infusion—8 weeks of biweekly titration dosing, then 10 mg/kg biweekly induction dosing through 96 weeks to clear aggregated Ab, followed by 10 mg/kg every four weeks maintenance dosing through 216 weeks to prevent reaccumulation of Aβ. Result Longitudinal cognitive, safety, amyloid and tau PET, MRI and fluid biomarker assessments will be performed. The primary outcome of the A3 Trial is prevention of brain amyloid accumulation by amyloid PET at 216 weeks, with delay of tau PET accumulation as a key secondary outcome. The primary outcome measure of the A45 Trial is the Preclinical Alzheimer’s Disease Cognitive Composite 5 (PACC5) scale at 216 weeks. Conclusion The AHEAD 3‐45 Study will test whether BAN2401 can prevent the accumulation and spread of Aβ deposition, downstream tau pathology, and cognitive decline in at‐risk cognitively normal individuals prior to significant irreversible neurodegeneration.

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BackgroundUsing a data set of works councils of trade union IG Metal, this paper investigates psychosocial stress and strain on this specific group in comparison to employees working in administration in general (leadership and non-leadership-role) and a national reference value.MethodsFor assessing psychosocial work factors on works councils within the sector represented by the trade union IG Metal in Germany, a research by using the German standard version of COPSOQ (Copenhagen Psychosocial Questionnaire) was performed. The instrument includes 87 single items forming 25 aspects of strain and stress. Results from the study group of works councils were compared to those from employees working in administration and to the general population mean (COPSOQ database). Statistical analysis included t-tests, analysis of variance and multiple comparisons of means. To be significant in terms of statistics, p<0.05 (two-tailed) and a minimum deviation of 5 or more points between groups′ mean values identify the relevant values.ResultsAll in all, 309 works councils from a national survey of the German chemical and metalworking industries took part in the study. 113 were full-time works council members (exempted from the duty to perform their regular work), 196 were voluntary members (acting as employee representatives on an honorary basis alongside their normal duties). Comparison between works councils and employees working in administration (leadership roles (N=1810) and non-leadership roles (N=2970)) and for employees in general (N=35.000) showed unfavourable values for works councils for most scales. Significantly higher values indicating higher strain and stress were found for the scales: emotional demands, work-privacy conflict, role conflicts, mobbing, cognitive stress symptoms and burnout. Unfavourable results were obtained for the aspects: quality of leadership, social support, sense of community and general health. Favourable findings were found on the scales: influence at work, quantity of social relations and the partly positive values for quantitative demands and commitment to the workplace.ConclusionCompared to the reference groups, works council members perceive the psychosocial demands of working life as more exhausting for the majority of aspects. This allows several conclusions. One reason may be the extended tasks employee representatives face, an other may be that the education of most works council members does not seem appropriate to the high demands of their managerial and executive tasks.