GCS-fMRI, Koelliker Hospital and Department of Psychology, University of Turin, Turin, Italy.
FOCUSLAB, Department of Psychology, University of Turin, Turin, Italy.
J Alzheimers Dis. 2023;95(3):1059-1065. doi: 10.3233/JAD-230589.
Clinical trials targeting Alzheimer's disease (AD) aim to alleviate clinical symptoms and alter the course of this complex neurodegenerative disorder. However, the conventional approach of null hypothesis significance testing (NHST) commonly employed in such trials has inherent limitations in assessing clinical significance and capturing nuanced evidence of effectiveness on a continuous scale.
In this study, we conducted a re-analysis of the phase III trial of lecanemab, a recently proposed humanized IgG1 monoclonal antibody with high affinity for Aβ soluble protofibrils, using a Bayesian approach with informed t-test priors.
To achieve this, we carefully selected trial data and derived effect size estimates for the primary endpoint, the Clinical Dementia Rating Scale-Sum of Boxes (CDR-SB). Subsequently, a series of Bayes Factor analyses were performed to compare evidence supporting the null hypothesis (no treatment effect) versus the alternative hypothesis (presence of an effect). Drawing on relevant literature and the lecanemab phase III trial, we incorporated different minimal clinically important difference (MCID) values for the primary endpoint CDR-SB as prior information.
Our findings, based on a standard prior, revealed anecdotal evidence favoring the null hypothesis. Additional robustness checks yielded consistent results. However, when employing informed priors, we observed varying evidence across different MCID values, ultimately indicating no support for the effectiveness of lecanemab over placebo.
Our study underscores the value of Bayesian analysis in clinical trials while emphasizing the importance of incorporating MCID and effect size granularity to accurately assess treatment efficacy.
针对阿尔茨海默病（AD）的临床试验旨在缓解临床症状并改变这种复杂的神经退行性疾病的进程。然而，此类试验中常用的零假设显著性检验（NHST）方法在评估临床意义和捕捉连续尺度上的细微疗效证据方面存在固有局限性。
在这项研究中，我们使用具有信息的 t 检验先验的贝叶斯方法，对 lecanemab 的 III 期试验进行了重新分析，lecanemab 是一种最近提出的与人源 IgG1 单克隆抗体亲和力高的可溶性 Aβ原纤维的抗体。
为此，我们仔细选择了试验数据，并为主要终点——临床痴呆评定量表总和（CDR-SB）计算了效应大小估计值。随后，进行了一系列贝叶斯因子分析，以比较支持零假设（无治疗效果）和替代假设（存在效果）的证据。我们借鉴了相关文献和 lecanemab III 期试验，将不同的最小临床重要差异（MCID）值作为主要终点 CDR-SB 的先验信息纳入分析。
基于标准先验，我们的发现表明支持零假设的证据只是传闻。额外的稳健性检查得到了一致的结果。然而，当使用知情先验时，我们观察到不同 MCID 值下的证据存在差异，最终表明 lecanemab 与安慰剂相比没有疗效。
我们的研究强调了贝叶斯分析在临床试验中的价值，同时强调了纳入 MCID 和效应大小粒度以准确评估治疗效果的重要性。
