Merck & Co., Inc., Rahway, NJ, USA.
MedAvante-ProPhase, Hamilton, NJ, USA and Department of Neurology,Loyola University Medical Center, Maywood, IL, USA.
J Alzheimers Dis. 2023;92(1):341-348. doi: 10.3233/JAD-220836.
Delay of progression from prodromal Alzheimer's disease (AD) to dementia is an important outcome in AD trials. Centralized adjudication is intended to improve the consistency of dementia diagnosis but has not been scrutinized.
To evaluate centralized adjudication for determining progression to dementia compared with Site Investigator opinion or change in Clinical Dementia Rating (CDR).
We used data from the 2-year APECS trial of verubecestat versus placebo in 1,451 prodromal AD participants. Cases were triggered for central adjudication if: 1) the Site Investigator judged the participant had progressed to dementia, or 2) the participant's CDR sum-of-boxes score increased ≥2 points from baseline. Post-hoc analyses were performed on pooled treatment-group data to compare methods of assessing progression.
581/1,451 (40%) participants had changes triggering adjudication and most (83%) were confirmed as progression to dementia. Only 66% of those who met CDR criteria (regardless of whether they also met Site Investigator criteria) were adjudicated to have progressed to dementia and just 15% of those who met only CDR criteria were adjudicated to have progressed, representing 5% of progressors. In contrast, 99% of those who met Site Investigator criteria (regardless of whether they also met CDR criteria) were adjudicated to have progressed, and the same was true for those who met only Site Investigator criteria.
A positive Site Investigator opinion is an excellent predictor for a positive adjudication decision regarding onset of dementia. Conversely, sole use of CDR sum-of-boxes change ≥2 is inadequate. The benefit of centralized adjudication appears doubtful.
从前驱阿尔茨海默病（AD）到痴呆的进展延迟是 AD 试验中的一个重要结果。集中裁决旨在提高痴呆诊断的一致性，但尚未受到审查。
评估与站点研究者意见或临床痴呆评定量表（CDR）变化相比，集中裁决确定进展为痴呆的效果。
我们使用了来自 verubecestat 与安慰剂在 1451 例前驱 AD 参与者的 2 年 APECS 试验的数据。如果：1）站点研究者判断参与者进展为痴呆，或 2）参与者的 CDR 总评分从基线增加≥2 分，则触发中央裁决。对汇总治疗组数据进行了事后分析，以比较评估进展的方法。
1451 名参与者中有 581 名（40%）发生了触发裁决的变化，其中大多数（83%）被确认为进展为痴呆。只有 66%符合 CDR 标准（无论是否符合站点研究者标准）的人被裁决为进展为痴呆，只有 15%符合 CDR 标准的人被裁决为进展为痴呆，占进展者的 5%。相比之下，99%符合站点研究者标准（无论是否符合 CDR 标准）的人被裁决为进展，仅符合站点研究者标准的人也是如此。
站点研究者的积极意见是发生痴呆起始的阳性裁决决策的极好预测指标。相反，仅使用 CDR 总评分变化≥2 是不够的。集中裁决的益处似乎值得怀疑。
