Edland Steven D, Ard M Colin, Sridhar Jaiashre, Cobia Derin, Martersteck Adam, Mesulam M Marsel, Rogalski Emily J
Division of Biostatistics, Department of Family Medicine & Public Health, University of California San Diego, La Jolla, CA, USA; Department of Neurosciences, University of California San Diego, La Jolla, CA, USA.
Department of Neurosciences, University of California San Diego, La Jolla, CA, USA.
Alzheimers Dement (N Y). 2016 Sep;2(3):177-181. doi: 10.1016/j.trci.2016.05.002.
Atrophy measures derived from structural MRI are promising outcome measures for early phase clinical trials, especially for rare diseases such as primary progressive aphasia (PPA), where the small available subject pool limits our ability to perform meaningfully powered trials with traditional cognitive and functional outcome measures.
We investigated a composite atrophy index in 26 PPA participants with longitudinal MRIs separated by two years. Rogalski . [ 2014;83:1184-1191] previously demonstrated that atrophy of the left perisylvian temporal cortex (PSTC) is a highly sensitive measure of disease progression in this population and a promising endpoint for clinical trials. Using methods described by Ard . [ 2015;14:418-426], we constructed a composite atrophy index composed of a weighted sum of volumetric measures of 10 regions of interest within the left perisylvian cortex using weights that maximize signal-to-noise and minimize sample size required of trials using the resulting score. Sample size required to detect a fixed percentage slowing in atrophy in a two-year clinical trial with equal allocation of subjects across arms and 90% power was calculated for the PSTC and optimal composite surrogate biomarker endpoints.
The optimal composite endpoint required 38% fewer subjects to detect the same percent slowing in atrophy than required by the left PSTC endpoint.
Optimal composites can increase the power of clinical trials and increase the probability that smaller trials are informative, an observation especially relevant for PPA, but also for related neurodegenerative disorders including Alzheimer's disease.
源自结构磁共振成像（MRI）的萎缩测量指标是早期临床试验中很有前景的疗效指标，尤其是对于像原发性进行性失语（PPA）这样的罕见疾病，因为可用的受试者群体较小，限制了我们使用传统认知和功能疗效指标进行有意义的大样本量试验的能力。
我们对26名PPA参与者进行了研究，他们接受了间隔两年的纵向MRI检查。Rogalski等人[2014年；83：1184 - 1191]先前证明，左侧颞叶周围皮质（PSTC）萎缩是该人群疾病进展的高度敏感指标，也是临床试验中有前景的终点指标。我们使用Ard等人[2015年；14：418 - 426]描述的方法，构建了一个复合萎缩指数，该指数由左侧颞叶周围皮质内10个感兴趣区域的体积测量值的加权和组成，权重的选择旨在最大化信噪比并最小化使用所得分数的试验所需的样本量。针对PSTC以及最佳复合替代生物标志物终点指标，计算了在一项两年期临床试验中，双臂受试者分配相等且检验效能为90%时，检测萎缩固定百分比减缓所需的样本量。
与左侧PSTC终点指标相比，最佳复合终点指标检测相同百分比萎缩减缓所需的受试者数量少38%。
最佳复合指标可以提高临床试验的效能，并增加小型试验提供信息的可能性，这一观察结果不仅与PPA相关，对于包括阿尔茨海默病在内的相关神经退行性疾病也同样重要。
