MGH Interdisciplinary Brain Center, Department of Neurology, Massachusetts General Hospital, Boston, MA, USA.
University of Heidelberg, Heidelberg, Baden Württemberg, Germany.
Trials. 2020 Dec 11;21(1):1016. doi: 10.1186/s13063-020-04752-x.
The conventional clinical trial design in Alzheimer's disease (AD) and AD-related disorders (ADRDs) is the parallel-group randomized controlled trial. However, in heterogeneous disorders like AD/ADRDs, this design requires large sample sizes to detect meaningful effects in an "average" patient. They are very costly and, despite many attempts, have not yielded new treatments for many years. An alternative, the multi-crossover, randomized control trial (MCRCT) is a design in which each patient serves as their own control across successive, randomized blocks of active treatment and placebo. This design overcomes many limitations of parallel-group trials, yielding an unbiased assessment of treatment effect at the individual level ("N-of-1") regardless of unique patient characteristics. The goal of the present study is to pilot a MCRCT of a potential symptomatic treatment, methylphenidate, for mild-stage AD/ADRDs, testing feasibility and compliance of participants in this design and efficacy of the drug using both standard and novel outcome measures suited for this design.
Ten participants with mild cognitive impairment or mild-stage dementia due to AD/ADRDs will undergo a 4-week lead-in period followed by three, month-long treatment blocks (2 weeks of treatment with methylphenidate, 2 weeks placebo in random order). This trial will be conducted entirely virtually with an optional in-person screening visit. The primary outcome of interest is feasibility as measured by compliance and retention, with secondary and exploratory outcomes including cognition as measured by neuropsychological assessment at the end of each treatment period and daily brain games played throughout the study, actigraphy, and neuropsychiatric and functional assessments.
This pilot study will gauge the feasibility of conducting a virtual MCRCT for symptomatic treatment in early AD/ADRD. It will also compare home-based daily brain games with standard neuropsychological measures within a clinical trial for AD/ADRD. Particular attention will be paid to compliance, tolerability of drug and participation, learning effects, trends and stability of daily measures across blocks, medication carryover effects, and correlations between standard and brief daily assessments. These data will provide guidance for more efficient trial design and the use of potentially more robust, ecological outcome measures in AD/ADRD research.
ClinicalTrials.gov, NCT03811847 . Registered on 21 January 2019.
在阿尔茨海默病（AD）和与 AD 相关的障碍（ADRDs）中，传统的临床试验设计是平行组随机对照试验。然而，在像 AD/ADRDs 这样的异质障碍中，这种设计需要大样本量才能在“平均”患者中检测到有意义的效果。它们非常昂贵，尽管进行了多次尝试，但多年来仍未产生新的治疗方法。一种替代方法是多交叉、随机对照试验（MCRCT），它是一种设计，其中每个患者在连续的、随机的活性治疗和安慰剂块中作为自己的对照。这种设计克服了平行组试验的许多限制，无论患者的独特特征如何，都可以在个体水平上对治疗效果进行无偏评估（“N-of-1”）。本研究的目的是为一种潜在的有症状治疗药物哌醋甲酯在轻度 AD/ADRDs 中进行 MCRCT 试验，测试这种设计中参与者的可行性和依从性，以及使用适合这种设计的标准和新型结果测量方法来评估药物的疗效。
10 名轻度认知障碍或轻度痴呆症患者将进行为期 4 周的导入期，然后进行三个为期 1 个月的治疗期（哌醋甲酯治疗 2 周，随机顺序治疗 2 周安慰剂）。这项试验将完全在虚拟环境中进行，可选进行现场筛查访问。主要观察指标是依从性和保留率，次要和探索性观察指标包括每个治疗期结束时神经心理学评估的认知，以及整个研究期间进行的日常大脑游戏、活动记录仪和神经精神和功能评估。
这项试验旨在评估在早期 AD/ADRD 中进行虚拟 MCRCT 治疗的可行性。它还将比较家庭日常大脑游戏与 AD/ADRD 临床试验中的标准神经心理学测量方法。特别关注药物的依从性、耐受性和参与度、学习效应、各治疗期之间日常测量的趋势和稳定性、药物持续效应以及标准和简短日常评估之间的相关性。这些数据将为更有效的试验设计和在 AD/ADRD 研究中使用潜在更强大、生态的结果测量方法提供指导。
ClinicalTrials.gov，NCT03811847。于 2019 年 1 月 21 日注册。
