Synthesis of Longer-Term Alzheimer Disease Studies in Order to Model and Improve

综合长期阿尔茨海默病研究以建模和改进

• 批准号: 8447482
• 负责人: LON S SCHNEIDER
• 金额: $ 50.79万
• 依托单位: UNIVERSITY OF SOUTHERN CALIFORNIA
• 依托单位国家: 美国
• 财政年份: 2011
• 资助国家: 美国
• 起止时间: 2011-04-01 至 2016-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8447482
• 关键词: Address; Alzheimer' s Disease; Area; Biological; Biological Markers; Characteristics; Cholinesterase Inhibitors; Clinical; Clinical Research; Clinical Trials; Clinical Trials Design; Cognitive; Common Data Element; Complement; Complex; Data; Databases; Development; Early treatment; Evaluation; Future; Goals; Impaired cognition; Individual; Intervention; Knowledge; Lead; Mediator of activation protein; Methods; Modeling; National Institute of Neurological Disorders and Stroke; Neurodegenerative Disorders; Neuropsychological Tests; Observational Study; Online Systems; Outcome; Patients; Pharmaceutical Preparations; Phase; Phase II Clinical Trials; Population; Problem Solving; Procedures; Process; Protocols documentation; Research; Research Design; Research Methodology; Sample Size; Sampling; Selection Criteria; Severities; Simulate; Site; Techniques; Testing; Therapeutic; Training; Variant; base; clinically relevant; cooperative study; data sharing; database structure; design; drug testing; effective therapy; experience; improved; innovation; mild cognitive impairment; models and simulation; neuroimaging; neuropathology; novel; novel strategies; prospective; public health relevance; research study; screening; simulation; trend; web site

DESCRIPTION (provided by applicant): Phase 2 and 3 clinical trials in Alzheimer disease (AD) and mild cognitive impairment (MCI) have been generally unsuccessful over the past decades. Efficacy mainly has been demonstrated in trials of 6 months or less, only with cholinesterase inhibitors for mild AD, and not in MCI or longer-term trials. Recent therapies based on the neuropathology of AD have not demonstrated efficacy in 18 month trials. Although this may reflect lack of knowledge of the biological targets and consequently the testing of ineffective drugs, it also reflects inadequacies of trials methods such that a modestly effective drug - if tested - may likely not be recognized as effective. In particular, the trials appear to choose patient samples based on assumptions about desired characteristics and outcomes that may not be valid because they are based on selected experiences from previous individual trials, further raising questions about design and validity. This project's broad, long-term objectives are to develop rational bases for designing pilot and phase 2 trials based on systematic evaluation of previous trials and testing design features prospectively. A broader goal is to encourage, complement, and accelerate the process of testing new and innovative treatments by providing models and simulations for clinical trials methods and designs. The research design and methods for achieving the objectives involves integrating patient data from 14 clinical trials and studies from the NIA's ADCS and ADNI over the last decade - including over 5200 followed from 1 to 4 years - into a common database. This allows for prospective analyses using hypothesis-based statistical techniques including simulations to better understand design parameters, outcomes, and to design better and more clinically relevant trials that would have the ability to detect change. The ADCS studies have inherent similarities that allow for combining, including common data base structures, outcomes, sites, training, and procedures. An expert steering committee formulates guiding principles and hypothesis-based research plans. Specific protocols address issues such as selection criteria, predictors of decline, and simulations to assess new trials designs. For example, we will examine the effects on outcomes of selecting patients for trials based on concomitant medication or severity using regression estimates and regression to the mean adjusted estimates, and follow this with trials simulations to empirically test validity and to plan future trials. Results of this research will have broad and lasting impact on trials designs in this therapeutic area, and especially on early phase trials in that designs can be tested and refined prior to implementing trials. The project is highly innovative in that it provides new approaches in this research area to examine the underlying patient data from numerous studies, and takes advantage of the rich database to empirically probe the assumptions under which current trials have been instigated. This will lead to improvement in trials methods and increase the likelihood for identifying effective treatments earlier in development.

描述（由申请人提供）：过去几十年来，阿尔茨海默病（AD）和轻度认知障碍（MCI）的 2 期和 3 期临床试验普遍不成功。疗效主要在 6 个月或更短的试验中得到证实，仅使用胆碱酯酶抑制剂治疗轻度 AD，而没有在 MCI 或长期试验中得到证实。最近基于 AD 神经病理学的疗法尚未在 18 个月的试验中显示出疗效。虽然这可能反映出缺乏对生物靶标的了解以及因此对无效药物的测试，但它也反映出试验方法的不足，例如适度有效的药物 - 如果经过测试 - 可能不会被认为是有效的。特别是，这些试验似乎是根据对所需特征和结果的假设来选择患者样本，但这些假设可能无效，因为它们是基于先前个别试验的选定经验，这进一步引发了有关设计和有效性的问题。该项目的广泛、长期目标是根据对先前试验的系统评估和前瞻性测试设计特征，为设计试点和第二阶段试验奠定合理的基础。更广泛的目标是通过为临床试验方法和设计提供模型和模拟来鼓励、补充和加速测试新的和创新的治疗方法的过程。实现这些目标的研究设计和方法涉及将 NIA 的 ADCS 和 ADNI 过去 10 年 14 项临床试验和研究的患者数据（包括 1 至 4 年跟踪的 5200 多个患者数据）整合到一个通用数据库中。这允许使用基于假设的统计技术（包括模拟）进行前瞻性分析，以更好地理解设计参数、结果，并设计更好、更具有临床相关性的试验，从而能够检测变化。 ADCS 研究具有允许组合的固有相似性，包括共同的数据库结构、结果、站点、培训和程序。专家指导委员会制定指导原则和基于假设的研究计划。具体方案解决了选择标准、衰退预测因素以及评估新试验设计的模拟等问题。例如，我们将使用回归估计和平均调整估计回归来检查根据伴随药物或严重程度选择患者进行试验对结果的影响，并通过试验模拟来根据经验测试有效性并计划未来的试验。这项研究的结果将对这一治疗领域的试验设计产生广泛而持久的影响，特别是对早期试验，因为设计可以在实施试验之前进行测试和完善。该项目具有高度创新性，因为它在该研究领域提供了新方法来检查来自大量研究的潜在患者数据，并利用丰富的数据库对当前试验所依据的假设进行实证探索。这将导致试验方法的改进，并增加在开发早期确定有效治疗方法的可能性。