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）：在过去的几十年中，阿尔茨海默氏病（AD）和轻度认知障碍（MCI）的第2阶段和第3阶段试验（MCI）通常一直没有成功。在6个月或更短的试验中仅证明了功效，仅在轻度AD的胆碱酯酶抑制剂中，而不是在MCI或长期试验中。基于AD的神经病理学的最新疗法尚未在18个月的试验中表现出功效。尽管这可能反映了对生物学靶标的知识缺乏知识，因此还反映了无效药物的测试，但它也反映了试验方法的不足，因此可能无法将适度有效的药物（如果经过测试）被认为是有效的。特别是，这些试验似乎是根据有关所需特征和结果的假设选择患者样本，这些样本可能是无效的，因为它们基于以前的个人试验中选定的经验，进一步提出了有关设计和有效性的问题。该项目的广泛长期目标是基于对先前试验的系统评估和前瞻性测试设计功能的系统评估来开发设计试验和2阶段试验的理性基础。一个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治疗的过程。实现目标的研究设计和方法涉及将14个临床试验的患者数据和NIA ADC和ADNI的研究整合到过去十年中（包括超过5200多年的1至4年），将其整合到一个公共数据库中。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，以更好地了解设计参数，结果，并设计更好，更临床相关的试验，这些试验将具有检测变化的能力。 ADCS研究具有固有的相似性，允许组合包括常见的数据库结构，结果，站点，培训和程序。专家指导委员会制定了指导原则和基于假设的研究计划。特定协议解决了选择标准，衰落预测因素和评估新试验设计的模拟问题。例如，我们将使用回归估计值和对平均调整后的估计值的回归进行基于药物或严重程度的患者选择患者的结果的影响，并通过试验模拟进行经验测试有效性并计划未来的试验。这项研究的结果将对该治疗领域的试验设计产生广泛而持久的影响，尤其是在早期试验中，可以在实施试验之前对设计进行测试和完善。该项目具有很高的创新性，因为它提供了该研究领域的新方法来检查许多研究的潜在患者数据，并利用富裕的数据库来验证当前试验的假设。这将导致试验方法的改善，并增加鉴定早期开发中有效治疗的可能性。