PHASE II/III trial for Slowing Progression in Mild Cognitive Impairment

减缓轻度认知障碍进展的 II/III 期试验

• 批准号: 9962226
• 负责人: MARILYN S. ALBERT
• 金额: $ 131.06万
• 依托单位: JOHNS HOPKINS UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2015
• 资助国家: 美国
• 起止时间: 2015-09-15 至 2023-01-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9962226
• 关键词: Abeta synthesis; Address; Alzheimer disease prevention; Alzheimer' s Disease; Amyloid; Animal Model; Animals; Antiepileptic Agents; Award; Biological Markers; Biometry; Brain region; Caregivers; Characteristics; Clinical; Clinical Data; Clinical Trials; Clinical Trials Design; Cognition; Cognitive; Complement; Complement component C7; Control Groups; DNA; Data; Data Analyses; Data Set; Databases; Dementia; Development; Diagnosis; Diffusion Magnetic Resonance Imaging; Disease; Disease Progression; Dose; Enrollment; Ensure; Epilepsy; Episodic memory; FDA approved; Failure; Formulation; Functional Magnetic Resonance Imaging; Funding; Genetic; Genotype; Healthcare Systems; Hippocampus (Brain); Human; Hyperactivity; Image; Impaired cognition; Intervention Trial; Levetiracetam; Magnetic Resonance Imaging; Measures; Modeling; Nerve Degeneration; Neuronal Injury; Neuropsychological Tests; Outcome; Outcome Measure; Patients; Pattern; Pharmaceutical Preparations; Pharmacology; Pharmacotherapy; Phase; Phase II/III Trial; Placebos; Presenile Alzheimer Dementia; Prevention; Process; Protocols documentation; Randomized; Research; Research Personnel; Rest; Risk; Safety; Scanning; Secondary to; Specific qualifier value; Standardization; Statistical Models; Structure; Sum; Testing; Thick; Thinness; Time; United States National Institutes of Health; Work; amnestic mild cognitive impairment; amyloid precursor protein processing; apolipoprotein E-4; base; biomarker development; clinical efficacy; clinical predictors; cognitive function; cognitive testing; cost; data sharing networks; dementia risk; design; efficacy outcomes; efficacy testing; entorhinal cortex; follow-up; high risk; imaging modality; improved; longitudinal analysis; medication safety; meetings; mild cognitive impairment; novel; novel marker; novel strategies; novel therapeutic intervention; patient population; pre-clinical; predictive marker; primary outcome; public health relevance; public-private partnership; randomized placebo controlled trial; randomized placebo-controlled clinical trial; relating to nervous system; response; secondary outcome; treatment effect; treatment group; treatment response; trial design

 DESCRIPTION: No therapy has FDA approval for amnestic MCI, a symptomatic stage of Alzheimer's disease when patients are at increased risk for progression to dementia. Using an agent with proven safety/tolerability, we propose a novel approach for slowing progression in MCI due to AD. The use of the atypical antiepileptic levetiracetam (LEV) is indicated by evidence that hippocampal hyperactivity is characteristic of this stage of disease, predicts subsequent longitudinal cognitive decline/conversion to a dementia diagnosis, and is correlated with the extent of neuronal injury as measured in structural MRI. Supporting the proposed therapy, low dose treatment with LEV reduces hippocampal hyperactivity in both animal models and aMCI subjects, concurrently improving cognitive function. In the longer-term, treatment with LEV is expected to reduce degenerative processes driven by failure to control excess neural activity in the vulnerable entorhinal/hippocampal network. The proposed randomized, placebo-controlled 24 month trial will test the efficacy of LEV therapy on a sole primary outcome, the CDR sum of boxes, and a key secondary measure of entorhinal cortex thinning to assess neuronal injury. The trial will also acquire a rich database, e.g. genetic/DNA, additional imaging modalities (resting state fMRI, and diffusion tensor imaging scans), along with both standardized neuropsychological testing and novel cognitive assessments as secondary measures. Funding under this application would provide partial support (approximately 15% of total trial cost) in a public/private partnership for this Phase II/III trial, which would be the first to target hippocamal hyperactivity and will be registered with the FDA. A pre-IND meeting with the FDA (March 2014) on the proposed protocol provided supportive background on all aspects of the trial plan including appropriate enrollment criteria, adequacy of outcome measures, drug safety, and CMC formulation of an extended release medication. Importantly, the FDA confirmed that no further preclinical or clinical data are required to proceed with the trial. The Hopkins investigators under this award, who have exceptional expertise in biostatistics, imaging, clinical trial design, and data analysis have worked together with the Sponsor (AgeneBio, Inc) and its CRO to develop the protocol and plans to implement it. NIH support would not only contribute to the main purpose of the trial, but also ensure an open resource for data sharing to advance clinical trial design in AD prevention, including biomarker development.

 描述：没有FDA批准的遗忘型MCI的治疗方法，遗忘型MCI是阿尔茨海默病的一个症状阶段，患者进展为痴呆症的风险增加。使用一种已证实的安全性/耐受性的药物，我们提出了一种新的方法来减缓由于AD引起的MCI的进展。使用非典型抗癫痫药左乙拉西坦(LEV)的证据表明，海马区过度活跃是这一阶段疾病的特征，可以预测随后的纵向认知能力下降/转变为痴呆症诊断，并与结构MRI测量的神经元损伤程度相关。支持所提出的治疗方法的是，低剂量的LEV治疗减少了动物模型和aMCI受试者的海马区过度活动，同时改善了认知功能。从长远来看，LEV治疗有望减少由于未能控制脆弱的内嗅觉/海马区网络中过度的神经活动而导致的退行性变过程。这项拟议的随机、安慰剂对照的24个月试验将测试LEV治疗对唯一的主要结果、CDR总和和内嗅皮层变薄的关键次要指标的有效性，以评估神经元损伤。试验还将获得丰富的数据库，例如遗传/DNA、额外的成像方式(静息状态功能磁共振成像和扩散张量成像扫描)，以及标准化的神经心理测试和新的认知评估作为次要测量。这项申请下的资金将在公私合作伙伴关系中为这项II/III期试验提供部分支持(约占总试验成本的15%)，这将是第一个针对海马区多动的试验，并将在FDA注册。IND前与FDA就拟议方案举行的会议(2014年3月)就试验计划的所有方面提供了支持性背景，包括适当的登记标准、结果衡量标准的充分性、药物安全性以及CMC制定的缓释药物。重要的是，FDA证实，不需要进一步的临床前或临床数据来继续试验。获得该奖项的霍普金斯大学的研究人员在生物统计学、成像、临床试验设计和数据分析方面拥有非凡的专业知识，他们与赞助商(Agene Bio，Inc.)及其CRO合作开发了该协议并计划实施该协议。NIH的支持不仅有助于试验的主要目的，还将确保数据共享的开放资源，以促进AD预防方面的临床试验设计，包括生物标记物的开发。