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

 产品说明：FDA还没有批准用于遗忘型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。使用已证实安全性/耐受性的药物，我们提出了一种减缓AD所致MCI进展的新方法。使用非典型抗癫痫药物左乙拉西坦（LEV）的证据表明，海马活动过度是该阶段疾病的特征，可预测随后的纵向认知下降/转化为痴呆诊断，并与结构MRI中测量的神经元损伤程度相关。支持所提出的疗法，用LEV的低剂量治疗减少了动物模型和aMCI受试者中的海马活动过度，同时改善了认知功能。从长远来看，LEV治疗有望减少因无法控制脆弱的内嗅/海马网络中的过度神经活动而导致的退行性过程。拟定的随机、安慰剂对照的24个月试验将测试LEV治疗对唯一主要结局、CDR总和和内嗅皮质变薄的关键次要指标的疗效，以评估神经元损伤。该试验还将获得丰富的数据库，例如遗传/DNA、其他成像方式（静息状态功能磁共振成像和弥散张量成像扫描），沿着标准化神经心理学测试和新型认知评估作为次要指标。该申请下的资金将在公共/私人合作伙伴关系中为该II/III期试验提供部分支持（约占总试验成本的15%），该试验将是第一个针对糖尿病多动症的试验，并将在FDA注册。与FDA就拟定方案举行的IND前会议（2014年3月）提供了试验计划所有方面的支持性背景，包括适当的入组标准、结局指标的充分性、药物安全性和缓释药物的CMC制剂。重要的是，FDA证实，不需要进一步的临床前或临床数据来进行试验。该奖项下的霍普金斯研究者在生物统计学、成像、临床试验设计和数据分析方面具有卓越的专业知识，他们与申办者合作NIH的支持不仅有助于实现试验的主要目的，而且还确保了数据共享的开放资源，以推进AD预防的临床试验设计，包括生物标志物的开发。

 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.