The LUCINDA Trial

项目摘要 该项目旨在重新利用安全和耐受性良好的促性腺激素释放激素类似物 鲁普隆用于治疗阿尔茨海默病(AD)。路普隆目前被FDA批准用于前列腺癌， 成人子宫内膜异位症和子宫肌瘤，以及儿童中枢性性早熟。我们建议 确认并扩展之前的第二阶段研究(Bowen等人，2015)的结果，该研究表明Lupron 轻-中度AD患者中的一组女性认知和功能下降停止，她们也在服用 一种乙酰胆碱酯酶抑制剂(AChEI)。我们的目标是在同一小组中复制Lupron的 这项先前试验的临床疗效，并添加神经成像和血浆生物标志物，将有助于阐明 路普隆在AD中可能有多种作用机制。这些机制包括降低 黄体生成素基于广泛的临床前证据，即降低黄体生成素可以保留认知和 减少AD动物模型中淀粉样蛋白的沉积和tau的磷酸化，以及新的证据表明 促性腺激素释放激素类似物可能具有重要的抗炎作用。 我们将(1)进行卢普隆(22.5 mg/12周)的三点双盲随机试验，与 安慰剂用于评估轻中度AD患者48周内认知和功能的变化 他们也在服用稳定剂量的AChEI。我们假设服用路普隆AChEI的患者会表现出 与服用安慰剂的患者相比，治疗前后认知和功能下降较小 AChEI。(2)我们将评估路普隆对脑脊髓瘤结构和功能(ASL-MRI)神经成像生物标志物的影响。 广告。我们假设，接受路普隆AChEI治疗的患者在AD相关的患者中表现出较少的萎缩 与那些接受安慰剂AChEI的人相比，他们的大脑区域和保存的海马体灌注量。(3) 我们将评估血浆炎症标志物的变化。我们假设服用鲁普隆的患者 与服用安慰剂的患者相比，AChEI患者的血浆促炎作用降低 细胞因子。 如果Lupron AChEI治疗AD的第二阶段试验是阳性的，我们将继续进行第三阶段试验，目标是 获得FDA批准的这一治疗AD的新型联合疗法。通过重新调整现有药物的用途，在 与目前的AD治疗相结合，我们将能够建立在广泛的先前研究和 开发努力，减少向患者提供这种有希望的疗法的时间框架和成本 使用AD。该项目的结果有可能对患者产生重大的近期临床影响。 目前患有或有患上阿尔茨海默病的风险。

Project Summary This project aims to re-purpose the safe and well-tolerated gonadotropin-releasing hormone (GnRH) analogue Lupron for use in Alzheimer's Disease (AD). Lupron is currently FDA-approved for prostate cancer, endometriosis and uterine fibroids in adults and for central precocious puberty in children. We propose to confirm and extend results from a prior phase II study (Bowen et al, 2015) that demonstrated that Lupron halted cognitive and functional decline in a subgroup of women with mild-moderate AD who were also taking an acetylcholinesterase inhibitor (AChEI). Our objectives are to replicate, in the same subgroup, Lupron's clinical EFFICACY in this prior trial and to add neuroimaging and plasma BIOMARKERS that will help elucidate Lupron's likely multiple mechanisms of action in AD. These mechanisms include decreasing levels of Luteinizing Hormone (LH) based on extensive preclinical evidence that decreasing LH preserves cognition and decreases amyloid deposition and tau phosphorylation in animal models of AD, as well as new evidence that GnRH analogues may have important anti-inflammatory effects. We will (1) Conduct a three site, double-blind, randomized trial of Lupron (22.5 mg/12 weeks) compared with placebo to evaluate the changes over 48 weeks in cognition and function in women with mild-moderate AD who are also taking a stable dose of AChEI. We hypothesize that patients taking Lupron + AChEI will show a smaller pre- to post-treatment decline in cognition and function when compared to patients taking placebo + AChEI. (2) We will assess Lupron’s effect on structural and functional (ASL-MRI) neuroimaging biomarkers of AD. We hypothesize that patients who receive Lupron + AChEI will demonstrate less atrophy in AD-related brain regions and preserved hippocampal perfusion as compared to those who receive placebo + AChEI. (3) We will assess changes in plasma markers of inflammation. We hypothesize that patients taking Lupron + AChEI, as compared to those taking placebo + AChEI, will show decreased plasma pro-inflammatory cytokines. If this second phase II trial of Lupron + AChEI for AD is positive we will proceed to a phase III trial with the goal of gaining FDA approval for this novel combination therapy for AD. By re-purposing an existing medication, in combination with a current AD treatment, we will be able to build upon extensive previous research and development efforts, reducing the time frame and costs of making this promising therapy available to patients with AD. Results from this project have the potential for significant, near term clinical impact in patients currently suffering from or at risk of AD.