The LUCINDA Trial

项目摘要 该项目旨在重新使用安全和耐受性良好的促性腺激素释放激素（GnRH）类似物 用于阿尔茨海默病（AD）的Lupron。Lupron目前被FDA批准用于前列腺癌， 子宫内膜异位症和子宫肌瘤在成人和中枢性早熟儿童。我们建议 证实并扩展了先前II期研究（Bowen et al，2015）的结果，该研究证明Lupron 在一个患有轻度-中度AD的女性亚组中， 乙酰胆碱酯酶抑制剂（AChEI）。我们的目标是在同一亚组中复制Lupron的 临床疗效，并增加神经影像学和血浆生物标志物，这将有助于阐明 Lupron在AD中可能的多种作用机制。这些机制包括降低 促黄体生成激素（LH）基于大量临床前证据，即降低LH可保护认知和 在AD动物模型中减少淀粉样蛋白沉积和tau蛋白磷酸化，以及新的证据表明， GnRH类似物可能具有重要的抗炎作用。 我们将（1）进行一项Lupron（22.5 mg/12周）与 安慰剂，以评估轻度-中度AD女性患者48周内认知和功能的变化 他们也在服用稳定剂量的乙酰胆碱酯酶抑制剂我们假设服用Lupron + AChEI的患者将显示出 与服用安慰剂+的患者相比，治疗前至治疗后认知和功能下降较小 乙酰胆碱酯酶(2)我们将评估Lupron对结构和功能（ASL-MRI）神经成像生物标志物的影响， AD.我们假设接受Lupron + AChEI治疗的患者在AD相关性脑萎缩中表现出较少的萎缩。 与接受安慰剂+ AChEI的患者相比，脑区和保留的海马灌注。（三） 我们将评估炎症的血浆标志物的变化。我们假设服用Lupron +的患者 与服用安慰剂+ AChEI的患者相比， 细胞因子 如果Lupron + AChEI治疗AD的第二个II期试验是积极的，我们将进行III期试验，目标是 获得FDA对这种新型AD联合疗法的批准。通过重新利用现有的药物， 结合目前的AD治疗，我们将能够建立在广泛的先前研究的基础上， 开发工作，减少时间框架和成本，使这种有前途的治疗提供给患者 与AD该项目的结果可能对患者产生重大的近期临床影响 目前患有AD或有AD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.