The LUCINDA Trial

项目概要 该项目旨在重新利用安全且耐受性良好的促性腺激素释放激素 (GnRH) 类似物 Lupron 用于治疗阿尔茨海默病 (AD)。 Lupron 目前已获得 FDA 批准用于治疗前列腺癌， 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 确认并扩展了之前的 II 期研究（Bowen 等人，2015）的结果，该研究表明 Lupron 患有轻度至中度 AD 的女性亚组的认知和功能下降得到了阻止，这些女性也服用了 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 在此先前试验中的临床疗效，并添加神经影像学和血浆生物标志物，这将有助于阐明 Lupron 在 AD 中可能有多种作用机制。这些机制包括降低 黄体生成激素 (LH) 基于大量临床前证据，表明降低 LH 可以保护认知能力和 减少 AD 动物模型中的淀粉样蛋白沉积和 tau 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) 进行一项三中心、双盲、随机试验，将 Lupron（22.5 毫克/12 周）与 安慰剂用于评估患有轻中度 AD 的女性 48 周内认知和功能的变化 同时服用稳定剂量的 AChEI 的人。我们假设服用 Lupron 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 乙酰胆碱酯酶抑制剂。 (2) 我们将评估 Lupron 对结构和功能 (ASL-MRI) 神经影像生物标志物的影响 公元。我们假设接受 Lupron AChEI 的患者将表现出较少的 AD 相关萎缩 与接受安慰剂 AChEI 的患者相比，大脑区域和海马灌注得以保留。 (3) 我们将评估血浆炎症标志物的变化。我们假设服用 Lupron 的患者 与服用安慰剂 AChEI 的患者相比，AChEI 会表现出血浆促炎性降低 细胞因子。 如果 Lupron AChEI 治疗 AD 的第二期 II 期试验结果积极，我们将继续进行 III 期试验，目标是 这种新型 AD 联合疗法获得 FDA 批准。通过重新利用现有药物， 与当前的 AD 治疗相结合，我们将能够在广泛的先前研究和 开发工作，减少了向患者提供这种有前途的疗法的时间框架和成本 与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 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.