The LUCINDA Trial

露辛达审判

• 批准号: 9933921
• 负责人: Craig S Atwood
• 金额: $ 146.31万
• 依托单位: WEILL MEDICAL COLL OF CORNELL UNIV
• 依托单位国家: 美国
• 财政年份: 2018
• 资助国家: 美国
• 起止时间: 2018-08-15 至 2024-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9933921
• 关键词: Acetylcholinesterase Inhibitors; Adult; Aftercare; Alzheimer' s Disease; Alzheimer' s disease model; Alzheimer' s disease risk; Alzheimer’s disease biomarker; Amyloid deposition; Animal Model; Antiinflammatory Effect; Atrophic; Biological Markers; Brain region; C-reactive protein; Child; Clinical; Clinical Research; Cognition; Cognitive; Combined Modality Therapy; Data; Disease Progression; Dose; Double-Blind Method; Drug usage; Enantone; Erythrocyte Sedimentation Rate; FDA approved; Functional Magnetic Resonance Imaging; Goals; Gonadal Steroid Hormones; Gonadotropin-Releasing Hormone Analog; Hippocampus (Brain); IL6 gene; Impaired cognition; Inflammatory; Interleukin-1 beta; Legal patent; Leuprolide Acetate; Luteinizing Hormone; Magnetic Resonance Imaging; Malignant neoplasm of prostate; Measures; Motivation; Patients; Perfusion; Pharmaceutical Preparations; Pharmacologic Substance; Placebos; Plasma; Precocious Puberty; Process; Randomized Controlled Trials; Research Project Grants; Serum; Site; Spin Labels; Structure; Subgroup; TNF gene; Therapeutic; Time; United States National Institutes of Health; Uterine Fibroids; Validation; Ventricular; Woman; Work; base; clinical efficacy; cognitive performance; cost; cytokine; endometriosis; epidemiology study; functional decline; gray matter; improved; inflammatory marker; magnetic resonance imaging biomarker; neuroimaging; neuroimaging marker; novel; off-patent; phase 2 study; phase II trial; phase III trial; pre-clinical; pre-clinical research; preservation; randomized trial; research and development; response; tau phosphorylation

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.

项目摘要 该项目的目的是重新使用安全且耐受良好的促性腺激素释放激素（GNRH）类似物 lupron用于阿尔茨海默氏病（AD）。 Lupron目前已批准为前列腺癌， 成人的子宫内膜异位症和子宫纤维和儿童中心早熟青春期。我们建议 确认并扩展了先前II期研究的结果（Bowen等，2015），该研究表明Lupron 在接受轻度中度广告的女性亚组的认知和功能下降，她们也在服用 乙酰胆碱酯酶抑制剂（ACHEI）。我们的目标是在同一子组中复制lupron的 在此前试验中的临床功效，并增加神经影像学和血浆生物标志物，以帮助阐明 Lupron就像AD中的多种作用机制。这些机制包括降低 基于广泛的临床前证据，LH保留认知和 在AD动物模型中降低淀粉样蛋白沉积和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）与Lupron的三个地点进行双盲，随机试验（22.5 mg/12周）相比 安慰剂以评估48周的认知和功能的变化 他们还服用了稳定的ACHEI。我们假设服用lupron + achei的患者将显示 与安慰剂 +的患者相比 achei。 （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 广告。我们假设接受Lupron + ACHEI的患者在广告中的萎缩率较小 与接受安慰剂 + ACHEI的人相比，大脑区域和保留的海马灌注。 （3） 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 与安慰剂 + ACHEI相比，ACHEI将显示血浆促炎的降低 细胞因子。 如果Lupron + Achei的AD第二阶段试验为正面，我们将继续进行III期试验 获得FDA批准为AD的新型组合疗法。通过重新定位现有药物， 结合当前的AD治疗，我们将能够建立在以前的广泛研究基础上 开发工作，减少为患者提供这种承诺治疗的时间范围和成本 与广告。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AD风险。