CLINICAL STUDIES OF NSAIDSs AS y-SECRETASE MODULATORS IN ALZHEIMER'S DISEASE

NSAIDS 作为 y-分泌酶调节剂治疗阿尔茨海默病的临床研究

• 批准号: 8380184
• 负责人: DOUGLAS R GALASKO
• 金额: $ 38.59万
• 依托单位: UNIVERSITY OF CALIFORNIA, SAN DIEGO
• 依托单位国家: 美国
• 资助国家: 美国
• 起止时间: 至
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/8380184
• 关键词: Abeta synthesis; Activities of Daily Living; Acute; Adult; Affect; Alzheimer' s Disease; Amyloid; Amyloid beta-Protein; Amyloid deposition; Anti-Inflammatory Agents; Anti-inflammatory; Atrophic; Basic Science; Biochemical; Biological Markers; Brain; Catheters; Clinical; Clinical Research; Clinical Trials; Cognition; Cognitive; Controlled Clinical Trials; Data; Diagnosis; Disease; Dose; Double-Blind Method; Drug Kinetics; Early treatment; Elderly; Enzyme-Linked Immunosorbent Assay; F2-Isoprostanes; Funding; Hippocampus (Brain); Hour; Human; Ibuprofen; Image; Label; Lead; Magnetic Resonance Imaging; Measurement; Measures; Methods; Monitor; Neurons; Neuropsychological Tests; Non-Steroidal Anti-Inflammatory Agents; Omeprazole; Outcome Measure; Pathology; Patients; Performance; Pharmaceutical Preparations; Pharmacodynamics; Pharmacologic Substance; Phase; Phase III Clinical Trials; Placebo Control; Placebos; Plasma; Principal Investigator; Process; Production; Program Development; Questionnaires; R-flurbiprofen; Randomized; Randomized Clinical Trials; Relative (related person); Safety; Sampling; Spectrometry, Mass, Matrix-Assisted Laser Desorption-Ionization; Stable Isotope Labeling; Staging; Synapses; Techniques; Testing; Time; Work; attenuation; beta-site APP cleaving enzyme 1; brain volume; cerebral atrophy; design; gamma secretase; healthy volunteer; indexing; mild neurocognitive impairment; notch protein; novel; oxidative damage; primary outcome; programs; response; secondary outcome; secretase; tau Proteins; trend

Decreasing the production of Abeta may be beneficial in the treatment of Alzheimer's Disease (AD). Basic research carried out through Projects 1 and 2 previously identified that allosteric modulators of gamma- secretase selectively lower Abeta42, without affecting Notch processing, and screened several Nonsteriodal anti-inflammatory drugs (NSAIDS) as candidates. We designed and conducted'a clinical trial to determine :he safety, tolerability and pharmacokinetics of R-flurbiprofen in healthy older adults. The data was used by Myriad Pharmaceuticals, Inc.,to plan and implement phase 2 and an ongoing program of phase 3 clinical trials of R-flurbiprofen in AD. In this renewal of Project 3, we aim to optimize biomarker measurements of Abeta in CSF to characterize Abeta lowering effects of R-flurbiprofen. We also aim to test ibuprofen, an NSAID with gamma-secretase modulating activity and anti-inflammatory actions, by carrying out a controlled clinical trial in patients with amnestic Mild Cognitive Impairment (aMCI), the earliest clinically diagnosable stage of AD. This targets early intervention, before patients have developed extensive amyloid deposition and damage to neurons and synapses. We hypothesize that lowering Abeta42 very early in AD may have beneficial effects on imaging and biochemical biomarkers. We have 2 aims: (1) To evaluate CSF levels of Abeta42 after acute treatment with R-flurbiprofen at a high dose of 1600mg in healthy adults, using a lumbar CSF catheter to obtain CSF samples during 24 hours, and the technique of stable isotopic labeling to calculate Abeta synthesis rates. This will characterize the timing and duration of Abeta lowering actions. (2) To evaluate biomarker changes in CSF and brain atrophy measures on MRI,in 100 patients with aMCI who will be randomized to treatment with ibuprofen 800 mg three times per day (+ omeprazole 20 mg/day for gastroprotection), or to placebo, for 12 months. CSF and MRI will be obtained at baseline and 12 months and a brief neuropsychological test battery (NTB) and lADL-questionnaire will be given at baseline, 6 and 12 months. Primary outcome measures will be change in hippocampal and total brain volume (MRI); concentrations of total tau, phosphotau 181,Abeta42 and Abeta38, and F2-isoprostanes (CSF). Secondary outcome measures will be change in NTB and ADCS ADL-MCI scores. Significance: No treatment has been shown to have disease-modifying effects in AD. CSF biomarkers and MRI measures allow us to monitor whether treatment that targets modulation of gamma-secretase will (1) selectively lower Abeta42 in humans following acute treatment; (2) have beneficial effects on biomarkers related to Abeta and to damage from the resulting cascade of pathology in aMCI, the earliest clinical stage at which AD can be diagnosed. These results will support further efforts to develop gamma-secretase modulators for early clinical use.

减少 Abeta 的产生可能有益于治疗阿尔茨海默病 (AD)。基本的 通过项目 1 和 2 进行的研究先前发现，γ-的变构调节剂 分泌酶选择性降低Abeta42，不影响Notch加工，并筛选了几种Nonsteriodal 抗炎药（NSAIDS）作为候选药物。我们设计并进行了一项临床试验以确定 ：R-氟比洛芬在健康老年人中的安全性、耐受性和药代动力学。该数据被使用于 Myriad Pharmaceuticals, Inc. 计划并实施 2 期和正在进行的 3 期临床计划 R-氟比洛芬治疗 AD 的试验。在项目 3 的更新中，我们的目标是优化生物标志物测量 CSF 中的 Abeta 表征 R-氟比洛芬的 Abeta 降低作用。我们还旨在测试布洛芬，一种 NSAID 具有 γ-分泌酶调节活性和抗炎作用，通过进行受控的 针对遗忘性轻度认知障碍 (aMCI) 患者的临床试验，最早的临床可诊断患者 AD阶段。其目标是在患者出现广泛的淀粉样蛋白沉积之前进行早期干预 以及神经元和突触的损伤。我们假设在 AD 早期降低 Abeta42 可能会产生 对成像和生化生物标志物的有益影响。我们有 2 个目标：(1) 评估 CSF 水平 在健康成人中使用腰椎注射器以 1600 毫克高剂量 R-氟比洛芬进行急性治疗后的 Abeta42 脑脊液导管24小时内获取脑脊液样本，稳定同位素标记技术 计算 Abeta 合成率。这将表征 Abeta 降低行动的时间和持续时间。 (2) 评估 100 名 aMCI 患者的脑脊液生物标志物变化和 MRI 脑萎缩测量结果 将随机接受布洛芬 800 毫克每天 3 次治疗（+ 奥美拉唑 20 毫克/天） 胃保护），或安慰剂，持续 12 个月。将在基线和 12 个月时获取 CSF 和 MRI 并将在基线、6 点和 12 点进行简短的神经心理学测试 (NTB) 和 LADL 问卷 几个月。主要结果指标是海马体和总脑容量（MRI）的变化； 总 tau、磷酸 tau 181、Abeta42 和 Abeta38 以及 F2-异前列腺素 (CSF) 的浓度。中学 结果衡量标准将改变 NTB 和 ADCS ADL-MCI 分数。意义：尚未进行任何治疗 已被证明对 AD 具有缓解疾病的作用。 CSF 生物标志物和 MRI 测量使我们能够监测 以调节 γ 分泌酶为目标的治疗是否会 (1) 选择性降低人类的 Abeta42 急性治疗后； (2) 对与 Abeta 相关的生物标志物以及 Abeta 造成的损害具有有益的影响 由此产生的 aMCI 病理级联，是诊断 AD 的最早临床阶段。这些 结果将支持进一步努力开发γ-分泌酶调节剂以供早期临床使用。