Pilot Trial of Carvedilol in Alzheimer's Disease

卡维地洛治疗阿尔茨海默病的初步试验

• 批准号: 8261319
• 负责人: Giulio Maria Pasinetti
• 金额: $ 59.25万
• 依托单位: ICAHN SCHOOL OF MEDICINE AT MOUNT SINAI
• 依托单位国家: 美国
• 财政年份: 2011
• 资助国家: 美国
• 起止时间: 2011-05-01 至 2014-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8261319
• 关键词: Adrenergic Antagonists; Adverse event; Aging; Alzheimer' s Disease; Amyloid; Attenuated; Biological Markers; Blood Pressure; Blood Vessels; Brain; Brain Ischemia; Cardiac; Caregivers; Cell Culture Techniques; Cerebrospinal Fluid; Chemistry; Chronic; Clinical; Cognitive; Congestive Heart Failure; Data; Deterioration; Development; Disease; Dose; Double-Blind Method; Effectiveness; Episodic memory; FDA approved; Generic Drugs; Healthcare Systems; Hematology; Human; Impaired cognition; Laboratories; Measures; Methods; Modeling; Neurodegenerative Disorders; Oral Administration; Outcome; Patients; Perfusion; Pharmaceutical Preparations; Phase; Placebo Control; Placebos; Public Health; Randomized; Research Personnel; Risk Factors; Safety; Sampling; Site; Staging; Synaptic Transmission; Testing; Therapeutic Effect; Time; Transgenic Mice; Verbal Learning; carvedilol; cerebrovascular; cost effective; effective therapy; epidemiologic data; functional decline; gamma secretase; hypertension treatment; improved; inhibitor/antagonist; mouse model; neuron loss; neurotransmission; novel; pilot trial; population based; prevent; primary outcome; public health relevance; secondary outcome

DESCRIPTION (provided by applicant): Alzheimer's disease (AD) is the most prevalent neurodegenerative disease of aging and the cause of major burden for AD patients, caregivers, and the health care system. Current FDA-approved AD treatments have modest symptomatic effects at best and do not significantly modify disease course. In a population-based sample of incident AD, we observed that use of ¿-adrenergic antagonists was associated with slower functional decline. Our data combined with other epidemiologic data point to the potential therapeutic effect of ¿-adrenergic antagonists in patients with AD. This observation prompted us to screen ¿-adrenergic antagonists for effects on amyloid-¿ (A¿) synthesis in cell culture. One agent that passed the screen was carvedilol, a ¿-adrenergic antagonist FDA-approved for several cardiac indications. In two different transgenic mouse models of AD chronic oral administration of carvedilol decreased brain monomeric and oligomeric A¿ content, attenuated cognitive deterioration, and improved basal neuronal transmission in the brain. The effect on lowering A¿ oligomers is especially relevant, since there is growing evidence that these soluble oligomers (rather than the insoluble A¿ fibrils in plaques) disrupt synaptic transmission early in AD prior to neuronal loss. Thus, a treatment that lowers brain A¿ oligomer levels may be of particular benefit in early AD. Additionally, carvedilol may have a beneficial effect on vascular risk factors for AD by stabilizing blood pressure and improving brain perfusion, since it is an approved treatment for hypertension and congestive heart failure and has been shown to be neuroprotective in brain ischemia models. These preliminary data suggests that carvedilol may have a dual mechanism of action, by decreasing brain A¿ oligomer levels and by having a beneficial effect on cerebrovascular conditions. Since carvedilol is a generic drug, already FDA approved, with a well understood, generally well tolerated safety profile and if carvedilol has a beneficial effect in AD it offers the advantages of being relatively safe and inexpensive. For these reasons, we propose to administer a target dose of 25 mg daily of carvedilol to 50 AD patients in a 6-month randomized, placebo-controlled, double-blind, single-site trial, with change in episodic recall as the primary outcome and biomarker change and safety/tolerability as secondary measures. Significance: The results of this proof-of-concept trial will underlie a "Go-No-Go" decision. If we observe a significant improvement in clinical outcomes, we will propose a definitive trial of carvedilol in AD. If we observe change only in biomarker outcomes, this will inform further studies of similar treatment mechanisms (whether carvedilol or alternative agents). Should carvedilol prove to be effective in AD, it has several advantages over novel agents in human trials since it has a well-characterized, generally well tolerated safety profile and is available as a generic drug. PUBLIC HEALTH RELEVANCE: Alzheimer's disease is a major public health problem for which there is not currently an effective treatment. The investigators have preliminary data from epidemiologic (Dr. Rosenberg) and laboratory (Dr. Pasinetti) studies suggesting that carvedilol, a commonly used beta-blocking medication, might be effective in preventing cognitive and functional decline in Alzheimer's disease. We propose a trial to test carvedilol's effectiveness in 50 Alzheimer's patients, this study offers the possibility of developing a completely new treatment method for Alzheimer's.

描述（由适用提供）：阿尔茨海默氏病（AD）是衰老的最普遍的神经退行性疾病，是AD患者，看护人和医疗保健系统的重大烧伤原因。当前，FDA批准的AD治疗充其量具有适度的症状作用，并且不会显着改变疾病病程。在基于人群的事件AD样本中，我们观察到使用 - 肾上腺素拮抗剂与功能下降较慢有关。我们的数据与其他流行病学数据相结合，表明 - 肾上腺素拮抗剂在AD患者中的潜在治疗作用。这一观察结果促使我们筛选了 - 肾上腺素拮抗剂对细胞培养中淀粉样蛋白（a。）合成的影响。通过屏幕的一种代理是卡维洛尔，A肾上腺素拮抗剂FDA批准了几种心脏适应症。在两种不同的转基因小鼠模型中，Carvedilol的慢性口服给药改善了脑单体和寡聚的含量，认知测定减弱，并改善了脑中的基本神经元传播。由于越来越多的证据表明，这些固体寡聚物（而不是斑块中不溶性的纤维）在神经元丧失之前破坏了合成传递，因此对降低A寡聚物的影响特别相关。这是一种降低大脑A的寡聚体水平的治疗方法在早期的AD中可能特别有益。此外，卡维迪尔通过稳定血压和改善脑灌注对血管危险因素可能具有有益的影响，因为它是一种批准的高血压和充血性心力衰竭的治疗方法，并已被证明是脑缺血模型中的神经保护作用。这些初步数据表明，Carvedilol可以通过降低大脑A寡体水平并对脑血管条件产生有益作用来具有双重作用机理。由于Carvedilol是一种通用药物，已经批准了，并且具有良好的耐受性安全性，而且卡维迪洛尔在广告中具有有益的效果，因此具有相对安全和便宜的优势。由于这些原因，我们建议在6个月的随机，安慰剂对照，双盲，单位点试验中给50例AD患者的靶剂量每天25 mg Carvedilol，并且发作回忆的变化是主要结果和生物标志物变化和安全性/销售性作为次级测量。意义：这项概念验证审判的结果将是“ go-no-go”决定的基础。如果我们观察到临床结局的显着改善，我们将提出对AD中卡维迪尔的明确试验。如果我们仅观察到生物标志物结果的变化，这将为相似的治疗机制（无论是卡维醇还是替代剂）提供进一步的研究。如果Carvedilol证明在AD中有效，它在人体试验中具有多个优势，因为它具有良好的特征性，耐受性良好的安全性，并且可作为仿制药。 公共卫生相关性：阿尔茨海默氏病是目前没有有效治疗的主要公共卫生问题。研究人员拥有来自流行病学（Rosenberg博士）和实验室（Pasinetti博士）研究的初步数据，这表明Carvedilol是一种常用的β受体阻滞剂，可能有效预防阿尔茨海默氏病的认知和功能下降。我们提出了一项试验，以测试卡维迪尔在50名阿尔茨海默氏症患者中的有效性，这项研究提供了为阿尔茨海默氏症开发全新治疗方法的可能性。