Pilot Trial of Carvedilol in Alzheimer's Disease

描述(申请人提供)：阿尔茨海默病(AD)是最常见的神经退行性疾病，是AD患者、照顾者和医疗保健系统的主要负担。目前FDA批准的AD治疗充其量只有适度的症状效应，并不能显著改变病程。在发生AD的人群样本中，我们观察到肾上腺素能拮抗剂的使用与较慢的功能衰退有关。我们的数据结合其他流行病学数据表明，肾上腺素能拮抗剂在AD患者中具有潜在的治疗效果。这一观察结果促使我们筛选肾上腺素能拮抗剂，以观察其对细胞培养中淀粉样蛋白(A)合成的影响。通过筛选的药物之一是卡维地洛，一种FDA批准用于几种心脏适应症的肾上腺素能拮抗剂。在两种不同的阿尔茨海默病转基因小鼠模型中，长期口服卡维地洛可降低脑内单体和寡聚体A‘的含量，减轻认知退化，并改善大脑中的基础神经元传递。降低A？寡聚体的效果尤其重要，因为越来越多的证据表明，这些可溶低聚物(而不是斑块中不可溶的A？纤维)在AD早期神经元丢失之前扰乱了突触传递。因此，降低脑A低聚体水平的治疗在早期AD中可能特别有益。此外，卡维地洛通过稳定血压和改善脑血流灌注，可能对AD的血管危险因素有有益的影响，因为它是被批准的治疗高血压和充血性心力衰竭的药物，并已被证明在脑缺血模型中具有神经保护作用。这些初步数据表明，卡维地洛可能具有双重作用机制，通过降低脑组织低聚体水平和对脑血管疾病产生有益影响。由于卡维地洛是一种仿制药，已经得到FDA的批准，具有众所周知的、普遍耐受性良好的安全性概况，如果卡维地洛对AD有好处，它提供了相对安全和廉价的优势。出于这些原因，我们建议对50名AD患者进行为期6个月的随机、安慰剂对照、双盲、单部位试验，目标剂量为每天25 mg卡维地洛，主要结果是发作回忆的变化，生物标记物的变化和安全性/耐受性是次要指标。意义：这项概念验证试验的结果将成为“进行-不进行”决定的基础。如果我们观察到临床结果有显著改善，我们将建议对卡维地洛进行明确的AD试验。如果我们只观察到生物标记物结果的变化，这将有助于进一步研究类似的治疗机制(无论是卡维地洛还是替代药物)。如果卡维地洛被证明对阿尔茨海默病有效，它在人体试验中比新型药物有几个优势，因为它具有良好的特性，通常耐受性好，并且可以作为仿制药使用。 与公共卫生相关：阿尔茨海默病是一个主要的公共卫生问题，目前还没有有效的治疗方法。调查人员有来自流行病学(罗森伯格博士)和实验室(帕西内蒂博士)研究的初步数据，表明卡维地洛，一种常用的β阻断药物，可能在预防阿尔茨海默病的认知和功能衰退方面有效。我们提出了一项试验，以测试卡维地洛在50名阿尔茨海默病患者中的有效性，这项研究为开发一种全新的阿尔茨海默病治疗方法提供了可能性。

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.