Prazosin Treatment for Disruptive Agitation in Alzheimer's Disease

描述（由申请人提供）：在大多数阿尔茨海默病（AD）患者的疾病过程中，破坏性躁动是一种令人痛苦且经常持续的行为。它大大增加了家庭和长期护理环境中护理人员的负担，是养老院安置的主要诱因，给病人带来痛苦和压力，并增加了护理环境中的负担。破坏性躁动可能是阿尔茨海默病及相关痴呆患者广泛使用精神药物的最重要原因。在精神类药物中，只有抗精神病药物在治疗这些令人痛苦的症状方面一直被证明优于安慰剂。然而，在非典型抗精神病药物的多个大型临床试验中，效应大小适中，无反应频繁，不良反应常见，死亡和脑血管不良事件风险增加，促使FDA对其在痴呆症患者中的使用发出“黑盒警告”。很明显，寻找新的药理学方法来减少阿尔茨海默病的破坏性躁动是一个重要的临床目标。本申请提出了一项安慰剂对照先导试验，一般可用的脑活性α -1肾上腺素受体（AR）拮抗剂，吡唑嗪，用于阿尔茨海默病的破坏性躁动。AD患者和AD脑组织的临床研究表明，中枢神经系统(CNS) α -1 ARs对去甲肾上腺素（NE）的反应性增强有助于AD患者的破坏性躁动。一项开放标签试验和一项小型安慰剂对照可行性试验的初步数据显示，prazosin在AD患者重度破坏性躁动中具有潜在的疗效和良好的耐受性。在为期12周的双盲试验中，我们将128例持续性破坏性躁动的AD患者随机分配到哌唑嗪组（最大剂量4mg b.i.d）或安慰剂组。维持药物在试验期间将保持不变。主要结果测量是阿尔茨海默病合作研究（ADCS）临床总体印象变化和神经精神量表总分。次要观察指标为简短精神病学评定量表（BPRS）总分、BPRS躁动因子、日常生活活动量表(adcs) -19、迷你精神状态测验。以下假设将被检验：1a)随机分配到吡嗪组的AD患者的破坏性激动行为比随机分配到安慰剂组的患者有更大的减少；1b)哌唑嗪组的“救死性”劳拉西泮总剂量低于安慰剂组；1c)与安慰剂组相比，哌唑嗪组因持续躁动而中断研究的时间更长；由于不良反应而停止研究的时间（“辍学”）在哌唑嗪组和安慰剂组之间没有差异。在12周的安慰剂对照期结束后，所有受试者将接受另外12周的开放标签prazosin，以收集有关prazosin对破坏性躁动的预测治疗效果的弹性的观察数据。如果这项初步研究的结果是积极的，我们将通过阿尔茨海默病合作研究机制进行大规模的多地点研究。公共卫生相关性：阿尔茨海默病（AD）的破坏性躁动发生在大多数患者的病程中。这种综合征是患者和护理人员痛苦和养老院安置的主要来源，目前的治疗方法往往是不足的。本申请提出了一项安慰剂对照试验的仿制药普拉唑嗪的破坏性躁动在AD。Prazosin阻断AD患者过度的脑肾上腺素唤醒，导致躁动，我们的Prazosin可行性研究的治疗和耐受性结果都是非常有希望的。

DESCRIPTION (provided by applicant): Disruptive agitation emerges as a distressing and often persistent group of behaviors during the disease course of the majority of persons with Alzheimer's disease (AD). It greatly increases caregiver burden in both the home and long-term care settings, is a leading precipitant of nursing home placement, and causes suffering in patients and stress and increased burden in the caregiving environment. Disruptive agitation is likely the most important reason for the widespread prescription of psychotropic medications in AD and related dementias. Among the psychotropics, only the antipsychotics have been consistently demonstrated superior to placebo for these distressing symptoms. However, effect sizes are modest, nonresponders frequent, adverse effects common, and an increased risk for death and cerebrovascular adverse events in multiple large clinical trials of atypical antipsychotics prompted a "black box warning" from the FDA re: their use in persons with dementia. It is clear that finding new pharmacologic approaches to reducing disruptive agitation in AD is an important clinical goal. This application proposes a placebo-controlled pilot trial of the generically available brain active alpha-1 adrenoreceptor (AR) antagonist, prazosin, for disruptive agitation in AD. Clinical studies in AD patients and AD brain tissue suggest that enhanced responsiveness to norepinephrine (NE) at central nervous system (CNS) alpha-1 ARs contributes to disruptive agitation in AD. Strongly positive preliminary data from an open label trial and a small placebo-controlled feasibility trial of prazosin in AD patients with severe disruptive agitation support potential efficacy and good tolerability in this frail elderly population. We will randomize 128 AD patients with persistent disruptive agitation to prazosin (maximum dose 4 mg b.i.d.) or placebo in a 12-week double-blind trial. Maintenance medications will be kept constant during the trial. Primary outcome measures are the Alzheimer's Disease Cooperative Study (ADCS) Clinical Global Impression of Change and the Neuropsychiatric Inventory total score. Secondary outcome measures are the Brief Psychiatric Rating Scale (BPRS) total score, BPRS Agitation Factor, ADCS-Activities of Daily Living-19, and the Mini Mental State Exam. The following hypotheses will be tested: 1a) AD patients randomized to prazosin will have a greater reduction in disruptive agitated behaviors than those randomized to placebo; 1b) total dose of "rescue" lorazepam will be lower in prazosin than placebo subjects; 1c) time to study discontinuation ("dropout") due to continued agitation will be greater in prazosin than placebo groups; and 1d) time to study discontinuation ("dropout") due to adverse effects will not differ between prazosin and placebo groups. At the completion of the 12-week placebo-controlled phase, all subjects will receive an additional 12 weeks of open label prazosin to gather observational data on the resiliency of the predicted therapeutic effect of prazosin for disruptive agitation. If results of this pilot study are positive, we will pursue a large definitive multisite study through the Alzheimer's Disease Cooperative Study mechanism. PUBLIC HEALTH RELEVANCE: Disruptive agitation in Alzheimer's disease (AD) occurs in the majority of patients over the course of their illness. This syndrome is a major source of patient and caregiver distress and nursing home placement, and current treatment approaches often are inadequate. This application proposes a placebo-controlled trial of the generic drug prazosin for disruptive agitation in AD. Prazosin blocks the excessive brain adrenaline arousal that contributes to agitation in AD and both therapeutic and tolerability results of our prazosin feasibility study are very promising.