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)患者的病程中，破坏性激动是一种令人痛苦的、通常是持续的行为群体。它极大地增加了家庭和长期护理环境中的照顾者负担，是养老院安置的主要诱因，并在护理环境中造成患者痛苦和压力和增加负担。颠覆性激动可能是AD和相关痴呆患者普遍使用精神药物的最重要原因。在精神药物中，只有抗精神病药物一直被证明对这些令人痛苦的症状优于安慰剂。然而，在非典型抗精神病药物的多个大型临床试验中，效应规模适中，无应答者频繁，不良反应常见，死亡和脑血管不良事件的风险增加促使FDA Re发出“黑箱警告”：它们用于痴呆症患者。很明显，寻找新的药物治疗方法来减少阿尔茨海默病的破坏性激动是一个重要的临床目标。这项申请提出了一项安慰剂对照的先导试验，该试验是一种普遍存在的脑活性α-1肾上腺素受体(AR)拮抗剂，用于治疗阿尔茨海默病的破坏性兴奋。对AD患者和AD脑组织的临床研究表明，中枢神经系统(CNS)α-1受体对去甲肾上腺素(NE)的反应增强有助于AD的破坏性兴奋。来自一项开放标签试验和一项小型安慰剂对照可行性试验的强阳性初步数据支持了在这一虚弱的老年人群中使用哌唑嗪治疗严重扰乱情绪的AD患者的潜在疗效和良好的耐受性。我们将对128名持续服用哌唑嗪(最大剂量为4 mg，每天2次)的AD患者进行随机分组。或在为期12周的双盲试验中服用安慰剂。在试验期间，维持性药物将保持不变。主要的结果衡量标准是阿尔茨海默病合作研究(ADCS)临床全球变化印象和神经精神病学问卷总分。次要结果测量是简明精神病评定量表(BPRS)总分、BPRS激越因子、ADCS-日常生活能力-19和迷你精神状态检查。将检验以下假设：1)随机服用哌唑嗪的AD患者将比随机服用安慰剂的患者在破坏性激动行为方面有更大的减少；1b)服用哌唑嗪的“救援”劳拉西潘的总剂量将低于服用安慰剂的受试者；1c)由于持续激动而停止研究的时间将比服用安慰剂的组更长；以及1D)由于不良反应而停止研究的时间(“退出”)在哌唑嗪组和安慰剂组之间将没有区别。在为期12周的安慰剂对照阶段结束时，所有受试者将再接受12周的开放标签哌唑嗪治疗，以收集关于哌唑嗪对颠覆性煽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一项大型、确凿的多点研究。与公共卫生相关：阿尔茨海默病(AD)中的破坏性激动发生在大多数患者的整个病程中。这种综合征是患者和照顾者痛苦和养老院安置的主要来源，目前的治疗方法往往是不够的。本申请建议对非专利药物哌唑嗪进行安慰剂对照试验，以治疗AD中的破坏性激越。哌唑嗪可阻止导致AD激越的过度脑肾上腺素兴奋，我们的哌唑嗪可行性研究的治疗和耐受性结果都非常有希望。

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.