Pilot trial of dronabinol adjunctive treatment of agitation in Alzheimer's disease (AD)

 描述（由申请人提供）：背景：阿尔茨海默病（AD）是最常见的神经退行性疾病，影响美国估计500万人，预计到2030年将增加两倍。这些症状不仅是认知的，而且是情感的，并且神经精神症状如激动、抑郁和冷漠在AD中非常普遍，并且是患者、家庭和社会负担的主要原因。AD患者的激越（Agit-AD）是造成护理人员负担的一个特别严重的原因，目前针对Agit-AD的治疗方法并不十分有效，尤其是对于严重受损的患者。因此，需要改善对Agit-AD的治疗。具体目的1：评价屈大麻酚与安慰剂连续治疗3周对80例重度Agit-AD住院患者的疗效。假设1：与安慰剂相比，屈大麻酚治疗将与通过PAS和神经精神量表-临床医生版（NPI-C）的激越域测量的激越症状的更大减少相关。具体目的2：在80例重度Agit-AD住院患者中评价屈大麻酚与安慰剂连续治疗的安全性特征。假设2：屈大麻酚治疗耐受性良好，不良事件（AE）不超过轻度。公共卫生意义：非常需要针对Agit-AD的更好的干预措施，这是护理人员负担和压力的主要来源，特别是对于中度至重度激越。这可能为“重新利用”屈大麻酚作为一种新的安全治疗药物打开大门，对公共卫生产生重大影响。创新：1）首个用于治疗焦虑-AD的屈大麻酚北美RCT; 2）首个10 mg剂量屈大麻酚RCT。目前在该领域的试验将剂量限制在每天4-6 mg，并且在早期阶段试验中应努力避免剂量不足，以避免错过潜在的益处; 3）首个多中心RCT的屈大麻酚治疗Agit-AD。方法：我们提出了一个为期三周的安慰剂对照，双盲，随机临床试验的屈大麻酚10毫克，每天作为一个辅助目前使用的精神药物在80例严重的焦虑-AD住院患者。本试验将在两家临床研究中心（约翰霍普金斯医院和姆克林医院）进行，并使用匹兹堡激越量表作为主要结局，其他激越量表（Cohen-Mansfield激越量表和神经精神病学量表-临床版）、认知测量（简易精神状态检查）以及睡眠和药物中毒测量作为次要结局。数据分析将按意向治疗进行。受试者、临床工作人员和评估者对治疗分配不知情。预期结果：如果我们观察到屈大麻酚的益处，这可能导致对公众健康具有潜在影响的确定性假设检验的3期试验。如果我们在这种相对高剂量的屈大麻酚下没有观察到益处，这可能不会导致这种干预的进一步发展。对其他研究领域的影响：激越在其他神经精神疾病中很常见，屈大麻酚可能对这些疾病也有帮助，包括帕金森氏症，亨廷顿氏症和额颞叶痴呆症。

 DESCRIPTION (provided by applicant): Background: Alzheimer's disease (AD) is the commonest neurodegenerative disease of aging affecting an estimated 5 million persons in the U.S. and anticipated to triple by 2030. The symptoms are not only cognitive but emotional, and neuropsychiatric symptoms such as agitation, depression, and apathy are highly prevalent in AD and a major cause of burden to patients, families, and society. Agitation in AD (Agit-AD) is a particularly acute cause of caregiver burden, and current treatments for Agit-AD are not highly effective particularly for severely impaired patients. Thus, there is a need for improved treatments for Agit-AD. Specific aim 1: To evaluate the efficacy of 3 weeks dronabinol vs. placebo adjunctive treatment in 80 inpatients with severe Agit-AD. Hypothesis 1: Compared to placebo, dronabinol treatment will be associated with a greater reduction in symptoms of agitation as measured by the PAS and the agitation domain of the Neuropsychiatric Inventory-Clinician Version (NPI-C). Specific Aim 2: To evaluate the safety profile of dronabinol vs. placebo adjunctive treatment in 80 inpatients with severe Agit-AD. Hypothesis 2: Dronabinol treatment will be well tolerated with no more than mild adverse events (AEs). Public Health Significance: There is a great need for better interventions that target Agit-AD, which is a major source of caregiver burden and stress, particularly for moderate to severe agitation. This could open the door to "repurposing" dronabinol as a novel and safe treatment for Agit-AD with significant public health impact. Innovation: 1) first North American RCT of dronabinol for Agit-AD; 2) first RCT of dronabinol at 10 mg dose. Current trials in the field limit the dose to 4-6 mg daily and underdosing should be assiduously avoided in an early phase trial to avoid missing potential benefit; 3) first multi-site RCT of dronabinol for Agit-AD. Method: We propose a three -week placebo-controlled, double-blind, randomized clinical trial of 10 mg daily dronabinol as an adjunct to currently used psychotropic medications in 80 inpatients with severe Agit-AD. The trial will be undertaken at two clinical research sites (Johns Hopkins and McLean Hospitals) and use the Pittsburgh Agitation Scale as primary outcome, with additional agitation scales (Cohen-Mansfield Agitation Inventory and Neuropsychiatry Inventory - Clinican Version), cognitive measures (MiniMental State Exam), and sleep and drug intoxication measures as secondary outcomes. Data analyses will be by intent-to-treat. Participants, clinical staff, and raters will b blinded to treatment assignment. Expected Results: if we observe benefit from dronabinol this could lead to a definitive hypothesis-testing phase 3 trial with potential impacts on public health If we observe no benefit at this relatively high dronabinol dose this will likely not lead to furthr development of this intervention. Impact on other research areas: agitation is common in other neuropsychiatric diseases and dronabinol might be helpful in those as well, including Parkinsons', Huntingtons', and frontotemporal dementia.