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

 描述(申请人提供)：背景：阿尔茨海默病(AD)是最常见的老年神经退行性疾病，在美国估计有500万人受到影响，预计到2030年将增加两倍。这些症状不仅是认知的，而且是情绪的，神经精神症状，如激越、抑郁和冷漠在AD中非常普遍，是给患者、家庭和社会带来负担的主要原因。激动型阿尔茨海默病(AGIT-AD)是造成照顾者负担的一个特别严重的原因，目前对AGIT-AD的治疗并不是非常有效，特别是对严重受损的患者。因此，有必要改进对agit-AD的治疗。具体目的1：评价屈诺比诺与安慰剂3周辅助治疗重症老年性阿尔茨海默病的疗效。假设1：与安慰剂相比，屈诺比诺治疗将与PAS和神经精神病学临床版(NPI-C)的激动域测量的激越症状的更大程度的减少相关。具体目的2：评价屈诺比诺与安慰剂辅助治疗在80例重症老年性AD住院患者中的安全性。假设2：屈诺比诺治疗耐受性良好，不良反应不超过轻微。公共卫生意义：非常需要针对agit-AD的更好的干预措施，agit-AD是照顾者负担和压力的主要来源，特别是对于中度到严重的激动。这可能会为将屈诺比诺作为一种新的、安全的治疗agit-AD的方法打开大门，并对公共卫生产生重大影响。创新：1)首次在北美进行用于AGIT-AD的随机对照试验；2)首次进行随机对照试验，剂量为10毫克。目前的现场试验将剂量限制在每天4-6毫克，在早期试验中应努力避免剂量不足，以避免错过潜在的益处；3)首次进行多部位随机对照试验治疗AGIT-AD。方法：我们提出了一项为期三周的安慰剂对照、双盲、随机临床试验，在80例重症老年性AD住院患者中，每日服用10毫克屈诺比诺作为目前使用的精神药物的辅助治疗。这项试验将在两个临床研究地点(约翰·霍普金斯医院和麦克莱恩医院)进行，并使用匹兹堡激越量表作为主要结果，附加的激越量表(科恩-曼斯菲尔德激越量表和神经精神病学量表-诊所版)、认知测量(最低限度州立考试)以及睡眠和药物中毒测量作为次要结果。数据分析将采用意向处理。参与者、临床工作人员和评分员将对治疗分配视而不见。预期结果：如果我们观察到屈诺比诺的益处，这可能导致最终的假设检验阶段3试验，对公众健康有潜在影响如果我们观察到相对较高的屈诺比诺剂量没有益处，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：激动症在其他神经精神疾病中很常见，屈奴比诺可能对那些疾病也有帮助，包括帕金森氏症、亨廷顿氏症和额颞痴呆。

 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.