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

屈大麻酚辅助治疗阿尔茨海默病 (AD) 躁动的初步试验

• 批准号: 9706077
• 负责人: Brent Peter Forester
• 金额: $ 99.77万
• 依托单位: JOHNS HOPKINS UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2016
• 资助国家: 美国
• 起止时间: 2016-09-01 至 2022-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9706077
• 关键词: Acquired Immunodeficiency Syndrome; Acute; Adult; Adverse event; Affect; Aggressive behavior; Aging; Agitation; Agonist; Alzheimer' s Disease; American; Anorexia; Anti-Anxiety Agents; Anti-Inflammatory Agents; Antidepressive Agents; Antipsychotic Agents; Area; Behavioral; Blinded; Body Weight decreased; CNR1 gene; Cannabis; Caregiver Burden; Caregivers; Caring; Case Series; Citalopram; Clinical; Cognition; Cognitive; Consensus; Controlled Study; Data; Data Analyses; Delirium; Dementia; Desire for food; Dose; Double-Blind Method; Dronabinol; Endocannabinoids; Equipment and supply inventories; FDA approved; Family; Formulation; Frail Elderly; Frontotemporal Dementia; Geriatric Psychiatry; Hospitals; Huntington Disease; Impaired cognition; Impairment; Inpatients; International; Intervention; Intoxication; Laboratory Study; Lead; Lorazepam; Marijuana; Marinol; Measures; Mental Depression; Methods; Motor; Multicenter Trials; Nausea; Netherlands; Neurodegenerative Disorders; Oral; Outcome; Parkinson Disease; Participant; Patients; Persons; Pharmaceutical Preparations; Pharmacology; Pharmacotherapy; Placebos; Plants; Problem behavior; Public Health; Publishing; Randomized Clinical Trials; Reporting; Research; Role; Safety; Severities; Site; Sleep; Sleeplessness; Societies; Source; Sum; Symptoms; Testing; Tetrahydrocannabinol; Toxic effect; Treatment Efficacy; Vomiting; advanced disease; antidepressant effect; chemotherapy; clinical research site; combat; comparative efficacy; confusion assessment method; disability; early phase trial; emotional symptom; improved; innovation; mortality risk; neuropsychiatric disorder; neuropsychiatric symptom; neuropsychiatry; novel; off-label use; older patient; phase 3 testing; phase III trial; pilot trial; primary outcome; psychosocial; public health relevance; receptor; secondary outcome; therapy development; vocalization

 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.

 描述（由申请人提供）： 背景：阿尔茨海默氏病 (AD) 是最常见的衰老神经退行性疾病，估计影响美国 500 万人，预计到 2030 年将增加两倍。其症状不仅涉及认知，还涉及情感，焦虑、抑郁和冷漠等神经精神症状在 AD 中非常普遍，是给患者、家庭和社会带来负担的主要原因。 AD 中的躁动 (Agit-AD) 是造成护理人员负担的一个特别严重的原因，目前的 Agit-AD 治疗方法并不是非常有效，特别是对于严重受损的患者。因此，需要改进 Agit-AD 的治疗。具体目标 1：评估 3 周屈大麻酚与安慰剂辅助治疗对 80 名严重 Agit-AD 住院患者的疗效。假设 1：与安慰剂相比，屈大麻酚治疗与躁动症状的更大程度减轻相关，根据 PAS 和神经精神病学清单-临床医生版本 (NPI-C) 的躁动范围进行测量。具体目标 2：评估屈大麻酚与安慰剂辅助治疗对 80 名严重 Agit-AD 住院患者的安全性。假设 2：屈大麻酚治疗耐受性良好，不良事件 (AE) 不超过轻微。公共卫生意义：非常需要针对躁动性 AD 采取更好的干预措施，躁动性 AD 是护理人员负担和压力的主要来源，尤其是中度至重度躁动。这可能为“重新利用”屈大麻酚作为一种新颖且安全的 Agit-AD 治疗方法打开了大门，对公共健康产生了重大影响。创新点：1）北美首例屈大麻酚用于 Agit-AD 的随机对照试验； 2) 屈大麻酚 10 mg 剂量的首次 RCT。目前的现场试验将剂量限制为每天 4-6 毫克，在早期试验中应尽量避免剂量不足，以免错过潜在的益处； 3) 屈大麻酚治疗 Agit-AD 的首次多中心随机对照试验。方法：我们建议对 80 名患有严重躁动性 AD 的住院患者进行为期三周的安慰剂对照、双盲、随机临床试验，将每天 10 毫克的屈大麻酚作为目前使用的精神药物的辅助药物。该试验将在两个临床研究中心（约翰霍普金斯大学和麦克莱恩医院）进行，并使用匹兹堡激越量表作为主要结果，并以额外的激越量表（科恩-曼斯菲尔德激越量表和神经精神病学量表 - 临床版本）、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果。数据分析将按意向治疗进行。参与者、临床工作人员和评估者将对治疗分配不知情。预期结果：如果我们观察到屈大麻酚的益处，这可能会导致明确的假设检验第 3 阶段试验，对公众健康产生潜在影响。如果我们观察到在相对较高的屈大麻酚剂量下没有益处，这可能不会导致这种干预措施的进一步发展。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，包括帕金森病、亨廷顿病和额颞叶痴呆。