DIADS-3: An RCT of venlafaxine for depression in AD

DIADS-3：文拉法辛治疗 AD 抑郁症的随机对照试验

• 批准号: 8337846
• 负责人: PAUL B ROSENBERG
• 金额: $ 55.21万
• 依托单位: JOHNS HOPKINS UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2011
• 资助国家: 美国
• 起止时间: 2011-09-30 至 2014-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8337846
• 关键词: Adverse event; Affect; Alzheimer' s Disease; Antidepressive Agents; Brain; Caregivers; Caring; Clinical; Cognitive; Data; Data Analyses; Dementia; Depressed mood; Development; Disease remission; Distress; Dose; Double-Blind Method; Effexor; Elderly; Emotional; Failure; Family Caregiver; Funding; Health; Intervention; Knowledge; Lead; Light; Measures; Mental Depression; Methods; Mirtazapine; Mood Disorders; Moods; Neurodegenerative Disorders; Norepinephrine; Outcome; Participant; Patients; Performance; Persons; Pharmaceutical Preparations; Phase; Placebo Control; Placebos; Publishing; Quality of life; Randomized; Randomized Controlled Trials; Recruitment Activity; Reporting; Research Infrastructure; Research Personnel; Safety; Sampling; Selective Serotonin Reuptake Inhibitor; Serious Adverse Event; Serotonin; Sertraline; Serum; Site; Societies; Symptoms; Testing; United Kingdom; United States National Institutes of Health; Universities; alternative treatment; base; cooperative study; disability; double-blind placebo controlled trial; effective therapy; experience; impression; improved; inhibitor/antagonist; neuropsychiatry; noradrenergic; primary outcome; psychosocial; response; reuptake; secondary outcome; single episode major depressive disorder; venlafaxine

DESCRIPTION (provided by applicant): DIADS-3: A randomized double-blind, placebo-controlled trial of venlafaxine for depression in Alzheimer's Disease Alzheimer's disease (AD) is a growing health problem currently affecting 5.3 million persons in the U.S., a number that is estimated to triple by 2050. Neuropsychiatric symptoms are near-universal in AD and are a major contributor to patient and caregiver distress. One of the most prominent and distressing neuropsychiatric symptoms is depression, affecting up to 50% of patients with AD. There is currently no pharmacologic or non-pharmacologic intervention proven to be effective in depression of AD (dAD), and we have recently published results from a hypothesis-testing randomized controlled trial (RCT) of sertraline for dAD which showed no drug effect. Thus, there is a great need for development of new treatments for dAD. Most of the prior trials have studied serotonin-selective reuptake inhibitors, but there is considerable for the involvement of noradrenaline (NA) as well as serotonin (5-HT) in brain mechanisms underlying depression and AD. Thus, serotonin-noradrenaline reuptake inhibitors (SNRIs) are attractive alternatives for treatment of dAD. To date there are no SNRI RCTs in dAD with adequate dosing for SNRI effect and adequate duration to detect lasting changes in mood outcomes; the one RCT of venlafaxine is underdosed (at a dose with only SSRI effect) and too brief to adequately assess mood outcomes (6 weeks). Thus, we propose DIADS-3: a proof-of-concept RCT of venlafaxine for dAD. 64 participants with dAD will be randomized to Effexor XR (target dose of 225 mg daily) vs. placebo for 12 weeks' double-blind randomized treatment. The trial will be conducted at Johns Hopkins University by a highly experienced AD trials team that has recruited >800 participants for trials since 2004. Primary outcomes at 12 weeks are 1) rates of response on the modified AD Cooperative Study-Clinical Global Impression of Change (mADCS-CGIC); 2) rates of remission defined as a Cornell Scale for Depression in Dementia (CSDD) score d6 PLUS a mADCS-CGIC d2; 3) CSDD scores on CSDD. Secondary outcomes will include safety assessments and examination of the association of serum venlaxine + metabolite levels with response. Data analyses will be on an intent-to-treat basis, and multiple imputation will be utilized as appropriate for missing data. DIADS-3 has the potential to significantly impact on treatment of dAD and, if drug effect is observed, to lead to a definitive hypothesis- testing trial of venlafaxine for dAD.

描述（由申请人提供）：DIADS-3：文拉法辛治疗阿尔茨海默病抑郁症的随机双盲、安慰剂对照试验阿尔茨海默病 (AD) 是一个日益严重的健康问题，目前影响美国 530 万人，预计到 2050 年这一数字将增加两倍。神经精神症状在 AD 中几乎普遍存在，是导致患者和护理人员痛苦的主要原因。最突出、最令人痛苦的神经精神症状之一是抑郁症，影响高达 50% 的 AD 患者。目前尚无药物或非药物干预措施被证明对 AD 抑郁症 (dAD) 有效，我们最近发表了舍曲林治疗 dAD 的假设检验随机对照试验 (RCT) 的结果，结果显示没有药物作用。因此，非常需要开发新的 dAD 治疗方法。大多数先前的试验都研究了血清素选择性再摄取抑制剂，但去甲肾上腺素 (NA) 和血清素 (5-HT) 在抑郁症和 AD 的大脑机制中的作用相当大。因此，5-羟色胺-去甲肾上腺素再摄取抑制剂（SNRI）是治疗 dAD 的有吸引力的替代品。迄今为止，尚无针对 dAD 的 SNRI 随机对照试验，其剂量足以发挥 SNRI 效应，并且持续时间足以检测情绪结果的持久变化；文拉法辛的一项 RCT 剂量不足（仅具有 SSRI 作用的剂量）且时间太短，无法充分评估情绪结果（6 周）。因此，我们提出 DIADS-3：文拉法辛治疗 dAD 的概念验证 RCT。 64 名患有 dAD 的参与者将被随机分配至 Effexor XR（目标剂量为每天 225 毫克）与安慰剂组，进行为期 12 周的双盲随机治疗。该试验将在约翰·霍普金斯大学由经验丰富的 AD 试验团队进行，自 2004 年以来，该团队已招募了超过 800 名参与者进行试验。12 周时的主要结果是 1) 改良 AD 合作研究 - 临床总体变化印象 (mADCS-CGIC) 的反应率； 2) 缓解率定义为康奈尔痴呆症抑郁量表 (CSDD) 评分 d6 加上 mADCS-CGIC d2； 3）CSDD在CSDD上的分数。次要结果将包括安全性评估以及血清文拉辛+代谢物水平与反应之间关系的检查。数据分析将建立在意向治疗的基础上，并且将酌情利用多重插补来处理缺失的数据。 DIADS-3 有可能对 dAD 的治疗产生显着影响，如果观察到药物效应，将导致文拉法辛治疗 dAD 的明确假设检验试验。