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

描述（由申请人提供）：DIADS-3：一项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，目前影响着美国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中几乎是普遍的，并且是患者和护理者痛苦的主要原因。最突出和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。目前没有药理学或非药理学干预被证明是有效的抑郁症的AD（dAD），我们最近发表的结果从假设检验随机对照试验（RCT）舍曲林dAD显示没有药物作用。因此，非常需要开发新的dAD治疗方法。大多数先前的试验已经研究了选择性重摄取抑制剂，但是去甲肾上腺素（NA）以及5-羟色胺（5-HT）在抑郁症和AD的脑机制中的参与是相当大的。因此，降钙素-去甲肾上腺素再摄取抑制剂（SNRI）是治疗dAD的有吸引力的替代方案。迄今为止，在dAD中没有SNRI RCT具有足够的剂量以产生SNRI效应和足够的持续时间以检测情绪结局的持久变化;一项文拉法辛RCT剂量不足（仅产生SSRI效应的剂量），并且时间太短，无法充分评估情绪结局（6周）。因此，我们提出了DIADS-3：文拉法辛治疗dAD的概念验证随机对照试验。64例dAD受试者将随机接受Effexor XR（目标剂量为每日225 mg）与安慰剂，进行12周的双盲随机治疗。该试验将在约翰霍普金斯大学由一个经验丰富的AD试验团队进行，该团队自2004年以来已招募了800多名参与者进行试验。12周时的主要结局为1）改良AD合作研究-临床总体印象变化（mADCS-CGIC）的缓解率; 2）定义为康奈尔痴呆抑郁量表（CSDD）评分d 6 + mADCS-CGIC d2的缓解率; 3）CSDD的CSDD评分。次要结局将包括安全性评估和检查血清文拉辛+代谢物水平与反应的相关性。数据分析将基于意向治疗，对于缺失数据将酌情采用多重插补。DIADS-3有可能对dAD的治疗产生显著影响，如果观察到药物效应，则可能导致文拉法辛治疗dAD的确定性假设检验试验。

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.