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

描述(申请人提供)：DIADS-3：文拉法辛治疗阿尔茨海默病(AD)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，目前影响着美国的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中几乎是普遍存在的，是患者和照顾者痛苦的主要原因。最突出和最令人痛苦的神经精神症状之一是抑郁症，影响多达50%的AD患者。目前还没有药物或非药物干预被证明对AD抑郁(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，显示没有药物作用。因此，迫切需要为DAD开发新的治疗方法。以前的大多数试验都研究了5-羟色胺选择性再摄取抑制剂，但有相当多的研究涉及去甲肾上腺素(NA)以及5-羟色胺(5-HT)在抑郁症和AD的大脑机制中的作用。因此，5-羟色胺-去甲肾上腺素再摄取抑制剂(SNRI)是治疗DAD的有吸引力的替代药物。到目前为止，DAD中还没有SNRI随机对照试验，具有足够的SNRI效应剂量和足够的持续时间来检测情绪结果的持久变化；文拉法辛的一项随机对照试验剂量不足(仅有SSRI效应)，且时间太短，无法充分评估情绪结果(6周)。因此，我们提出了DIADS-3：一种用于DAD的文拉法辛的概念验证RCT。患有DAD的患者将被随机分为Effexor XR(目标剂量为每天225毫克)和安慰剂，进行为期12周的双盲随机治疗。这项试验将在约翰·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年以来已经招募了800名参与者进行试验。12周后的主要结果是1)修改后的AD合作研究-临床总体变化印象(mADCS-CGIC)的应答率；2)康奈尔痴呆量表(CSDD)评分d6加上mADCS-CGIC D2的缓解率；3)CSDD评分。次要结果将包括安全性评估和检查血清文拉帕辛+代谢物水平与反应的关系。数据分析将在意向处理的基础上进行，并将适当地对丢失的数据进行多重归罪。DIADS-3有可能对DAD的治疗产生重大影响，如果观察到药物效果，将导致文拉法辛对DAD进行决定性的假设检验试验。

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.