Efficacy and Safety of Stellate Ganglion Block for Post-traumatic Stress Disorder in Veterans

项目概要/摘要（40行） 星状神经节阻滞（SGB）是一种快速作用的干预措施，可能直接针对PTSD生物学。积极 我们团队的病例研究和初步结果表明，对于6- 10岁的儿童， 个月然而，两项随机对照试验得出了相互矛盾的结果， 局限性，使结果的解释不确定。两项试验均未评估超过8周的耐久性， 安全性或生物学机制沿着临床结果。退伍军人对SGB治疗创伤后应激障碍的需求很高， 为更明确的VA研究创造了时间敏感的紧迫性。我们提出了一个为期4年，多地点，两阶段， 三组，（SGB-实验条件，假手术-安慰剂对照，等待列表对照（WLC）-时间，预期 和安全性）的平行组，三盲，前瞻性随机对照试验（RCT）的SGB创伤后应激障碍。的 样本将包括360名寻求治疗的慢性创伤后应激障碍退伍军人，按1：1：1的比例随机分为三组， 使用自适应随机化程序的治疗组。I期是一项为期12周的RCT，主要目的是 a）组内和组间PTSD症状严重程度从术前到术后8天的变化差异， 干预后12周，B）SGB后12周内症状减轻的持久性，和c）安全性（即，SGB 将与Sham和WLC一样安全）。II期是一个为期12周的开放标签扩展期，其中所有受试者 如果符合条件，则向组提供活动SGB（PTSD分数>在初级阶段I的纳入标准分数 8周结束）。第二阶段是重要的，因为它允许评估“增强剂量”（第二SGB， SGB组的受试者），它允许所有受试者在需要时接受积极干预，这也提供了一个 用于探索性汇总分析的SGBs样本更大，并且允许在更长时间内分析耐久性 I期后缓解期的患者。另一个次要目的是检验SGB将 比Sham或WLC更具生物活性，表现出更大的干预前至干预后高度 PTSD相关恐惧增强惊吓。我们还将探讨SGB的临床和生物学预测因素 响应（即，CAPS-5评分显著降低）。本优效性研究旨在预期并检测 从基线到8周终点，PTSD症状减少30%，具有统计学和临床意义， 在中重度创伤后应激障碍（基线）样本中，假手术组SGB降低15%，WLC降低5% 65+18）。在这些假设下，我们需要262名受试者的样本量来测试主要的 临床疗效假设。我们将对360名受试者进行抽样调查，以弥补15%的流失、缺失数据、5%的 故障块率和站点可变性。确保这项时间敏感的研究具有足够的功率至关重要。 将使用多变量方差分析（MANOVA）检验以下无差异的零假设： 基线PTSD症状和随后的PTSD症状的重新测试，同时调整任何 显著协变量。将对失访导致的缺失数据进行分析，以便 一旦缺失数据被撤回，确定是否存在任何潜在偏倚。将进行其他分析 确定相互作用和调节/介导效应，同时调整其他协变量 在模型中。我们的三个主要目标的分析细节在研究的数据分析部分 计划我们的领导团队拥有丰富的临床和研究经验，包括临床试验、使用和 为创伤后应激障碍调整SGB，并在全国范围内主动向创伤后应激障碍患者提供SGB， 护理基础。拟议的确定性研究将指导合理使用SGB治疗VA中的PTSD， 研究剂量，时间，生物机制和临床预测结果，并将有 已建立的VA站点准备进一步SGB研究和临床实践。

Project Summary / Abstract (40 lines) Stellate Ganglion Block (SGB) is a rapid-acting intervention that may directly target PTSD biology. Positive case-studies and preliminary results from our team suggest clinically robust and significant benefits for up to 6- months. Two randomized controlled trials, however, yielded conflicting results and had methodological limitations, making interpretation of results inconclusive. Neither trial evaluated durability beyond 8-weeks, safety, or biological mechanisms along with clinical outcomes. Veteran demand for SGB for PTSD is high, creating time-sensitive urgency for a more definitive study in VA. We propose a 4-year, multi-site, two-phase, three-arm, (SGB-experimental condition, Sham-placebo control, Wait-List Control (WLC)-for time, expectancy and safety) parallel-group, triple-blind, prospective randomized controlled trial (RCT) of SGB for PTSD. The sample will include 360 treatment-seeking Veterans with chronic PTSD randomized 1:1:1 to the three treatment arms using an adaptive randomization procedure. Phase I is a 12-week RCT with the primary aims of evaluating: a) within and between group differences in the change in PTSD symptom severity from pre- to 8- weeks post-intervention, b) durability of symptom reduction after SGB over 12 weeks, and c) safety (i.e., SGB will be as safe as Sham and WLC). Phase II is a 12-week open-label extension period where subjects in all groups are offered active SGB if eligible (PTSD scores > inclusion criteria scores at the primary Phase I endpoint of 8-weeks). Phase II is important because it allows evaluation of “enhanced dosing” (second SGB for those in the SGB arm), it allows all subjects to receive active intervention if they want, which also provides a larger sample of SGBs for exploratory pooled analyses, and it allows for analyses of durability over a longer time period for those in remission after Phase I. Another secondary aim is to test the hypothesis that SGB will be more biologically active than Sham or WLC by showing greater pre- to post-intervention reduction in highly PTSD-relevant fear-potentiated startle. We will also explore clinical and biological predictors of an SGB response (i.e., significant reduction in CAPS-5 scores). This superiority study is designed to expect and detect statistically and clinically important 30% PTSD symptom reduction from baseline to 8-week endpoint for SGB,15% reduction for Sham and 5% reduction for WLC in a sample with moderately severe PTSD (baseline score of 65+18). With these assumptions we require a sample size of 262 subjects to test the primary hypothesis of clinical efficacy. We will sample 360 subjects to account for 15% attrition, missing data, a 5% failed-block rate and site variability. It is critical to ensure adequate power for this time-sensitive study. Multivariate analysis of variance (MANOVA) will be used to test the null hypothesis of no differences in baseline PTSD symptoms and subsequent retest of PTSD symptoms while simultaneously adjusting for any significant covariates. Analyses will be performed on missing data due to loss-to-follow-up in order to determine if any potential bias exists once missing data are withdrawn. Additional analyses will be conducted to determine interactions and moderating/mediating effects while simultaneously adjusting for other covariates in the model. Details for analyses of our three primary aims are in the data analysis section of the Research Plan. Our leadership team has extensive clinical and research experience with clinical trials, the use and adaptation of SGB for PTSD, and a national initiative to provide SGB to PTSD patients on a compassionate care basis. The proposed definitive study will guide rational use of SGB for PTSD in VA, will stimulate further research about dose, timing, biological mechanisms and clinical predictors of outcome, and will have established VA sites poised for further SGB research and clinical practice.