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

项目摘要/摘要(40行) 星状神经节阻滞(SGB)是一种可能直接针对创伤后应激障碍生物学的快速干预措施。正性 我们团队的案例研究和初步结果表明，在临床上有强大和显著的益处，可达6- 月份。然而，两个随机对照试验产生了相互矛盾的结果，并且具有方法学。 限制，使得对结果的解释不是决定性的。两项试验都没有评估超过8周的耐用性， 安全性，或生物学机制以及临床结果。退伍军人对创伤后应激障碍的SGB需求很高， 为在退伍军人管理局进行更明确的研究创造时间敏感型紧迫感。我们建议四年，多地点，分两个阶段， 三臂，(SGB-实验条件，假-安慰剂对照，等待名单对照(WLC)-时间，预期 安全性)SGB治疗PTSD的平行组、三盲、前瞻性随机对照试验(RCT)。这个 样本将包括360名患有慢性创伤后应激障碍的寻求治疗的退伍军人，随机分为1：1：1到3 使用自适应随机化程序治疗手臂。第一阶段是为期12周的随机对照试验，主要目标是 评估：a)组内和组间的创伤后应激障碍症状严重程度从治疗前改变为8- 干预后几周，b)SGB后症状减轻的持久性超过12周，以及c)安全性(即SGB 将与Sham和WLC一样安全)。第二阶段是为期12周的开放标签延展期，所有受试者 如果符合条件，将向小组提供活动的SGB(初级阶段I的PTSD分数和纳入标准分数 8周的终点)。第二阶段很重要，因为它允许评估“强化剂量”(第二个SGB用于 那些在SGB ARM中的人)，它允许所有受试者接受积极干预，如果他们愿意的话，这也提供了 更大的SGB样本，用于探索性池分析，并允许进行更长时间的耐久性分析 第一阶段后缓解者的时间段另一个次要目标是检验SGB将 比Sham或WLC更活跃，表现出干预前到干预后更大的减少 与创伤后应激障碍相关的恐惧--强化惊吓。我们还将探索SGB的临床和生物学预测因素 答复(即CAPS-5分数显著降低)。这项优势研究旨在预期和检测 在统计和临床上重要的创伤后应激障碍症状从基线减少30%至8周终点 SGB，在患有中度严重PTSD的样本中，Sham减少15%，WLC减少5%(基线 (65+18分)。在这些假设下，我们需要262名受试者的样本大小来测试初级 临床疗效假说。我们将对360名受试者进行抽样，以解决15%的自然减员、数据缺失和5%的损失 失败-阻塞率和站点变异性。确保这项时间敏感的研究有足够的动力是至关重要的。 将使用多变量方差分析(MANOVA)来检验无差异的零假设 基线PTSD症状和随后的PTSD症状重新测试，同时调整 显著的协变量。将对因跟踪丢失而丢失的数据进行分析，以便 确定一旦丢失的数据被撤回，是否存在任何潜在的偏差。将进行更多的分析 确定相互作用和调节/调节效应，同时调整其他协变量 在模型中。我们的三个主要目标的详细分析在研究的数据分析部分 计划一下。我们的领导团队在临床试验、使用和研究方面拥有丰富的临床和研究经验 适应创伤后应激障碍的SGB，以及一项为PTSD患者提供SGB的国家倡议 护理基础。拟议的最终研究将指导SGB治疗退伍军人中的创伤后应激障碍的合理使用，将进一步刺激 关于剂量、时机、生物学机制和临床预后预测因素的研究，并将有 已建立的退伍军人管理局为进一步的SGB研究和临床实践做好了准备。

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.