Novel Regenerative Therapeutic in Chronic Complex TBI

慢性复合性脑损伤的再生治疗新方法 别孕酮(Allo)是脑内产生的一种神经类固醇，具有多效性。 与神经生物学和慢性复合性脑外伤的治疗高度相关。Allo展品宣布 除了显著的神经保护、镇痛和抗炎作用外，啮齿动物的再生作用 模特们。此外，我们最近的人类数据表明，等位基因在脑损伤中减少，这表明 改善这种神经类固醇的缺陷可能在临床上是有疗效的。我们最近还确定， 在MRI上，Allo水平与皮质灰质厚度呈正相关。此外，多个小组 现已报告称，在经常与脑损伤并存的患者中，ALLO的减少， 包括抑郁症和疼痛障碍。因此，补充Allo可能会产生巨大的治疗作用 承诺出现多种症状星座，极大地影响功能结局和生活质量。 因此，该项目的目标是进行概念验证阶段2随机对照试验(RCT) 对患有慢性复杂性脑外伤的退伍军人进行研究这种再生疗法的有效性和耐受性， 在这一人群中提供关键的基础数据，可能导致一种新的治疗方法 颅脑损伤的多维病理生理基础和常见的共生情况 抑郁和痛苦。因此，这项研究将为Allo的潜在治疗效果提供初步数据 对于同时出现的抑郁症状和疼痛症状(主要终点)，以及尽可能 增强功能结局(次要终点)。此外，我们还将检查仅适用于TBI的组 没有抑郁或疼痛症状(也随机分为Allo或安慰剂)。因此，现在这将是一个四臂 每组22名参与者的研究(总共88名参与者)：复杂的脑外伤组(随机分为ALLO或ALLO或 安慰剂)和单纯脑损伤组(随机分为ALLO或安慰剂)。由于Allo具有消炎作用，我们 还将调查治疗后炎性生物标记物的可能减少(探索性终点)和 心率变异性(探查终点)。此外，我们还将获得重要的药代动力学数据。 干预(等位基因水平用质谱仪进行量化)。 患有慢性复杂脑损伤的退伍军人，HAM-D评分最低为14分(与中度抑郁症一致) 将被随机分为静脉安慰剂(6%环糊精)或Allo(0.5 mg/ml GMP级Allo in 6%环糊精)；n=22/组/n=44。我们还将仅对退伍军人进行TBI随机化(否 抑郁或疼痛症状)改为Allo或安慰剂；每组22人/n=44人，仅接受TBI。研究总数 轻度脑外伤的OEF/OIF/OND资深参与者现在将为88人(4支手臂，每组22名参与者)。 在负荷量之后，退伍军人将接受4小时的安慰剂或Allo输液，以获得目标血清 等位基因水平为50纳摩尔(NM)，到目前为止，这在其他人群的小型研究中得到了很好的耐受。 参与者在整个研究过程中将接受密集的监测，包括持续的心电监测。鲜血将会是 在输液过程中和输注后6小时每小时抽血一次，以确定药物动力学 该队列中等位基因的参数。由于等位基因的潜在抗抑郁作用可能非常迅速，我们将 在输液过程中、输液后6小时和24小时进行行为评估。在……里面 此外，我们将在输液后7天和14天检查这些症状群。 我们假设Allo对这些慢性复杂的脑损伤和单纯脑损伤是有效的和耐受性良好的。 这一干预措施将产生快速的抗抑郁和止痛作用(除了 对功能结果的积极影响)。我们还假设炎症标志物和疾病的改善 心率变异性可预测对该治疗方案的临床反应。

Novel Regenerative Therapeutic in Chronic Complex TBI Allopregnanolone (ALLO) is a neurosteroid endogenously produced in brain that exhibits pleiotropic actions highly relevant to the neurobiology and treatment of chronic complex TBI. ALLO exhibits pronounced regenerative actions, in addition to marked neuroprotective, analgesic, and anti-inflammatory effects in rodent models. Furthermore, our recent human data suggest that ALLO is decreased in TBI, suggesting that ameliorating deficits of this neurosteroid may be clinically therapeutic. We have also recently determined that ALLO levels are positively correlated with cortical gray matter thickness on MRI. In addition, multiple groups have now reported reductions in ALLO among patients with conditions that frequently co-occur with TBI, including depression and pain disorders. Replenishing ALLO could thus have tremendous therapeutic promise for multiple symptom constellations that greatly impact functional outcome and quality of life. The goal of this project is thus to conduct a proof-of-concept Phase 2 randomized controlled trial (RCT) in Veterans with chronic complex TBI to investigate the efficacy and tolerability of this regenerative therapeutic, providing critical foundational data in this population that could lead to a novel treatment addressing the multidimensional pathophysiological underpinnings of TBI and frequently co-occurring conditions such as depression and pain. This study will therefore provide initial data for the potential therapeutic efficacy of ALLO for co-occurring depression symptoms and pain symptoms (primary endpoints), as well as possible enhancement of functional outcome (secondary endpoint). In addition, we will examine TBI-only groups without depression or pain symptoms (also randomized to ALLO or placebo). This will now thus be a 4-arm study with 22 participants per group (88 total participants): Complex TBI groups (randomized to ALLO or placebo) and TBI-only groups (randomized to ALLO or placebo). As ALLO has anti-inflammatory actions, we will also investigate possible reductions in inflammatory biomarkers post-treatment (exploratory endpoint) and heart rate variability (exploratory endpoint). In addition, we will obtain important pharmacokinetic data for this intervention (ALLO levels to be quantified by mass spectrometry). Veterans with chronic complex TBI and a minimum HAM-D score of 14 (consistent with moderate depression) will be randomized to either intravenous placebo (6% cyclodextrin) or ALLO (0.5mg/ml of GMP-grade ALLO in 6% cyclodextrin); n=22 per group/n=44 with complex TBI. We will also randomize Veterans with TBI-only (no depression or pain symptoms) to ALLO or placebo; n=22 per group/n=44 with TBI-only. Total study number of OEF/OIF/OND Veteran participants with mild TBI will now be 88 (4 arms; 22 participants per group). Following a loading dose, Veterans will receive a 4-hour placebo or ALLO infusion targeted to achieve a serum ALLO level of 50 nanomolar (nM), which has been well-tolerated in small studies of other populations to date. Participants will receive intensive monitoring throughout the study, including continuous ECG. Blood will be drawn at hourly intervals during the infusion and 6 hours post-infusion to determine the pharmacokinetic parameters of ALLO in this cohort. As the potential antidepressant effect of ALLO may be very rapid, we will conduct behavioral assessments during the infusion, 6 hours post-infusion, and 24 hours post-infusion. In addition, we will examine these symptom constellations 7 days and 14 days post-infusion. We hypothesize that ALLO will be efficacious and well-tolerated in these chronic complex TBI and TBI-only populations, and that this intervention will have rapid antidepressant and analgesic actions (in addition to positive effects on functional outcome). We also hypothesize that inflammatory markers and improvements in heart rate variability may predict clinical response to this therapeutic candidate.