Novel Regenerative Therapeutic in Chronic Complex TBI

慢性复杂性TBI的新型再生治疗 别孕烯醇酮（Allopregnanolone，ALLO）是一种脑内内源性神经甾体，具有多种作用 与慢性复杂TBI的神经生物学和治疗高度相关。ALLO显示， 在啮齿类动物中，除了显著的神经保护、镇痛和抗炎作用外， 模型此外，我们最近的人类数据表明，ALLO在TBI中减少，这表明， 改善这种神经类固醇的不足可能是临床治疗性的。我们最近还确定， ALLO水平与MRI上皮质灰质厚度呈正相关。此外，多个团体 现在已经报道了在患有经常与TBI同时发生的疾病的患者中ALLO的减少， 包括抑郁症和疼痛障碍。因此，补充ALLO可能具有巨大的治疗效果。 有可能出现多种症状，极大地影响功能结果和生活质量。 因此，本项目的目标是进行一项概念验证的2期随机对照试验（RCT）， 患有慢性复杂性TBI的退伍军人研究这种再生治疗的疗效和耐受性， 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， TBI的多维病理生理学基础和经常共同发生的条件， 抑郁和疼痛。因此，本研究将为ALLO的潜在治疗效果提供初步数据 共发抑郁症状和疼痛症状（主要终点），以及可能的 功能结局改善（次要终点）。此外，我们将研究仅TBI组 无抑郁或疼痛症状（也随机分配至ALLO或安慰剂组）。因此，这将是一个4臂 每组22名参与者的研究（总共88名参与者）：复杂TBI组（随机分配至ALLO或 安慰剂组）和仅TBI组（随机分配至ALLO组或安慰剂组）。由于ALLO具有抗炎作用，我们 还将研究治疗后炎症生物标志物的可能减少（探索性终点）， 心率变异性（探索性终点）。此外，我们将获得重要的药代动力学数据， 干预（ALLO水平通过质谱法定量）。 患有慢性复杂性TBI的退伍军人，最低HAM-D评分为14（与中度抑郁一致） 将随机接受静脉安慰剂（6%环糊精）或ALLO（0.5mg/ml GMP级ALLO， 6%环糊精）;每组n=22/n=44，使用复合物TBI。我们还将随机分配仅接受TBI的退伍军人（不接受 抑郁或疼痛症状）与ALLO或安慰剂的比较;每组n=22/n=44，仅TBI。研究总数 患有轻度TBI的OEF/OIF/OND退伍军人参与者现在将为88人（4组;每组22名参与者）。 在负荷剂量后，退伍军人将接受4小时的安慰剂或ALLO输注，以达到血清 ALLO水平为50纳摩尔（nM），迄今为止在其他人群的小型研究中耐受良好。 参与者将在整个研究期间接受强化监测，包括连续ECG。罪要归 在输注期间和输注后6小时每小时抽取一次，以确定药代动力学 在这个队列中的ALLO参数。由于ALLO的潜在抗抑郁作用可能非常迅速，我们将 在输注期间、输注后6小时和输注后24小时进行行为评估。在 此外，我们将在输注后7天和14天检查这些症状群。 我们假设ALLO在这些慢性复杂性TBI和单纯TBI患者中有效且耐受性良好。 这种干预措施将具有快速的抗抑郁和镇痛作用（除了 对功能结果的积极影响）。我们还假设，炎症标志物和改善， 心率变异性可以预测对该治疗候选物的临床反应。

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.