TTI-0102, a Cysteamine Precursor for Mild to Moderate TBI: Dosing and Feasibility Study

大约12-23%的返回服务成员报告创伤性脑损伤的历史，大多数是轻度的 （mTBI）。脑震荡后的症状，如记忆问题、易怒和难以集中注意力， 创伤性脑损伤后常见，可能成为慢性病，干扰成功重返岗位或重返平民生活， 降低生活质量，提高退伍军人的医疗保健利用率。在那些TBI相关症状 持续存在，有越来越多的证据表明发病率增加（例如，更严重的PTSD症状，慢性 垂体功能减退症，痴呆症），促进努力改善诊断和干预。在原发性TBI损伤后， 继发性损伤和持续性症状可能通过复杂的级联事件发展， 炎症，线粒体生物能量学的改变，以及血脑屏障完整性的降低，最终 从而导致慢性疾病状态。迄今为止，接受基于策略的TBI认知康复的退伍军人 (CCT/CogSMART）在认知和主观神经精神症状方面表现出改善。CCT是一种 以证据为基础的认知康复干预，强调认知策略的训练，以改善术后 脑震荡症状、注意力、学习/记忆和执行功能。然而，没有药物 已开发用于直接或间接CCT使用，以最大限度地提高治疗效果。 鉴于在TBI、PTSD和同时发生的TBI/PTSD中观察到炎症， TBI/PTSD疾病状态的一个重要方面，可以被操纵以促进愈合。我们提议 研究TTI-0102，一种显示抗炎活性的半胱胺前体，作为CCT的潜在辅助药物 有创伤性脑损伤相关症状的退伍军人TTI-0102是一种安全、易于给药、水溶性高的化合物 很容易穿过血脑屏障与半胱胺相比，TTI-0102降解更慢， 抑制峰值药物浓度并将药物血浆浓度维持在狭窄的治疗范围内。 开发用于治疗胱氨酸病，现在认为半胱胺具有治疗神经退行性疾病的潜力。 紊乱 这项概念验证研究的目标是首先在第一阶段（第一年）使用症状变化（即，目的 认知表现和主观认知和神经精神症状）和生物学特征（即， 代谢组学、炎症肽[白细胞介素-6和C反应蛋白]和脑源性神经营养因子 因子）以了解TTI-0102的最佳剂量并评估作用机制，并且在II期（第2年）中， 在有轻度至中度创伤性脑损伤和创伤后应激障碍病史的退伍军人中进行可行性试验。在第一阶段， 10名退伍军人将被随机分配接受TTI-0102 2克/天，4克/天，或安慰剂12 周客观认知和主观认知的基线和治疗后测量， 将给予神经精神症状，并收集血浆以测量代谢组学， 炎症和蛋白质生物标志物。在II期（第2年），将入组12名不同的退伍军人（每组6名） 在一项初步随机对照试验（RCT）中评估试验程序的可行性和可接受性。 II期的参与者将随机接受TTI-0102（在I期中确定的剂量）或安慰剂，持续12周。 作为循证CCT的辅助治疗。这些双盲、安慰剂对照试验的结果将 用来计划一个更大的全动力试验

Approximately 12-23% of returning service members report a history of traumatic brain injury, mostly mild (mTBI). Post-concussive symptoms such as memory problems, irritability, and difficulty concentrating are common after TBI and may become chronic, interfering with successful return to duty or civilian reintegration, reducing quality of life, and increasing health care utilization for Veterans. In those whose TBI-related symptoms persist, there is accumulating evidence for increased morbidity (e.g., worse PTSD symptoms, chronic hypopituitarism, dementia), spurring efforts to improve diagnosis and intervention. Following a primary TBI injury, secondary injury and persistent symptoms may evolve through a complex cascade of events that culminate in inflammation, alterations in mitochondrial bioenergetics, and diminished blood brain barrier integrity, ultimately yielding a chronic disease state. To date, Veterans receiving strategy-based cognitive rehabilitation for TBI (CCT/CogSMART) have shown improvement in cognition and subjective neuropsychiatric symptoms. CCT is an evidence-based cognitive rehabilitation intervention emphasizing training in cognitive strategies to improve post- concussive symptoms, attention, learning/memory, and executive functioning. However, no pharmaceuticals have been developed for direct or adjunct-to CCT use to maximize treatment outcomes. Given that inflammation has been observed in TBI, PTSD, and in co-occurring TBI/PTSD, it may be an important aspect of the TBI/PTSD disease state that could be manipulated to promote healing. We are proposing to study TTI-0102, a cysteamine precursor that shows anti-inflammatory activity, as a potential adjunct to CCT for Veterans with TBI-related symptoms. TTI-0102 is a safe, easily administered, highly-water soluble compound that readily crosses the blood brain barrier. Compared with cysteamine, TTI-0102 degrades more slowly, dampening peak drug concentrations and sustaining drug plasma concentrations in a narrow therapeutic range. Developed to treat cystinosis, cysteamine is now believed to have potential for treatment of neurodegenerative disorders. The goal of this proof of concept study is first, in Phase I (Year 1), to use symptom change (i.e., objective cognitive performance and subjective cognitive and neuropsychiatric symptoms) and biological profiles (i.e., metabolomics, inflammatory peptides [interleukin-6 and C-reactive protein], and brain-derived neurotrophic factor) to learn optimal dosing of TTI-0102 and to assess mechanism of action, and in Phase II (Year 2), to implement a feasibility trial in Veterans with a history of mild to moderate TBI and PTSD. In Phase I, 3 groups of 10 Veterans each will be randomly assigned to receive TTI-0102 2 grams/day, 4 grams/day, or placebo for 12 weeks. Baseline and post-treatment measures of objective cognition and subjective cognitive and neuropsychiatric symptoms will be administered, and plasma will be collected to measure the metabolomic, inflammatory, and protein biomarkers. In Phase II (Year 2), 12 different Veterans (6 per group) will be enrolled in a pilot randomized controlled trial (RCT) to assess the feasibility and acceptability of trial procedures. Participants in Phase II will be randomized to receive TTI-0102 (dose determined in Phase I) or placebo for 12 weeks as an adjunct to evidence-based CCT. The results of these double-blind, placebo-controlled trials will be used to plan a larger, fully-powered trial.