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

TTI-0102，一种用于轻度至中度 TBI 的半胱胺前体：剂量和可行性研究

• 批准号: 9890123
• 负责人: Elizabeth W Twamley
• 金额: --
• 依托单位: VA SAN DIEGO HEALTHCARE SYSTEM
• 依托单位国家: 美国
• 财政年份: 2020
• 资助国家: 美国
• 起止时间: 2020-04-01 至 2022-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9890123
• 关键词: Aftercare; Anti-Inflammatory Agents; Area; Attention; Behavior; Bioenergetics; Biological; Blood - brain barrier anatomy; Brain; Brain Injuries; Brain-Derived Neurotrophic Factor; C-reactive protein; Chronic; Chronic Disease; Clinical; Clinical Trials; Cognition; Cognitive; Complex; Cysteamine; Cystinosis; Data; Dementia; Diagnosis; Disease; Dose; Double-Blind Method; Eicosanoids; Enrollment; Event; Feasibility Studies; Goals; Headache; Hypopituitarism; Immune; Individual; Inflammation; Inflammatory; Injury; Interleukin-6; Intervention; Kynurenine; Lead; Learning; Measurement; Measures; Memory; Mental Depression; Mental Health; Mitochondria; Morbidity - disease rate; Neurobehavioral Manifestations; Neurodegenerative Disorders; Outcome Measure; Pain; Participant; Peptides; Pharmaceutical Preparations; Pharmacologic Substance; Phase; Pilot Projects; Placebos; Plasma; Post-Concussion Syndrome; Post-Traumatic Stress Disorders; Problem Solving; Procedures; Production; Purines; Quality of life; Randomized; Randomized Controlled Trials; Recording of previous events; Reporting; Resources; Sleep; Sphingolipids; Stress; Sulfur Amino Acids; Symptoms; Testing; Therapeutic; Thinking; Training; Traumatic Brain Injury; Treatment outcome; Veterans; War; Water; Work; amino acid metabolism; base; cognitive performance; cognitive rehabilitation; cognitive training; daily functioning; double-blind placebo controlled trial; drug mechanism; evidence base; executive function; feasibility trial; healing; health care service utilization; improved; metabolomics; mild traumatic brain injury; neuropsychiatric symptom; persistent symptom; protein biomarkers; service member; wound

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.

大约12-23％的返回服务成员报告了创伤性脑损伤病史 （mtbi）。令人困惑的症状，例如记忆问题，易怒和集中精力的困难 在TBI并可能变得长期之后，很常见，干扰了成功恢复职责或平民的重返社会， 降低生活质量，并增加退伍军人的医疗保健利用。在与TBI相关症状的人中 持续存在，有累积的证据表明发病率升高（例如，PTSD症状较差，慢性 肌次症，痴呆症），促进了改善诊断和干预的努力。主要TBI受伤后， 继发性伤害和持续性症状可能会通过一系列复杂的事件而发展 炎症，线粒体生物能学的改变以及血脑屏障完整性降低 产生慢性疾病状态。迄今为止，接受基于策略的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有所改善。 CCT是一个 基于证据的认知康复干预措施强调了认知策略的培训，以改善后 脑震荡症状，注意力，学习/记忆和执行功能。但是，没有药物 已开发用于直接或辅助的CCT使用，以最大程度地提高治疗结果。 鉴于在TBI，PTSD和同时发生的TBI/PTSD中观察到炎症，可能是 TBI/PTSD疾病状态的重要方面可以被操纵以促进愈合。我们正在提议 研究TTI-0102，这是一种显示抗炎活性的cysteamine前体，作为CCT的潜在辅助 对于具有TBI相关症状的退伍军人。 TTI-0102是一种安全的，易于施用的，高水的可溶性化合物 这很容易越过血脑屏障。与cysteamine相比，TTI-0102降解较慢， 在狭窄的治疗范围内抑制峰值药物浓度和维持药物血浆浓度。 为治疗膀胱变性而开发的cysteamine现在被认为具有治疗神经退行性的潜力 疾病。 这项概念研究证明的目的是使用症状变化（即客观）在第一阶段（第1年）首先 认知表现以及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[白介素6和C反应蛋白]以及脑衍生的神经营养 因素）学习TTI-0102的最佳剂量并评估行动机理，以及在第二阶段（第2年）中 在具有轻度至中度TBI和PTSD病史的退伍军人中实施可行性试验。在第一阶段，3组 每个退伍军人将被随机分配以接收TTI-0102 2克/天，4克/天或安慰剂12 几周。基准和治疗后的客观认知和主观认知的度量 将施用神经精神症状，并收集血浆以测量代谢组学， 炎症和蛋白质生物标志物。在第二阶段（第2年）中，将招募12名不同的退伍军人（每组6名） 在一项试验随机对照试验（RCT）中，以评估试验程序的可行性和可接受性。 第二阶段的参与者将被随机分配以接收TTI-0102（在I期确定的剂量）或安慰剂12 几周作为基于证据的CCT的辅助手段。这些双盲，安慰剂对照试验的结果将是 用于计划更大的，全功能的试验。