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%的退伍军人报告有创伤性脑损伤史，大多数是轻微的