Sildenafil for the treatment of cerebrovascular dysfunction in chronic TBI

西地那非治疗慢性TBI脑血管功能障碍

• 批准号: 9157573
• 负责人: Ramon Diaz-Arrastia
• 金额: $ 1.16万
• 依托单位: NATIONAL INSTITUTE OF NEUROLOGICAL DISORDERS AND STROKE
• 依托单位国家: 美国
• 资助国家: 美国
• 起止时间: 至
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/9157573
• 关键词: Acute; Adult; Age; Animals; Biological Assay; Biological Markers; Blinded; Blood; Blood Vessels; Blood specimen; Cerebrovascular Circulation; Cerebrum; Chronic; Clinical; Clinical Trials; Consent; Control Groups; Cross-Over Studies; DNA; Data; Emission-Computed Tomography; Enrollment; Female; Functional disorder; Future; Gender; Goals; Health; Hour; Human; Hypercapnia; Impaired cognition; Injury; Interview; Long-Term Effects; MRI Scans; Magnetic Resonance Imaging; Measurement; Measures; Medical; Medical center; Methods; Military Personnel; Neurologic; Neuropsychological Tests; Outcome Measure; Participant; Patients; Performance; Phenotype; Photons; Pilot Projects; Placebo Control; Population; Population Study; Positron-Emission Tomography; Post-Concussion Syndrome; Procedures; Protocols documentation; Randomized; Recovery of Function; Recruitment Activity; Research Design; Safety; Signal Transduction; Staging; Stem cells; Stimulus; Symptoms; Techniques; Traumatic Brain Injury; United States Department of Veterans Affairs; United States National Institutes of Health; Viagra; Visit; angiogenesis; biobank; blood oxygen level dependent; cerebrovascular; design; experience; functional disability; imaging modality; improved; inhibitor/antagonist; male; mild traumatic brain injury; neurogenesis; non-invasive imaging; novel; phase 2 study; phosphodiesterase V; primary outcome; response; secondary outcome; sildenafil; vasculogenesis; volunteer

Study Population The study population for this protocol includes 64 male and female volunteers, with and without TBI between the ages of 18 and 55 recruited from Walter Reed National Military Medical Center (WRNMMC), National Intrepid Center of Excellence (NiCoE), NIH Clinical Center, CNRM Phenotyping Core, CNRM Recruitment Core, and the McGuire Veterans Administration Medical Center in Richmond, VA. The study design will consist of three study groups; the experimental group and two control groups. Design This is a randomized, blinded, placebo-controlled, pilot study in which we will study CVR in chronic TBI patients using MRI BOLD with hypercapnia challenge before and after administration of sildenafil. We will collect and assay blood samples from these patients to determine whether the PDE5 inhibitor sildenafil is effective in improving cerebrovascular reactivity, and will assess the safety and tolerability of sildenafil in a TBI population. In addition, we will assay circulating endothelial progenitor cells in TBI, in order to examine the relationship between this biomarker of vascular health and persistent chronic symptoms, as well as to assess long-term effect of sildenafil on vasculogenesis. The study design will consist of three study groups; the experimental group and two control groups. In the Experimental Group (Group 1) we will enroll twenty four (24) male and female adult participants with persistent TBI symptoms lasting more than six months after the injury. Participants in Group 1 (the experimental group) will be randomized into a blinded, placebo-controlled, double cross-over study. In Group 2 we will enroll twenty male and female adult participants to serve as age and gender-matched healthy controls. In Group 3 we will enroll twenty male and female adult participants who have experienced a TBI, have recovered, are asymptomatic six months or more post injury, and are matched for age and gender to groups 1 and 2. Participants in all three groups will have an MRI scan at baseline, which will include a hypercapnia challenge to measure the increase in BOLD signal during hypercapnia. Participants enrolled in Group 1 (experimental) will have three study visits over period of approximately eighteen (18) weeks. The Baseline Visit (Visit 1) procedures including consenting, MRI with and without hypercapnia, blood sampling, medical interview and physical and neurological exam and administration of sildenafil during the hypercapnia challenge, will take about 5 hours. Procedures at the subsequent two study visits for Group 1 which are similar to Visit 1 will take approximately 4 hours. Participants enrolled in Groups 2 and 3 participate only in the Baseline Visit. Outcome Measures The primary outcome measure will be global CVR to hypercapnia, 1 hour after the administration of sildenafil 50 mg orally. The secondary outcome measure will be an assessment of safety and tolerability of sildenafil, 25 mg orally twice daily for approximately 8 weeks, in a symptomatic, chronic TBI population. Tertiary outcome measures will explore the effect of sildenafil on post-concussive symptoms, neuropsychometric performance, number of circulating endothelial progenitor cells (EPCs), and whether the acute effect of sildenafil on CVR persists after 8 weeks of therapy. Blood will also be collected and sent to a biorepository for future analysis, including DNA. In addition, neuropsychological testing will be performed to assess functional and cognitive impairment.

研究人群 本方案的研究人群包括64名男性和女性志愿者，年龄在18 - 55岁之间，有和没有TBI，招募自Walter Reed国家军事医学中心（WRNMMC）、国家无畏卓越中心（NioE）、NIH临床中心、CNRM表型分析中心、CNRM招募中心和弗吉尼亚州里士满的McGuire退伍军人管理医疗中心。 研究设计将包括三个研究组;实验组和两个对照组。 设计 这是一项随机、设盲、安慰剂对照、初步研究，我们将在慢性TBI患者中使用MRI BOLD和高碳酸血症激发在西地那非给药前后研究CVR。 我们将收集并分析这些患者的血液样本，以确定PDE 5抑制剂西地那非是否能有效改善脑血管反应性，并将评估西地那非在TBI人群中的安全性和耐受性。此外，我们还将检测TBI患者的循环内皮祖细胞，以检查这种血管健康生物标志物与持续慢性症状之间的关系，以及评估西地那非对血管发生的长期影响。 研究设计将包括三个研究组;实验组和两个对照组。 在实验组（第1组）中，我们将招募二十四（24）名男性和女性成年参与者，这些参与者在受伤后具有持续超过六个月的持续TBI症状。 第1组（实验组）的受试者将被随机分配至一项设盲、安慰剂对照、双交叉研究。 在第2组中，我们将招募20名男性和女性成年参与者作为年龄和性别匹配的健康对照。 在第3组中，我们将招募20名男性和女性成年参与者，他们经历了TBI，已经康复，在受伤后6个月或更长时间内没有症状，并且年龄和性别与第1组和第2组相匹配。 所有三组的参与者将在基线时进行MRI扫描，其中包括高碳酸血症挑战，以测量高碳酸血症期间BOLD信号的增加。 入组第1组（实验）的受试者将在约十八（18）周的时间内接受三次研究访视。 基线访视（访视1）程序包括知情同意、伴和不伴高碳酸血症的MRI、血样采集、医学访谈和体格检查及神经系统检查以及高碳酸血症激发期间的西地那非给药，将持续约5小时。 第1组后续两次研究访视的程序与访视1相似，约需4小时。 入组第2组和第3组的受试者仅参加基线访视。 观察指标 主要结局指标为西地那非50 mg口服给药后1小时的高碳酸血症总体CVR。 次要结局指标将是在有症状的慢性TBI人群中评估西地那非25 mg口服每日两次持续约8周的安全性和耐受性。 三级结局指标将探索西地那非对脑震荡后症状、神经心理测量表现、循环内皮祖细胞（EPCs）数量的影响，以及西地那非对CVR的急性影响在治疗8周后是否持续存在。血液也将被收集并送往生物储存库进行未来的分析，包括DNA。 此外，还将进行神经心理学测试，以评估功能和认知障碍。