Sildenafil for the treatment of cerebrovascular dysfunction in chronic TBI

研究人群 该方案的研究人群包括男性和女性志愿者，年龄在18岁到55岁之间，患有和不患有颅脑损伤，来自沃尔特里德国家军事医学中心、国家英勇医学中心、美国国立卫生研究院临床中心、CNRM表型核心、CNRM招募核心和弗吉尼亚州里士满的麦奎尔退伍军人管理局医疗中心。研究设计将包括三个研究组：试验组和两个控制组。 设计 这是一项随机、盲法、安慰剂对照的先导性研究，我们将在使用西地那非前后使用MRI BOLD研究慢性颅脑损伤患者的CVR。我们将收集和分析这些患者的血液样本，以确定PDE5抑制剂西地那非在改善脑血管反应性方面是否有效，并将评估西地那非在脑损伤人群中的安全性和耐受性。此外，我们还将对脑外伤患者的循环内皮祖细胞进行检测，以检验这一反映血管健康的生物标志物与持续性慢性症状之间的关系，以及评估西地那非对血管生成的长期影响。 研究设计将包括三个研究组：试验组和两个控制组。在试验组(第1组)，我们将招募24(24)名成年男性和女性，他们在受伤后持续6个月以上的脑损伤症状。第一组(试验组)的参与者将被随机分成一项双盲、安慰剂对照、双交叉研究。在第二组中，我们将招募20名成年男性和女性作为年龄和性别匹配的健康对照组。在第三组中，我们将招募20名成年男性和女性，他们经历过脑外伤，已经康复，受伤后六个月或更长时间没有症状，年龄和性别与第一组和第二组相匹配。 所有三组的参与者都将在基线上进行MRI扫描，其中将包括一项高碳酸血症挑战，以衡量高碳酸血症期间BOLD信号的增加。 第一组(试验组)的参与者将在大约十八(18)周的时间内进行三次考察访问。基线访视(访视1)程序包括同意、有或不有高碳酸血症的MRI、采血、体格和神经检查以及在高碳酸血症挑战期间服用西地那非，大约需要5个小时。第一组随后两次类似于第一次访问的考察访问程序将需要大约4个小时。第二组和第三组的参与者只参加基线访问。 结果衡量标准 主要的结果将是在口服西地那非50毫克后1小时的整体CVR到高碳酸血症。次要结果评估将是对西地那非的安全性和耐受性的评估，西地那非每天口服两次，25毫克，持续约8周，用于有症状的慢性脑损伤人群。三级预后评估将探索西地那非对脑震荡后症状、神经心理功能、循环内皮祖细胞(EPC)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。血液也将被采集并送往生物库进行未来分析，包括DNA。此外，还将进行神经心理测试，以评估功能和认知障碍。

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.