Cerebrovascular Reactivity (CVR) Assessed With Functional Near Infrared Spectroscopy (fNIRS) as a Biomarker of Traumatic Cerebrovascular Injury (TCVI) Measured Longitudinally After Acute TBI in Military Personnel
试验速览
- 阶段
- 2 期
- 状态
- 终止
- 入组人数
- 1
- 试验地点
- 1
- 主要终点
- Detection of variation of oxyhemoglobin and deoxyhemoglobin concentration using a power analysis between groups during the hypercapnia challenge pre and post a single dose of sildenafil 50 mg at the specified time points after a TBI.
研究概览
简要总结
The study includes people who have recently had a traumatic brain injury (TBI) and healthy controls who have not had a TBI and is designed to measure brain blood flow serially after a TBI. Studies have shown that small blood vessels in the brain may be injured during a TBI. The goal is to learn about brain blood vessel function from as early as the first week to 6 months after a TBI . The study uses Near Infrared Spectroscopy (NIRS) which uses small lights that detect oxygen levels in the blood, measuring blood flow in the brain. This is compared with magnetic resonance imaging (MRI). When blood flow increases in the brain in response to a stimulus, this is called cerebral vascular reactivity (CVR).
The study aims to learn about CVR using a few minutes of special breathing similar to breath holding while in an MRI (magnetic resonance imaging), and CVR measures after one dose of a common drug called sildenafil (generic Viagra) 50 mg taken once during CVR measurements at each of up to 4 visits. The investigators will measure CVR at different times during a 6-month period in participants who have had a TBI to see how CVR measures and blood vessels function during the first 6 months after a brain injury.
详细描述
Background and significance:
Currently, more that 5.3 million Americans (or 2% of the population) live with disabilities resulting from TBI. Among OEF/OIF Veterans, TBI incidence estimates as high as 23% have been reported, with mild TBI (mTBI) being the most common.1 This proposal addresses the recommendations of the consensus of scientific conferences by aiming to develop a biomarker of traumatic cerebrovascular injury (TCVI) which can be useful in clinical trials of therapies.
Substantial data point to traumatic cerebrovascular injury (TCVI) underlying a significant portion of TBI-related disability. 2 The cerebral vasculature is a highly plastic tissue making TCVI an attractive target for therapeutic intervention after TBI. Preliminary studies indicate that PDE5 inhibitors such as sildenafil (Viagra®) show promise as treatment for cerebrovascular dysfunction after TBI. 3,4
The investigators adapted MRI-Blood Oxygenation Level Dependent (BOLD) with hypercapnia challenge, to the portable, less expensive, office-based Near InfraRed Spectroscopy (NIRS) technology and incorporated hypercapnia challenge as the functional challenge with NIRS.
MRI- BOLD BOLD (with 5% carbon dioxide (CO2) hypercapnia challenge via the Douglas Bag method) and fNIRS (also with 5% CO2 hypercapnia challenge via the Douglas Bag method) in traumatic brain injury (TBI) and healthy controls. The complementary methods give similar results with a high degree of correlation in TBI patients compared to healthy controls. 5 Nitric Oxide (NO), the primary endogenous vasodilator in the brain, plays a prominent role. Specific PDE5 inhibitors have come into widespread use, the first is Sildenafil (Viagra®) for the treatment of erectile dysfunction and primary pulmonary hypertension. The beneficial effect of sildenafil is related to increased local CBF and enhanced neurogenesis, vasculogenesis, and axonal remodeling in the peri-infarct zone. 6-9 To date, there have been no longitudinal studies of CVR using functional NIRS from the acute to the subacute/chronic stages of TBI in humans.
研究设计
- 研究类型
- Interventional
- 分配方式
- Non Randomized
- 干预模型
- Parallel
- 主要目的
- Basic Science
- 盲法
- None
入排标准
- 年龄范围
- 18 Years 至 55 Years（Adult）
- 性别
- All
- 接受健康志愿者
- 是
入选标准
- 未提供
排除标准
- •Unstable respiratory or hemodynamic status
- •Evidence of penetrating brain injury
- •TBI requiring craniotomy or craniectomy
- •History of disabling pre-existing neurologic disorder, e.g. dementia, uncontrolled epilepsy, multiple sclerosis, strokes, brain tumors, prior severe TBI, or other disorder that confounds interpretation of NIRS testing or neuropsychological results
- •History of pre-existing disabling mental illness, e.g. major depression or schizophrenia
- •Exclusion criteria for sildenafil:
- •History of melanoma; Current use of organic nitrate vasodilators; Use of ritonavir (HIV-protease inhibitor); Current use of erythromycin, ketoconazole, or itraconazole; Current use of cimetidine; Current use of Alpha-blockers such as doxazosin (Cardura), tamsulosin (Flomax), and terazosin (Hytrin) prazosin (Minipress); Resting hypotension (systolic BP <90); Severe renal insufficiency; Hepatic cirrhosis; Cardiac failure or coronary artery disease causing unstable angina; Retinitis pigmentosa; Pregnant or breastfeeding female; Known hypersensitivity or allergy to sildenafil.
- •Inability to read and communicate in English
- •Exclusion criterion for healthy subjects only: History of TBI.
- •Current use of a PDE5 inhibitor (a drug such as Sildenafil, Tadalafil, Vardenafil, Avanafil, Udenafil,Dipyridamole, Vardenafil hydrochloride)
研究组 & 干预措施
Group 1: acute/subacute Traumatic Brain Injury
Any gender, age 18-55 years who have had a traumatic brain injury within 30 days
干预措施: Sildenafil Citrate 50Mg Tab (Drug)
Group 1: acute/subacute Traumatic Brain Injury
Any gender, age 18-55 years who have had a traumatic brain injury within 30 days
干预措施: functional Near-infrared Spectroscopy (fNIRS) (Device)
Group 1: acute/subacute Traumatic Brain Injury
Any gender, age 18-55 years who have had a traumatic brain injury within 30 days
干预措施: Carbon Dioxide (CO2) 5% (Other)
Group 1: acute/subacute Traumatic Brain Injury
Any gender, age 18-55 years who have had a traumatic brain injury within 30 days
干预措施: Neuropsychological Assessments (Other)
Group 1: acute/subacute Traumatic Brain Injury
Any gender, age 18-55 years who have had a traumatic brain injury within 30 days
干预措施: Gadolinium contrast infusion (Drug)
Group 1: acute/subacute Traumatic Brain Injury
Any gender, age 18-55 years who have had a traumatic brain injury within 30 days
干预措施: Blood sample collection for research purposes (Procedure)
Group 1: acute/subacute Traumatic Brain Injury
Any gender, age 18-55 years who have had a traumatic brain injury within 30 days
干预措施: Structural brain Magnetic Resonance Imaging (MRI (Other)
Group 2: Non-TBI healthy control (HC)
Any gender, age 18-55 years with no history of traumatic brain injury
干预措施: Sildenafil Citrate 50Mg Tab (Drug)
Group 2: Non-TBI healthy control (HC)
Any gender, age 18-55 years with no history of traumatic brain injury
干预措施: functional Near-infrared Spectroscopy (fNIRS) (Device)
Group 2: Non-TBI healthy control (HC)
Any gender, age 18-55 years with no history of traumatic brain injury
干预措施: Carbon Dioxide (CO2) 5% (Other)
Group 2: Non-TBI healthy control (HC)
Any gender, age 18-55 years with no history of traumatic brain injury
干预措施: Neuropsychological Assessments (Other)
Group 2: Non-TBI healthy control (HC)
Any gender, age 18-55 years with no history of traumatic brain injury
干预措施: Gadolinium contrast infusion (Drug)
Group 2: Non-TBI healthy control (HC)
Any gender, age 18-55 years with no history of traumatic brain injury
干预措施: Blood sample collection for research purposes (Procedure)
Group 2: Non-TBI healthy control (HC)
Any gender, age 18-55 years with no history of traumatic brain injury
干预措施: Structural brain Magnetic Resonance Imaging (MRI (Other)
结局指标
主要结局
Detection of variation of oxyhemoglobin and deoxyhemoglobin concentration using a power analysis between groups during the hypercapnia challenge pre and post a single dose of sildenafil 50 mg at the specified time points after a TBI.
时间窗: 2 years
This is a pilot study, whose primary aim is to obtain pilot data that can be used to design a carefullypowered Phase III clinical trial. Thus, a power analysis is only an approximation.This compares favorably with the effect size of 1.3 noted in our preliminary study in chronic TBI (Figs. 2 and 4). For the observed effect size of 1.3, power will be 90%. Since we anticipate that the reduction in CVR will be greater in the acute period than in the chronic period, the proposed study has adequate sample size to measure the evolution of CVR over the subacute period after TBI. Sample size was calculated using GraphPad StatMate, v. 2.0 for Windows (GraphPad Software, San Diego, CA). The following assumptions were made: alpha =0.05, delta = 0.44, sigma = 0.40.
Longitudinal measure of CVR between groups
时间窗: 2 years
For each TBI, we will perform a one way ANOVA test between CVR measure for all the source/detectors pair at the different time point. At each time point of the study, we will also perform a t test on the mean CVR between the TBI group and the HC group.
次要结局
未报告次要终点
研究者
Kimbra Kenney
Service Chief, Research Operations, NICoE, WRNMMC & Professor, USUHS Service and Department: NICoE, WRNMMC & Neurology, USUHS
Uniformed Services University of the Health Sciences