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Trial record 68 of 157 for:    (Dementia pugilistica OR chronic traumatic encephalopathy) AND Injuries

Cerebrovascular Reactivity Assessed With fNIRS as a Biomarker of TCVI After Acute Traumatic Brain Injury in Military

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ClinicalTrials.gov Identifier: NCT04058132
Recruitment Status : Recruiting
First Posted : August 15, 2019
Last Update Posted : August 19, 2019
Sponsor:
Collaborator:
Walter Reed National Military Medical Center
Information provided by (Responsible Party):
Kimbra Kenney, Uniformed Services University of the Health Sciences

Brief Summary:

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.


Condition or disease Intervention/treatment Phase
Traumatic Brain Injury Drug: Sildenafil Citrate 50Mg Tab Device: functional Near-infrared Spectroscopy (fNIRS) Other: Carbon Dioxide (CO2) 5% Other: Neuropsychological Assessments Drug: Gadolinium contrast infusion Procedure: Blood sample collection for research purposes Other: Structural brain Magnetic Resonance Imaging (MRI Phase 2

  Show Detailed Description

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Study Type : Interventional  (Clinical Trial)
Estimated Enrollment : 50 participants
Allocation: Non-Randomized
Intervention Model: Parallel Assignment
Intervention Model Description: Exposures/interventions will be the same for healthy controls and participants with traumatic brain injury No blinding and no treatments.
Masking: None (Open Label)
Primary Purpose: Basic Science
Official Title: 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
Actual Study Start Date : August 9, 2019
Estimated Primary Completion Date : April 1, 2021
Estimated Study Completion Date : April 1, 2021

Resource links provided by the National Library of Medicine


Arm Intervention/treatment
Group 1: acute/subacute Traumatic Brain Injury
Any gender, age 18-55 years who have had a traumatic brain injury within 30 days
Drug: Sildenafil Citrate 50Mg Tab
sildenafil citrate (Viagra®, Pfizer. Inc., NY, NY). Sildenafil citrate is designated chemically as 1-[[3-(6,7-dihydro-1-methyl-7-oxo-3-propyl-1Hpyrazolo[4,3-d]pyrimidin-5-yl)-4- ethoxyphenyl]sulfonyl]-4-methylpiperazine citrate. Sildenafil citrate is a white to off-white crystalline powder with a solubility of 3.5 mg/mL in water and a molecular weight of 666.7. For this study, we will use 50 mg tablets for the single dose studies.
Other Name: Viagra®

Device: functional Near-infrared Spectroscopy (fNIRS)
Functional Near-Infrared Spectroscopy (fNIRS): Functional near-infrared spectroscopy (fNIRS) a noninvasive technique that can measure cerebrovascular reactivity (CVR) will be used to measure regional cerebral blood flow and cerebrovascular reactivity in the brain. The device (fNRIS100, fNIR Device LLC), uses laser emission diodes (730nm and 850nm)which in a headband that is worn on the front of the scalp and forehead. Surrounding detectors a few centimeters away detect the light as it scatters through the underlying tissues. The technique is able to detect changes in the absorption spectrum of the tissue corresponding to the concentrations of oxyhemoglobin (HbO2) and deoxyhemoglobin (HbR), and indicate local perfusion changes. fNIRS will be performed twice at each study visit, once before and once about 45 minutes after single dose administration of sildenafil 50 mg.

Other: Carbon Dioxide (CO2) 5%

Carbon Dioxide (CO2) 5% mixed with room air. Both the fNIRS procedure and one Magnetic Resonance Imaging (MRI) session at visits that include imaging will be done with a hypercapnia challenge for comparison.

CO2 (hypercapnia) challenge is similar to holding one's breath. Participant will wear a nose clip and a mouth breathing apparatus while in the MRI scanner or sitting in a chair during the fNIRS procedure.

During the 7-minute hypercapnia procedure, participants will breathe room air and then switch to room air mixed with 5% CO2, from one to the other for one minute each.


Other: Neuropsychological Assessments
TBI Neuropsychological Assessments: Study participants will be administered a set of Neuropsychological Tests designed by the NINDS Common Data Elements (CDEs) initiative for TBI, in order to provide a comprehensive and broad assessment of deficits commonly found after TBI. We anticipate that the neuropsychological battery will require approximately 1 hour to complete. The measures (pencil and paper exercises, questionnaires, and interview by the examiner) to be administered are: Glasgow Outcome Scale-Extended (GOS-E). Learning trials portion of the California Verbal Learning Test (CVLT-II): The Trail Making Tests A and B (TMT): Subsets of the Wechsler Adult Intelligence Scale (WAIS-IV) (Digit Symbol and Symbol Search): Behavioral Symptoms Inventory-18: Satisfaction with Life Scale (SWLS): Word Reading subtest of Wide Range Achievement Test (WRAT)-4: Rivermead Post-Concussion Symptom Questionnaire.

Drug: Gadolinium contrast infusion
Gadolinium contrast infusion: Brain MRI with gadolinium contrast: Dynamic contrast-enhanced (DCE) MRI with intravenous gadolinium-based contrast agents (GBCAs) to measure their transfer rate between intravascular and extravascular compartments as a marker of blood-brain barrier (BBB) permeability. For the DCE sequence, the participant is injected with the contrast agent through a heplock/iv in the scanner and the sequence takes about 15 min. Half-life of gadolinium is about 1 ½ hours and 90-98% clearance from the body in 24 hours in people with normal kidney function.

Procedure: Blood sample collection for research purposes
Serum and plasma (5 ml each) will be collected at at each study visit 10 m or 2 tsp. per visit or up to 40 ml or 8 tsp. over the 180 day course of the study). Samples will be collected by study personnel.

Other: Structural brain Magnetic Resonance Imaging (MRI

Structural brain Magnetic Resonance Imaging (MRI): The scanner used is a 3.0 Tesla MR (Model 750, General Electric Healthcare), which is equipped with a high-performance gradient subsystem and a 32-channel head coil (General Electric Healthcare). These scans involve lying still in a scanner for several minutes at a time which is tube shaped, using magnetism to take images of the brain. There is no radiation in MRI. The participants will have up to 3 research brain MRIs. Healthy controls will have 1 MRI session.

Common TBI MRI techniques will be performed. Block-design BOLD fMRI during which there will be a 7 minute hypercapnia challenge will be done to assess brain blood flow and measure cerebral vascular reactivity (CVR).


Group 2: Non-TBI healthy control (HC)
Any gender, age 18-55 years with no history of traumatic brain injury
Drug: Sildenafil Citrate 50Mg Tab
sildenafil citrate (Viagra®, Pfizer. Inc., NY, NY). Sildenafil citrate is designated chemically as 1-[[3-(6,7-dihydro-1-methyl-7-oxo-3-propyl-1Hpyrazolo[4,3-d]pyrimidin-5-yl)-4- ethoxyphenyl]sulfonyl]-4-methylpiperazine citrate. Sildenafil citrate is a white to off-white crystalline powder with a solubility of 3.5 mg/mL in water and a molecular weight of 666.7. For this study, we will use 50 mg tablets for the single dose studies.
Other Name: Viagra®

Device: functional Near-infrared Spectroscopy (fNIRS)
Functional Near-Infrared Spectroscopy (fNIRS): Functional near-infrared spectroscopy (fNIRS) a noninvasive technique that can measure cerebrovascular reactivity (CVR) will be used to measure regional cerebral blood flow and cerebrovascular reactivity in the brain. The device (fNRIS100, fNIR Device LLC), uses laser emission diodes (730nm and 850nm)which in a headband that is worn on the front of the scalp and forehead. Surrounding detectors a few centimeters away detect the light as it scatters through the underlying tissues. The technique is able to detect changes in the absorption spectrum of the tissue corresponding to the concentrations of oxyhemoglobin (HbO2) and deoxyhemoglobin (HbR), and indicate local perfusion changes. fNIRS will be performed twice at each study visit, once before and once about 45 minutes after single dose administration of sildenafil 50 mg.

Other: Carbon Dioxide (CO2) 5%

Carbon Dioxide (CO2) 5% mixed with room air. Both the fNIRS procedure and one Magnetic Resonance Imaging (MRI) session at visits that include imaging will be done with a hypercapnia challenge for comparison.

CO2 (hypercapnia) challenge is similar to holding one's breath. Participant will wear a nose clip and a mouth breathing apparatus while in the MRI scanner or sitting in a chair during the fNIRS procedure.

During the 7-minute hypercapnia procedure, participants will breathe room air and then switch to room air mixed with 5% CO2, from one to the other for one minute each.


Other: Neuropsychological Assessments
TBI Neuropsychological Assessments: Study participants will be administered a set of Neuropsychological Tests designed by the NINDS Common Data Elements (CDEs) initiative for TBI, in order to provide a comprehensive and broad assessment of deficits commonly found after TBI. We anticipate that the neuropsychological battery will require approximately 1 hour to complete. The measures (pencil and paper exercises, questionnaires, and interview by the examiner) to be administered are: Glasgow Outcome Scale-Extended (GOS-E). Learning trials portion of the California Verbal Learning Test (CVLT-II): The Trail Making Tests A and B (TMT): Subsets of the Wechsler Adult Intelligence Scale (WAIS-IV) (Digit Symbol and Symbol Search): Behavioral Symptoms Inventory-18: Satisfaction with Life Scale (SWLS): Word Reading subtest of Wide Range Achievement Test (WRAT)-4: Rivermead Post-Concussion Symptom Questionnaire.

Drug: Gadolinium contrast infusion
Gadolinium contrast infusion: Brain MRI with gadolinium contrast: Dynamic contrast-enhanced (DCE) MRI with intravenous gadolinium-based contrast agents (GBCAs) to measure their transfer rate between intravascular and extravascular compartments as a marker of blood-brain barrier (BBB) permeability. For the DCE sequence, the participant is injected with the contrast agent through a heplock/iv in the scanner and the sequence takes about 15 min. Half-life of gadolinium is about 1 ½ hours and 90-98% clearance from the body in 24 hours in people with normal kidney function.

Procedure: Blood sample collection for research purposes
Serum and plasma (5 ml each) will be collected at at each study visit 10 m or 2 tsp. per visit or up to 40 ml or 8 tsp. over the 180 day course of the study). Samples will be collected by study personnel.

Other: Structural brain Magnetic Resonance Imaging (MRI

Structural brain Magnetic Resonance Imaging (MRI): The scanner used is a 3.0 Tesla MR (Model 750, General Electric Healthcare), which is equipped with a high-performance gradient subsystem and a 32-channel head coil (General Electric Healthcare). These scans involve lying still in a scanner for several minutes at a time which is tube shaped, using magnetism to take images of the brain. There is no radiation in MRI. The participants will have up to 3 research brain MRIs. Healthy controls will have 1 MRI session.

Common TBI MRI techniques will be performed. Block-design BOLD fMRI during which there will be a 7 minute hypercapnia challenge will be done to assess brain blood flow and measure cerebral vascular reactivity (CVR).





Primary Outcome Measures :
  1. 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. [ Time Frame: 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.

  2. Longitudinal measure of CVR between groups [ Time Frame: 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.



Information from the National Library of Medicine

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Ages Eligible for Study:   18 Years to 55 Years   (Adult)
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   Yes
Criteria

Inclusion Criteria (See Table 2 for more details)

  1. Age 18 to 55 years, inclusive
  2. Either gender
  3. TBI subjects ONLY: Meets DoD criteria for moderate or severe TBI and TBI occurred less than 30 days prior to study enrollment (Sustained a traumatically induced physiological disruption of brain function, as manifested by at least one of the following:

    1. . Period of loss of consciousness > 30 minutes
    2. . Loss of memory for events lasting> 24 hours after the accident
    3. . Alteration of mental state lasting> 24 hours after the accident (e.g., feeling dazed, disoriented, and confused)
    4. . Clinical neuroimaging intracranial abnormality.

      • Traumatically induced includes the head being struck, the head striking an object, or the brain undergoing an acceleration/deceleration movement (i.e. whiplash) without direct external trauma to the head.
  4. Ability to undergo fNIRS testing with hypercapnia challenge serially
  5. Ability to provide informed consent.

Exclusion Criteria:

  1. Unstable respiratory or hemodynamic status
  2. Evidence of penetrating brain injury
  3. TBI requiring craniotomy or craniectomy
  4. 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
  5. History of pre-existing disabling mental illness, e.g. major depression or schizophrenia
  6. 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.

  7. Inability to read and communicate in English
  8. Exclusion criterion for healthy subjects only: History of TBI.
  9. Current use of a PDE5 inhibitor (a drug such as Sildenafil, Tadalafil, Vardenafil, Avanafil, Udenafil,Dipyridamole, Vardenafil hydrochloride)

Information from the National Library of Medicine

To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.

Please refer to this study by its ClinicalTrials.gov identifier (NCT number): NCT04058132


Contacts
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Contact: Kimbra Kenney, MD 301-400-0942 kimbra.kenney@usuhs.edu
Contact: Cora Davis, BA 301-319-3780 cora.davis.ctr@usuhs.edu

Locations
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United States, Maryland
Walter Reed National Military Medical Center Recruiting
Bethesda, Maryland, United States, 20889
Contact: Cora Davis    301-319-3780    cora.davis.ctr@usuhs.edu   
Contact: Kimbra Kenney, MD    301 400 0942    kimbra.kenney@usuhs.edu   
Sponsors and Collaborators
Uniformed Services University of the Health Sciences
Walter Reed National Military Medical Center
Investigators
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Principal Investigator: Kimbra Kenney, MD Uniformed Services University of the Health Sciences

Publications of Results:

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Responsible Party: Kimbra Kenney, Service Chief, Research Operations, NICoE, WRNMMC & Associate Professor, USUHS Service and Department: NICoE, WRNMMC & Neurology, USUHS, Uniformed Services University of the Health Sciences
ClinicalTrials.gov Identifier: NCT04058132     History of Changes
Other Study ID Numbers: WRNMMC-2017-0048
First Posted: August 15, 2019    Key Record Dates
Last Update Posted: August 19, 2019
Last Verified: August 2019

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Studies a U.S. FDA-regulated Drug Product: Yes
Studies a U.S. FDA-regulated Device Product: No
Product Manufactured in and Exported from the U.S.: Yes
Keywords provided by Kimbra Kenney, Uniformed Services University of the Health Sciences:
traumatic cerebrovascular injury
Functional Near Infrared Spectroscopy (fNIRS)
Additional relevant MeSH terms:
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Brain Injuries
Brain Injuries, Traumatic
Wounds and Injuries
Craniocerebral Trauma
Trauma, Nervous System
Brain Diseases
Central Nervous System Diseases
Nervous System Diseases
Sildenafil Citrate
Citric Acid
Sodium Citrate
Anticoagulants
Calcium Chelating Agents
Chelating Agents
Sequestering Agents
Molecular Mechanisms of Pharmacological Action
Vasodilator Agents
Phosphodiesterase 5 Inhibitors
Phosphodiesterase Inhibitors
Enzyme Inhibitors
Urological Agents