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

NCT04058132 | Terminated Phase 2 FDA Drug

• 1 other identifier: WRNMMC-2017-0048
• Study Type: interventional
• Target: 1
• Locations: 1 country
• Sites: 1

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.

Conditions

Traumatic Brain Injury

Keywords

traumatic cerebrovascular injury; Functional Near Infrared Spectroscopy (fNIRS)

Outcome Measures

Primary Outcomes (2)

• 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.

  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 years

• Longitudinal measure of CVR between groups

  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.

  2 years

Study Arms (2)

Group 1: acute/subacute Traumatic Brain Injury

OTHER

Any gender, age 18-55 years who have had a traumatic brain injury within 30 days

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

Group 2: Non-TBI healthy control (HC)

OTHER

Any gender, age 18-55 years with no history of 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

Interventions

Sildenafil Citrate 50Mg Tab DRUG

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.

Also known as: Viagra®

Group 1: acute/subacute Traumatic Brain Injury; Group 2: Non-TBI healthy control (HC)

functional Near-infrared Spectroscopy (fNIRS) DEVICE

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.

Group 1: acute/subacute Traumatic Brain Injury; Group 2: Non-TBI healthy control (HC)

Carbon Dioxide (CO2) 5% OTHER

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.

Group 1: acute/subacute Traumatic Brain Injury; Group 2: Non-TBI healthy control (HC)

Neuropsychological Assessments OTHER

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.

Group 1: acute/subacute Traumatic Brain Injury; Group 2: Non-TBI healthy control (HC)

Gadolinium contrast infusion DRUG

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.

Group 1: acute/subacute Traumatic Brain Injury; Group 2: Non-TBI healthy control (HC)

Blood sample collection for research purposes PROCEDURE

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.

Group 1: acute/subacute Traumatic Brain Injury; Group 2: Non-TBI healthy control (HC)

Structural brain Magnetic Resonance Imaging (MRI OTHER

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 1: acute/subacute Traumatic Brain Injury; Group 2: Non-TBI healthy control (HC)

Eligibility Criteria

• Age: 18 Years - 55 Years
• Sex: all
• Healthy Volunteers: Yes
• Age Groups: Adult (18-64)

You may qualify if:

• Age 18 to 55 years, inclusive
• Either gender
• 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:
• Period of loss of consciousness \> 30 minutes
• Loss of memory for events lasting\> 24 hours after the accident
• Alteration of mental state lasting\> 24 hours after the accident (e.g., feeling dazed, disoriented, and confused)
• 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.
• Ability to undergo fNIRS testing with hypercapnia challenge serially
• Ability to provide informed consent.

You may not qualify if:

• 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
• 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
• Current use of a PDE5 inhibitor (a drug such as Sildenafil, Tadalafil, Vardenafil, Avanafil, Udenafil,Dipyridamole, Vardenafil hydrochloride)

Sponsors & Collaborators

• Uniformed Services University of the Health Sciences: lead
• Walter Reed National Military Medical Center: collaborator

Study Sites (1)

Walter Reed National Military Medical Center

Bethesda, Maryland, 20889, United States

Location

Related Publications (9)

• Hoge CW, McGurk D, Thomas JL, Cox AL, Engel CC, Castro CA. Mild traumatic brain injury in U.S. Soldiers returning from Iraq. N Engl J Med. 2008 Jan 31;358(5):453-63. doi: 10.1056/NEJMoa072972. Epub 2008 Jan 30.

  PMID: 18234750 RESULT

• Washington CW, Derdeyn CP, Dhar R, Arias EJ, Chicoine MR, Cross DT, Dacey RG Jr, Han BH, Moran CJ, Rich KM, Vellimana AK, Zipfel GJ. A Phase I proof-of-concept and safety trial of sildenafil to treat cerebral vasospasm following subarachnoid hemorrhage. J Neurosurg. 2016 Feb;124(2):318-27. doi: 10.3171/2015.2.JNS142752. Epub 2015 Aug 28.

  PMID: 26314998 RESULT

• Nicolakakis N, Aboulkassim T, Aliaga A, Tong XK, Rosa-Neto P, Hamel E. Intact memory in TGF-beta1 transgenic mice featuring chronic cerebrovascular deficit: recovery with pioglitazone. J Cereb Blood Flow Metab. 2011 Jan;31(1):200-11. doi: 10.1038/jcbfm.2010.78. Epub 2010 Jun 23.

  PMID: 20571524 RESULT

• Nicolakakis N, Hamel E. Neurovascular function in Alzheimer's disease patients and experimental models. J Cereb Blood Flow Metab. 2011 Jun;31(6):1354-70. doi: 10.1038/jcbfm.2011.43. Epub 2011 Apr 6.

  PMID: 21468088 RESULT

• Amyot F, Kenney K, Moore C, Haber M, Turtzo LC, Shenouda C, Silverman E, Gong Y, Qu BX, Harburg L, Lu HY, Wassermann EM, Diaz-Arrastia R. Imaging of Cerebrovascular Function in Chronic Traumatic Brain Injury. J Neurotrauma. 2018 May 15;35(10):1116-1123. doi: 10.1089/neu.2017.5114. Epub 2018 Mar 20.

  PMID: 29065769 RESULT

• Zhang R, Wang Y, Zhang L, Zhang Z, Tsang W, Lu M, Zhang L, Chopp M. Sildenafil (Viagra) induces neurogenesis and promotes functional recovery after stroke in rats. Stroke. 2002 Nov;33(11):2675-80. doi: 10.1161/01.str.0000034399.95249.59.

  PMID: 12411660 RESULT

• Li L, Jiang Q, Zhang L, Ding G, Gang Zhang Z, Li Q, Ewing JR, Lu M, Panda S, Ledbetter KA, Whitton PA, Chopp M. Angiogenesis and improved cerebral blood flow in the ischemic boundary area detected by MRI after administration of sildenafil to rats with embolic stroke. Brain Res. 2007 Feb 9;1132(1):185-92. doi: 10.1016/j.brainres.2006.10.098. Epub 2006 Dec 26.

  PMID: 17188664 RESULT

• Ding G, Jiang Q, Li L, Zhang L, Zhang ZG, Ledbetter KA, Panda S, Davarani SP, Athiraman H, Li Q, Ewing JR, Chopp M. Magnetic resonance imaging investigation of axonal remodeling and angiogenesis after embolic stroke in sildenafil-treated rats. J Cereb Blood Flow Metab. 2008 Aug;28(8):1440-8. doi: 10.1038/jcbfm.2008.33. Epub 2008 Apr 16.

  PMID: 18418368 RESULT

• Atalay B, Caner H, Cekinmez M, Ozen O, Celasun B, Altinors N. Systemic administration of phosphodiesterase V inhibitor, sildenafil citrate, for attenuation of cerebral vasospasm after experimental subarachnoid hemorrhage. Neurosurgery. 2006 Nov;59(5):1102-7; discussion 1107-8. doi: 10.1227/01.NEU.0000245605.22817.44.

  PMID: 17143244 RESULT

MeSH Terms

Conditions

Brain Injuries, Traumatic

Interventions

Sildenafil Citrate; Carbon Dioxide; Magnetic Resonance Spectroscopy

Condition Hierarchy (Ancestors)

Brain Injuries; Brain Diseases; Central Nervous System Diseases; Nervous System Diseases; Craniocerebral Trauma; Trauma, Nervous System; Wounds and Injuries

Intervention Hierarchy (Ancestors)

Sulfonamides; Amides; Organic Chemicals; Sulfones; Sulfur Compounds; Piperazines; Heterocyclic Compounds, 1-Ring; Heterocyclic Compounds; Purines; Heterocyclic Compounds, 2-Ring; Heterocyclic Compounds, Fused-Ring; Carbon Compounds, Inorganic; Inorganic Chemicals; Gases; Oxides; Oxygen Compounds; Spectrum Analysis; Chemistry Techniques, Analytical; Investigative Techniques

Study Officials

• Kimbra Kenney, MD

  Uniformed Services University of the Health Sciences

  PRINCIPAL INVESTIGATOR

Study Design

• Study Type: interventional
• Phase: phase 2
• Allocation: NON RANDOMIZED
• Masking: NONE
• Purpose: BASIC SCIENCE
• Intervention Model: PARALLEL
• Sponsor Type: FED
• Responsible Party: PRINCIPAL INVESTIGATOR
• PI Title: Service Chief, Research Operations, NICoE, WRNMMC & Professor, USUHS Service and Department: NICoE, WRNMMC & Neurology, USUHS

Model Details: Exposures/interventions will be the same for healthy controls and participants with traumatic brain injury No blinding and no treatments.

Study Record Dates

• First Submitted: August 7, 2019
• First Posted: August 15, 2019
• Study Start: August 9, 2019
• Primary Completion: March 1, 2020
• Study Completion: March 1, 2020
• Last Updated: February 28, 2024

Record last verified: 2024-02

Data Sharing

• IPD Sharing: Will not share

Locations

US (1)