Traumatic Brain Injury

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.

Sildenafil Citrate 50Mg Tab

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.

functional Near-infrared Spectroscopy (fNIRS)

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.

Carbon Dioxide (CO2) 5%

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.

Neuropsychological Assessments

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.

Gadolinium contrast infusion

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.

Blood sample collection for research purposes

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).

Structural brain Magnetic Resonance Imaging (MRI

Walter Reed National Military Medical Center

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

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

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.

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.

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

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

Bolus injection of 0.025 mmol/kg body weight (0.1 ml/kg BW) of Gadoxetic Acid Disodium (Primovist, BAY86-4873). Single i.v. injection during MRI procedure, with one contrast-enhanced MRI procedure per patient

Gadoxetic Acid Disodium (Primovist, BAY86-4873)

Sex: Female, Male

Characterization of first liver lesion type of referral diagnosis

Characterization of second liver lesion type of referral diagnosis

Characterization of third liver lesion type of referral diagnosis

Three Blinded Readers performed lesion detection in pre- and post-contrast MRI image sets. Per Blinded Reader/image set combination, sensitivity of lesion detection was calculated, as: (number of lesions detected in the reader/image set combination)/(number of lesions in Standard of Reference)*100%. Then, difference in sensitivity of lesion detection for post- minus pre-contrast MRI images (in percentage points) was calculated for each Blinded Reader.

Difference in Sensitivity of Lesion Detection in MRI Images (Post-contrast MRI Minus Pre-contrast MRI) Measured as Percentage Points

The on-site investigators performed lesion detection in pre- and post-contrast MRI image sets. Per image set, sensitivity of lesion detection was calculated, as: (number of lesions detected in image set)/(number of lesions in Standard of Reference)*100%. Then, difference in sensitivity of lesion detection for post- minus pre-contrast MRI (in percentage points) was calculated.

Difference in Sensitivity of Lesion Detection in MRI Images (Post-contrast MRI Minus Pre-contrast MRI) Assessed by Investigators Measured in Percentage Points

Three Blinded Reader performed lesion characterization in pre- and combined pre-/post-contrast MRI image set. Per Blinded Reader/image set combination, precision of lesion characterization was calculated: (number of unique Standard of Reference-matched characterizations detected for the Reader/image set combination)/(number of unique lesion characterizations in Standard of Reference)*100%. Then, difference in precision of lesion characterization for post- minus combined pre-/post-contrast MRI (in percentage points) was calculated for each Blinded Reader.

Difference in Precision of Lesion Characterization (Combined Pre- and Post-contrast Minus Pre-contrast MRI) Measured in Percentage Points

Overall Study

Therapeutic Area Head

Known or Suspected Focal Liver Lesions

Efficacy and Safety of Primovist in Chinese Patients

A Multicenter, Open-label Phase III Study of the Efficacy and Safety of Primovist as a Contrast Agent for Enhanced MR Imaging of Focal Liver Lesions in Chinese Patients

nephrogenic fibrosing dermopathy/fatigue

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

Efficacy and Safety of Primovist in Chinese Patients

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