Cerebrovascular Reactivity in American Football Players

Study Overview
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Brief Summary
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Investigators will measure cerebrovascular reactivity (CVR) using functional near-infrared spectroscopy (fNIRS) and magnetic resonance imaging (MRI) during the chronic phase after repetitive mild traumatic brain injury (rmTBI) as a biomarker of traumatic cerebrovascular injury (TCVI). We hypothesize that CVR will be decreased in patients with rmTBI and that these decreases will correlate with clinical outcomes. Furthermore, we predict that 5 week administration of a phosphodiesterase 5 (PDE5) inhibitor, sildenafil citrate, will augment CVR in patients with a history rmTBI.

Official Title
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Cerebrovascular Reactivity Assessed With Functional Near-infrared Spectroscopy and Magnetic Resonance Imaging as a Biomarker of Traumatic Microvascular Injury in American Football Players

Conditions
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Traumatic Brain Injury, Mild Traumatic Brain Injury, Post-Concussion Syndrome

Intervention / Treatment
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* Drug: Sildenafil Citrate


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Age 40-65 years Former National Football League (NFL) players or former varsity college football players Ability to undergo MRI scanning Ability to read, write, and speak English Stable doses of concomitant medications for last 2 weeks prior to enrollment Diagnosis of post-concussive syndrome according to Diagnostic and Statistical Manual 5 (DSM-5) criteria Exclusion Criteria: Contraindication to sildenafil Past medical history or evidence of penetrating brain injury Daily therapy with a PDE5 inhibitor within the past 2 months, or taken as needed within past 4 weeks History or evidence of pre-existing disabling neurological or psychiatric disorder not related to previous head injuries History of melanoma History of diagnosed obstructive/ restrictive pulmonary disease 7 .) Contraindication to MRI

Ages Eligible for Study
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Minimum Age: 40 Years
Maximum Age: 65 Years

Sexes Eligible for Study
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Male

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Intervention Model: Single Group Assignment
Interventional Model Description: Open-label, non-placebo controlled
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Sildenafil Citrate<br>Open label treatment with forced titration of sildenafil citrate. | Drug: Sildenafil Citrate<br>* Three 20 mg capsules for the single dose studies. For the 5-week treatment phase, subjects will be assigned to a titration of doses for the 5 week duration of the study. Subjects will be instructed to take 20mg twice per day for 3 days, then 40mg twice per day for 3 days, and then 80mg twice per day for 4 weeks.<br>* Other names: Open label forced titration with sildenafil citrate.;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Effect of single dose sildenafil citrate treatment on global blood oxygen level-dependent (BOLD) response to hypercapnia. | Determine if single dose treatment with sildenafil (60 mg orally) is effective in increasing the global BOLD response to hypercapnia (5% CO2). | Immediate | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Effect of single dose sildenafil citrate treatment on functional near-infrared spectroscopy (fNIRS) response to hypercapnia. | Determine if single dose treatment with sildenafil (60 mg orally) is effective in increasing the functional near-infrared spectroscopy (fNIRS) response to hypercapnia (5% CO2). | Immediate | 
| Maximum tolerable dose of sildenafil therapy without severe adverse events. | The number of participants reporting treatment-related adverse events (AEs) and serious adverse events (SAEs) will be monitored after each dose increase. AEs and SAEs are assessed using CTCAE, v4.0. | 5 weeks | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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TBI, CVR, Hypercapnia, fNIRS, functional magnetic resonance imaging (fMRI), American football