Mild Traumatic Brain Injury, Post-Concussion Syndrome, Traumatic Brain Injury
Conditions
Keywords
TBI, CVR, Hypercapnia, fNIRS, functional magnetic resonance imaging (fMRI), American football
Brief summary
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.
Interventions
DRUGSildenafil Citrate
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.
Sponsors
Boston University
University of Pennsylvania
Study design
Allocation
NA
Intervention model
SINGLE_GROUP
Primary purpose
TREATMENT
Masking
NONE
Intervention model description
Open-label, non-placebo controlled
Eligibility
Sex/Gender
MALE
Age
40 Years to 65 Years
Healthy volunteers
No
Inclusion criteria
1. Age 40-65 years 2. Former National Football League (NFL) players or former varsity college football players 3. Ability to undergo MRI scanning 4. Ability to read, write, and speak English 5. Stable doses of concomitant medications for last 2 weeks prior to enrollment 6. Diagnosis of post-concussive syndrome according to Diagnostic and Statistical Manual 5 (DSM-5) criteria
Exclusion criteria
1. Contraindication to sildenafil 2. Past medical history or evidence of penetrating brain injury 3. Daily therapy with a PDE5 inhibitor within the past 2 months, or taken as needed within past 4 weeks 4. History or evidence of pre-existing disabling neurological or psychiatric disorder not related to previous head injuries 5. History of melanoma 6. History of diagnosed obstructive/ restrictive pulmonary disease 7 .) Contraindication to MRI
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Effect of single dose sildenafil citrate treatment on global blood oxygen level-dependent (BOLD) response to hypercapnia. | Immediate | Determine if single dose treatment with sildenafil (60 mg orally) is effective in increasing the global BOLD response to hypercapnia (5% CO2). |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Effect of single dose sildenafil citrate treatment on functional near-infrared spectroscopy (fNIRS) response to hypercapnia. | Immediate | 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). |
| Maximum tolerable dose of sildenafil therapy without severe adverse events. | 5 weeks | 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. |
Other
| Measure | Time frame | Description |
|---|---|---|
| Effect of 5 weeks of sildenafil treatment on attention using the Digit Symbol Modalities Test. | 5 weeks | To evaluate the effects of 5 weeks of treatment with sildenafil citrate on attention, measured using the Digit Symbol Modalities Test. |
| Effect of 5 weeks of sildenafil treatment on executive function using the Trail Making Test Part B. | 5 weeks | To evaluate the effects of 5 weeks of treatment with sildenafil citrate on executive function, measured using the Trail Making Test Part B. |
| Effect of 5 weeks of sildenafil treatment on executive function using the Neuropsychological Assessment Battery (NAB) mazes. | 5 weeks | To evaluate the effects of 5 weeks of treatment with sildenafil citrate on executive function, measured using the Neuropsychological Assessment Battery (NAB) mazes. |
| Effect of 5 weeks sildenafil treatment on CVR as measured by BOLD response to hypercapnia. | 5 weeks | To evaluate the effects of 5 weeks of treatment on CVR by measuring BOLD signal in response to hypercapnia after 5 week treatment with sildenafil, compared to within-subject CVR response before sildenafil treatment. |
| Effect of 5 weeks of sildenafil treatment on language and memory using the Animal Fluency test. | 5 weeks | To evaluate the effects of 5 weeks of treatment with sildenafil citrate on language and memory, measured using the Animal Fluency test. |
| Effect of 5 weeks of sildenafil treatment on language and memory using the NAB List Learning test. | 5 weeks | To evaluate the effects of 5 weeks of treatment with sildenafil citrate on language and memory, measured using the NAB List Learning test. |
| Effect of 5 weeks of sildenafil treatment on daily function using the Functional Activities Questionnaire. | 5 weeks | To evaluate the effects of 5 weeks of treatment with sildenafil citrate on daily function, measured using the Functional Activities Questionnaire. The questionnaire requires the subject to rate the level of difficulty/dependency of each task listed (rating range from 0-3). A lower score indicates less difficulty in the listed activities while a higher score indicates more difficulty. The ratings are summed and the total score is reported (range 0-30). |
| Effect of 5 weeks of sildenafil treatment on executive function using the Controlled Oral Word Association Test (COWAT). | 5 weeks | To evaluate the effects of 5 weeks of treatment with sildenafil citrate on executive function, measured using the Controlled Oral Word Association Test (COWAT). |
| Effect of 5 weeks sildenafil treatment on CVR as measured by fNIRS response to hypercapnia. | 5 weeks | To evaluate the effects of 5 weeks of treatment on CVR by measuring fNIRS signal in response to hypercapnia after 5 week treatment with sildenafil, compared to within-subject CVR response before sildenafil treatment. |
| Effect of 5 weeks of sildenafil treatment on attention using Trail Making Test Part A. | 5 weeks | To evaluate the effects of 5 weeks of treatment with sildenafil citrate on attention, measured using the Trail Making Test Part A. |
Countries
United States
Outcome results
None listed