Cerebrovascular Reactivity in American Football Players

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

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.

Study Overview

• Status: Terminated
• Conditions: Traumatic Brain Injury; Post-Concussion Syndrome; Mild Traumatic Brain Injury
• Intervention / Treatment: Drug: Sildenafil Citrate

• Study Type: Interventional
• Enrollment (Actual): 7
• Phase: Phase 1

Contacts and Locations

Study Locations

• United States
  • Pennsylvania
    • Philadelphia, Pennsylvania, United States, 19104
      • Penn Presbyterian Medical Center

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 40 years to 65 years (ADULT, OLDER_ADULT)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: Male

Description

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

Study Plan

How is the study designed?

Design Details

• Primary Purpose: TREATMENT
• Allocation: NA
• Interventional Model: SINGLE_GROUP
• Masking: NONE

Number of Arms

1

Arms and Interventions

Participant Group / Arm

Intervention / Treatment

EXPERIMENTAL: Sildenafil Citrate; Open label treatment with forced titration of sildenafil citrate.

Drug: Sildenafil 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.; Other Names: Open label forced titration with sildenafil citrate.

What is the study measuring?

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

Other Outcome Measures

Outcome Measure	Measure Description	Time Frame
Effect of 5 weeks sildenafil treatment on CVR as measured by BOLD response to hypercapnia.	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.	5 weeks
Effect of 5 weeks sildenafil treatment on CVR as measured by fNIRS response to hypercapnia.	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.	5 weeks
Effect of 5 weeks of sildenafil treatment on attention using Trail Making Test Part A.	To evaluate the effects of 5 weeks of treatment with sildenafil citrate on attention, measured using the Trail Making Test Part A.	5 weeks
Effect of 5 weeks of sildenafil treatment on attention using the Digit Symbol Modalities Test.	To evaluate the effects of 5 weeks of treatment with sildenafil citrate on attention, measured using the Digit Symbol Modalities Test.	5 weeks
Effect of 5 weeks of sildenafil treatment on executive function using the Trail Making Test Part B.	To evaluate the effects of 5 weeks of treatment with sildenafil citrate on executive function, measured using the Trail Making Test Part B.	5 weeks
Effect of 5 weeks of sildenafil treatment on executive function using the Neuropsychological Assessment Battery (NAB) mazes.	To evaluate the effects of 5 weeks of treatment with sildenafil citrate on executive function, measured using the Neuropsychological Assessment Battery (NAB) mazes.	5 weeks
Effect of 5 weeks of sildenafil treatment on executive function using the Controlled Oral Word Association Test (COWAT).	To evaluate the effects of 5 weeks of treatment with sildenafil citrate on executive function, measured using the Controlled Oral Word Association Test (COWAT).	5 weeks
Effect of 5 weeks of sildenafil treatment on language and memory using the Animal Fluency test.	To evaluate the effects of 5 weeks of treatment with sildenafil citrate on language and memory, measured using the Animal Fluency test.	5 weeks
Effect of 5 weeks of sildenafil treatment on language and memory using the NAB List Learning test.	To evaluate the effects of 5 weeks of treatment with sildenafil citrate on language and memory, measured using the NAB List Learning test.	5 weeks
Effect of 5 weeks of sildenafil treatment on daily function using the Functional Activities Questionnaire.	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).	5 weeks

Collaborators and Investigators

• Sponsor: University of Pennsylvania
• Collaborators: Boston University

Study record dates

Study Major Dates

• Study Start (ACTUAL): March 1, 2018
• Primary Completion (ACTUAL): June 30, 2022
• Study Completion (ACTUAL): June 30, 2022

Study Registration Dates

• First Submitted: October 11, 2017
• First Submitted That Met QC Criteria: January 24, 2018
• First Posted (ACTUAL): January 31, 2018

Study Record Updates

• Last Update Posted (ACTUAL): September 21, 2022
• Last Update Submitted That Met QC Criteria: September 16, 2022
• Last Verified: September 1, 2022

More Information

Terms related to this study

• Keywords: TBI; fNIRS; Hypercapnia; functional magnetic resonance imaging (fMRI); CVR; American football
• Additional Relevant MeSH Terms: Brain Diseases; Central Nervous System Diseases; Nervous System Diseases; Craniocerebral Trauma; Trauma, Nervous System; Head Injuries, Closed; Wounds, Nonpenetrating; Brain Injuries; Wounds and Injuries; Brain Injuries, Traumatic; Post-Concussion Syndrome; Brain Concussion; Molecular Mechanisms of Pharmacological Action; Vasodilator Agents; Urological Agents; Enzyme Inhibitors; Anticoagulants; Phosphodiesterase Inhibitors; Chelating Agents; Sequestering Agents; Phosphodiesterase 5 Inhibitors; Calcium Chelating Agents; Sildenafil Citrate; Citric Acid; Sodium Citrate
• Other Study ID Numbers: 827103

Drug and device information, study documents

• 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.: No