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Cerebrovascular Reactivity in American Football Players

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ClinicalTrials.gov Identifier: NCT03417492
Recruitment Status : Recruiting
First Posted : January 31, 2018
Last Update Posted : April 12, 2018
Sponsor:
Collaborator:
Boston University
Information provided by (Responsible Party):
Ramon Diaz-Arrastia,, University of Pennsylvania

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.

Condition or disease Intervention/treatment Phase
Traumatic Brain Injury Mild Traumatic Brain Injury Post-Concussion Syndrome Drug: Sildenafil Citrate Phase 1

Study Type : Interventional  (Clinical Trial)
Estimated Enrollment : 30 participants
Intervention Model: Single Group Assignment
Intervention Model Description: Open-label, non-placebo controlled
Masking: None (Open Label)
Primary Purpose: Treatment
Official Title: Cerebrovascular Reactivity Assessed With Functional Near-infrared Spectroscopy and Magnetic Resonance Imaging as a Biomarker of Traumatic Microvascular Injury in American Football Players
Actual Study Start Date : March 1, 2018
Estimated Primary Completion Date : September 1, 2019
Estimated Study Completion Date : September 1, 2019

Resource links provided by the National Library of Medicine


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 Name: Open label forced titration with sildenafil citrate.




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


Secondary Outcome Measures :
  1. Effect of single dose sildenafil citrate treatment on functional near-infrared spectroscopy (fNIRS) response to hypercapnia. [ Time Frame: 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).

  2. Maximum tolerable dose of sildenafil therapy without severe adverse events. [ Time Frame: 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 Outcome Measures:
  1. Effect of 5 weeks sildenafil treatment on CVR as measured by BOLD response to hypercapnia. [ Time Frame: 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.

  2. Effect of 5 weeks sildenafil treatment on CVR as measured by fNIRS response to hypercapnia. [ Time Frame: 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.

  3. Effect of 5 weeks of sildenafil treatment on attention using Trail Making Test Part A. [ Time Frame: 5 weeks ]
    To evaluate the effects of 5 weeks of treatment with sildenafil citrate on attention, measured using the Trail Making Test Part A.

  4. Effect of 5 weeks of sildenafil treatment on attention using the Digit Symbol Modalities Test. [ Time Frame: 5 weeks ]
    To evaluate the effects of 5 weeks of treatment with sildenafil citrate on attention, measured using the Digit Symbol Modalities Test.

  5. Effect of 5 weeks of sildenafil treatment on executive function using the Trail Making Test Part B. [ Time Frame: 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.

  6. Effect of 5 weeks of sildenafil treatment on executive function using the Neuropsychological Assessment Battery (NAB) mazes. [ Time Frame: 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.

  7. Effect of 5 weeks of sildenafil treatment on executive function using the Controlled Oral Word Association Test (COWAT). [ Time Frame: 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).

  8. Effect of 5 weeks of sildenafil treatment on language and memory using the Animal Fluency test. [ Time Frame: 5 weeks ]
    To evaluate the effects of 5 weeks of treatment with sildenafil citrate on language and memory, measured using the Animal Fluency test.

  9. Effect of 5 weeks of sildenafil treatment on language and memory using the NAB List Learning test. [ Time Frame: 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.

  10. Effect of 5 weeks of sildenafil treatment on daily function using the Functional Activities Questionnaire. [ Time Frame: 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).



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Ages Eligible for Study:   40 Years to 65 Years   (Adult, Older Adult)
Sexes Eligible for Study:   Male
Accepts Healthy Volunteers:   No
Criteria

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

Information from the National Library of Medicine

To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.

Please refer to this study by its ClinicalTrials.gov identifier (NCT number): NCT03417492


Contacts
Contact: Ramon Diaz-Arrastia, MD, PhD 215-662-9732 ramon.diaz-arrastia@uphs.upenn.edu
Contact: Danielle Sandsmark, MD, PhD danielle.sandsmark@uphs.upenn.edu

Locations
United States, Pennsylvania
Penn Presbyterian Medical Center Recruiting
Philadelphia, Pennsylvania, United States, 19104
Contact    800-789-7366      
Principal Investigator: Ramon Diaz-Arrastia, MD, PhD         
Sub-Investigator: Danielle Sandsmark, MD, PhD         
Sponsors and Collaborators
University of Pennsylvania
Boston University

Responsible Party: Ramon Diaz-Arrastia,, Presidential Professor, University of Pennsylvania
ClinicalTrials.gov Identifier: NCT03417492     History of Changes
Other Study ID Numbers: 827103
First Posted: January 31, 2018    Key Record Dates
Last Update Posted: April 12, 2018
Last Verified: April 2018

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

Keywords provided by Ramon Diaz-Arrastia,, University of Pennsylvania:
TBI
CVR
Hypercapnia
fNIRS
functional magnetic resonance imaging (fMRI)
American football

Additional relevant MeSH terms:
Wounds and Injuries
Brain Injuries
Brain Injuries, Traumatic
Brain Concussion
Post-Concussion Syndrome
Brain Diseases
Central Nervous System Diseases
Nervous System Diseases
Craniocerebral Trauma
Trauma, Nervous System
Head Injuries, Closed
Wounds, Nonpenetrating
Citric Acid
Sildenafil Citrate
Anticoagulants
Calcium Chelating Agents
Chelating Agents
Sequestering Agents
Molecular Mechanisms of Pharmacological Action
Vasodilator Agents
Phosphodiesterase 5 Inhibitors
Phosphodiesterase Inhibitors
Enzyme Inhibitors
Urological Agents