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Sildenafil Treatment for Mild TBI

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ClinicalTrials.gov Identifier: NCT03598140
Recruitment Status : Recruiting
First Posted : July 26, 2018
Last Update Posted : September 10, 2019
Sponsor:
Information provided by (Responsible Party):
Joshua Gatson, University of Texas Southwestern Medical Center

Brief Summary:
About 300,000 people are hospitalized for traumatic brain injury (TBI) each year. After TBI, secondary brain injury escalates due in part to heightened levels of oxidant injury, inflammation, and vascular injury. Traumatic cerebral vascular injury (TCVI) may begin almost immediately after the primary injury and evolve into chronic neurodegenerative conditions. TCVI is a very complex TBI endophenotype and microvascular injuries have been described in a plethora of animal and human TBI studies. These injuries consist of endothelial injury, disruption of the blood brain barrier (BBB), a reduction of capillary density, intravascular microthrombi, and white-matter degeneration. Recently, use of magnetic resonance imaging (MRI)-Blood Oxygen Level Dependent (BOLD) combined with hypercapnia (high spatial and temporal resolution) by our research group has proven to be more sensitive at measuring alterations of cerebral blood flow (CBF) in TBI subjects. The goal of the proposed research is to test the efficacy of Viagra® (sildenafil) at normalizing CBF and improving cognitive outcomes in people that have experienced a TBI. Sildenafil is a phosphodiesterase-5 (PDE-5) inhibitor that has previously been administered as a therapy for high blood pressure and erectile dysfunction. In people that have been affected by stroke-induce neurotrauma, sildenafil improved CBF and was found to be neuroprotective. With respect to chronic TBI, previous studies have demonstrated that sildenafil therapy potentiates cardiovascular reactivity (CVR) in areas of the brain with damaged endothelium. In this proposal, the investigators will test the hypothesis that sildenafil treatment in boxers/Mixed Martial Arts (MMA) fighters soon after concussion normalizes CBF, potentiates CVR, reduces post-concussion symptoms, and improves cognition.

Condition or disease Intervention/treatment Phase
Vascular System Injuries Concussion, Brain Post-Concussion Syndrome Drug: Sildenafil Citrate Drug: Placebo oral capsule Phase 2

Detailed Description:
In this study, 100 professional boxers that experience a concussion will be enrolled, randomized to either placebo or sildenafil (60mg) drug treatment, and arterial spin labeling and BOLD-MRI with hypercapnia will used to assess CBF and CVR, respectively. Symptom reporting, blood biomarkers, and neuropsychological testing will also be conducted. The timepoints for this study are baseline (pre-fight), and once between days 1 and 3 and day 30 after injury.

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Study Type : Interventional  (Clinical Trial)
Estimated Enrollment : 180 participants
Allocation: Randomized
Intervention Model: Parallel Assignment
Intervention Model Description: This study is a placebo-controlled, double-blinded clinical trial. Randomization will be 1:1 sildenafil:placebo, and will be in blocks of 10. In this study, 100 boxers and 80 controls will be enrolled and randomized.
Masking: Double (Participant, Investigator)
Masking Description: Investigators associated with this study will not have access to the randomization schedule. The principal investigator, study team, and study subjects will be blinded in this study.
Primary Purpose: Treatment
Official Title: Sildenafil Treatment for Traumatic Vascular Injury in Athletes
Actual Study Start Date : July 25, 2018
Estimated Primary Completion Date : June 30, 2021
Estimated Study Completion Date : December 31, 2021

Resource links provided by the National Library of Medicine


Arm Intervention/treatment
Placebo Comparator: Placebo oral capsule
If randomized to placebo, the participant will receive single (Group 1) or multiple (once-a-day for 14 days; Group 2) treatments.
Drug: Placebo oral capsule
Placebo once (Group 1) or daily for 2 weeks (Group 2)
Other Name: Placebo

Active Comparator: Sildenafil Citrate
If randomized to sildenafil (60mg), the participant will receive single (Group 1) or multiple (once-a-day for 14 days; Group 2) treatments.
Drug: Sildenafil Citrate
Sildenafil 60mg once (Group 1) or daily for 2 weeks (Group 2)
Other Name: Viagra




Primary Outcome Measures :
  1. Arterial Spin Labeling [ Time Frame: 3 years ]
    Prior to and after sildenafil treatment (60mg) cerebral blood flow will be measured in the athletes and healthy controls.


Secondary Outcome Measures :
  1. Rivermead Post Concussion Symptoms Questionnaire (RPQ) [ Time Frame: 3 years ]

    This test will measure a range of injury severities:

    0= Not experienced at all

    1. No more of a problem
    2. A mild problem
    3. A moderate problem
    4. A severe problem Improvement or worsening of symptoms (headaches, nausea, fatigue, feeling depressed, light sensitivity, double vision, etc.) will be recorded. The combined score from all symptoms will be recorded at the indicated time-points.

  2. Hopkins Verbal Learning Task (HVLT) [ Time Frame: 3 years ]
    Using the HVLT, performance in learning and memory will be measured in concussed athletes and healthy controls.

  3. BOLD MRI with hypercapnia [ Time Frame: 3 years ]
    Before and after sildenafil treatment, cerebrovascular reactivity will be measured in the athletes and healthy controls.



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Ages Eligible for Study:   18 Years to 35 Years   (Adult)
Sexes Eligible for Study:   Male
Accepts Healthy Volunteers:   Yes
Criteria

Inclusion Criteria:

For Athletes

  1. Age 18-35
  2. Male or female professional boxers/MMA fighters
  3. Ability to undergo MR imaging procedures
  4. At least one of the following:

    1. Knockout (KO)/Technical Knockout (TKO) scored by fight referee.
    2. Greater than 25 blows to the head.
  5. Significant post-concussive symptoms (Symptom Score > 1 on at least 3 items from the Rivermead Post-Concussion Questionnaire)

For Controls

  1. Age 18-35
  2. Male of female who do not participate in contact sports
  3. Screen negative for mild TBI (mTBI) using Ohio State TBI Identification

Exclusion Criteria:

  1. Contraindication to sildenafil which includes the following:

    1. Current use of organic nitrate vasodilators
    2. Use of ritonavir (HIV-protease inhibitor)
    3. Current use of erythromycin, ketoconazole, or itraconazole
    4. Current use of cimetidine
    5. Current resting hypotension (BP < 90/50 mm Hg)
    6. Current severe renal insufficiency (Creatinine Clearance < 30 milliliters/minute)
    7. Current hepatic cirrhosis
    8. Current cardiac failure or coronary artery disease causing unstable angina
    9. Retinitis pigmentosa
    10. Known hypersensitivity or allergy to sildenafil of any of its components
  2. Daily therapy with a PDE5 inhibitor within the past 2 months
  3. Immediate hospitalization for severe concussion
  4. History of neurological or psychiatric disorder not related to TBI
  5. Known inclusion in another interventional clinical trial
  6. Subjects with metal implants that would interfere with the MR imaging procedures
  7. Sickle cell disease
  8. History of priapism

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): NCT03598140


Contacts
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Contact: Joshua Gatson, PhD 214-648-0499 ext 80499 joshua.gatson@utsouthwestern.edu

Locations
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United States, Texas
University of Texas Southwestern Medical Center Recruiting
Dallas, Texas, United States, 75390
Contact: Joshua W. Gatson, Ph.D.    214-648-0499 ext 80499    joshua.gatson@utsouthwestern.edu   
Sponsors and Collaborators
University of Texas Southwestern Medical Center

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Responsible Party: Joshua Gatson, Assistant Professor, University of Texas Southwestern Medical Center
ClinicalTrials.gov Identifier: NCT03598140    
Other Study ID Numbers: 032018-063
First Posted: July 26, 2018    Key Record Dates
Last Update Posted: September 10, 2019
Last Verified: September 2019

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Studies a U.S. FDA-regulated Drug Product: Yes
Studies a U.S. FDA-regulated Device Product: No
Keywords provided by Joshua Gatson, University of Texas Southwestern Medical Center:
Sildenafil
Concussion
CBF
CVR
Additional relevant MeSH terms:
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Post-Concussion Syndrome
Brain Concussion
Vascular System Injuries
Wounds and Injuries
Head Injuries, Closed
Craniocerebral Trauma
Trauma, Nervous System
Nervous System Diseases
Wounds, Nonpenetrating
Brain Injuries, Traumatic
Brain Injuries
Brain Diseases
Central Nervous System Diseases
Vascular Diseases
Cardiovascular Diseases
Sildenafil Citrate
Citric Acid
Sodium 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