Sildenafil Treatment for Mild TBI
Condition: Vascular System Injuries; Concussion, Brain; Post-Concussion Syndrome
MeSH terms: Post-Concussion Syndrome; Brain Concussion; Vascular System Injuries
Intervention: Sildenafil Citrate; Placebo oral capsule
Intervention description: Sildenafil 60mg once (Group 1) or daily for 2 weeks (Group 2); Placebo once (Group 1) or daily for 2 weeks (Group 2)
Intervention MeSH terms: Sildenafil Citrate
Phase: Phase 2
Study type: Interventional
Primary purpose: Treatment
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.
Enrollment: 22.0
Sex: Male
Minimum age: 18 Years
Maximum age: 35 Years
Healthy volunteers: Accepts Healthy Volunteers
Keywords: Sildenafil; Concussion; CBF; CVR

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.
    

Eligibility 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