Sildenafil Treatment for Mild TBI

The University of Texas System (UT)

Status and phase: Terminated; Phase 2

Conditions: Vascular System Injuries; Post-Concussion Syndrome; Concussion, Brain

Treatments: Drug: Placebo oral capsule; Drug: Sildenafil Citrate

Study type: Interventional

Funder types: Other

Identifiers

NCT03598140

STU 032018-063

Details and patient eligibility

About

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.

Full 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.

Enrollment: 22 patients

Sex: Male

Ages: 18 to 35 years old

Volunteers: Accepts Healthy Volunteers

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

Trial design

Primary purpose: Treatment

Allocation: Randomized

Interventional model: Parallel Assignment

Masking: Double Blind

---

22 participants in 2 patient groups, including a placebo group

Placebo oral capsule

Placebo Comparator group

Description:

If randomized to placebo, the participant will receive single (Group 1) or multiple (once-a-day for 14 days; Group 2) treatments.

Treatment:

Drug: Placebo oral capsule

Sildenafil Citrate

Active Comparator group

Description:

If randomized to sildenafil (60mg), the participant will receive single (Group 1) or multiple (once-a-day for 14 days; Group 2) treatments.

Treatment:

Drug: Sildenafil Citrate