Sildenafil Treatment for Mild TBI

NCT03598140 | Terminated Phase 2 Results DMC FDA Drug

• 1 other identifier: STU 032018-063
• Study Type: interventional
• Target: 22
• Locations: 1 country
• Sites: 1

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.

Conditions

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

Keywords

Sildenafil; Concussion; CBF; CVR

Outcome Measures

Primary Outcomes (1)

• Arterial Spin Labeling

  Prior to and after sildenafil treatment (60mg) cerebral blood flow will be measured in the athletes and healthy controls.

  3 years

Secondary Outcomes (3)

• Rivermead Post Concussion Symptoms Questionnaire (RPQ)

  3 years

• Hopkins Verbal Learning Task (HVLT)

  3 years

• BOLD MRI With Hypercapnia

  3 years

Study Arms (2)

Placebo oral capsule

PLACEBO COMPARATOR

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

Sildenafil Citrate

ACTIVE COMPARATOR

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

Interventions

Sildenafil Citrate DRUG

Sildenafil 60mg once (Group 1) or daily for 2 weeks (Group 2)

Also known as: Viagra

Sildenafil Citrate

Placebo oral capsule DRUG

Placebo once (Group 1) or daily for 2 weeks (Group 2)

Also known as: Placebo

Placebo oral capsule

Eligibility Criteria

• Age: 18 Years - 35 Years
• Sex: male
• Healthy Volunteers: Yes
• Age Groups: Adult (18-64)

You may qualify if:

• For Athletes
• Age 18-35
• Male or female professional boxers/MMA fighters
• Ability to undergo MR imaging procedures
• At least one of the following:
• Knockout (KO)/Technical Knockout (TKO) scored by fight referee.
• Greater than 25 blows to the head.
• Significant post-concussive symptoms (Symptom Score \> 1 on at least 3 items from the Rivermead Post-Concussion Questionnaire)
• For Controls
• Age 18-35
• Male of female who do not participate in contact sports
• Screen negative for mild TBI (mTBI) using Ohio State TBI Identification

You may not qualify if:

• Contraindication to sildenafil which includes the following:
• Current use of organic nitrate vasodilators
• Use of ritonavir (HIV-protease inhibitor)
• Current use of erythromycin, ketoconazole, or itraconazole
• Current use of cimetidine
• Current resting hypotension (BP \< 90/50 mm Hg)
• Current severe renal insufficiency (Creatinine Clearance \< 30 milliliters/minute)
• Current hepatic cirrhosis
• Current cardiac failure or coronary artery disease causing unstable angina
• Retinitis pigmentosa
• Known hypersensitivity or allergy to sildenafil of any of its components
• Daily therapy with a PDE5 inhibitor within the past 2 months
• Immediate hospitalization for severe concussion
• History of neurological or psychiatric disorder not related to TBI
• Subjects with metal implants that would interfere with the MR imaging procedures

Sponsors & Collaborators

• University of Texas Southwestern Medical Center: lead

Study Sites (1)

University of Texas Southwestern Medical Center

Dallas, Texas, 75390, United States

Location

MeSH Terms

Conditions

Vascular System Injuries; Brain Concussion; Post-Concussion Syndrome

Interventions

Sildenafil Citrate

Condition Hierarchy (Ancestors)

Vascular Diseases; Cardiovascular Diseases; Wounds and Injuries; Brain Injuries, Traumatic; Brain Injuries; Brain Diseases; Central Nervous System Diseases; Nervous System Diseases; Craniocerebral Trauma; Trauma, Nervous System; Head Injuries, Closed; Wounds, Nonpenetrating

Intervention Hierarchy (Ancestors)

Sulfonamides; Amides; Organic Chemicals; Sulfones; Sulfur Compounds; Piperazines; Heterocyclic Compounds, 1-Ring; Heterocyclic Compounds; Purines; Heterocyclic Compounds, 2-Ring; Heterocyclic Compounds, Fused-Ring

Limitations and Caveats

Dr. Gaston who was the initial PI, left the institution and the study has been stopped.The Department was able to manage to report the results that they could gather as the previous PI didn't disclose the information before leaving the institution.

Results Point of Contact

• Title: Dr. Joshua Gaston
• Organization: UTexas Southwestern

drgaston@outlook.com

817-637-8043

Publication Agreements

• PI is Sponsor Employee: Yes

Study Design

• Study Type: interventional
• Phase: phase 2
• Allocation: RANDOMIZED
• Masking: DOUBLE
• Who Masked: PARTICIPANT, INVESTIGATOR
• Masking Details: 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.
• Purpose: TREATMENT
• Intervention Model: PARALLEL
• Sponsor Type: OTHER
• Responsible Party: PRINCIPAL INVESTIGATOR
• PI Title: Assistant Professor

Model Details: 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.

Study Record Dates

• First Submitted: June 11, 2018
• First Posted: July 26, 2018
• Study Start: July 25, 2018
• Primary Completion: May 29, 2019
• Study Completion: May 29, 2019
• Last Updated: November 19, 2020
• Results First Posted: November 19, 2020

Record last verified: 2020-10

Locations

US (1)