Sildenafil Treatment for Mild TBI

• Sponsor: University of Texas Southwestern Medical Center (Other)
• Overall Status: Terminated
• CT.gov ID: NCT03598140
• Collaborator: (none)
• Enrollment: 22
• Location: 1
• Arms: 2
• Actual Duration (Months): 10.1
• Patients Per Site Per Month: 2.2

Study Details

Study Description

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.

Study Design

• Study Type: Interventional
• Actual Enrollment: 22 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.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: Jul 25, 2018
• Actual Primary Completion Date: May 29, 2019
• Actual Study Completion Date: May 29, 2019

Arms and Interventions

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 Names: 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 Names: Viagra

Outcome Measures

Primary Outcome Measures

1. Arterial Spin Labeling [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) [3 years]

   This test will measure a range of injury severities: 0= Not experienced at all No more of a problem A mild problem A moderate problem 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) [3 years]

   Using the HVLT, performance in learning and memory will be measured in concussed athletes and healthy controls.

3. BOLD MRI With Hypercapnia [3 years]

   Before and after sildenafil treatment, cerebrovascular reactivity will be measured in the athletes and healthy controls.

Eligibility Criteria

Criteria

• Ages Eligible for Study: 18 Years to 35 Years
• Sexes Eligible for Study: Male
• Accepts Healthy Volunteers: Yes

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:

5. Knockout (KO)/Technical Knockout (TKO) scored by fight referee.

6. Greater than 25 blows to the head.

7. 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:

2. Current use of organic nitrate vasodilators

3. Use of ritonavir (HIV-protease inhibitor)

4. Current use of erythromycin, ketoconazole, or itraconazole

5. Current use of cimetidine

6. Current resting hypotension (BP < 90/50 mm Hg)

7. Current severe renal insufficiency (Creatinine Clearance < 30 milliliters/minute)

8. Current hepatic cirrhosis

9. Current cardiac failure or coronary artery disease causing unstable angina

10. Retinitis pigmentosa

11. Known hypersensitivity or allergy to sildenafil of any of its components

12. Daily therapy with a PDE5 inhibitor within the past 2 months

13. Immediate hospitalization for severe concussion

14. History of neurological or psychiatric disorder not related to TBI

15. Known inclusion in another interventional clinical trial

16. Subjects with metal implants that would interfere with the MR imaging procedures

17. Sickle cell disease

18. History of priapism

Contacts and Locations

Locations

	Site	City	State	Country	Postal Code
1	University of Texas Southwestern Medical Center	Dallas	Texas	United States	75390

Sponsors and Collaborators

• University of Texas Southwestern Medical Center

Investigators

None specified.

Study Documents (Full-Text)

• Study Protocol and Statistical Analysis Plan - Mar 1, 2018

More Information

Publications

None provided.

• Responsible Party: Kan Ding, Assistant Professor, University of Texas Southwestern Medical Center
• ClinicalTrials.gov Identifier: NCT03598140
• Other Study ID Numbers: STU 032018-063
• First Posted: Jul 26, 2018
• Last Update Posted: Nov 19, 2020
• Last Verified: Oct 1, 2020

• Studies a U.S. FDA-regulated Drug Product: Yes
• Studies a U.S. FDA-regulated Device Product: No
• Keywords provided by Kan Ding, Assistant Professor, University of Texas Southwestern Medical Center: Sildenafil; Concussion; CBF; CVR
• Additional relevant MeSH terms: Post-Concussion Syndrome; Brain Concussion; Vascular System Injuries; Sildenafil Citrate

Study Results

Participant Flow

Arm/Group Title	Placebo Oral Capsule	Sildenafil Citrate
Arm/Group Description	If randomized to placebo, the participant will receive single (Group 1) or multiple (once-a-day for 14 days; Group 2) treatments. Placebo oral capsule: Placebo once (Group 1) or daily for 2 weeks (Group 2)	If randomized to sildenafil (60mg), the participant will receive single (Group 1) or multiple (once-a-day for 14 days; Group 2) treatments. Sildenafil Citrate: Sildenafil 60mg once (Group 1) or daily for 2 weeks (Group 2)
Period Title: Overall Study
STARTED	10	11
COMPLETED	9	11
NOT COMPLETED	1	0

Baseline Characteristics

Arm/Group Title	Placebo Oral Capsule	Sildenafil Citrate	Total
Arm/Group Description	If randomized to placebo, the participant will receive single (Group 1) or multiple (once-a-day for 14 days; Group 2) treatments. Placebo oral capsule: Placebo once (Group 1) or daily for 2 weeks (Group 2)	If randomized to sildenafil (60mg), the participant will receive single (Group 1) or multiple (once-a-day for 14 days; Group 2) treatments. Sildenafil Citrate: Sildenafil 60mg once (Group 1) or daily for 2 weeks (Group 2)	Total of all reporting groups
Overall Participants	0	0	0
Age () []
<=18 years
Between 18 and 65 years
>=65 years
Sex: Female, Male () []
Female
Male
Race and Ethnicity Not Collected () []

Outcome Measures

1. Primary Outcome

Title	Arterial Spin Labeling
Description	Prior to and after sildenafil treatment (60mg) cerebral blood flow will be measured in the athletes and healthy controls.
Time Frame	3 years

Outcome Measure Data

Analysis Population Description

The PI has left the institution, all efforts to locate the data have been exhausted and therefore no results are available to be reported

Arm/Group Title	Placebo Oral Capsule	Sildenafil Citrate
Arm/Group Description	If randomized to placebo, the participant will receive single (Group 1) or multiple (once-a-day for 14 days; Group 2) treatments. Placebo oral capsule: Placebo once (Group 1) or daily for 2 weeks (Group 2)	If randomized to sildenafil (60mg), the participant will receive single (Group 1) or multiple (once-a-day for 14 days; Group 2) treatments. Sildenafil Citrate: Sildenafil 60mg once (Group 1) or daily for 2 weeks (Group 2)
Measure Participants	0	0

2. Secondary Outcome

Title	Rivermead Post Concussion Symptoms Questionnaire (RPQ)
Description	This test will measure a range of injury severities: 0= Not experienced at all No more of a problem A mild problem A moderate problem 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.
Time Frame	3 years

Outcome Measure Data

Analysis Population Description

The PI has left the institution, all efforts to locate the data have been exhausted and therefore no results are available to be reported

Arm/Group Title	Placebo Oral Capsule	Sildenafil Citrate
Arm/Group Description	If randomized to placebo, the participant will receive single (Group 1) or multiple (once-a-day for 14 days; Group 2) treatments. Placebo oral capsule: Placebo once (Group 1) or daily for 2 weeks (Group 2)	If randomized to sildenafil (60mg), the participant will receive single (Group 1) or multiple (once-a-day for 14 days; Group 2) treatments. Sildenafil Citrate: Sildenafil 60mg once (Group 1) or daily for 2 weeks (Group 2)
Measure Participants	0	0

3. Secondary Outcome

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

Outcome Measure Data

Analysis Population Description

The PI has left the institution, all efforts to locate the data have been exhausted and therefore no results are available to be reported

Arm/Group Title	Placebo Oral Capsule	Sildenafil Citrate
Arm/Group Description	If randomized to placebo, the participant will receive single (Group 1) or multiple (once-a-day for 14 days; Group 2) treatments. Placebo oral capsule: Placebo once (Group 1) or daily for 2 weeks (Group 2)	If randomized to sildenafil (60mg), the participant will receive single (Group 1) or multiple (once-a-day for 14 days; Group 2) treatments. Sildenafil Citrate: Sildenafil 60mg once (Group 1) or daily for 2 weeks (Group 2)
Measure Participants	0	0

4. Secondary Outcome

Title	BOLD MRI With Hypercapnia
Description	Before and after sildenafil treatment, cerebrovascular reactivity will be measured in the athletes and healthy controls.
Time Frame	3 years

Outcome Measure Data

Analysis Population Description

The PI has left the institution, all efforts to locate the data have been exhausted and therefore no results are available to be reported

Arm/Group Title	Placebo Oral Capsule	Sildenafil Citrate
Arm/Group Description	If randomized to placebo, the participant will receive single (Group 1) or multiple (once-a-day for 14 days; Group 2) treatments. Placebo oral capsule: Placebo once (Group 1) or daily for 2 weeks (Group 2)	If randomized to sildenafil (60mg), the participant will receive single (Group 1) or multiple (once-a-day for 14 days; Group 2) treatments. Sildenafil Citrate: Sildenafil 60mg once (Group 1) or daily for 2 weeks (Group 2)
Measure Participants	0	0

Adverse Events

Time Frame	The PI has left the institution, all efforts to locate the data have been exhausted and therefore no adverse events available to be reported
Adverse Event Reporting Description	Study closed, all efforts to obtain data have been exhausted, data cannot be reported
Arm/Group Title	Placebo Oral Capsule		Sildenafil Citrate
Arm/Group Description	If randomized to placebo, the participant will receive single (Group 1) or multiple (once-a-day for 14 days; Group 2) treatments. Placebo oral capsule: Placebo once (Group 1) or daily for 2 weeks (Group 2)		If randomized to sildenafil (60mg), the participant will receive single (Group 1) or multiple (once-a-day for 14 days; Group 2) treatments. Sildenafil Citrate: Sildenafil 60mg once (Group 1) or daily for 2 weeks (Group 2)
All Cause Mortality
	Placebo Oral Capsule		Sildenafil Citrate
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	0/0 (NaN)		0/0 (NaN)
Serious Adverse Events
	Placebo Oral Capsule		Sildenafil Citrate
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	0/0 (NaN)		0/0 (NaN)
Other (Not Including Serious) Adverse Events
	Placebo Oral Capsule		Sildenafil Citrate
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	0/0 (NaN)		0/0 (NaN)

Limitations/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.

More Information

Certain Agreements

All Principal Investigators ARE employed by the organization sponsoring the study.

There is NOT an agreement between Principal Investigators and the Sponsor (or its agents) that restricts the PI's rights to discuss or publish trial results after the trial is completed.