Sildenafil for Cerebrovascular Dysfunction in Chronic Traumatic Brain Injury.

NCT01762475 | Completed Phase 2

• 1 other identifier: T-N-2215
• Study Type: interventional
• Target: 59
• Locations: 1 country
• Sites: 1

Brief Summary

The purpose of this study is to determine whether sildenafil (Viagra®) is effective in improving cerebral blood flow and cerebrovascular reactivity inpatients who have persistent symptoms at least 6 months after a traumatic brain injury (TBI).

Conditions

Traumatic Brain Injury; Post-concussive Syndrome

Keywords

Magnetic resonance imaging; Blood oxygen level dependent signal; Hypercapnia; Endothelial progenitor cells

Outcome Measures

Primary Outcomes (1)

• Cerebrovascular reactivity

  Single dose treatment with sildenafil (50 mg orally) is effective in increasing the global BOLD response to hypercapnia in symptomatic patients in the chronic stage after TBI.

  24 months

Secondary Outcomes (1)

• Safety and tolerability

  24 months

Other Outcomes (9)

• Regional cerebrovascular reactivity

  24 months

• Cerebrovascular reactivity in TBI patients vs. healthy controls

  24 months

• Cerebrovascular reactivity in symptomatic TBI vs. asymptomatic TBI

  24 months

Study Arms (3)

Experimental: Group 1--Symptomatic TBI

EXPERIMENTAL

Experimental Group, Group 1, will consist of twenty-four male and female adult participants who have persistent TBI symptoms lasting more than six months. Participants in the experimental group will be randomized in a 1:1 ratio, assigned to group a or b. Participants randomized into Group 1a will take placebo twice daily for 8 weeks, followed by 8 weeks of sildenafil 25 mg twice daily with a 2-week washout period between the two 8-week periods. Participants randomized into Group 1b will take sildenafil 25 mg twice daily for 8 weeks, followed by 8 weeks of placebo twice daily with a 2-week washout period between the two treatment periods.

Drug: Sildenafil

Active Comparator: Group 2--Healthy Controls

ACTIVE COMPARATOR

Group 2 will be comprised of twenty male and female adult participants who have never experienced a TBI or concussion to serve as age and gender-matched healthy controls. Participants in Group 2 will have a single visit to measure cerebrovascular reactivity before and after a single dose of sildenafil (50 mg by mouth).

Drug: Sildenafil

Group 3--Recovered TBI

ACTIVE COMPARATOR

Group 3 will be comprised of twenty male and female adult participants who have experienced a TBI, have recovered, and are asymptomatic at the time of screening, to serve as age and gender-matched asymptomatic TBI controls. Participants in Group 3 will have a single visit to measure cerebrovascular reactivity before and after a single dose of sildenafil (50 mg by mouth).

Drug: Sildenafil

Interventions

Sildenafil DRUG

Also known as: Viagra

Active Comparator: Group 2--Healthy Controls; Experimental: Group 1--Symptomatic TBI; Group 3--Recovered TBI

Eligibility Criteria

• Age: 18 Years - 55 Years
• Sex: all
• Healthy Volunteers: Yes
• Age Groups: Adult (18-64)

You may qualify if:

• In order to be included in this study, all participants must meet the following minimum criteria:
• Age 18 - 55 years, inclusive
• Ability to undergo MRI scanning.
• Ability to read, write, and speak English.
• Stable doses of concomitant medications for at least 2 weeks prior to enrollment.
• Likelihood of completing 18 weeks of study procedures. Likelihood of ability to complete the study procedures means that the person has 1) a low probability of being deployed during the 18-week period 2) verbalizes intent to complete the study.
• In order to be included in the symptomatic TBI Group, study participants must meet the following criteria:
• A history of having sustained a TBI \> 6 months and \< 10 years prior to enrollment. Evidence will be any one of the following 3 criteria:
• GCS 3 - 12 (GCS obtained in Emergency Room and noted in medical record)
• Post-traumatic amnesia \> 24 hours
• Persistent post-concussive symptoms, according to the DSM-IV Research Criteria for Post-Concussional Disorder, including:
• Evidence from neuropsychological testing of difficulty in attention or memory. (refers to neuropsychological testing done as a part of the patient's hospital or rehabilitation care not as a part of screening for this study)
• Three or more of the following symptoms, which started shortly after the trauma and persist for at least three months:
• i) Fatigability ii) Disordered sleep iii) Headache iv) Vertigo or dizziness v) Irritability or aggression vi) Anxiety, depression, or affective instability vii) Changes in personality (e.g. social or sexual inappropriateness) viii) Apathy or lack of spontaneity c) Symptoms in criteria (a) and (b) must have their onset after trauma, or there was a significant worsening of pre-existing symptoms after trauma.
• d) Disturbance from these symptoms causes significant impairment of social or occupational functioning and represents a significant decline from previous level of functioning.

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
• Alpha-blockers such as doxazosin (Cardura), tamsulosin (Flomax), and terazosin (Hytrin) prazosin (Minipres). These medications are usually used for the treatment of enlarged prostate.
• Current resting hypotension (BP \< 90/50 mm Hg)
• Current severe renal insufficiency (Creatinine Clearance \< 30 mL/min)
• Current hepatic cirrhosis
• Current cardiac failure or coronary artery disease causing unstable angina
• Retinitis pigmentosa
• Known hypersensitivity or allergy to sildenafil or any component of the tablet
• Evidence of penetrating injury
• Daily therapy with a PDE5 inhibitor within the past 2 months
• History or evidence of pre-existing neurological or psychiatric disorder not related to TBI, such as:

Sponsors & Collaborators

• Uniformed Services University of the Health Sciences: lead
• Center for Neuroscience and Regenerative Medicine (CNRM): collaborator
• National Institute of Neurological Disorders and Stroke (NINDS): collaborator
• National Institutes of Health (NIH): collaborator

Study Sites (1)

National Institute of Health

Bethesda, Maryland, 20892, United States

Location

Related Publications (1)

• Reddy P, Izzetoglu M, Shewokis PA, Sangobowale M, Diaz-Arrastia R, Izzetoglu K. Evaluation of fNIRS signal components elicited by cognitive and hypercapnic stimuli. Sci Rep. 2021 Dec 6;11(1):23457. doi: 10.1038/s41598-021-02076-7.

  PMID: 34873185 DERIVED

MeSH Terms

Conditions

Brain Injuries, Traumatic; Post-Concussion Syndrome; Hypercapnia

Interventions

Sildenafil Citrate

Condition Hierarchy (Ancestors)

Brain Injuries; Brain Diseases; Central Nervous System Diseases; Nervous System Diseases; Craniocerebral Trauma; Trauma, Nervous System; Wounds and Injuries; Brain Concussion; Head Injuries, Closed; Wounds, Nonpenetrating; Signs and Symptoms, Respiratory; Signs and Symptoms; Pathological Conditions, Signs and Symptoms

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

Study Officials

• Ramon R. Diaz-Arrastia, MD, PhD

  Uniformed Services University of the Health Sciences

  STUDY DIRECTOR

• Eric Wassermann, MD

  National Institute of Neurological Disorders and Stroke (NINDS)

  PRINCIPAL INVESTIGATOR

Study Design

• Study Type: interventional
• Phase: phase 2
• Allocation: RANDOMIZED
• Masking: QUADRUPLE
• Who Masked: PARTICIPANT, CARE PROVIDER, INVESTIGATOR, OUTCOMES ASSESSOR
• Purpose: TREATMENT
• Intervention Model: CROSSOVER
• Sponsor Type: FED
• Responsible Party: PRINCIPAL INVESTIGATOR
• PI Title: Professor of Neurology

Study Record Dates

• First Submitted: January 3, 2013
• First Posted: January 7, 2013
• Study Start: January 1, 2013
• Primary Completion: December 1, 2015
• Study Completion: December 1, 2015
• Last Updated: January 1, 2016

Record last verified: 2015-12

Locations

US (1)