Traumatic Brain InjuryPhase 2NCT01762475

Sildenafil for Cerebrovascular Dysfunction in Chronic Traumatic Brain Injury.

A Phase 2 study testing Sildenafil in people with Traumatic Brain Injury and Post-concussive Syndrome, run by Uniformed Services University of the Health Sciences at 1 site in United States.

Completed

Finished. The study has ended and is not enrolling. Results may be posted on the official record.

Official record

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Trial 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). Read more about this study

Who is it for?: Ages 18 to 55 yearsHealthy volunteers can take part
Conditions the study is for: Traumatic Brain Injury, Post-concussive Syndrome
What is being tested?: Sildenafil
Type of treatment: Pill or oral medicine
Could I receive a placebo?: No, everyone receives an active treatment
How many people: 59 participants
Where: 1 siteUnited States
Study dates: Jan 2013to Dec 2015
Phase: Phase 2
Are there results?: None posted in the registry

Key requirements

Who can take part, as listed by the sponsor. Only the study team can confirm whether you are eligible, so take this list to your doctor.

Ages 18 to 55 years
All sexes
Healthy volunteers accepted
Adult

Who may be able to join

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.

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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
TBI-related abnormality on neuroimaging (either CT or MRI). (Some missing information about the initial injury (i.e. documentation of initial GCS) is not necessarily exclusionary if the bulk of the available history is indicative that the patient suffered a TBI and meets the inclusion criteria)
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:
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.
Disturbance from these symptoms causes significant impairment of social or occupational functioning and represents a significant decline from previous level of functioning.
Inclusion Criteria Group 2-Healthy controls In order to be included in this study, participants must meet the inclusion criteria for all participants listed in 4.2.
3.2.3 Inclusion Criteria Group 3-Recovered TBI
1. History of having sustained a TBI > 6 months and < 10 years prior to enrollment. This evidence will be any one of the following:
GCS 3 - 12 (GCS obtained in Emergency Room after injury and noted in medical record) b) Post-traumatic amnesia > 24 hours c) TBI-related abnormality on neuroimaging (either CT or MRI) 2. Does not meet criteria for persistent post-concussive symptoms, according to the DSM-IV Research Criteria for Post-concussional Disorder defined by the following:
No evidence from neuropsychological testing of difficulty in attention or memory.
No more than 1 of the following symptoms, which started shortly after the trauma and persists for at least three months:
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) No impairment of social or occupational functioning or a significant decline from previous level of functioning.

Who cannot join

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.

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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:
Multiple sclerosis, pre- or co-existing
Stroke (other than stroke at the time of TBI)
Pre-existing developmental disorder
Pre-existing epilepsy
Pre-existing major depressive disorder
Pre-existing schizophrenia
Women who are pregnant or breast-feeding.
Exclusion for Healthy Control Group Any evidence or history of a TBI or concussion is exclusionary for the Control Group.

Trial locations and contacts

1 site in 1 country.

United States1 site

National Institute of Health
Bethesda, Maryland, 20892

Other trials in United States

About this study

Official title: Sildenafil for the Treatment of Cerebrovascular Dysfunction During the Chronic Stage After Traumatic Brain Injury.

Read the detailed description

The goal of this Phase II study is to generate pilot data that will allow for the design of a clinical trial of sildenafil (Viagra®) to treat patients with traumatic vascular injury in the chronic state after traumatic brain injury (TBI). Injury to small and medium-sized blood cerebral blood vessels is a well-recognized consequence of traumatic brain injury (TBI). Non-invasive imaging with positron emission tomography (PET) and single photon emission computerized tomography (SPECT) have long demonstrated deficits in cerebral blood flow in TBI, including in symptomatic patients years after mild TBI (mTBI). Recently, magnetic resonance imaging (MRI) methods have been developed which allow reliable and non-invasive measurement of cerebrovascular reactivity (CVR) to vasodilatory stimuli such as hypercapnia in humans. These techniques have never been applied to symptomatic patients in the chronic stage after mTBI. These methods are particularly promising due to the recent discovery that phosphodiesterase-5 (PDE5) inhibitors improve cerebral blood flow, induce angiogenesis and neurogenesis, and improve functional recovery in animals after experimental stroke and cryoinjury. This pilot study will use novel MRI methods (Blood Oxygen Level Dependent (BOLD) response to hypercapnia) to noninvasively measure cerebrovascular reactivity in the chronic stage after TBI, and the first to use sildenafil in patients with chronic TBI.

The study has one primary objective and 10 secondary objectives:

Primary objective:

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. Secondary objective (Safety and Tolerability):
Sildenafil therapy (25 mg orally twice daily) is well tolerated in symptomatic patients in the chronic stage after TBI, with few adverse effects and treatment discontinuations in less than 10% of patients. Tertiary (Exploratory) objectives:
Single dose treatment with sildenafil (50 mg orally) is effective in increasing the regional BOLD response to hypercapnia in symptomatic patients in the chronic stage after TBI.
Patients with persistent symptoms in the chronic stage after TBI have deficits in cerebrovascular reactivity compared to uninjured healthy controls.
Patients with persistent symptoms in the chronic stage after TBI have deficits in cerebrovascular reactivity compared to asymptomatic patients after TBI.
Patients with persistent symptoms in the chronic stage after TBI have reduced numbers of circulating EPCs compared to uninjured healthy controls.
Patients with persistent symptoms in the chronic stage after TBI have reduced numbers of circulating EPCs compared to asymptomatic patients after TBI.
The effect on cerebrovascular reactivity of single dose treatment with sildenafil persists after 8 weeks of chronic therapy (25 mg orally, twice daily).
Treatment with sildenafil for 8 weeks (25 mg orally twice daily) increases the number of circulating endothelial progenitor cells (EPCs) in symptomatic chronic TBI patients.
Treatment with sildenafil for 8 weeks (25 mg orally twice daily) reduces the prevalence of post-concussive symptoms, compared to placebo treatment.
Treatment with sildenafil for 8 weeks (25 mg orally twice daily) improves performance in neuropsychometric tests, compared to placebo treatment.

Conditions: Traumatic Brain Injury, Post-concussive Syndrome
Being tested: Sildenafil
Keywords: Magnetic resonance imaging, Blood oxygen level dependent signal, Hypercapnia, Endothelial progenitor cells
Medical subject headings: Brain Injuries, Traumatic, Post-Concussion Syndrome, Hypercapnia

What participants receive

What participants receive. In a randomised study each person is assigned to one group by chance.

SildenafilDrug
Also called Viagra

Study groups in NCT01762475
Study group	Role	What they receive
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. Receives: 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). Receives: 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). Receives: Drug: Sildenafil

What is being measured

The primary outcome is the main question the study is designed to answer.

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.
Measured: 24 months

Secondary outcomes (1)

Safety and tolerability
Sildenafil therapy (25 mg orally twice daily) is well tolerated in symptomatic patients in the chronic stage after TBI, with few adverse effects and treatment discontinuations in less than 10% of patients.
Measured: 24 months

Timeline

From the start of the study to its completion; the mark is today. Estimated dates are the sponsor’s plan.

Jan 2013Dec 2015

First posted7 Jan 2013 (estimated)
Study startJan 2013
Primary completionDec 2015
Study completionDec 2015

Resources

Official record on ClinicalTrials.govThe registry entry this page is built from, with its full change history.
Publications (1)Papers the sponsor has linked to this study.
Other trials for Traumatic Brain InjuryStudies of the same condition, open and under way.
What the trial phases meanHow a treatment moves from first tests in people to approval.

More details

For doctors and researchers: how the study is designed, who runs it, and its registry IDs.

Study design

Study type: Interventional
Phase: Phase 2
Primary purpose: Treatment
Allocation: Randomised
Intervention model: Crossover
Masking: Quadruple blind
Who is masked: Participant, Care provider, Investigator, Outcomes assessor
Enrolment: 59 participants (actual)

IDs, dates and publications

ClinicalTrials.gov ID: NCT01762475
Sponsor's protocol ID: T-N-2215
Other IDs: T-N-2215
Status last verified: Dec 2015
First submitted: 3 Jan 2013
Last updated: 1 Jan 2016
Results posted: No
Data monitoring committee: No

Publications

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.
PubMed 34873185

Want to know more?

The sponsor has not listed a contact. The official record may have more details.

Talk to your doctor first and take this page with you. Only the study team can confirm whether you can join.

Questions to ask the study team

What is the study trying to find out?
What would I need to do, and how often would I visit?
Could I receive a placebo instead of the treatment?
What are the possible risks and benefits for me?
Will it cost me anything? Are travel or time paid for?
Can I keep seeing my own doctor during the study?
What happens when the study ends?

See locations

Active, not recruitingObservational study
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Pilot Safety and Exploratory Efficacy of PSC-05 for the Treatment of Chronic Mild Traumatic Brain Injury
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Intracranial Pressure Monitoring in Moderate Traumatic Brain Injury
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All Traumatic Brain Injury trials

Study at a glance

From the registry record, last updated by the sponsor on 1 Jan 2016. Recruitment status is as the sponsor reported it: confirm with the study team.

Official title: Sildenafil for the Treatment of Cerebrovascular Dysfunction During the Chronic Stage After Traumatic Brain Injury.
ClinicalTrials.gov ID: NCT01762475
Acronym / sponsor ID: T-N-2215
Conditions: Traumatic Brain Injury, Post-concussive Syndrome
Keywords: Magnetic resonance imaging, Blood oxygen level dependent signal, Hypercapnia, Endothelial progenitor cells
Phase: Phase 2
Study type: Interventional
Recruitment status: Completed
Enrolment: 59 participants (actual)
Lead sponsor: Uniformed Services University of the Health SciencesUS federal agency
Collaborators: Center for Neuroscience and Regenerative Medicine (CNRM), National Institute of Neurological Disorders and Stroke (NINDS), National Institutes of Health (NIH)
Study start: Jan 2013
Primary completion: Dec 2015 (actual)
Study completion: Dec 2015 (actual)
First posted: 7 Jan 2013 (estimated)
Results: Not posted in the source record

Clinical summary

The research question as the sponsor registered it. This describes what the study plans to test, not what it found.

Detailed description

The study has one primary objective and 10 secondary objectives:

Primary objective:

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. Secondary objective (Safety and Tolerability):
Sildenafil therapy (25 mg orally twice daily) is well tolerated in symptomatic patients in the chronic stage after TBI, with few adverse effects and treatment discontinuations in less than 10% of patients. Tertiary (Exploratory) objectives:
Single dose treatment with sildenafil (50 mg orally) is effective in increasing the regional BOLD response to hypercapnia in symptomatic patients in the chronic stage after TBI.
Patients with persistent symptoms in the chronic stage after TBI have deficits in cerebrovascular reactivity compared to uninjured healthy controls.
Patients with persistent symptoms in the chronic stage after TBI have deficits in cerebrovascular reactivity compared to asymptomatic patients after TBI.
Patients with persistent symptoms in the chronic stage after TBI have reduced numbers of circulating EPCs compared to uninjured healthy controls.
Patients with persistent symptoms in the chronic stage after TBI have reduced numbers of circulating EPCs compared to asymptomatic patients after TBI.
The effect on cerebrovascular reactivity of single dose treatment with sildenafil persists after 8 weeks of chronic therapy (25 mg orally, twice daily).
Treatment with sildenafil for 8 weeks (25 mg orally twice daily) increases the number of circulating endothelial progenitor cells (EPCs) in symptomatic chronic TBI patients.
Treatment with sildenafil for 8 weeks (25 mg orally twice daily) reduces the prevalence of post-concussive symptoms, compared to placebo treatment.
Treatment with sildenafil for 8 weeks (25 mg orally twice daily) improves performance in neuropsychometric tests, compared to placebo treatment.

Study design

Primary purpose: Treatment
Allocation: Randomised
Intervention model: Crossover
Masking: Quadruple blind (participant, care provider, investigator, outcomes assessor)
Number of arms: 3

Arm	Type	Receives
Experimental: Group 1--Symptomatic TBI	Experimental	Drug: SildenafilExperimental 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.
Active Comparator: Group 2--Healthy Controls	Active comparator	Drug: SildenafilGroup 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).
Group 3--Recovered TBI	Active comparator	Drug: SildenafilGroup 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).

Who may qualify

Ages: 18 to 55 years
Sex: All
Healthy volunteers: Accepted
Age groups: Adult

Key inclusion criteria (23 listed)

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.

Key exclusion criteria (23 listed)

Contraindication to sildenafil which includes the following:
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:
Women who are pregnant or breast-feeding.

Eligibility is decided by the study team after screening; this overview does not establish that a patient qualifies. Full inclusion and exclusion criteria.

Interventions

Intervention	Type	Arms
SildenafilAlso: Viagra	Drug	Active Comparator: Group 2--Healthy Controls, Experimental: Group 1--Symptomatic TBI, Group 3--Recovered TBI

Primary outcome

Cerebrovascular reactivity
Time frame: 24 months
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.

1 secondary outcome

Safety and tolerability
Time frame: 24 months

Results and safety

The study is completed, but results are not available in the source record. That does not mean the treatment did or did not work.

Research links

Official record on ClinicalTrials.govLast updated by the sponsor 1 Jan 2016.
Derived from this study: PubMed 34873185Reddy 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.

Related trials for Traumatic Brain Injury

Active, not recruitingObservational study
Transforming Research and Clinical Knowledge in Traumatic Brain Injury Epileptogenesis Project (TRACK-TBI EPI)
Traumatic Brain Injury, Post-traumatic Epilepsy
Enrolling by invitationPhase 1
Pilot Safety and Exploratory Efficacy of PSC-05 for the Treatment of Chronic Mild Traumatic Brain Injury
Mild Traumatic Brain Injury
RecruitingObservational study
Intracranial Pressure Monitoring in Moderate Traumatic Brain Injury
Moderate Traumatic Brain Injury
Not yet recruitingPhase 1
Nanopulse Laser Therapy
TBI (Traumatic Brain Injury)
RecruitingObservational study
Effect of Different Intravenous Fluids on Post-operative Chronic Subdural Hematoma Size and Recurrence
Chronic Subdural Hematoma

Referral and contact

AzTrials does not enrol participants or take referrals. Contact the study team or a site listed below; they decide who can take part. This study is not recruiting at the moment.

Ramon R. Diaz-Arrastia, MD, PhD study director

Uniformed Services University of the Health Sciences

Eric Wassermann, MD principal investigator

National Institute of Neurological Disorders and Stroke (NINDS)

1 site in 1 country: see every site and its status.

Questions about this trial

What is this clinical trial studying?

A Phase 2 study testing Sildenafil in people with Traumatic Brain Injury and Post-concussive Syndrome, run by Uniformed Services University of the Health Sciences at 1 site in United States.

The full registered description is in the About this study section and the official record.

Who may be eligible to take part?

The sponsor lists 23 inclusion and 23 exclusion criteria. Eligibility is decided by the study team after screening, so read the full criteria and contact a listed site.

Is this clinical trial currently recruiting?

The record says: finished, as of the sponsor's last update on 1 Jan 2016. Status can change between updates, so confirm with the study contact before making plans.

Where is the study taking place?

The record lists 1 site in United States. Whether a site is taking part right now should be confirmed with that site. See every site.

What are the possible benefits and risks?

They depend on the study and the treatment, and no study can promise a benefit. The study team explains the known risks during informed consent, before anyone joins; the record itself does not list them.

What does this phase mean?

Phase 2 studies give the treatment to a larger group to see whether it has the intended effect and to keep checking safety.

Not every study follows the same path, and some studies (observational studies, device studies) have no phase.

Are results available for this study?

The study is completed, but results are not available in the source record. That does not mean the treatment did or did not work.

How can a doctor refer a patient or contact the research team?

The record lists no contact. The official record names the sponsor, who can be asked directly. AzTrials does not enrol participants or take referrals.

What does the primary outcome measure?

Cerebrovascular reactivity (time frame: 24 months). It is what the study was designed to measure, not a finding.

Where can I read the original study information?

On the ClinicalTrials.gov record for NCT01762475, which also lists 1 linked publication.

Does a listing mean the treatment is approved or proven to work?

No. A listing means the study is registered. It does not show that the treatment is safe, works, or is approved by a regulator.

How often is this information updated?

AzTrials copies changed records from ClinicalTrials.gov every night and reloads the whole registry every week. The sponsor last updated this record on 1 Jan 2016.