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Sildenafil for Cerebrovascular Dysfunction in Chronic Traumatic Brain Injury.

Primary Purpose

Traumatic Brain Injury, Post-concussive Syndrome

Status
Completed
Phase
Phase 2
Locations
United States
Study Type
Interventional
Intervention
Sildenafil
Sponsored by
Uniformed Services University of the Health Sciences
About
Eligibility
Locations
Arms
Outcomes
Full info

About this trial

This is an interventional treatment trial for Traumatic Brain Injury focused on measuring Magnetic resonance imaging, Blood oxygen level dependent signal, Hypercapnia, Endothelial progenitor cells

Eligibility Criteria

18 Years - 55 Years (Adult)All SexesAccepts Healthy Volunteers

Inclusion Criteria:

Inclusion Criteria applied to all participants

In order to be included in this study, all participants must meet the following minimum criteria:

  1. Age 18 - 55 years, inclusive
  2. Ability to undergo MRI scanning.
  3. Ability to read, write, and speak English.
  4. Stable doses of concomitant medications for at least 2 weeks prior to enrollment.
  5. 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.

Inclusion Criteria for Group 1 (symptomatic TBI)

In order to be included in the symptomatic TBI Group, study participants must meet the following criteria:

  1. 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:

    1. GCS 3 - 12 (GCS obtained in Emergency Room and noted in medical record)
    2. Post-traumatic amnesia > 24 hours
    3. 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)
  2. Persistent post-concussive symptoms, according to the DSM-IV Research Criteria for Post-Concussional Disorder, including:

    1. 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)
    2. 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.

    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:

a) 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:

  1. No evidence from neuropsychological testing of difficulty in attention or memory.
  2. No more than 1 of the following symptoms, which started shortly after the trauma and persists 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) No impairment of social or occupational functioning or a significant decline from previous level of functioning.

Exclusion Criteria:

Exclusion Criteria for all Groups:

  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. Alpha-blockers such as doxazosin (Cardura), tamsulosin (Flomax), and terazosin (Hytrin) prazosin (Minipres). These medications are usually used for the treatment of enlarged prostate.
    6. Current resting hypotension (BP < 90/50 mm Hg)
    7. Current severe renal insufficiency (Creatinine Clearance < 30 mL/min)
    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 or any component of the tablet
  2. Evidence of penetrating injury
  3. Daily therapy with a PDE5 inhibitor within the past 2 months
  4. History or evidence of pre-existing neurological or psychiatric disorder not related to TBI, such as:

    1. Multiple sclerosis, pre- or co-existing
    2. Stroke (other than stroke at the time of TBI)
    3. Pre-existing developmental disorder
    4. Pre-existing epilepsy
    5. Pre-existing major depressive disorder
    6. Pre-existing schizophrenia
  5. 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.

Sites / Locations

  • National Institute of Health

Arms of the Study

Arm 1

Arm 2

Arm 3

Arm Type

Experimental

Active Comparator

Active Comparator

Arm Label

Experimental: Group 1--Symptomatic TBI

Active Comparator: Group 2--Healthy Controls

Group 3--Recovered TBI

Arm Description

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.

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).

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).

Outcomes

Primary Outcome Measures

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.

Secondary Outcome Measures

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.

Full Information

First Posted
January 3, 2013
Last Updated
December 30, 2015
Sponsor
Uniformed Services University of the Health Sciences
Collaborators
Center for Neuroscience and Regenerative Medicine (CNRM), National Institute of Neurological Disorders and Stroke (NINDS), National Institutes of Health (NIH)
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1. Study Identification

Unique Protocol Identification Number
NCT01762475
Brief Title
Sildenafil for Cerebrovascular Dysfunction in Chronic Traumatic Brain Injury.
Official Title
Sildenafil for the Treatment of Cerebrovascular Dysfunction During the Chronic Stage After Traumatic Brain Injury.
Study Type
Interventional

2. Study Status

Record Verification Date
December 2015
Overall Recruitment Status
Completed
Study Start Date
January 2013 (undefined)
Primary Completion Date
December 2015 (Actual)
Study Completion Date
December 2015 (Actual)

3. Sponsor/Collaborators

Responsible Party, by Official Title
Principal Investigator
Name of the Sponsor
Uniformed Services University of the Health Sciences
Collaborators
Center for Neuroscience and Regenerative Medicine (CNRM), National Institute of Neurological Disorders and Stroke (NINDS), National Institutes of Health (NIH)

4. Oversight

Data Monitoring Committee
No

5. Study Description

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).
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.

6. Conditions and Keywords

Primary Disease or Condition Being Studied in the Trial, or the Focus of the Study
Traumatic Brain Injury, Post-concussive Syndrome
Keywords
Magnetic resonance imaging, Blood oxygen level dependent signal, Hypercapnia, Endothelial progenitor cells

7. Study Design

Primary Purpose
Treatment
Study Phase
Phase 2
Interventional Study Model
Crossover Assignment
Masking
ParticipantCare ProviderInvestigatorOutcomes Assessor
Allocation
Randomized
Enrollment
59 (Actual)

8. Arms, Groups, and Interventions

Arm Title
Experimental: Group 1--Symptomatic TBI
Arm Type
Experimental
Arm Description
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.
Arm Title
Active Comparator: Group 2--Healthy Controls
Arm Type
Active Comparator
Arm Description
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).
Arm Title
Group 3--Recovered TBI
Arm Type
Active Comparator
Arm Description
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).
Intervention Type
Drug
Intervention Name(s)
Sildenafil
Other Intervention Name(s)
Viagra
Primary Outcome Measure Information:
Title
Cerebrovascular reactivity
Description
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.
Time Frame
24 months
Secondary Outcome Measure Information:
Title
Safety and tolerability
Description
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.
Time Frame
24 months
Other Pre-specified Outcome Measures:
Title
Regional cerebrovascular reactivity
Description
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.
Time Frame
24 months
Title
Cerebrovascular reactivity in TBI patients vs. healthy controls
Description
Patients with persistent symptoms in the chronic stage after TBI have deficits in cerebrovascular reactivity compared to uninjured healthy controls.
Time Frame
24 months
Title
Cerebrovascular reactivity in symptomatic TBI vs. asymptomatic TBI
Description
Patients with persistent symptoms in the chronic stage after TBI have deficits in cerebrovascular reactivity compared to asymptomatic patients after TBI.
Time Frame
24 months
Title
Endothelial progenitor cells in TBI vs. healthy controls
Description
Patients with persistent symptoms in the chronic stage after TBI have reduced numbers of circulating EPCs compared to uninjured healthy controls.
Time Frame
24 months
Title
Endothelial progenitor cells in symptomatic TBI vs. asymptomatic TBI
Description
Patients with persistent symptoms in the chronic stage after TBI have reduced numbers of circulating EPCs compared to asymptomatic patients after TBI.
Time Frame
24 months
Title
Persistence of cerebrovascular reactivity effect.
Description
The effect on cerebrovascular reactivity of single dose treatment with sildenafil persists after 8 weeks of chronic therapy (25 mg orally, twice daily).
Time Frame
24 months
Title
Persistence of endothelial progenitor cell effect.
Description
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.
Time Frame
24 months
Title
Benefit on post-concussive symptoms
Description
Treatment with sildenafil for 8 weeks (25 mg orally twice daily) reduces the prevalence of post-concussive symptoms, compared to placebo treatment.
Time Frame
24 months
Title
Benefit on neuropsychologic testing
Description
Treatment with sildenafil for 8 weeks (25 mg orally twice daily) improves performance in neuropsychometric tests, compared to placebo treatment.
Time Frame
24 months

10. Eligibility

Sex
All
Minimum Age & Unit of Time
18 Years
Maximum Age & Unit of Time
55 Years
Accepts Healthy Volunteers
Accepts Healthy Volunteers
Eligibility Criteria
Inclusion Criteria: Inclusion Criteria applied to all participants 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. Inclusion Criteria for Group 1 (symptomatic TBI) 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: 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. 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: a) 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: 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) No impairment of social or occupational functioning or a significant decline from previous level of functioning. Exclusion Criteria: Exclusion Criteria for all Groups: 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: 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.
Overall Study Officials:
First Name & Middle Initial & Last Name & Degree
Ramon R. Diaz-Arrastia, MD, PhD
Organizational Affiliation
Uniformed Services University of the Health Sciences
Official's Role
Study Director
First Name & Middle Initial & Last Name & Degree
Eric Wassermann, MD
Organizational Affiliation
National Institute of Neurological Disorders and Stroke (NINDS)
Official's Role
Principal Investigator
Facility Information:
Facility Name
National Institute of Health
City
Bethesda
State/Province
Maryland
ZIP/Postal Code
20892
Country
United States

12. IPD Sharing Statement

Citations:
PubMed Identifier
34873185
Citation
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.
Results Reference
derived

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Sildenafil for Cerebrovascular Dysfunction in Chronic Traumatic Brain Injury.

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