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Non-invasive Measurement of Cerebrovascular Reactivity After Traumatic Brain Injury

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ClinicalTrials.gov Identifier: NCT02990078
Recruitment Status : Recruiting
First Posted : December 12, 2016
Last Update Posted : January 17, 2019
Sponsor:
Information provided by (Responsible Party):
Ramon Diaz-Arrastia, University of Pennsylvania

Brief Summary:
The investigators will longitudinally measure cerebrovascular reactivity (CVR) by functional near-infrared spectroscopy (fNIRS) in acute (≤3 days from injury), subacute, and chronic phases after TBI as a biomarker of TCVI as compared to healthy controls. CVR will be measured by fNIRS response to hypercapnia. The investigators hypothesize that CVR will be decreased after TBI and that these decreases will correlate with clinical outcomes. Furthermore, the investigators predict that administration of a vasodilatory medication (sildenafil) will augment CVR after TBI.

Condition or disease Intervention/treatment
TBI Drug: Sildenafil citrate Device: Functional Near Infared Spectroscopy Other: Hypercapnia Challenge

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Study Type : Observational
Estimated Enrollment : 168 participants
Observational Model: Cohort
Time Perspective: Prospective
Official Title: Cerebrovascular Reactivity Assessed With Functional Near-infrared Spectroscopy as a Biomarker of Traumatic Microvascular Injury After Moderate-severe Traumatic Brain Injury
Study Start Date : December 2016
Estimated Primary Completion Date : January 2025
Estimated Study Completion Date : December 2025

Resource links provided by the National Library of Medicine


Group/Cohort Intervention/treatment
Acute TBI
Subjects will be recruited from the neurointensive care unit within 72 hours of their injury. At the time of informed consent, the investigators will perform fNIRS testing with a hypercapnia challenge, fNIRS with hypercapnia challenge 60 minutes after a single oral dose of 50mg sildenafil citrate, outcome qustionaires and symptom checklists (including: Glasgow Outcomes Scale-Extended, Rivermead Post-Concussive Symptom Questionnaire, Brief Symptom Inventory, Alcohol Consumption Questionnaire, Patient Health Questionnaire, and Insomnia Severity Index). This will all be administered again at 14 days, 90 days, 180 days, 1 year, 2 years, 3 years, and 4 years after injury.
Drug: Sildenafil citrate
Sildenafil is a potent and specific PDE5 inhibitor, which was initially developed for the treatment of hypertension and angina. Its effectiveness as a treatment for male erectile dysfunction became apparent during Phase I clinical trials, and the focus of drug development shifted to this indication. In patients with cerebrovascular dysfunction, a few preliminary studies have used sildenafil to increase CVR. Participants in the pilot study had CVR tested in response to hypercapnia measured twice, at baseline and then 1 hour after administration of sildenafil citrate, 50 mg by mouth. The investigators have an IND exemption for the uses in this study.
Other Name: Viagra

Device: Functional Near Infared Spectroscopy
Functional near-infrared spectroscopy (fNIRS) will be used to measure regional cerebral blood flow and cerebrovascular reactivity. are connected to the scalp and surrounding detectors a few cm away detect the light as it scatters through the underlying tissues. The technique is able to detect changes in the absorption spectrum of the tissue corresponding to the concentrations of oxyhemoglobin (HbO2) and deoxyhemoglobin (HbR), and indicate local perfusion changes.
Other Name: fNIRS

Other: Hypercapnia Challenge
The study device is a Douglas Bag that traditionally is designed to measure respiratory exchange. It consists of large bag attached to a mouthpiece utilized to hold either expired air from the subject or filled with different concentrations of air to be aspired. For the purposes of this study, the Douglas Bag will be utilized to induce hypercapnia in the subject. The bag is equipped with a switch that allows rapid shifting from room air to 5% CO2 each minute over 7 minutes.

Sub-acute/Chronic TBI
Subjects who suffered a TBI previously and have now entered a subacute or chronic phase of their TBI will be approached by the research team at their clinic visit with a TBI specialist. In those subjects, study timing will be based on the time of their original injury, therefore will start study visits at the next possible time point.
Drug: Sildenafil citrate
Sildenafil is a potent and specific PDE5 inhibitor, which was initially developed for the treatment of hypertension and angina. Its effectiveness as a treatment for male erectile dysfunction became apparent during Phase I clinical trials, and the focus of drug development shifted to this indication. In patients with cerebrovascular dysfunction, a few preliminary studies have used sildenafil to increase CVR. Participants in the pilot study had CVR tested in response to hypercapnia measured twice, at baseline and then 1 hour after administration of sildenafil citrate, 50 mg by mouth. The investigators have an IND exemption for the uses in this study.
Other Name: Viagra

Device: Functional Near Infared Spectroscopy
Functional near-infrared spectroscopy (fNIRS) will be used to measure regional cerebral blood flow and cerebrovascular reactivity. are connected to the scalp and surrounding detectors a few cm away detect the light as it scatters through the underlying tissues. The technique is able to detect changes in the absorption spectrum of the tissue corresponding to the concentrations of oxyhemoglobin (HbO2) and deoxyhemoglobin (HbR), and indicate local perfusion changes.
Other Name: fNIRS

Other: Hypercapnia Challenge
The study device is a Douglas Bag that traditionally is designed to measure respiratory exchange. It consists of large bag attached to a mouthpiece utilized to hold either expired air from the subject or filled with different concentrations of air to be aspired. For the purposes of this study, the Douglas Bag will be utilized to induce hypercapnia in the subject. The bag is equipped with a switch that allows rapid shifting from room air to 5% CO2 each minute over 7 minutes.

Healthy Controls
The investigators will also enroll healthy "peer controls". These control subjects will be family members and friends of TBI subjects. These peer controls are likely to have similar environmental and socioeconomic exposures/support which may impact recovery after TBI and may also impact CVR. These control subjects will meet the same inclusion/exclusion criteria as TBI subjects without the requirement for an injury or acute brain imaging. These subjects will be tested in the same way as both TBI groups, but will only have one visit.
Drug: Sildenafil citrate
Sildenafil is a potent and specific PDE5 inhibitor, which was initially developed for the treatment of hypertension and angina. Its effectiveness as a treatment for male erectile dysfunction became apparent during Phase I clinical trials, and the focus of drug development shifted to this indication. In patients with cerebrovascular dysfunction, a few preliminary studies have used sildenafil to increase CVR. Participants in the pilot study had CVR tested in response to hypercapnia measured twice, at baseline and then 1 hour after administration of sildenafil citrate, 50 mg by mouth. The investigators have an IND exemption for the uses in this study.
Other Name: Viagra

Device: Functional Near Infared Spectroscopy
Functional near-infrared spectroscopy (fNIRS) will be used to measure regional cerebral blood flow and cerebrovascular reactivity. are connected to the scalp and surrounding detectors a few cm away detect the light as it scatters through the underlying tissues. The technique is able to detect changes in the absorption spectrum of the tissue corresponding to the concentrations of oxyhemoglobin (HbO2) and deoxyhemoglobin (HbR), and indicate local perfusion changes.
Other Name: fNIRS

Other: Hypercapnia Challenge
The study device is a Douglas Bag that traditionally is designed to measure respiratory exchange. It consists of large bag attached to a mouthpiece utilized to hold either expired air from the subject or filled with different concentrations of air to be aspired. For the purposes of this study, the Douglas Bag will be utilized to induce hypercapnia in the subject. The bag is equipped with a switch that allows rapid shifting from room air to 5% CO2 each minute over 7 minutes.




Primary Outcome Measures :
  1. Change in CVR prior to sildenafil administration [ Time Frame: < 72hrs, 14 days, 90 days, 180 days, 1 year, 2 years, 3 years, 4 years ]

Secondary Outcome Measures :
  1. Change CVR after sildenafil administration [ Time Frame: <72 hours, 14 days, 90 days, 180 days, 1 year, 2 years, 3 years, 4 years ]
  2. Relationship of CVR with symptom reports, as measured by the Neurobehavioral Symptom Inventory (NBSI). [ Time Frame: < 72hrs, 14 days, 90 days, 180 days, 1 year, 2 years, 3 years, 4 years ]


Information from the National Library of Medicine

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Ages Eligible for Study:   18 Years and older   (Adult, Older Adult)
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   Yes
Sampling Method:   Non-Probability Sample
Study Population
Male and female, aged 18 or older, presenting with a diagnosis of traumatic brain injury (TBI) and healthy peer control volunteers .
Criteria

Inclusion Criteria:

  1. Men and women, aged ≥18
  2. CT evidence of TBI-linked abnormality

    • Traumatic subarachnoid hemorrhage
    • Intracerebral hemorrhage/contusion
    • Subdural/epidural hematoma
  3. Ability to undergo fNIRS testing with hypercapnia challenge
  4. Subject able to provide informed consent
  5. Attending of record agrees to include subject in study

Exclusion Criteria:

  1. Unstable respiratory or hemodynamic status
  2. Evidence of penetrating brain injury
  3. TBI requiring craniotomy or craniectomy
  4. Evidence or risk of ICP crisis
  5. History of disabling pre-existing neurologic disorder (e.g. dementia, uncontrolled epilepsy, multiple sclerosis, strokes, brain tumors, prior severe TBI, or other disorder that confounds interpretation of NIRS testing or neuropsychological results)
  6. History of pre-existing disabling mental illness (e.g. major depression or schizophrenia)
  7. Exclusion criteria for sildenafil administration:

    • History of melanoma
    • current use of organic nitrate vasodilators
    • current use of ritonavir (HIV-protease inhibitor)
    • current use of erythromycin, ketoconazole, or itraconazole; current use of cimetidine
    • current use of alpha-blockers such as doxazosin (Cardura), tamsulosin (Flomax), and terazosin (Hytrin) prazosin (Minipres)
    • resting hypotension (systolic BP <90)
    • severe renal insufficiency
    • hepatic cirrhosis
    • acute ischemic stroke within past 2 months
    • acute myocardial infarction within past 2 months
    • unstable angina pectoris
    • acute or chronic heart failure
    • retinitis pigmentosa
    • pregnant or breastfeeding female
    • known hypersensitivity or allergy to sildenafil
  8. Unstable cardiac status that constitutes a contraindication to sexual activity
  9. Inability to read and communicate in English (necessary to obtain reliable neuropsychometric data)
  10. Nursing mothers

Information from the National Library of Medicine

To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.

Please refer to this study by its ClinicalTrials.gov identifier (NCT number): NCT02990078


Contacts
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Contact: Ramon Diaz-Arrastia, MD, PhD ramon.diaz-arrastia@uphs.upenn.edu

Locations
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United States, Pennsylvania
Penn Presbyterian Medical Center Recruiting
Philadelphia, Pennsylvania, United States, 19104
Contact    800-789-7366      
Principal Investigator: Ramon Diaz-Arrastia, MD, PhD         
Sub-Investigator: Danielle Sandsmark, MD, PhD         
Sponsors and Collaborators
University of Pennsylvania
Investigators
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Principal Investigator: Ramon Diaz-Arrastia, MD, PhD University of Pennsylvania Perelman School of Medicine, Department of Neurology

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Responsible Party: Ramon Diaz-Arrastia, Presidential Professor, University of Pennsylvania
ClinicalTrials.gov Identifier: NCT02990078     History of Changes
Other Study ID Numbers: 825942
First Posted: December 12, 2016    Key Record Dates
Last Update Posted: January 17, 2019
Last Verified: January 2019
Individual Participant Data (IPD) Sharing Statement:
Plan to Share IPD: No

Keywords provided by Ramon Diaz-Arrastia, University of Pennsylvania:
TBI
CVR
Hypercapnia
fNIRS

Additional relevant MeSH terms:
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Brain Injuries, Traumatic
Brain Injuries
Brain Diseases
Central Nervous System Diseases
Nervous System Diseases
Craniocerebral Trauma
Trauma, Nervous System
Wounds and Injuries
Citric Acid
Sodium Citrate
Sildenafil Citrate
Anticoagulants
Calcium Chelating Agents
Chelating Agents
Sequestering Agents
Molecular Mechanisms of Pharmacological Action
Vasodilator Agents
Phosphodiesterase 5 Inhibitors
Phosphodiesterase Inhibitors
Enzyme Inhibitors
Urological Agents