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出境医 / 临床实验 / Imaging of Neuro-Inflammation and the Risk for Post-Traumatic Epilepsy

Imaging of Neuro-Inflammation and the Risk for Post-Traumatic Epilepsy

Study Description
Brief Summary:
This study plans to evaluate the time course of inflammation in the brain after a moderate to severe traumatic brain injury using positron emission tomography (PET) brain imaging. Patients will undergo PET scans of the brain at two weeks and two months after injury to measure neuro-inflammation. The results of the PET scans will be analyzed and correlated with the risk of post-traumatic epilepsy.

Condition or disease Intervention/treatment Phase
Epilepsy, Post-Traumatic Drug: [18F]DPA-714 Positron Emission Tomography Scan Phase 1

Detailed Description:

The development of post-traumatic epilepsy (PTE) is associated with neurobiological, cognitive, psychological, and social consequences that are far-reaching for the patient. Despite our keen awareness of this significant public health issue, little is known regarding the biological mechanisms leading to PTE. One plausible mechanism is that unchecked neuroinflammation, a process that occurs in animal and human models of both traumatic brain injury (TBI) and epilepsy, leads to altered synaptic transmission and neuronal excitability. However, the direct relationship between neuroinflammation and PTE has been difficult to ascertain from pre-clinical studies as they may not accurately reflect the human condition, as few animal models can induce the progression of PTE without a pharmacological enhancer and are predominately limited to studies of mild-to-moderate TBI given high animal mortality rates from more severe injuries. Measurements of neuroinflammation in human TBI and epilepsy has also proven difficult without invasive monitoring or post-mortem evaluations, and measurements of inflammatory mediators in blood or serum may not meaningfully reflect the extent of neuroinflammation.

Encouragingly though, positron emission tomography (PET) can be used to measure the degree of in vivo glial activation in the central nervous system through radiotracer binding of the translocator protein (TSPO), serving as a surrogate of neuroinflammation. Minimally expressed in the uninjured brain, TSPO binding is increased in a number of brain disorders associated with neuroinflammation, including Alzheimer's disease, ischemic stroke, recurrent head trauma in football, brain metastases, TBI, and epilepsy, and is expressed predominately by activated microglia, the main mediators of neuroinflammation. Currently, no pre-clinical or clinical study has analyzed the relationship between glia activation, as measured by TSPO PET, and the risk for developing PTE. Accordingly, we plan to use [18F]DPA-714 to characterize neuro-inflammation following moderate-to-severe TBI in order to better understand the temporal time course of neuro-inflammation following injury and its potential role in epileptogenesis.

Study Design
Layout table for study information
Study Type : Interventional  (Clinical Trial)
Estimated Enrollment : 30 participants
Allocation: N/A
Intervention Model: Single Group Assignment
Masking: None (Open Label)
Primary Purpose: Basic Science
Official Title: Imaging of Glial Activation and Risk for Post-Traumatic Epilepsy
Actual Study Start Date : February 1, 2020
Estimated Primary Completion Date : August 14, 2022
Estimated Study Completion Date : August 14, 2022
Arms and Interventions
Arm Intervention/treatment
Experimental: Moderate to Severe Traumatic Brain Injury
All patients will undergo a [18F]DPA-714 PET scan of the brain 2 weeks and 2 months following moderate to severe traumatic brain injury to quantify neuroinflammation.
 Drug: [18F]DPA-714 Positron Emission Tomography Scan
All patients will undergo a [18F]DPA-714 PET scan of the brain 2 weeks and 2 months following moderate to severe traumatic brain injury to quantify neuroinflammation.
Outcome Measures
Primary Outcome Measures :
  1. Quantification of [18F]DPA-714 binding in the brain following moderate to severe traumatic brain injury [ Time Frame: 2 weeks ]
  2. Quantification of [18F]DPA-714 binding in the brain following moderate to severe traumatic brain injury [ Time Frame: 2 months ]

Secondary Outcome Measures :
  1. Frequency of early seizures, epileptiform discharges, and post-traumatic epilepsy [ Time Frame: Admission - two years ]
  2. Modified Rankin Scale [ Time Frame: 3 and 6 months ]
    All patients will undergo a phone survey at 3 and 6 months post-injury to assess functional outcome using the Modified Rankin Scale. The Modified Rankin Scale measures the degree of disability or dependence in daily activities of patients who have suffered an neurological injury, ranging from 0 (no symptoms) to 6 (dead).

  3. Quantify the association between contusion volume and adjacent cerebral edema with [18F]DPA-714 binding on PET scans [ Time Frame: 2 weeks ]
    All patients will undergo multi-modal MRI brain (Fluid-attenuated inversion recovery (FLAIR), susceptibility weighted imaging(SWI), diffusion weighted imaging(DWI)) two weeks post-injury to assess for acute structural abnormalities


Eligibility Criteria
Layout table for eligibility information
Ages Eligible for Study:   18 Years to 100 Years   (Adult, Older Adult)
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   No
Criteria

Inclusion Criteria:

  • Acute Traumatic Brain Injury (TBI)
  • Age 18-100 are eligible
  • Glasgow Coma Scale (GCS) 3-13 without continuous sedation at time of enrollment
  • Ability to enroll within 72 hours of injury
  • Hemorrhagic contusional injuries to frontal and/or temporal lobes.
  • Polytrauma including long bone fractures, blunt trauma, abdominal trauma or similar will be allowed
  • Penetrating TBI if continuous electroencephalography (cEEG) is feasible and survival for 2 years is feasible, recognizing that MRI may not be feasible with some forms of penetrating trauma

Exclusion Criteria:

  • Low-affinity TSPO binding profile
  • Ages 17 years or younger
  • Patients with diffuse axonal injury in the absence of hemorrhagic contusions or skull fracture, and isolated epidural hemorrhages that improve after evacuation
  • No planned continuous EEG monitoring during injury day 1-7
  • Inability to undergo MRI at 14 days (± 4 days) due to bullet, metal implant, or pacemaker
  • Pregnancy
  • Pre-existing Neurodegenerative Disorders
  • Pre-existing epilepsy/seizure disorder
  • Pre-existing dementia
  • Isolated anoxic brain injury
  • Incarceration present or pending
  • Devastating cervical spine injury
Contacts and Locations

Contacts
Layout table for location contacts
Contact: Ryan M Martin, MD 9167343650 rymartin@ucdavis.edu

Locations
Layout table for location information
United States, California
University of California, Davis Recruiting
Sacramento, California, United States, 95817
Contact: Ryan Martin, MD    916-734-6518    rymartin@ucdavis.edu   
Sponsors and Collaborators
University of California, Davis
Tracking Information
First Submitted Date  ICMJE June 24, 2019
First Posted Date  ICMJE June 26, 2019
Last Update Posted Date June 9, 2021
Actual Study Start Date  ICMJE February 1, 2020
Estimated Primary Completion Date August 14, 2022   (Final data collection date for primary outcome measure)
Current Primary Outcome Measures  ICMJE
 (submitted: June 25, 2019)
  • Quantification of [18F]DPA-714 binding in the brain following moderate to severe traumatic brain injury [ Time Frame: 2 weeks ]
  • Quantification of [18F]DPA-714 binding in the brain following moderate to severe traumatic brain injury [ Time Frame: 2 months ]
Original Primary Outcome Measures  ICMJE Same as current
Change History
Current Secondary Outcome Measures  ICMJE
 (submitted: June 25, 2019)
  • Frequency of early seizures, epileptiform discharges, and post-traumatic epilepsy [ Time Frame: Admission - two years ]
  • Modified Rankin Scale [ Time Frame: 3 and 6 months ]
    All patients will undergo a phone survey at 3 and 6 months post-injury to assess functional outcome using the Modified Rankin Scale. The Modified Rankin Scale measures the degree of disability or dependence in daily activities of patients who have suffered an neurological injury, ranging from 0 (no symptoms) to 6 (dead).
  • Quantify the association between contusion volume and adjacent cerebral edema with [18F]DPA-714 binding on PET scans [ Time Frame: 2 weeks ]
    All patients will undergo multi-modal MRI brain (Fluid-attenuated inversion recovery (FLAIR), susceptibility weighted imaging(SWI), diffusion weighted imaging(DWI)) two weeks post-injury to assess for acute structural abnormalities
Original Secondary Outcome Measures  ICMJE Same as current
Current Other Pre-specified Outcome Measures Not Provided
Original Other Pre-specified Outcome Measures Not Provided
 
Descriptive Information
Brief Title  ICMJE Imaging of Neuro-Inflammation and the Risk for Post-Traumatic Epilepsy
Official Title  ICMJE Imaging of Glial Activation and Risk for Post-Traumatic Epilepsy
Brief Summary This study plans to evaluate the time course of inflammation in the brain after a moderate to severe traumatic brain injury using positron emission tomography (PET) brain imaging. Patients will undergo PET scans of the brain at two weeks and two months after injury to measure neuro-inflammation. The results of the PET scans will be analyzed and correlated with the risk of post-traumatic epilepsy.
Detailed Description

The development of post-traumatic epilepsy (PTE) is associated with neurobiological, cognitive, psychological, and social consequences that are far-reaching for the patient. Despite our keen awareness of this significant public health issue, little is known regarding the biological mechanisms leading to PTE. One plausible mechanism is that unchecked neuroinflammation, a process that occurs in animal and human models of both traumatic brain injury (TBI) and epilepsy, leads to altered synaptic transmission and neuronal excitability. However, the direct relationship between neuroinflammation and PTE has been difficult to ascertain from pre-clinical studies as they may not accurately reflect the human condition, as few animal models can induce the progression of PTE without a pharmacological enhancer and are predominately limited to studies of mild-to-moderate TBI given high animal mortality rates from more severe injuries. Measurements of neuroinflammation in human TBI and epilepsy has also proven difficult without invasive monitoring or post-mortem evaluations, and measurements of inflammatory mediators in blood or serum may not meaningfully reflect the extent of neuroinflammation.

Encouragingly though, positron emission tomography (PET) can be used to measure the degree of in vivo glial activation in the central nervous system through radiotracer binding of the translocator protein (TSPO), serving as a surrogate of neuroinflammation. Minimally expressed in the uninjured brain, TSPO binding is increased in a number of brain disorders associated with neuroinflammation, including Alzheimer's disease, ischemic stroke, recurrent head trauma in football, brain metastases, TBI, and epilepsy, and is expressed predominately by activated microglia, the main mediators of neuroinflammation. Currently, no pre-clinical or clinical study has analyzed the relationship between glia activation, as measured by TSPO PET, and the risk for developing PTE. Accordingly, we plan to use [18F]DPA-714 to characterize neuro-inflammation following moderate-to-severe TBI in order to better understand the temporal time course of neuro-inflammation following injury and its potential role in epileptogenesis.
Study Type  ICMJE Interventional
Study Phase  ICMJE Phase 1
Study Design  ICMJE Allocation: N/A
Intervention Model: Single Group Assignment
Masking: None (Open Label)
Primary Purpose: Basic Science
Condition  ICMJE Epilepsy, Post-Traumatic
Intervention  ICMJE Drug: [18F]DPA-714 Positron Emission Tomography Scan
All patients will undergo a [18F]DPA-714 PET scan of the brain 2 weeks and 2 months following moderate to severe traumatic brain injury to quantify neuroinflammation.
Study Arms  ICMJE Experimental: Moderate to Severe Traumatic Brain Injury
All patients will undergo a [18F]DPA-714 PET scan of the brain 2 weeks and 2 months following moderate to severe traumatic brain injury to quantify neuroinflammation.
Intervention: Drug: [18F]DPA-714 Positron Emission Tomography Scan
Publications * Not Provided

*   Includes publications given by the data provider as well as publications identified by ClinicalTrials.gov Identifier (NCT Number) in Medline.
 
Recruitment Information
Recruitment Status  ICMJE Recruiting
Estimated Enrollment  ICMJE
 (submitted: June 25, 2019) 		30
Original Estimated Enrollment  ICMJE Same as current
Estimated Study Completion Date  ICMJE August 14, 2022
Estimated Primary Completion Date August 14, 2022   (Final data collection date for primary outcome measure)
Eligibility Criteria  ICMJE

Inclusion Criteria:

  • Acute Traumatic Brain Injury (TBI)
  • Age 18-100 are eligible
  • Glasgow Coma Scale (GCS) 3-13 without continuous sedation at time of enrollment
  • Ability to enroll within 72 hours of injury
  • Hemorrhagic contusional injuries to frontal and/or temporal lobes.
  • Polytrauma including long bone fractures, blunt trauma, abdominal trauma or similar will be allowed
  • Penetrating TBI if continuous electroencephalography (cEEG) is feasible and survival for 2 years is feasible, recognizing that MRI may not be feasible with some forms of penetrating trauma

Exclusion Criteria:

  • Low-affinity TSPO binding profile
  • Ages 17 years or younger
  • Patients with diffuse axonal injury in the absence of hemorrhagic contusions or skull fracture, and isolated epidural hemorrhages that improve after evacuation
  • No planned continuous EEG monitoring during injury day 1-7
  • Inability to undergo MRI at 14 days (± 4 days) due to bullet, metal implant, or pacemaker
  • Pregnancy
  • Pre-existing Neurodegenerative Disorders
  • Pre-existing epilepsy/seizure disorder
  • Pre-existing dementia
  • Isolated anoxic brain injury
  • Incarceration present or pending
  • Devastating cervical spine injury
Sex/Gender  ICMJE
Sexes Eligible for Study: All
Ages  ICMJE 18 Years to 100 Years   (Adult, Older Adult)
Accepts Healthy Volunteers  ICMJE No
Contacts  ICMJE
Contact: Ryan M Martin, MD 9167343650 rymartin@ucdavis.edu
Listed Location Countries  ICMJE United States
Removed Location Countries  
 
Administrative Information
NCT Number  ICMJE NCT03999164
Other Study ID Numbers  ICMJE 1437948
Has Data Monitoring Committee No
U.S. FDA-regulated Product
Studies a U.S. FDA-regulated Drug Product: Yes
Studies a U.S. FDA-regulated Device Product: No
IPD Sharing Statement  ICMJE
Plan to Share IPD: No
Responsible Party Ryan M Martin, University of California, Davis
Study Sponsor  ICMJE University of California, Davis
Collaborators  ICMJE Not Provided
Investigators  ICMJE Not Provided
PRS Account University of California, Davis
Verification Date June 2021

ICMJE     Data element required by the International Committee of Medical Journal Editors and the World Health Organization ICTRP

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