<clinical_study>
  <!-- This xml conforms to an XML Schema at:
    https://clinicaltrials.gov/ct2/html/images/info/public.xsd -->
  <required_header>
    <download_date>ClinicalTrials.gov processed this data on September 20, 2023</download_date>
    <link_text>Link to the current ClinicalTrials.gov record.</link_text>
    <url>https://clinicaltrials.gov/ct2/show/NCT03035838</url>
  </required_header>
  <id_info>
    <org_study_id>212176</org_study_id>
    <nct_id>NCT03035838</nct_id>
  </id_info>
  <brief_title>Importance of Substance P in Intracranial Pressure Elevation Following Traumatic Brain Injury</brief_title>
  <acronym>NK1</acronym>
  <official_title>Importance of Substance P in Intracranial Pressure Elevation Following Traumatic Brain Injury</official_title>
  <sponsors>
    <lead_sponsor>
      <agency>Arun Gupta</agency>
      <agency_class>Other</agency_class>
    </lead_sponsor>
    <collaborator>
      <agency>Cambridge University Hospitals NHS Foundation Trust</agency>
      <agency_class>Other</agency_class>
    </collaborator>
  </sponsors>
  <source>University of Cambridge</source>
  <oversight_info>
    <has_dmc>Yes</has_dmc>
    <is_fda_regulated_drug>No</is_fda_regulated_drug>
    <is_fda_regulated_device>No</is_fda_regulated_device>
    <is_us_export>No</is_us_export>
  </oversight_info>
  <brief_summary>
    <textblock>
      Traumatic brain (TBI) injury is the major cause of morbidity and mortality worldwide&#xD;
      especially in population under 40 years of age and has a significant socioeconomic impact.&#xD;
      TBI results from the head impacting with an object or from acceleration/deceleration forces&#xD;
      that produce vigorous movement of the brain within the skull, with the resultant mechanical&#xD;
      forces potentially damaging neurones and blood vessels and causing irreversible, primary&#xD;
      brain injury. Primary injury leads to activation of cellular and molecular responses which&#xD;
      lead to disruption of the blood-brain barrier causing the brain to swell. As the intracranial&#xD;
      space is not expandable (i.e. is fixed), this swelling leads to increase in intracranial&#xD;
      pressure (ICP) compromising blood supply to the rest of the brain leading to secondary brain&#xD;
      injury. As we are unable to reverse the primary injury, current protocols use supportive&#xD;
      measures to control the ICP and ensure optimal blood supply to the brain in an attempt to&#xD;
      minimize secondary injury. Our understanding of the factors involved in the initiation and&#xD;
      propagation of brain swelling in TBI is growing and the role of neuroinflammatory cytokines&#xD;
      in this process is increasingly recognized. In preclinical models of TBI, a specific&#xD;
      inflammatory cytokine termed substance P (SP) is found to be associated with blood-brain&#xD;
      barrier disruption and development of brain oedema in the immediate phase following injury.&#xD;
      The aim of this study is to examine the role of SP in the genesis of cerebral oedema and&#xD;
      elevation of ICP and thus secondary injury following human TBI. This would be achieved by&#xD;
      blocking SP function with a SP receptor antagonist Fosaprepitant (IVEMEND®, Merck) in the&#xD;
      first 24 hours following TBI and then continuously measuring ICP and assessing the evolvement&#xD;
      of TBI using magnetic resonance imaging.&#xD;
    </textblock>
  </brief_summary>
  <detailed_description>
    <textblock>
      All severe traumatic brain injury patients admitted to the Cambridge University Hospital's&#xD;
      Neurosciences Critical Care Unit who require insertion of a triple bolt for multimodal&#xD;
      neuromonitoring (intracranial pressure-ICP, microdialysis-MD and brain tissue oxygen partial&#xD;
      pressure-PbtO2) will be screened for participation in this study. Eligible patients will have&#xD;
      an initial MRI scan in the first 24 hours from injury. Following this, and within 24 hours&#xD;
      from injury, IVAMEND (the intravenous formulation of the NK-1 antagonist fosaprepitant)will&#xD;
      be administered at a dose of 300 mg, intravenously over 1 hour. Patients will then have a&#xD;
      follow up MRI scan in the 24 hour following IVAMEND administration. Continuous ICP and PbtO2&#xD;
      monitoring as well as hourly microdialysis sampling will start immediately following&#xD;
      insertion of monitors and at least 6 hours before and will continue for at least 12 hours&#xD;
      after IVAMEND administration. ICP will continue to be monitored continuously in the 5 days&#xD;
      following administration of IVAMEND. Microdialysis samples collected over the period of 6&#xD;
      hours before and 12 hours after the administration of Fosaprepitant will be stored and&#xD;
      consequently used to measure the concentration of Substance P, nitric oxide (NO) and&#xD;
      inflammatory cytokines.&#xD;
    </textblock>
  </detailed_description>
  <overall_status>Withdrawn</overall_status>
  <why_stopped>
    Alternate study commenced using different drug&#xD;
  </why_stopped>
  <start_date type="Anticipated">November 2021</start_date>
  <completion_date type="Anticipated">April 2023</completion_date>
  <primary_completion_date type="Anticipated">December 2022</primary_completion_date>
  <phase>Early Phase 1</phase>
  <study_type>Interventional</study_type>
  <has_expanded_access>No</has_expanded_access>
  <study_design_info>
    <allocation>N/A</allocation>
    <intervention_model>Single Group Assignment</intervention_model>
    <primary_purpose>Basic Science</primary_purpose>
    <masking>None (Open Label)</masking>
  </study_design_info>
  <primary_outcome>
    <measure>Reduction in intracranial pressure</measure>
    <time_frame>up to 5 days</time_frame>
    <description>Intracranial pressure will be measured continuously for up to 5 days after intervention</description>
  </primary_outcome>
  <secondary_outcome>
    <measure>Improvement in brain tissue oxygen tension</measure>
    <time_frame>up to 5 days</time_frame>
    <description>Brain Tissue Oxygen will be measured continuously for up to 5 days after intervention</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Improvement in lactate/pyruvate ratio on microdialysis monitoring</measure>
    <time_frame>up to 5 days</time_frame>
    <description>Microdialysis will be measured continuously for up to 5 days after intervention</description>
  </secondary_outcome>
  <number_of_arms>1</number_of_arms>
  <enrollment type="Actual">0</enrollment>
  <condition>Traumatic Brain Injury</condition>
  <arm_group>
    <arm_group_label>Treatment</arm_group_label>
    <arm_group_type>Other</arm_group_type>
    <description>There is only one arm in this study. Intracranial pressure and brain swelling will be monitored before and after administration of fosaprepitant</description>
  </arm_group>
  <intervention>
    <intervention_type>Drug</intervention_type>
    <intervention_name>Fosaprepitant</intervention_name>
    <description>Within 24 hours from injury, IVAMEND (the intravenous formulation of the NK-1 antagonist fosaprepitant) will be administered at a dose of 300 mg, intravenously over 1 hour.</description>
    <arm_group_label>Treatment</arm_group_label>
  </intervention>
  <eligibility>
    <criteria>
      <textblock>
        Inclusion Criteria:&#xD;
&#xD;
          -  Patients with traumatic brain injury requiring intracranial pressure monitoring&#xD;
&#xD;
          -  Age 18-65 years&#xD;
&#xD;
          -  Abnormal CT scan&#xD;
&#xD;
        Exclusion Criteria:&#xD;
&#xD;
          -  Bilateral fixed and dilated pupils&#xD;
&#xD;
          -  Bleeding diathesis&#xD;
&#xD;
          -  Devastating injuries; patient not expected to survive &gt; 24 hours&#xD;
&#xD;
          -  Brainstem damage&#xD;
&#xD;
          -  Pregnancy&#xD;
&#xD;
          -  Sedation with Midazolam&#xD;
&#xD;
          -  Patients under 18 years of age&#xD;
      </textblock>
    </criteria>
    <gender>All</gender>
    <minimum_age>18 Years</minimum_age>
    <maximum_age>65 Years</maximum_age>
    <healthy_volunteers>No</healthy_volunteers>
  </eligibility>
  <overall_official>
    <last_name>Arun Gupta, MD PhD</last_name>
    <role>Principal Investigator</role>
    <affiliation>Cambridge University Hospitals NHS Foundation Trust</affiliation>
  </overall_official>
  <verification_date>October 2022</verification_date>
  <study_first_submitted>January 21, 2017</study_first_submitted>
  <study_first_submitted_qc>January 26, 2017</study_first_submitted_qc>
  <study_first_posted type="Estimate">January 30, 2017</study_first_posted>
  <last_update_submitted>October 31, 2022</last_update_submitted>
  <last_update_submitted_qc>October 31, 2022</last_update_submitted_qc>
  <last_update_posted type="Actual">November 3, 2022</last_update_posted>
  <responsible_party>
    <responsible_party_type>Sponsor-Investigator</responsible_party_type>
    <investigator_affiliation>University of Cambridge</investigator_affiliation>
    <investigator_full_name>Arun Gupta</investigator_full_name>
    <investigator_title>Principal Investigator</investigator_title>
  </responsible_party>
  <condition_browse>
    <!-- CAUTION:  The following MeSH terms are assigned with an imperfect algorithm            -->
    <mesh_term>Brain Injuries</mesh_term>
    <mesh_term>Brain Injuries, Traumatic</mesh_term>
    <mesh_term>Intracranial Hypertension</mesh_term>
    <mesh_term>Wounds and Injuries</mesh_term>
  </condition_browse>
  <intervention_browse>
    <!-- CAUTION:  The following MeSH terms are assigned with an imperfect algorithm            -->
    <mesh_term>Fosaprepitant</mesh_term>
    <mesh_term>Aprepitant</mesh_term>
  </intervention_browse>
  <patient_data>
    <sharing_ipd>No</sharing_ipd>
  </patient_data>
  <!-- Results have not yet been posted for this study                                          -->
</clinical_study>


download date: ClinicalTrials.gov processed this data on September 20, 2023
link text: Link to the current ClinicalTrials.gov record.
url: https://clinicaltrials.gov/ct2/show/NCT03035838
org study id: 212176
nct id: NCT03035838
lead sponsor: 
collaborator: 
has dmc: Yes
is fda regulated drug: No
is fda regulated device: No
is us export: No
Traumatic brain (TBI) injury is the major cause of morbidity and mortality worldwide
      especially in population under 40 years of age and has a significant socioeconomic impact.
      TBI results from the head impacting with an object or from acceleration/deceleration forces
      that produce vigorous movement of the brain within the skull, with the resultant mechanical
      forces potentially damaging neurones and blood vessels and causing irreversible, primary
      brain injury. Primary injury leads to activation of cellular and molecular responses which
      lead to disruption of the blood-brain barrier causing the brain to swell. As the intracranial
      space is not expandable (i.e. is fixed), this swelling leads to increase in intracranial
      pressure (ICP) compromising blood supply to the rest of the brain leading to secondary brain
      injury. As we are unable to reverse the primary injury, current protocols use supportive
      measures to control the ICP and ensure optimal blood supply to the brain in an attempt to
      minimize secondary injury. Our understanding of the factors involved in the initiation and
      propagation of brain swelling in TBI is growing and the role of neuroinflammatory cytokines
      in this process is increasingly recognized. In preclinical models of TBI, a specific
      inflammatory cytokine termed substance P (SP) is found to be associated with blood-brain
      barrier disruption and development of brain oedema in the immediate phase following injury.
      The aim of this study is to examine the role of SP in the genesis of cerebral oedema and
      elevation of ICP and thus secondary injury following human TBI. This would be achieved by
      blocking SP function with a SP receptor antagonist Fosaprepitant (IVEMEND®, Merck) in the
      first 24 hours following TBI and then continuously measuring ICP and assessing the evolvement
      of TBI using magnetic resonance imaging.
All severe traumatic brain injury patients admitted to the Cambridge University Hospital's
      Neurosciences Critical Care Unit who require insertion of a triple bolt for multimodal
      neuromonitoring (intracranial pressure-ICP, microdialysis-MD and brain tissue oxygen partial
      pressure-PbtO2) will be screened for participation in this study. Eligible patients will have
      an initial MRI scan in the first 24 hours from injury. Following this, and within 24 hours
      from injury, IVAMEND (the intravenous formulation of the NK-1 antagonist fosaprepitant)will
      be administered at a dose of 300 mg, intravenously over 1 hour. Patients will then have a
      follow up MRI scan in the 24 hour following IVAMEND administration. Continuous ICP and PbtO2
      monitoring as well as hourly microdialysis sampling will start immediately following
      insertion of monitors and at least 6 hours before and will continue for at least 12 hours
      after IVAMEND administration. ICP will continue to be monitored continuously in the 5 days
      following administration of IVAMEND. Microdialysis samples collected over the period of 6
      hours before and 12 hours after the administration of Fosaprepitant will be stored and
      consequently used to measure the concentration of Substance P, nitric oxide (NO) and
      inflammatory cytokines.
allocation: N/A
intervention model: Single Group Assignment
primary purpose: Basic Science
masking: None (Open Label)
measure: Reduction in intracranial pressure
time frame: up to 5 days
description: Intracranial pressure will be measured continuously for up to 5 days after intervention
measure: Improvement in brain tissue oxygen tension
time frame: up to 5 days
description: Brain Tissue Oxygen will be measured continuously for up to 5 days after intervention
measure: Improvement in lactate/pyruvate ratio on microdialysis monitoring
time frame: up to 5 days
description: Microdialysis will be measured continuously for up to 5 days after intervention
arm group label: Treatment
arm group type: Other
description: There is only one arm in this study. Intracranial pressure and brain swelling will be monitored before and after administration of fosaprepitant
intervention type: Drug
intervention name: Fosaprepitant
description: Within 24 hours from injury, IVAMEND (the intravenous formulation of the NK-1 antagonist fosaprepitant) will be administered at a dose of 300 mg, intravenously over 1 hour.
arm group label: Treatment
criteria: 
gender: All
minimum age: 18 Years
maximum age: 65 Years
healthy volunteers: No
last name: Arun Gupta, MD PhD
role: Principal Investigator
affiliation: Cambridge University Hospitals NHS Foundation Trust
responsible party type: Sponsor-Investigator
investigator affiliation: University of Cambridge
investigator full name: Arun Gupta
investigator title: Principal Investigator
mesh term: Brain Injuries
mesh term: Brain Injuries, Traumatic
mesh term: Intracranial Hypertension
mesh term: Wounds and Injuries
mesh term: Fosaprepitant
mesh term: Aprepitant
sharing ipd: No