<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/NCT04489160</url>
  </required_header>
  <id_info>
    <org_study_id>NL7255105823</org_study_id>
    <nct_id>NCT04489160</nct_id>
  </id_info>
  <brief_title>Complement Inhibition: Attacking the Overshooting Inflammation @Fter Traumatic Brain Injury</brief_title>
  <acronym>CIAO@TBI</acronym>
  <official_title>A Phase II Trial on the Safety and Efficacy of C1 Inhibitor for the Acute Management of Severe Traumatic Brain Injury</official_title>
  <sponsors>
    <lead_sponsor>
      <agency>Leiden University Medical Center</agency>
      <agency_class>Other</agency_class>
    </lead_sponsor>
    <collaborator>
      <agency>Netherlands Brain Foundation</agency>
      <agency_class>Other</agency_class>
    </collaborator>
    <collaborator>
      <agency>Takeda</agency>
      <agency_class>Industry</agency_class>
    </collaborator>
  </sponsors>
  <source>Leiden University Medical Center</source>
  <oversight_info>
    <has_dmc>Yes</has_dmc>
    <is_fda_regulated_drug>Yes</is_fda_regulated_drug>
    <is_fda_regulated_device>No</is_fda_regulated_device>
    <is_us_export>Yes</is_us_export>
  </oversight_info>
  <brief_summary>
    <textblock>
      Severe Traumatic Brain Injury (s-TBI) is a major cause of death and disability across all&#xD;
      ages. Besides the primary impact, the pathophysiologic process of major secondary brain&#xD;
      damage consists of a neuroinflammation response that critically leads to irreversible brain&#xD;
      damage in the first days after the trauma. A key catalyst in this inflammatory process is the&#xD;
      complement system. Inhibiting the complement system is therefore considered to be a&#xD;
      potentially important new treatment for TBI, as has been shown in animal studies. This trial&#xD;
      aims to study the safety and efficacy of C1-inhibitor compared to placebo in TBI patients. By&#xD;
      temporarily blocking the complement system we hypothesize limitation of secondary brain&#xD;
      injury and more favourable clinical outcome for TBI patients due to a decrease in the&#xD;
      posttraumatic neuroinflammatory response.&#xD;
    </textblock>
  </brief_summary>
  <overall_status>Recruiting</overall_status>
  <start_date type="Actual">February 25, 2021</start_date>
  <completion_date type="Anticipated">July 2024</completion_date>
  <primary_completion_date type="Anticipated">July 2023</primary_completion_date>
  <phase>Phase 2</phase>
  <study_type>Interventional</study_type>
  <has_expanded_access>No</has_expanded_access>
  <study_design_info>
    <allocation>Randomized</allocation>
    <intervention_model>Parallel Assignment</intervention_model>
    <primary_purpose>Treatment</primary_purpose>
    <masking>Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor)</masking>
  </study_design_info>
  <primary_outcome>
    <measure>Therapy Intensity Level (TIL) Scale</measure>
    <time_frame>First four ICU days</time_frame>
    <description>TIL differentiated for various treatment modalities aimed at prevention or control of raised Intracranial Pressure (ICP) and/or for CPP management (0 to 38 points)</description>
  </primary_outcome>
  <primary_outcome>
    <measure>Glasgow Outcome Scale Extended (GOSE)</measure>
    <time_frame>At 6 months after trauma</time_frame>
    <description>Functional outcome (minimum score = 1, maximum score = 8)</description>
  </primary_outcome>
  <primary_outcome>
    <measure>Complication rate</measure>
    <time_frame>Up to 1 year</time_frame>
    <description>Adverse and serious adverse events related possibly related to study medication</description>
  </primary_outcome>
  <secondary_outcome>
    <measure>Intracranial pressure (ICP) burden</measure>
    <time_frame>First four ICU days</time_frame>
    <description>Minutes of ICP&gt;20 mm Hg</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>CT scan midline shift</measure>
    <time_frame>Up to 1 year</time_frame>
    <description>in mm</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Mortality</measure>
    <time_frame>Up to 1 year after trauma</time_frame>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Glasgow Outcome Scale Extended (GOSE)</measure>
    <time_frame>At discharge (an average of 14 days), 3 and 12 months after trauma</time_frame>
    <description>Functional outcome (minimum score = 1, maximum score = 8)</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>QoLiBri</measure>
    <time_frame>At 3, 6 and 12 months after trauma</time_frame>
    <description>Quality of Life</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>SF-36</measure>
    <time_frame>At 3, 6 and 12 months after trauma</time_frame>
    <description>Health-related quality of life</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>EQ-5D-5L</measure>
    <time_frame>At 6 and 12 months after trauma</time_frame>
    <description>Health-related quality of life</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>ICU length of stay</measure>
    <time_frame>Up to 1 year</time_frame>
    <description>in days</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Ventilator days</measure>
    <time_frame>Up to 1 year</time_frame>
    <description>in days</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Hospital length of stay</measure>
    <time_frame>Up to 1 year</time_frame>
    <description>in days</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Hospital disposition</measure>
    <time_frame>Up to 1 year</time_frame>
    <description>Discharged to home, rehabilitation or nursery home</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>UCH-L1 and GFAP biomarkers</measure>
    <time_frame>Baseline (Before adminstration of investigational product ) and 6, 12, 24, 48, 72 and 96 hours after adminstration of investigational product</time_frame>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Complement activation</measure>
    <time_frame>Baseline (Before adminstration of investigational product ) and 6, 12, 24, 48, 72 and 96 hours after adminstration of investigational product</time_frame>
    <description>WIESLAB, C3b/C, C4b/C, C5b-9 ELISA assays, CH50/AC50</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Coagulation cascade activation</measure>
    <time_frame>Baseline (Before adminstration of investigational product ) and 6, 12, 24, 48, 72 and 96 hours after adminstration of investigational product</time_frame>
    <description>PT, aPPT, PLT, D-dimer, fibrinogen</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Inflammatory markers</measure>
    <time_frame>Baseline (Before adminstration of investigational product ) and 6, 12, 24, 48, 72 and 96 hours after adminstration of investigational product</time_frame>
    <description>TNF-alpha, intraleukins</description>
  </secondary_outcome>
  <number_of_arms>2</number_of_arms>
  <enrollment type="Anticipated">106</enrollment>
  <condition>Traumatic Brain Injury</condition>
  <condition>Trauma, Head</condition>
  <arm_group>
    <arm_group_label>C1-inhibitor</arm_group_label>
    <arm_group_type>Experimental</arm_group_type>
    <description>One dose 6000 IU C1-inhibitor intravenously</description>
  </arm_group>
  <arm_group>
    <arm_group_label>Placebo</arm_group_label>
    <arm_group_type>Placebo Comparator</arm_group_type>
    <description>0.9% saline</description>
  </arm_group>
  <intervention>
    <intervention_type>Drug</intervention_type>
    <intervention_name>C1 Inhibitor, Human</intervention_name>
    <description>6000 IU C1-INH</description>
    <arm_group_label>C1-inhibitor</arm_group_label>
    <other_name>Cinryze</other_name>
  </intervention>
  <intervention>
    <intervention_type>Drug</intervention_type>
    <intervention_name>Placebo</intervention_name>
    <description>0.9% saline</description>
    <arm_group_label>Placebo</arm_group_label>
  </intervention>
  <eligibility>
    <criteria>
      <textblock>
        Inclusion Criteria:&#xD;
&#xD;
          -  Age at admission ≥ 18 years and &lt; 65 years;&#xD;
&#xD;
          -  Clinical diagnosis of traumatic brain injury with GCS &lt; 13 (with intracranial&#xD;
             deviations);&#xD;
&#xD;
          -  Catheter placement for monitoring and management of increased ICP for at least 24&#xD;
             hours;&#xD;
&#xD;
        Exclusion Criteria:&#xD;
&#xD;
          -  A clear, non-traumatic cause of low GCS (e.g. toxic, cardial) on admission;&#xD;
&#xD;
          -  Not expected to survive more than 24 hours after admission;&#xD;
&#xD;
          -  Brain death on arrival in the participating centers;&#xD;
&#xD;
          -  Severe pre-trauma disability, defined as being dependent on other people;&#xD;
&#xD;
          -  Known prior history of sensibility to blood products or Cinryze;&#xD;
&#xD;
          -  Patients with a history of hereditary angioedema;&#xD;
&#xD;
          -  Patients with a history of thrombosis;&#xD;
&#xD;
          -  Pregnant women.&#xD;
      </textblock>
    </criteria>
    <gender>All</gender>
    <minimum_age>18 Years</minimum_age>
    <maximum_age>64 Years</maximum_age>
    <healthy_volunteers>No</healthy_volunteers>
  </eligibility>
  <overall_official>
    <last_name>Wilco Peul, MD, MPH, PhD, MBa</last_name>
    <role>Principal Investigator</role>
    <affiliation>Leiden University Medical Center</affiliation>
  </overall_official>
  <overall_contact>
    <last_name>Inge van Erp, BSc</last_name>
    <phone>+31(0)715262109</phone>
    <email>i.a.m.van_erp@lumc.nl</email>
  </overall_contact>
  <location>
    <facility>
      <name>Haaglanden Medisch Centrum</name>
      <address>
        <city>Den Haag</city>
        <country>Netherlands</country>
      </address>
    </facility>
    <status>Recruiting</status>
    <contact>
      <last_name>Wilco Peul</last_name>
    </contact>
  </location>
  <location>
    <facility>
      <name>Leiden University Medical Center</name>
      <address>
        <city>Leiden</city>
        <country>Netherlands</country>
      </address>
    </facility>
    <status>Recruiting</status>
    <contact>
      <last_name>Wilco Peul</last_name>
    </contact>
  </location>
  <location>
    <facility>
      <name>Erasmus Medical Center</name>
      <address>
        <city>Rotterdam</city>
        <country>Netherlands</country>
      </address>
    </facility>
    <status>Not yet recruiting</status>
    <contact>
      <last_name>Wilco Peul</last_name>
    </contact>
  </location>
  <location_countries>
    <country>Netherlands</country>
  </location_countries>
  <reference>
    <citation>Fluiter K, Opperhuizen AL, Morgan BP, Baas F, Ramaglia V. Inhibition of the membrane attack complex of the complement system reduces secondary neuroaxonal loss and promotes neurologic recovery after traumatic brain injury in mice. J Immunol. 2014 Mar 1;192(5):2339-48. doi: 10.4049/jimmunol.1302793. Epub 2014 Jan 31.</citation>
    <PMID>24489093</PMID>
  </reference>
  <verification_date>September 2021</verification_date>
  <study_first_submitted>July 17, 2020</study_first_submitted>
  <study_first_submitted_qc>July 24, 2020</study_first_submitted_qc>
  <study_first_posted type="Actual">July 28, 2020</study_first_posted>
  <last_update_submitted>September 6, 2021</last_update_submitted>
  <last_update_submitted_qc>September 6, 2021</last_update_submitted_qc>
  <last_update_posted type="Actual">September 13, 2021</last_update_posted>
  <responsible_party>
    <responsible_party_type>Principal Investigator</responsible_party_type>
    <investigator_affiliation>Leiden University Medical Center</investigator_affiliation>
    <investigator_full_name>wcpeul</investigator_full_name>
    <investigator_title>Principal Investigator</investigator_title>
  </responsible_party>
  <keyword>Traumatic Brain Injury</keyword>
  <keyword>C1-inhibitor</keyword>
  <keyword>Neuroinflammation</keyword>
  <keyword>Efficacy</keyword>
  <keyword>Safety</keyword>
  <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>Craniocerebral Trauma</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>Complement C1 Inhibitor Protein</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/NCT04489160
org study id: NL7255105823
nct id: NCT04489160
lead sponsor: 
collaborator: 
collaborator: 
has dmc: Yes
is fda regulated drug: Yes
is fda regulated device: No
is us export: Yes
Severe Traumatic Brain Injury (s-TBI) is a major cause of death and disability across all
      ages. Besides the primary impact, the pathophysiologic process of major secondary brain
      damage consists of a neuroinflammation response that critically leads to irreversible brain
      damage in the first days after the trauma. A key catalyst in this inflammatory process is the
      complement system. Inhibiting the complement system is therefore considered to be a
      potentially important new treatment for TBI, as has been shown in animal studies. This trial
      aims to study the safety and efficacy of C1-inhibitor compared to placebo in TBI patients. By
      temporarily blocking the complement system we hypothesize limitation of secondary brain
      injury and more favourable clinical outcome for TBI patients due to a decrease in the
      posttraumatic neuroinflammatory response.
allocation: Randomized
intervention model: Parallel Assignment
primary purpose: Treatment
masking: Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor)
measure: Therapy Intensity Level (TIL) Scale
time frame: First four ICU days
description: TIL differentiated for various treatment modalities aimed at prevention or control of raised Intracranial Pressure (ICP) and/or for CPP management (0 to 38 points)
measure: Glasgow Outcome Scale Extended (GOSE)
time frame: At 6 months after trauma
description: Functional outcome (minimum score = 1, maximum score = 8)
measure: Complication rate
time frame: Up to 1 year
description: Adverse and serious adverse events related possibly related to study medication
measure: Intracranial pressure (ICP) burden
time frame: First four ICU days
description: Minutes of ICP>20 mm Hg
measure: CT scan midline shift
time frame: Up to 1 year
description: in mm
measure: Mortality
time frame: Up to 1 year after trauma
measure: Glasgow Outcome Scale Extended (GOSE)
time frame: At discharge (an average of 14 days), 3 and 12 months after trauma
description: Functional outcome (minimum score = 1, maximum score = 8)
measure: QoLiBri
time frame: At 3, 6 and 12 months after trauma
description: Quality of Life
measure: SF-36
time frame: At 3, 6 and 12 months after trauma
description: Health-related quality of life
measure: EQ-5D-5L
time frame: At 6 and 12 months after trauma
description: Health-related quality of life
measure: ICU length of stay
time frame: Up to 1 year
description: in days
measure: Ventilator days
time frame: Up to 1 year
description: in days
measure: Hospital length of stay
time frame: Up to 1 year
description: in days
measure: Hospital disposition
time frame: Up to 1 year
description: Discharged to home, rehabilitation or nursery home
measure: UCH-L1 and GFAP biomarkers
time frame: Baseline (Before adminstration of investigational product ) and 6, 12, 24, 48, 72 and 96 hours after adminstration of investigational product
measure: Complement activation
time frame: Baseline (Before adminstration of investigational product ) and 6, 12, 24, 48, 72 and 96 hours after adminstration of investigational product
description: WIESLAB, C3b/C, C4b/C, C5b-9 ELISA assays, CH50/AC50
measure: Coagulation cascade activation
time frame: Baseline (Before adminstration of investigational product ) and 6, 12, 24, 48, 72 and 96 hours after adminstration of investigational product
description: PT, aPPT, PLT, D-dimer, fibrinogen
measure: Inflammatory markers
time frame: Baseline (Before adminstration of investigational product ) and 6, 12, 24, 48, 72 and 96 hours after adminstration of investigational product
description: TNF-alpha, intraleukins
arm group label: C1-inhibitor
arm group type: Experimental
description: One dose 6000 IU C1-inhibitor intravenously
arm group label: Placebo
arm group type: Placebo Comparator
description: 0.9% saline
intervention type: Drug
intervention name: C1 Inhibitor, Human
description: 6000 IU C1-INH
arm group label: C1-inhibitor
other name: Cinryze
intervention type: Drug
intervention name: Placebo
description: 0.9% saline
arm group label: Placebo
criteria: 
gender: All
minimum age: 18 Years
maximum age: 64 Years
healthy volunteers: No
last name: Wilco Peul, MD, MPH, PhD, MBa
role: Principal Investigator
affiliation: Leiden University Medical Center
last name: Inge van Erp, BSc
phone: +31(0)715262109
email: i.a.m.van_erp@lumc.nl
facility: 
status: Recruiting
contact: 
facility: 
status: Recruiting
contact: 
facility: 
status: Not yet recruiting
contact: 
country: Netherlands
citation: Fluiter K, Opperhuizen AL, Morgan BP, Baas F, Ramaglia V. Inhibition of the membrane attack complex of the complement system reduces secondary neuroaxonal loss and promotes neurologic recovery after traumatic brain injury in mice. J Immunol. 2014 Mar 1;192(5):2339-48. doi: 10.4049/jimmunol.1302793. Epub 2014 Jan 31.
PMID: 24489093
responsible party type: Principal Investigator
investigator affiliation: Leiden University Medical Center
investigator full name: wcpeul
investigator title: Principal Investigator
mesh term: Brain Injuries
mesh term: Brain Injuries, Traumatic
mesh term: Craniocerebral Trauma
mesh term: Wounds and Injuries
mesh term: Complement C1 Inhibitor Protein
sharing ipd: No