<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/NCT03818451</url>
  </required_header>
  <id_info>
    <org_study_id>GLIA13_1</org_study_id>
    <nct_id>NCT03818451</nct_id>
  </id_info>
  <brief_title>Co-ultra PEALut Enhances Neuronal Recovery Following Moderate Traumatic Brain Injury</brief_title>
  <acronym>GLIA13</acronym>
  <official_title>Co-ultra PEALut Enhances Neuronal Recovery Following Moderate Traumatic Brain Injury</official_title>
  <sponsors>
    <lead_sponsor>
      <agency>University of Messina</agency>
      <agency_class>Other</agency_class>
    </lead_sponsor>
  </sponsors>
  <source>University of Messina</source>
  <oversight_info>
    <has_dmc>No</has_dmc>
    <is_fda_regulated_drug>No</is_fda_regulated_drug>
    <is_fda_regulated_device>No</is_fda_regulated_device>
  </oversight_info>
  <brief_summary>
    <textblock>
      Traumatic brain injury (TBI) typically provokes secondary injury mechanisms, including the&#xD;
      dynamic interplay between the ischemic, inflammatory, and cytotoxic processes. Moreover, such&#xD;
      an impact induces a substantial level of cell death and results in the degeneration of the&#xD;
      dendrites, thereby leading to persistent motor, sensory, and cognitive dysfunction. Previous&#xD;
      studies have shown that the adult-born immature granule neurons in the dentate gyrus are the&#xD;
      most susceptible of all the cell types in the hippocampus to damage following a moderate TBI&#xD;
      due to a controlled cortical impact (CCI) device. Currently, there is no efficient approach&#xD;
      available for avoiding immature neuron death or degeneration following TBI. Hence, this study&#xD;
      aimed to assess the neuro-regenerative properties of co-ultramicronized PEALut (Glialia®),&#xD;
      which is composed of palmitoylethanolamide (PEA) and the flavonoid luteolin (Lut), in an in&#xD;
      vivo model of TBI, as well as in patients affected by TBI.&#xD;
    </textblock>
  </brief_summary>
  <detailed_description>
    <textblock>
      Study Setting All patients affected by moderate TBI (Glasgow Coma Score 9-13) admitted to the&#xD;
      neurosurgical department of the University Hospital of Messina, Italy, will be screened for&#xD;
      recruitment.&#xD;
&#xD;
      Ethics The institutional review board (IRB) approved the study. Written consent will be&#xD;
      obtained from each patient or the closest family member prior to the start of the study.&#xD;
&#xD;
      Study Design A randomized controlled single-blind study to assess the effects of&#xD;
      co-ultraPEALut (Glialia®) administration in TBI patients will be carried out. The study is&#xD;
      set to recruit at least 30 patients.&#xD;
&#xD;
      Recruited patients are randomly allocated to one of the two branches of the study: standard&#xD;
      TBI treatment + Glialia® (Study Group) and standard TBI treatment (Control Group) in a 1:1&#xD;
      ratio using precompiled randomization tables.&#xD;
&#xD;
      General treatment&#xD;
&#xD;
      All patients will undergo standard treatments according to patterns of severity and in the&#xD;
      light of distinct variables, mainly represented by the conditions of cerebral hemodynamics.&#xD;
      These procedures can be summarized as follows:&#xD;
&#xD;
        -  Surgical evacuation of hemorrhagic masses and / or &quot;debridement&quot; of outbreaks brain&#xD;
           contusion;&#xD;
&#xD;
        -  Medical management aimed to maintenance of euvolemia and adequate brain perfusion. Goals&#xD;
           were a systolic blood pressure &gt;90 mmHg and a cerebral perfusion pressure &gt;60 mmHg.&#xD;
           Prevention of secondary complications of critical illness included: preventive therapy&#xD;
           of venous thromboembolism (VTE) using low molecular weight heparin (LMWH) and seizures&#xD;
           using levetiracetam prophylactically for the first seven days after injury;&#xD;
&#xD;
        -  Patient who underwent surgical treatment, received also postoperative intensive care&#xD;
           treatments including: position of the head high, lower values of end-tidal CO2, sedation&#xD;
           with reduced metabolic consumption of O2, increase in plasma osmolarity by&#xD;
           administration of mannitol in controlled doses or hypernatremia, therapeutic CSF&#xD;
           drainage.&#xD;
&#xD;
      Specific Treatment The investigations agent, the co-ultraPEALut, will be administered orally&#xD;
      twice daily (every 12 h) for 180 days in association with the specific therapy (e.g.,&#xD;
      antiplatelet agents, anticoagulants, antiepileptic drugs) commonly administered to these&#xD;
      patients and/or with drugs prescribed for comorbidities (i.e. diabetes, arterial&#xD;
      hypertension).&#xD;
    </textblock>
  </detailed_description>
  <overall_status>Unknown status</overall_status>
  <last_known_status>Recruiting</last_known_status>
  <start_date type="Actual">May 1, 2016</start_date>
  <completion_date type="Anticipated">December 31, 2019</completion_date>
  <primary_completion_date type="Anticipated">October 31, 2019</primary_completion_date>
  <phase>N/A</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>Double (Participant, Outcomes Assessor)</masking>
  </study_design_info>
  <primary_outcome>
    <measure>Cognitive outcome assessed Mini Mental State Examination (MMSE)</measure>
    <time_frame>All patients will undergo neurological and neuropsychological evaluations at baseline (T0), after 30 days (T30) and 6 months (T180)</time_frame>
    <description>Impairment of cognitive abilities will be evaluated by the Mini Mental State Examination (MMSE) (Folstein et al., 1975) adjusted for educational level and age. This is a 30-point questionnaire that is used extensively in clinical and research settings to measure cognitive impairment. It is commonly used in medicine and allied health to screen for dementia. It is also used to estimate the severity and progression of cognitive impairment and to follow the course of cognitive changes in an individual over time that is within the scope of this research. The threshold value for normal performance is set to 24 points. The outcome measure will be represented by the absolute score and by the change between the score recorded after 180 days and the baseline value</description>
  </primary_outcome>
  <primary_outcome>
    <measure>Cognitive outcome assessed by the Brief Neuropsychological Cognitive Examination (BNCE)</measure>
    <time_frame>All patients will undergo neurological and neuropsychological evaluations at baseline (T0), after 30 days (T30) and 6 months (T180)</time_frame>
    <description>Brief Neuropsychological Cognitive Examination (BNCE) (Ball et al., 2009). This consists in 10 subtests composed of easily administered tasks, none requiring more than minimal reading skills.Total score indicating overall severity of impairment (expressed in percentage), subtest scores, and two aggregate scores for the simple and complex subtests are provided as percentage of the maximum score. The outcome measure will be represented by the absolute score and by the difference between the score recorded after 180 days and the baseline value</description>
  </primary_outcome>
  <primary_outcome>
    <measure>Depression outcome assessed by Beck Depression Inventory</measure>
    <time_frame>Outcome measure will be assessed at 180 days (T180) after trauma</time_frame>
    <description>Depression will be assessed by the Beck inventory depression scale.This is a 21-question multiple-choice (scored 0-3 each) self-report inventory, one of the most widely used psychometric tests for measuring the severity of depression. Scores will be categorized as follows:&#xD;
0-9: indicates minimal depression 10-18: indicates mild depression 19-29: indicates moderate depression 30-63: indicates severe depression&#xD;
Depression score will be assessed at 180 days (T180) after trauma</description>
  </primary_outcome>
  <primary_outcome>
    <measure>Assessment of Independence by Barthel Index</measure>
    <time_frame>Outcome measure will be assessed at 180 days (T180) after trauma</time_frame>
    <description>Independence in activities of daily living and self-care will be assessed by the Barthel Index. This is an ordinal scale used to measure performance in activities of daily living (ADL). Each performance item is rated on this scale with a given number of points assigned to each level or ranking. Each domain is scored in one-point increments with a full score of 20 indicating functional independence. Independence will be assessed at 180 days (T180) after trauma</description>
  </primary_outcome>
  <number_of_arms>2</number_of_arms>
  <enrollment type="Anticipated">60</enrollment>
  <condition>Traumatic Brain Injury</condition>
  <arm_group>
    <arm_group_label>Control Group</arm_group_label>
    <arm_group_type>No Intervention</arm_group_type>
    <description>All patients are treated by standard treatments according to patterns of severity and in the light of different variables, mainly represented by the conditions of cerebral hemodynamics. These procedures can be summarized as follows:&#xD;
Surgical evacuation of hemorrhagic masses and brain contusion&#xD;
Medical management aimed to maintenance of euvolemia and adequate brain perfusion. Prevention of secondary complications of critical illness included: preventive treatment of venous thromboembolism (VTE) and seizures&#xD;
Patient who undergo surgical treatment, will recieve also postoperative intensive care treatments including: position of the head high, lower values of end-tidal CO2, sedation with reduced metabolic consumption of O2, increase in plasma osmolarity by administration of mannitol in controlled doses or hypernatremia, therapeutic CSF drainage</description>
  </arm_group>
  <arm_group>
    <arm_group_label>Study Group</arm_group_label>
    <arm_group_type>Experimental</arm_group_type>
    <description>Standard treatment plus specific treatment. The investigational agent, the co-ultraPEALut, is administered orally twice daily (every 12 h) for 180 days in association with the specific therapy (e.g., antiplatelet agents, anticoagulants, antiepileptic drugs) commonly administered to these patients and/or with drugs prescribed for comorbidities (i.e. diabetes, arterial hypertension).</description>
  </arm_group>
  <intervention>
    <intervention_type>Dietary Supplement</intervention_type>
    <intervention_name>Co-ultraPEALut (Glialia)</intervention_name>
    <description>Co-ultraPEALut is administered to moderate traumatic brain injured patients for 180 days</description>
    <arm_group_label>Study Group</arm_group_label>
    <other_name>Glialia</other_name>
  </intervention>
  <eligibility>
    <criteria>
      <textblock>
        Inclusion Criteria:&#xD;
&#xD;
          -  Traumatic brain injuries&#xD;
&#xD;
          -  Moderate trauma&#xD;
&#xD;
          -  Glasgow Coma Score 9-13&#xD;
&#xD;
          -  Loss of consciousness lasting &gt;1 min&#xD;
&#xD;
          -  post-traumatic amnesia &gt;20 minutes&#xD;
&#xD;
          -  CT scan Marshall Scale class II-VI.&#xD;
&#xD;
        Exclusion Criteria:&#xD;
&#xD;
          -  Spinal cord injuries&#xD;
&#xD;
          -  Pre-existing neurological disorders affecting the brain and/or the spinal cord&#xD;
&#xD;
          -  Severe hypertension&#xD;
&#xD;
          -  Diabetes, and chronic renal disease&#xD;
&#xD;
          -  Remarkable chronic cerebravasculopathy of the CT&#xD;
&#xD;
          -  Severe cognitive deficit.&#xD;
      </textblock>
    </criteria>
    <gender>All</gender>
    <minimum_age>18 Years</minimum_age>
    <maximum_age>75 Years</maximum_age>
    <healthy_volunteers>No</healthy_volunteers>
  </eligibility>
  <overall_contact>
    <last_name>Alfred Conti, MD, PhD; FEBNS</last_name>
    <phone>00393382131017</phone>
    <email>contia@unime.it</email>
  </overall_contact>
  <location>
    <facility>
      <name>Department of Neurosurgery, University of Messina</name>
      <address>
        <city>Messina</city>
        <zip>98125</zip>
        <country>Italy</country>
      </address>
    </facility>
    <status>Recruiting</status>
    <contact>
      <last_name>Alfredo Conti, MD, PhD, FEBNS</last_name>
      <phone>00393382131017</phone>
      <email>contia@unime.it</email>
    </contact>
  </location>
  <location_countries>
    <country>Italy</country>
  </location_countries>
  <verification_date>January 2019</verification_date>
  <study_first_submitted>January 18, 2019</study_first_submitted>
  <study_first_submitted_qc>January 23, 2019</study_first_submitted_qc>
  <study_first_posted type="Actual">January 28, 2019</study_first_posted>
  <last_update_submitted>January 25, 2019</last_update_submitted>
  <last_update_submitted_qc>January 25, 2019</last_update_submitted_qc>
  <last_update_posted type="Actual">January 29, 2019</last_update_posted>
  <responsible_party>
    <responsible_party_type>Principal Investigator</responsible_party_type>
    <investigator_affiliation>University of Messina</investigator_affiliation>
    <investigator_full_name>Alfredo Conti</investigator_full_name>
    <investigator_title>Associate Professor</investigator_title>
  </responsible_party>
  <keyword>Moderate brain trauma</keyword>
  <keyword>Glialia</keyword>
  <keyword>Neuroinflammation</keyword>
  <keyword>Neuroprotection</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>Wounds and Injuries</mesh_term>
  </condition_browse>
  <patient_data>
    <sharing_ipd>Undecided</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/NCT03818451
org study id: GLIA13_1
nct id: NCT03818451
lead sponsor: 
has dmc: No
is fda regulated drug: No
is fda regulated device: No
Traumatic brain injury (TBI) typically provokes secondary injury mechanisms, including the
      dynamic interplay between the ischemic, inflammatory, and cytotoxic processes. Moreover, such
      an impact induces a substantial level of cell death and results in the degeneration of the
      dendrites, thereby leading to persistent motor, sensory, and cognitive dysfunction. Previous
      studies have shown that the adult-born immature granule neurons in the dentate gyrus are the
      most susceptible of all the cell types in the hippocampus to damage following a moderate TBI
      due to a controlled cortical impact (CCI) device. Currently, there is no efficient approach
      available for avoiding immature neuron death or degeneration following TBI. Hence, this study
      aimed to assess the neuro-regenerative properties of co-ultramicronized PEALut (Glialia®),
      which is composed of palmitoylethanolamide (PEA) and the flavonoid luteolin (Lut), in an in
      vivo model of TBI, as well as in patients affected by TBI.
Study Setting All patients affected by moderate TBI (Glasgow Coma Score 9-13) admitted to the
      neurosurgical department of the University Hospital of Messina, Italy, will be screened for
      recruitment.

      Ethics The institutional review board (IRB) approved the study. Written consent will be
      obtained from each patient or the closest family member prior to the start of the study.

      Study Design A randomized controlled single-blind study to assess the effects of
      co-ultraPEALut (Glialia®) administration in TBI patients will be carried out. The study is
      set to recruit at least 30 patients.

      Recruited patients are randomly allocated to one of the two branches of the study: standard
      TBI treatment + Glialia® (Study Group) and standard TBI treatment (Control Group) in a 1:1
      ratio using precompiled randomization tables.

      General treatment

      All patients will undergo standard treatments according to patterns of severity and in the
      light of distinct variables, mainly represented by the conditions of cerebral hemodynamics.
      These procedures can be summarized as follows:

        -  Surgical evacuation of hemorrhagic masses and / or "debridement" of outbreaks brain
           contusion;

        -  Medical management aimed to maintenance of euvolemia and adequate brain perfusion. Goals
           were a systolic blood pressure >90 mmHg and a cerebral perfusion pressure >60 mmHg.
           Prevention of secondary complications of critical illness included: preventive therapy
           of venous thromboembolism (VTE) using low molecular weight heparin (LMWH) and seizures
           using levetiracetam prophylactically for the first seven days after injury;

        -  Patient who underwent surgical treatment, received also postoperative intensive care
           treatments including: position of the head high, lower values of end-tidal CO2, sedation
           with reduced metabolic consumption of O2, increase in plasma osmolarity by
           administration of mannitol in controlled doses or hypernatremia, therapeutic CSF
           drainage.

      Specific Treatment The investigations agent, the co-ultraPEALut, will be administered orally
      twice daily (every 12 h) for 180 days in association with the specific therapy (e.g.,
      antiplatelet agents, anticoagulants, antiepileptic drugs) commonly administered to these
      patients and/or with drugs prescribed for comorbidities (i.e. diabetes, arterial
      hypertension).
allocation: Randomized
intervention model: Parallel Assignment
primary purpose: Treatment
masking: Double (Participant, Outcomes Assessor)
measure: Cognitive outcome assessed Mini Mental State Examination (MMSE)
time frame: All patients will undergo neurological and neuropsychological evaluations at baseline (T0), after 30 days (T30) and 6 months (T180)
description: Impairment of cognitive abilities will be evaluated by the Mini Mental State Examination (MMSE) (Folstein et al., 1975) adjusted for educational level and age. This is a 30-point questionnaire that is used extensively in clinical and research settings to measure cognitive impairment. It is commonly used in medicine and allied health to screen for dementia. It is also used to estimate the severity and progression of cognitive impairment and to follow the course of cognitive changes in an individual over time that is within the scope of this research. The threshold value for normal performance is set to 24 points. The outcome measure will be represented by the absolute score and by the change between the score recorded after 180 days and the baseline value
measure: Cognitive outcome assessed by the Brief Neuropsychological Cognitive Examination (BNCE)
time frame: All patients will undergo neurological and neuropsychological evaluations at baseline (T0), after 30 days (T30) and 6 months (T180)
description: Brief Neuropsychological Cognitive Examination (BNCE) (Ball et al., 2009). This consists in 10 subtests composed of easily administered tasks, none requiring more than minimal reading skills.Total score indicating overall severity of impairment (expressed in percentage), subtest scores, and two aggregate scores for the simple and complex subtests are provided as percentage of the maximum score. The outcome measure will be represented by the absolute score and by the difference between the score recorded after 180 days and the baseline value
measure: Depression outcome assessed by Beck Depression Inventory
time frame: Outcome measure will be assessed at 180 days (T180) after trauma
description: Depression will be assessed by the Beck inventory depression scale.This is a 21-question multiple-choice (scored 0-3 each) self-report inventory, one of the most widely used psychometric tests for measuring the severity of depression. Scores will be categorized as follows:
0-9: indicates minimal depression 10-18: indicates mild depression 19-29: indicates moderate depression 30-63: indicates severe depression
Depression score will be assessed at 180 days (T180) after trauma
measure: Assessment of Independence by Barthel Index
time frame: Outcome measure will be assessed at 180 days (T180) after trauma
description: Independence in activities of daily living and self-care will be assessed by the Barthel Index. This is an ordinal scale used to measure performance in activities of daily living (ADL). Each performance item is rated on this scale with a given number of points assigned to each level or ranking. Each domain is scored in one-point increments with a full score of 20 indicating functional independence. Independence will be assessed at 180 days (T180) after trauma
arm group label: Control Group
arm group type: No Intervention
description: All patients are treated by standard treatments according to patterns of severity and in the light of different variables, mainly represented by the conditions of cerebral hemodynamics. These procedures can be summarized as follows:
Surgical evacuation of hemorrhagic masses and brain contusion
Medical management aimed to maintenance of euvolemia and adequate brain perfusion. Prevention of secondary complications of critical illness included: preventive treatment of venous thromboembolism (VTE) and seizures
Patient who undergo surgical treatment, will recieve also postoperative intensive care treatments including: position of the head high, lower values of end-tidal CO2, sedation with reduced metabolic consumption of O2, increase in plasma osmolarity by administration of mannitol in controlled doses or hypernatremia, therapeutic CSF drainage
arm group label: Study Group
arm group type: Experimental
description: Standard treatment plus specific treatment. The investigational agent, the co-ultraPEALut, is administered orally twice daily (every 12 h) for 180 days in association with the specific therapy (e.g., antiplatelet agents, anticoagulants, antiepileptic drugs) commonly administered to these patients and/or with drugs prescribed for comorbidities (i.e. diabetes, arterial hypertension).
intervention type: Dietary Supplement
intervention name: Co-ultraPEALut (Glialia)
description: Co-ultraPEALut is administered to moderate traumatic brain injured patients for 180 days
arm group label: Study Group
other name: Glialia
criteria: 
gender: All
minimum age: 18 Years
maximum age: 75 Years
healthy volunteers: No
last name: Alfred Conti, MD, PhD; FEBNS
phone: 00393382131017
email: contia@unime.it
facility: 
status: Recruiting
contact: 
country: Italy
responsible party type: Principal Investigator
investigator affiliation: University of Messina
investigator full name: Alfredo Conti
investigator title: Associate Professor
mesh term: Brain Injuries
mesh term: Brain Injuries, Traumatic
mesh term: Wounds and Injuries
sharing ipd: Undecided