<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/NCT04495192</url>
  </required_header>
  <id_info>
    <org_study_id>16606_OSS</org_study_id>
    <nct_id>NCT04495192</nct_id>
  </id_info>
  <brief_title>Predictors of Better Outcomes After Severe Acquired Brain Injuries</brief_title>
  <acronym>FP-GCA</acronym>
  <official_title>Clinical, Neurophysiological and Genetical Predictors of Consciousness Recovery and Functional Outcomes After Severe Acquired Brain Injuries</official_title>
  <sponsors>
    <lead_sponsor>
      <agency>Fondazione Don Carlo Gnocchi Onlus</agency>
      <agency_class>Other</agency_class>
    </lead_sponsor>
  </sponsors>
  <source>Fondazione Don Carlo Gnocchi Onlus</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>
  </oversight_info>
  <brief_summary>
    <textblock>
      Severe Acquired Brain Injury is defined as a traumatic, post-anoxic, vascular or other brain&#xD;
      damage that causes coma for at least 24 hours and leads to permanent disability with&#xD;
      sensorial, motor, cognitive or compartmental impairment. In this context, an accurate&#xD;
      characterization of individual patients' profile in terms of neuronal damage, potential for&#xD;
      neuroplasticity, neurofunctional and clinical state could allow to plan tailored&#xD;
      rehabilitation and care pathway on the basis of solid prognostic information, also for&#xD;
      optimizing resources of the National Health care systems and enhance ethical decisions.&#xD;
      Patient profiling should encompass measures and procedures easily available at the bedside,&#xD;
      and with affordable time, resource, and money-costs to determine a real impact on National&#xD;
      Health systems. The aim of the study is identifying patient profiles in terms of clinical,&#xD;
      neurophysiological and genetical aspects with better long-term outcome in order to plan&#xD;
      tailored therapeutic interventions.&#xD;
    </textblock>
  </brief_summary>
  <detailed_description>
    <textblock>
      Background:&#xD;
&#xD;
      After a severe Acquired Brain Injury (sABI) the consciousness, the functional and the&#xD;
      cognitive recovery of the patients depends on the severity of the damage suffered but also on&#xD;
      the vulnerability of the individual brain. Some patients with sABI may survive in a state of&#xD;
      Disorder of Consciousness (DoC) condition (i.e., patients in vegetative state/unresponsive&#xD;
      wakefulness syndrome, VS/UWS or in minimally conscious state, MCS). Other patients, despite&#xD;
      having a complete recovery of consciousness, can reach very variable degrees of functional&#xD;
      and cognitive autonomy. The prognostic factors of consciousness recovery of patients with&#xD;
      DoCs have been thoroughly investigated. Most of these studies investigated the acute phase,&#xD;
      while only a few studies have examined the role of early clinical factors emerging before the&#xD;
      complete recovery of consciousness . Further prognostic insights can be provided by analysis&#xD;
      of genes coding for Apolipoprotein E (APOE), dopamineD2 receptor (DRD2), and Brain Derived&#xD;
      Neutrophic Factors (BDNF), and by markers of axonal injury.&#xD;
&#xD;
      Study aim:&#xD;
&#xD;
      The present project aims at identifying patient profiles with better long-term outcome in&#xD;
      order to plan tailored therapeutic interventions.&#xD;
&#xD;
      The patient profiles will be drawn up by gathering patient's demographic (age, gender, social&#xD;
      and educational level), anamnestic (aetiology and time post-brain injury, Cognitive Reserve&#xD;
      Index), clinical state (Cumulative Illness Rating Scale (CIRS), CRS-R total score and&#xD;
      corresponding consciousness state; Disability Rating Scale, DRS, Functional Oral Intake&#xD;
      Scale; FOIS, Glasgow Outcome Scale Expanded; GOS-E, Level of Cognitive Functioning; LCF) and&#xD;
      neurophysiological data (Electroencephalogram (EEG), Somatosensory evoked potentials (SEP),&#xD;
      and Motor evoked potentials (MEP) nerve conduction aimed at evaluating occurrence of critical&#xD;
      illness polyneuropathy and myopathy (CIPNM)) at study entry (baseline), together with neural&#xD;
      biomarkers (genetic markers).&#xD;
&#xD;
      On the basis of the above mentioned stratification of patients by this multimodal approach,&#xD;
      the present study aimed to&#xD;
&#xD;
        1. Investigate the possible association of certain profiles with the consciousness recovery&#xD;
           at the time of discharge from the Intensive Rehabilitation Unit (IRU), at 1 year and 2&#xD;
           years from the acute event&#xD;
&#xD;
        2. Investigate the possible association of certain profiles with the functional outcomes at&#xD;
           the time of discharge from the Intensive Rehabilitation Unit (IRU), at 1 year and 2&#xD;
           years from the acute event.&#xD;
&#xD;
        3. Investigate the possible association of certain profiles with the long-term cognitive&#xD;
           profile and the level of familiar and social participation at 1 year and 2 years from&#xD;
           the acute event.&#xD;
&#xD;
      Setting , population and methods:&#xD;
&#xD;
      The proposed study is a longitudinal multi-location prospective observational cohort study.&#xD;
&#xD;
      Four centers of the Don Carlo Gnocchi Foundation will participate (Florence, La Spezia, Milan&#xD;
      and Sant'Angelo dei Lombardi and the neurogenetics laboratory of the University of Florence,&#xD;
      Department of Medical and Experimental Sciences, Neurology). The enrollment phase will last 3&#xD;
      years (June 2020-June 2023). 520 patients with severe brain injury will be included (200 for&#xD;
      the Florence and La Spezia units and 60 for the Milan and Sant'Angelo dei Lombardi units).&#xD;
&#xD;
      All patients admitted in the participant IRU with a history of sABI within 4 months, aged&#xD;
      18+, presenting a signed informed consent signature for the participation to the study and&#xD;
      for the genetic analysis will be consecutively enrolled.&#xD;
&#xD;
      A multidimodal evaluation including clinical examinations and neurophysiological assessments&#xD;
      will be performed by skilled professionals. The study foresees four steps in the late acute&#xD;
      phase and two in the long-term phase: 1) at the study entry time (T0), 2) at three months&#xD;
      from T0 (T1) 3) at 6 months from T0 (T2) 4) at discharge (T3) 5) at 12 months from the acute&#xD;
      event (T4) 6) at 24 months from the acute event.&#xD;
&#xD;
      Clinical assessment including :&#xD;
&#xD;
        1. Consciousness assessment using CRS-R&#xD;
&#xD;
        2. Care severity profile: including the comorbidity assessed thought the Cumulative Illness&#xD;
           Rating Scale (CIRS), the presence of medical devices, sepsis occurrence during the IRU&#xD;
           stay, neurosurgery interventions, bedsores, epileptic event and other complications&#xD;
&#xD;
        3. Functional evaluation using the following scales: ERBI, GOS-E, DRS, FIM, PAINED pain&#xD;
           scale, TCT, Ashworth, FOIS&#xD;
&#xD;
        4. Neurocognitive profile evaluation using the Galveston Orientation and Amnesia Test&#xD;
           (GOAT), the Level of Cognitive Functioning (LCF) and the International Classification of&#xD;
           Functioning, Disability and Health (ICF), ABS, AES and Cognitive Reserve Index (CRI)&#xD;
&#xD;
      Multimodal neurophysiological evaluation including:&#xD;
&#xD;
        1. Standard EEG recording at rest. EEG background activity and reactivity will be&#xD;
           classified according to recently proposed diagnostic criteria for DoC and to American&#xD;
           Clinical Neurophysiology Society Critical Care EEG Terminology.&#xD;
&#xD;
        2. Motor and sensory nerve conduction studies. Sensory nerve action potentials, and&#xD;
           compound muscle action potentials (CMAP) will be evaluated. Muscular activity at rest&#xD;
           and when possible during reflex contraction will be assessed.&#xD;
&#xD;
        3. PEM: Transcranial magnetic stimulation (TMS) will be performed according to the standard&#xD;
           criteria of the International Federation of Clinical Neurophysiology. MEP will be&#xD;
           recorded from abductor digiti minimi and tibialis anterior muscles and size of MEP&#xD;
           measured as MEP/CMAP amplitude ratio.&#xD;
&#xD;
        4. Bilateral upper limb SEP will be recorded according to the International Federation of&#xD;
           Clinical Neurophysiology. The presence or absence of N20/P25 cortical components will be&#xD;
           evaluated.&#xD;
&#xD;
      Genetic assessment Genomic DNA will be obtained from EDTA-whole venous blood sample by&#xD;
      Automated Systems QiaCube (Qiagen). The genetic analysis of 5 different single nucleotide&#xD;
      polymorphisms on ApoE, BDNF and DRD2 genes will be performed by high resolution melt (HRM)&#xD;
      analyses and direct sequencing on Automatic Genetic Analyzer. APOE genotypes will be&#xD;
      investigated by HRM with two sets of PCR primers designed to amplify the regions encompassing&#xD;
      rs7412 [NC_000019.9: g.45412079C&gt;T] and rs429358 (NC_000019.9: g.45411941T&gt;C). The samples&#xD;
      with known ApoE genotypes, which had been validated by DNA sequencing, will be used as&#xD;
      standard references. The genetic polymorphism data will be compared to sex- and age-matched&#xD;
      control of the DNA banking of the neurogenetic Laboratory of Careggi Hospital of Florence.&#xD;
&#xD;
      Statistic analysis:&#xD;
&#xD;
      All collected data will be analyzed using a machine learning algorithm, creating, for each&#xD;
      patient, a risk profile for the possible consciousness recovery and functional autonomy.&#xD;
&#xD;
      On the basis of the results of this study, partecipant will build on a &quot;decision support&#xD;
      tool&quot; for future sABI patients afferent to the Intensive Rehabilitative Unit, in order to&#xD;
      plan personalized rehabilitative and therapeutic interventions, allowing therefore an&#xD;
      optimization of resources (costs and resources) for National Health Service&#xD;
    </textblock>
  </detailed_description>
  <overall_status>Recruiting</overall_status>
  <start_date type="Actual">June 9, 2020</start_date>
  <completion_date type="Anticipated">June 10, 2025</completion_date>
  <primary_completion_date type="Anticipated">June 10, 2023</primary_completion_date>
  <study_type>Observational [Patient Registry]</study_type>
  <has_expanded_access>No</has_expanded_access>
  <study_design_info>
    <observational_model>Cohort</observational_model>
    <time_perspective>Prospective</time_perspective>
  </study_design_info>
  <target_duration>24 Months</target_duration>
  <primary_outcome>
    <measure>Consciousness recovery</measure>
    <time_frame>24 months</time_frame>
    <description>The Consciousness recovery will be measured throught the italian version of the CRS-R performed for at least 5 time during one week to avoid a misdiagnosis due to consciousness fluctuations.Consciousness recovery is defined as CRS_R &gt;23 and Improvement Responsiveness will be registred for patients transitioning from UWS to MCS or E-MCS, and from MCS to E-MCS.</description>
  </primary_outcome>
  <primary_outcome>
    <measure>Tracheostomy weaning</measure>
    <time_frame>24 months</time_frame>
    <description>Tracheostomy weaning will be reported as a dichotomic variable: decannulated yes/no</description>
  </primary_outcome>
  <primary_outcome>
    <measure>Total oral feeding recovery</measure>
    <time_frame>24 months</time_frame>
    <description>The swallowing severity will be assessed throught the Oral feeding recovery measured by Functional Oral Intake Scale (FOIS) scoring from 1 (severe dysphagia) to 7(absence of dysphagia). The outcome of &quot;oral feeding recovery&quot; corrispond to Functional Oral Intake Scale&gt;4</description>
  </primary_outcome>
  <primary_outcome>
    <measure>Functional autonomy</measure>
    <time_frame>24 months</time_frame>
    <description>Functional autonomy measured by Glasgow Outcome Scale Expanded scoring between 1 (death) and 8 (complete functional recovery). A good autonomy is defined for Glasgow Outcome Scale Expanded &gt;4</description>
  </primary_outcome>
  <primary_outcome>
    <measure>Time to decannulation</measure>
    <time_frame>24 months</time_frame>
    <description>In decannulated patients, time between admission in the IRU and decannulation will be reported</description>
  </primary_outcome>
  <secondary_outcome>
    <measure>Cognitive profile</measure>
    <time_frame>24 months</time_frame>
    <description>The cognitive profile will be assessed firstly investigating the &quot;post-event amnesia&quot; by the Galveston Orientation &amp; Amnesia Test. The date of &quot;post-event amnesia&quot; resolution will be reported when the Galveston Orientation &amp; Amnesia Test score &gt;75 for two consecutive days</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Degree of social and occupational reintegration</measure>
    <time_frame>24 months</time_frame>
    <description>Degree of social and occupational reintegration assessed by the Community Integration Questionnaire (CIQ). Minimum score is 10 and maximum score is 50. A higher score indicates a higher comunity integration</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Subjective and Objective Quality Of Life</measure>
    <time_frame>24 months</time_frame>
    <description>The Quality of Life after Brain Injury (QoLibri) scale allows to measure both the quality of life perceived by both the patient and the caregiver. Quality of Life after Brain Injury (QoLibri) scores are reported on a 0-100 scale.&#xD;
0=worst possible quality of life and 100=best possible quality of life.</description>
  </secondary_outcome>
  <number_of_groups>1</number_of_groups>
  <enrollment type="Anticipated">520</enrollment>
  <condition>Brain Injuries</condition>
  <condition>Disorder of Consciousness</condition>
  <arm_group>
    <arm_group_label>Patients affected by severe Acquired Brain Injury</arm_group_label>
    <description>All patients admitted in the participant IRU with a history of sABI and fulfilling our inclusion and exclusion criteria will be recruited.</description>
  </arm_group>
  <intervention>
    <intervention_type>Genetic</intervention_type>
    <intervention_name>Genetic analysis of different single nucleotide polymorphisms on ApoE, BDNF and DRD2 genes assessment</intervention_name>
    <description>Genomic DNA will be obtained from EDTA-whole venous blood sample by Automated Systems QiaCube (Qiagen). The genetic analysis of 5 different single nucleotide polymorphisms on ApoE, BDNF and DRD2 genes will be performed by HRM analyses and direct sequencing on Automatic Genetic Analyzer. All the aliquots will be amplified by a real-time PCR. The genetic polymorphism data will be compared to sex- and age-matched control of the DNA banking of the neurogenetic Laboratory of Florence Hospital.</description>
    <arm_group_label>Patients affected by severe Acquired Brain Injury</arm_group_label>
  </intervention>
  <biospec_retention>Samples With DNA</biospec_retention>
  <biospec_descr>
    <textblock>
      blood&#xD;
    </textblock>
  </biospec_descr>
  <eligibility>
    <study_pop>
      <textblock>
        Patients with severe Acquired Brain Injuries admitted in the Intensive Rehabilitative Unit&#xD;
        (IRU) of the four participant don Gnocchi Foundation Centers (Florence, La Spezia, Milano&#xD;
        and Sant'Angelo dei Lombardi) fulfilling the inclusion criteria will be included.&#xD;
      </textblock>
    </study_pop>
    <sampling_method>Non-Probability Sample</sampling_method>
    <criteria>
      <textblock>
        Inclusion Criteria:&#xD;
&#xD;
          -  patients admitted with a history of severe Acquired Brain Injury within 4 months,&#xD;
&#xD;
          -  aged 18+,&#xD;
&#xD;
          -  signed informed consent signature for the participation to the study&#xD;
&#xD;
          -  signed informed consent signature for the participation to for the genetic analysis&#xD;
&#xD;
        Exclusion Criteria:&#xD;
&#xD;
          -  patients admitted with a history of severe Acquired Brain Injury more then 4 months&#xD;
&#xD;
          -  Absence of informed consent to participate in the study&#xD;
      </textblock>
    </criteria>
    <gender>All</gender>
    <minimum_age>18 Years</minimum_age>
    <maximum_age>N/A</maximum_age>
    <healthy_volunteers>No</healthy_volunteers>
  </eligibility>
  <overall_official>
    <last_name>Bahia Hakiki, MD, Phd</last_name>
    <role>Principal Investigator</role>
    <affiliation>IRCCS Fondazione Don Carlo Gnocchi, Florence</affiliation>
  </overall_official>
  <overall_contact>
    <last_name>Bahia Hakiki, MD, Phd</last_name>
    <phone>0039-333-4018388</phone>
    <email>bhakiki@dongnocchi.it</email>
  </overall_contact>
  <location>
    <facility>
      <name>IRCCS-don Gnocchi Foundation</name>
      <address>
        <city>Florence</city>
        <zip>50143</zip>
        <country>Italy</country>
      </address>
    </facility>
    <status>Recruiting</status>
    <contact>
      <last_name>Maria Chiara Carozza, Prof.</last_name>
      <email>mccarrozza@dongnocchi.it</email>
    </contact>
  </location>
  <location_countries>
    <country>Italy</country>
  </location_countries>
  <reference>
    <citation>Bernat JL. Chronic disorders of consciousness. Lancet. 2006 Apr 8;367(9517):1181-92. doi: 10.1016/S0140-6736(06)68508-5. Erratum In: Lancet. 2006 Jun 24;367(9528):2060.</citation>
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    <citation>Hirschberg R, Giacino JT. The vegetative and minimally conscious states: diagnosis, prognosis and treatment. Neurol Clin. 2011 Nov;29(4):773-86. doi: 10.1016/j.ncl.2011.07.009.</citation>
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    <citation>Amantini A, Grippo A, Fossi S, Cesaretti C, Piccioli A, Peris A, Ragazzoni A, Pinto F. Prediction of 'awakening' and outcome in prolonged acute coma from severe traumatic brain injury: evidence for validity of short latency SEPs. Clin Neurophysiol. 2005 Jan;116(1):229-35. doi: 10.1016/j.clinph.2004.07.008.</citation>
    <PMID>15589201</PMID>
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    <citation>Cavinato M, Freo U, Ori C, Zorzi M, Tonin P, Piccione F, Merico A. Post-acute P300 predicts recovery of consciousness from traumatic vegetative state. Brain Inj. 2009 Nov;23(12):973-80. doi: 10.3109/02699050903373493.</citation>
    <PMID>19831494</PMID>
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  <reference>
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    <citation>Portaccio E, Morrocchesi A, Romoli AM, Hakiki B, Taglioli MP, Lippi E, Di Renzone M, Grippo A, Macchi C. Score on Coma Recovery Scale-Revised at admission predicts outcome at discharge in intensive rehabilitation after severe brain injury. Brain Inj. 2018;32(6):730-734. doi: 10.1080/02699052.2018.1440420. Epub 2018 Feb 26.</citation>
    <PMID>29482376</PMID>
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    <citation>Scarpino M, Lolli F, Hakiki B, Atzori T, Lanzo G, Sterpu R, Portaccio E, Romoli AM, Morrocchesi A, Amantini A, Macchi C, Grippo A; Intensive Rehabilitation Unit Study Group of the IRCCS Don Gnocchi Foundation, Italy. Prognostic value of post-acute EEG in severe disorders of consciousness, using American Clinical Neurophysiology Society terminology. Neurophysiol Clin. 2019 Sep;49(4):317-327. doi: 10.1016/j.neucli.2019.07.001. Epub 2019 Jul 18.</citation>
    <PMID>31327535</PMID>
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    <PMID>20554941</PMID>
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    <citation>Thelin EP, Nelson DW, Vehvilainen J, Nystrom H, Kivisaari R, Siironen J, Svensson M, Skrifvars MB, Bellander BM, Raj R. Evaluation of novel computerized tomography scoring systems in human traumatic brain injury: An observational, multicenter study. PLoS Med. 2017 Aug 3;14(8):e1002368. doi: 10.1371/journal.pmed.1002368. eCollection 2017 Aug.</citation>
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    <citation>Scarpino M, Lolli F, Hakiki B, Lanzo G, Sterpu R, Atzori T, Portaccio E, Draghi F, Amantini A, Grippo A; Intensive Rehabilitation Unit Study Group of the IRCCS Don Gnocchi Foundation, Italy. EEG and Coma Recovery Scale-Revised prediction of neurological outcome in Disorder of Consciousness patients. Acta Neurol Scand. 2020 Sep;142(3):221-228. doi: 10.1111/ane.13247. Epub 2020 Apr 14.</citation>
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  <verification_date>July 2020</verification_date>
  <study_first_submitted>July 17, 2020</study_first_submitted>
  <study_first_submitted_qc>July 30, 2020</study_first_submitted_qc>
  <study_first_posted type="Actual">July 31, 2020</study_first_posted>
  <last_update_submitted>August 4, 2020</last_update_submitted>
  <last_update_submitted_qc>August 4, 2020</last_update_submitted_qc>
  <last_update_posted type="Actual">August 5, 2020</last_update_posted>
  <responsible_party>
    <responsible_party_type>Principal Investigator</responsible_party_type>
    <investigator_affiliation>Fondazione Don Carlo Gnocchi Onlus</investigator_affiliation>
    <investigator_full_name>Bahia Hakiki</investigator_full_name>
    <investigator_title>Neurologist, MD, Ph D</investigator_title>
  </responsible_party>
  <keyword>Rehabilitation</keyword>
  <keyword>Machine Learning</keyword>
  <keyword>Brain-derived neurotrophic factor</keyword>
  <keyword>Apolipoprotein E</keyword>
  <keyword>Cognitive Reserve</keyword>
  <keyword>Predictive Factors</keyword>
  <condition_browse>
    <!-- CAUTION:  The following MeSH terms are assigned with an imperfect algorithm            -->
    <mesh_term>Brain Injuries</mesh_term>
    <mesh_term>Consciousness Disorders</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/NCT04495192
org study id: 16606_OSS
nct id: NCT04495192
lead sponsor: 
has dmc: Yes
is fda regulated drug: No
is fda regulated device: No
Severe Acquired Brain Injury is defined as a traumatic, post-anoxic, vascular or other brain
      damage that causes coma for at least 24 hours and leads to permanent disability with
      sensorial, motor, cognitive or compartmental impairment. In this context, an accurate
      characterization of individual patients' profile in terms of neuronal damage, potential for
      neuroplasticity, neurofunctional and clinical state could allow to plan tailored
      rehabilitation and care pathway on the basis of solid prognostic information, also for
      optimizing resources of the National Health care systems and enhance ethical decisions.
      Patient profiling should encompass measures and procedures easily available at the bedside,
      and with affordable time, resource, and money-costs to determine a real impact on National
      Health systems. The aim of the study is identifying patient profiles in terms of clinical,
      neurophysiological and genetical aspects with better long-term outcome in order to plan
      tailored therapeutic interventions.
Background:

      After a severe Acquired Brain Injury (sABI) the consciousness, the functional and the
      cognitive recovery of the patients depends on the severity of the damage suffered but also on
      the vulnerability of the individual brain. Some patients with sABI may survive in a state of
      Disorder of Consciousness (DoC) condition (i.e., patients in vegetative state/unresponsive
      wakefulness syndrome, VS/UWS or in minimally conscious state, MCS). Other patients, despite
      having a complete recovery of consciousness, can reach very variable degrees of functional
      and cognitive autonomy. The prognostic factors of consciousness recovery of patients with
      DoCs have been thoroughly investigated. Most of these studies investigated the acute phase,
      while only a few studies have examined the role of early clinical factors emerging before the
      complete recovery of consciousness . Further prognostic insights can be provided by analysis
      of genes coding for Apolipoprotein E (APOE), dopamineD2 receptor (DRD2), and Brain Derived
      Neutrophic Factors (BDNF), and by markers of axonal injury.

      Study aim:

      The present project aims at identifying patient profiles with better long-term outcome in
      order to plan tailored therapeutic interventions.

      The patient profiles will be drawn up by gathering patient's demographic (age, gender, social
      and educational level), anamnestic (aetiology and time post-brain injury, Cognitive Reserve
      Index), clinical state (Cumulative Illness Rating Scale (CIRS), CRS-R total score and
      corresponding consciousness state; Disability Rating Scale, DRS, Functional Oral Intake
      Scale; FOIS, Glasgow Outcome Scale Expanded; GOS-E, Level of Cognitive Functioning; LCF) and
      neurophysiological data (Electroencephalogram (EEG), Somatosensory evoked potentials (SEP),
      and Motor evoked potentials (MEP) nerve conduction aimed at evaluating occurrence of critical
      illness polyneuropathy and myopathy (CIPNM)) at study entry (baseline), together with neural
      biomarkers (genetic markers).

      On the basis of the above mentioned stratification of patients by this multimodal approach,
      the present study aimed to

        1. Investigate the possible association of certain profiles with the consciousness recovery
           at the time of discharge from the Intensive Rehabilitation Unit (IRU), at 1 year and 2
           years from the acute event

        2. Investigate the possible association of certain profiles with the functional outcomes at
           the time of discharge from the Intensive Rehabilitation Unit (IRU), at 1 year and 2
           years from the acute event.

        3. Investigate the possible association of certain profiles with the long-term cognitive
           profile and the level of familiar and social participation at 1 year and 2 years from
           the acute event.

      Setting , population and methods:

      The proposed study is a longitudinal multi-location prospective observational cohort study.

      Four centers of the Don Carlo Gnocchi Foundation will participate (Florence, La Spezia, Milan
      and Sant'Angelo dei Lombardi and the neurogenetics laboratory of the University of Florence,
      Department of Medical and Experimental Sciences, Neurology). The enrollment phase will last 3
      years (June 2020-June 2023). 520 patients with severe brain injury will be included (200 for
      the Florence and La Spezia units and 60 for the Milan and Sant'Angelo dei Lombardi units).

      All patients admitted in the participant IRU with a history of sABI within 4 months, aged
      18+, presenting a signed informed consent signature for the participation to the study and
      for the genetic analysis will be consecutively enrolled.

      A multidimodal evaluation including clinical examinations and neurophysiological assessments
      will be performed by skilled professionals. The study foresees four steps in the late acute
      phase and two in the long-term phase: 1) at the study entry time (T0), 2) at three months
      from T0 (T1) 3) at 6 months from T0 (T2) 4) at discharge (T3) 5) at 12 months from the acute
      event (T4) 6) at 24 months from the acute event.

      Clinical assessment including :

        1. Consciousness assessment using CRS-R

        2. Care severity profile: including the comorbidity assessed thought the Cumulative Illness
           Rating Scale (CIRS), the presence of medical devices, sepsis occurrence during the IRU
           stay, neurosurgery interventions, bedsores, epileptic event and other complications

        3. Functional evaluation using the following scales: ERBI, GOS-E, DRS, FIM, PAINED pain
           scale, TCT, Ashworth, FOIS

        4. Neurocognitive profile evaluation using the Galveston Orientation and Amnesia Test
           (GOAT), the Level of Cognitive Functioning (LCF) and the International Classification of
           Functioning, Disability and Health (ICF), ABS, AES and Cognitive Reserve Index (CRI)

      Multimodal neurophysiological evaluation including:

        1. Standard EEG recording at rest. EEG background activity and reactivity will be
           classified according to recently proposed diagnostic criteria for DoC and to American
           Clinical Neurophysiology Society Critical Care EEG Terminology.

        2. Motor and sensory nerve conduction studies. Sensory nerve action potentials, and
           compound muscle action potentials (CMAP) will be evaluated. Muscular activity at rest
           and when possible during reflex contraction will be assessed.

        3. PEM: Transcranial magnetic stimulation (TMS) will be performed according to the standard
           criteria of the International Federation of Clinical Neurophysiology. MEP will be
           recorded from abductor digiti minimi and tibialis anterior muscles and size of MEP
           measured as MEP/CMAP amplitude ratio.

        4. Bilateral upper limb SEP will be recorded according to the International Federation of
           Clinical Neurophysiology. The presence or absence of N20/P25 cortical components will be
           evaluated.

      Genetic assessment Genomic DNA will be obtained from EDTA-whole venous blood sample by
      Automated Systems QiaCube (Qiagen). The genetic analysis of 5 different single nucleotide
      polymorphisms on ApoE, BDNF and DRD2 genes will be performed by high resolution melt (HRM)
      analyses and direct sequencing on Automatic Genetic Analyzer. APOE genotypes will be
      investigated by HRM with two sets of PCR primers designed to amplify the regions encompassing
      rs7412 [NC_000019.9: g.45412079C>T] and rs429358 (NC_000019.9: g.45411941T>C). The samples
      with known ApoE genotypes, which had been validated by DNA sequencing, will be used as
      standard references. The genetic polymorphism data will be compared to sex- and age-matched
      control of the DNA banking of the neurogenetic Laboratory of Careggi Hospital of Florence.

      Statistic analysis:

      All collected data will be analyzed using a machine learning algorithm, creating, for each
      patient, a risk profile for the possible consciousness recovery and functional autonomy.

      On the basis of the results of this study, partecipant will build on a "decision support
      tool" for future sABI patients afferent to the Intensive Rehabilitative Unit, in order to
      plan personalized rehabilitative and therapeutic interventions, allowing therefore an
      optimization of resources (costs and resources) for National Health Service
observational model: Cohort
time perspective: Prospective
measure: Consciousness recovery
time frame: 24 months
description: The Consciousness recovery will be measured throught the italian version of the CRS-R performed for at least 5 time during one week to avoid a misdiagnosis due to consciousness fluctuations.Consciousness recovery is defined as CRS_R >23 and Improvement Responsiveness will be registred for patients transitioning from UWS to MCS or E-MCS, and from MCS to E-MCS.
measure: Tracheostomy weaning
time frame: 24 months
description: Tracheostomy weaning will be reported as a dichotomic variable: decannulated yes/no
measure: Total oral feeding recovery
time frame: 24 months
description: The swallowing severity will be assessed throught the Oral feeding recovery measured by Functional Oral Intake Scale (FOIS) scoring from 1 (severe dysphagia) to 7(absence of dysphagia). The outcome of "oral feeding recovery" corrispond to Functional Oral Intake Scale>4
measure: Functional autonomy
time frame: 24 months
description: Functional autonomy measured by Glasgow Outcome Scale Expanded scoring between 1 (death) and 8 (complete functional recovery). A good autonomy is defined for Glasgow Outcome Scale Expanded >4
measure: Time to decannulation
time frame: 24 months
description: In decannulated patients, time between admission in the IRU and decannulation will be reported
measure: Cognitive profile
time frame: 24 months
description: The cognitive profile will be assessed firstly investigating the "post-event amnesia" by the Galveston Orientation & Amnesia Test. The date of "post-event amnesia" resolution will be reported when the Galveston Orientation & Amnesia Test score >75 for two consecutive days
measure: Degree of social and occupational reintegration
time frame: 24 months
description: Degree of social and occupational reintegration assessed by the Community Integration Questionnaire (CIQ). Minimum score is 10 and maximum score is 50. A higher score indicates a higher comunity integration
measure: Subjective and Objective Quality Of Life
time frame: 24 months
description: The Quality of Life after Brain Injury (QoLibri) scale allows to measure both the quality of life perceived by both the patient and the caregiver. Quality of Life after Brain Injury (QoLibri) scores are reported on a 0-100 scale.
0=worst possible quality of life and 100=best possible quality of life.
arm group label: Patients affected by severe Acquired Brain Injury
description: All patients admitted in the participant IRU with a history of sABI and fulfilling our inclusion and exclusion criteria will be recruited.
intervention type: Genetic
intervention name: Genetic analysis of different single nucleotide polymorphisms on ApoE, BDNF and DRD2 genes assessment
description: Genomic DNA will be obtained from EDTA-whole venous blood sample by Automated Systems QiaCube (Qiagen). The genetic analysis of 5 different single nucleotide polymorphisms on ApoE, BDNF and DRD2 genes will be performed by HRM analyses and direct sequencing on Automatic Genetic Analyzer. All the aliquots will be amplified by a real-time PCR. The genetic polymorphism data will be compared to sex- and age-matched control of the DNA banking of the neurogenetic Laboratory of Florence Hospital.
arm group label: Patients affected by severe Acquired Brain Injury
blood
study pop: 
sampling method: Non-Probability Sample
criteria: 
gender: All
minimum age: 18 Years
maximum age: N/A
healthy volunteers: No
last name: Bahia Hakiki, MD, Phd
role: Principal Investigator
affiliation: IRCCS Fondazione Don Carlo Gnocchi, Florence
last name: Bahia Hakiki, MD, Phd
phone: 0039-333-4018388
email: bhakiki@dongnocchi.it
facility: 
status: Recruiting
contact: 
country: Italy
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responsible party type: Principal Investigator
investigator affiliation: Fondazione Don Carlo Gnocchi Onlus
investigator full name: Bahia Hakiki
investigator title: Neurologist, MD, Ph D
mesh term: Brain Injuries
mesh term: Consciousness Disorders
mesh term: Wounds and Injuries
sharing ipd: Undecided