<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/NCT02210221</url>
  </required_header>
  <id_info>
    <org_study_id>602150</org_study_id>
    <nct_id>NCT02210221</nct_id>
  </id_info>
  <brief_title>CENTER-TBI: Collaborative European NeuroTrauma Effectiveness Research in TBI</brief_title>
  <acronym>CENTER-TBI</acronym>
  <official_title>Collaborative European NeuroTrauma Effectiveness Research in TBI (CENTER-TBI)</official_title>
  <sponsors>
    <lead_sponsor>
      <agency>University Hospital, Antwerp</agency>
      <agency_class>Other</agency_class>
    </lead_sponsor>
    <collaborator>
      <agency>University of Cambridge</agency>
      <agency_class>Other</agency_class>
    </collaborator>
    <collaborator>
      <agency>Erasmus Medical Center</agency>
      <agency_class>Other</agency_class>
    </collaborator>
    <collaborator>
      <agency>San Gerardo Hospital</agency>
      <agency_class>Other</agency_class>
    </collaborator>
    <collaborator>
      <agency>University of Sheffield</agency>
      <agency_class>Other</agency_class>
    </collaborator>
    <collaborator>
      <agency>University of California, San Francisco</agency>
      <agency_class>Other</agency_class>
    </collaborator>
    <collaborator>
      <agency>Karolinska Institutet</agency>
      <agency_class>Other</agency_class>
    </collaborator>
    <collaborator>
      <agency>ICON plc</agency>
      <agency_class>Industry</agency_class>
    </collaborator>
    <collaborator>
      <agency>GABO:mi</agency>
      <agency_class>Industry</agency_class>
    </collaborator>
    <collaborator>
      <agency>icoMetrix NV, Leuven, Belgium</agency>
      <agency_class>Other</agency_class>
    </collaborator>
  </sponsors>
  <source>University Hospital, Antwerp</source>
  <oversight_info>
    <has_dmc>Yes</has_dmc>
  </oversight_info>
  <brief_summary>
    <textblock>
      The research aims of the CENTER-TBI study are to:&#xD;
&#xD;
        1. better characterize Traumatic Brain Injury (TBI) as a disease and describe it in a&#xD;
           European context, and&#xD;
&#xD;
        2. identify the most effective clinical interventions for managing TBI.&#xD;
&#xD;
      Specific aims&#xD;
&#xD;
        1. To collect high quality clinical and epidemiological data with repositories for&#xD;
           neuro-imaging, DNA, and serum from patients with TBI.&#xD;
&#xD;
        2. To refine and improve outcome assessment and develop health utility indices for TBI.&#xD;
&#xD;
        3. To develop multidimensional approaches to characterisation and prediction of TBI.&#xD;
&#xD;
        4. To define patient profiles which predict efficacy of specific interventions (&quot;Precision&#xD;
           Medicine&quot;).&#xD;
&#xD;
        5. To develop performance indicators for quality assurance and quality improvement in TBI&#xD;
           care.&#xD;
&#xD;
        6. To validate the common data elements (CDEs) for broader use in international settings,&#xD;
           and to develop a user-friendly web based data entry instrument and case report form&#xD;
           builder.&#xD;
&#xD;
        7. To develop an open database compatible with Federal Interagency Traumatic Brain Injury&#xD;
           Research (FITBIR).&#xD;
&#xD;
        8. To intensify networking activities and international collaborations in TBI.&#xD;
&#xD;
        9. To disseminate study results and management recommendations for TBI to health care&#xD;
           professionals, policy makers and consumers, aiming to improve health care for TBI at&#xD;
           individual and population levels.&#xD;
&#xD;
       10. To develop a &quot;knowledge commons&quot; for TBI, integrating CENTER-TBI outputs into systematic&#xD;
           reviews.&#xD;
    </textblock>
  </brief_summary>
  <detailed_description>
    <textblock>
      • Introduction:&#xD;
&#xD;
      CENTER-TBI (Collaborative European NeuroTrauma Effectiveness Research in TBI)&#xD;
      (www.center-tbi.eu) is a project embedded within the International Initiative on TBI Research&#xD;
      (InTBIR) (http://intbir.nih.gov/), as a collaboration between the European Commission (EC),&#xD;
      the US National Institute of Neurological Disorders and Stroke (NIH-NINDS) and the Canadian&#xD;
      Institute of Health Research (CIHR).&#xD;
&#xD;
        -  Research aims:&#xD;
&#xD;
      The basic concept of this project is to exploit the existing heterogeneity in biology, care&#xD;
      and outcome of TBI patients to discover underlying pathophysiology, to refine&#xD;
      characterisation, and to identify effective clinical interventions. The key driver of our&#xD;
      research plan is to collect data from a large number of European centres and sufficiently&#xD;
      large cohort to enable 'Comparative effectiveness research' (CER) analyses of differences in&#xD;
      clinical care and management pathways in TBI.&#xD;
&#xD;
      Improved disease characterization will aid Precision Medicine, a concept recently enunciated&#xD;
      by the US National Academy of Science. Such improved characterization and stratification will&#xD;
      allow for more targeted therapies. Further, CER provides a promising framework to identify&#xD;
      best practices and improve outcome after TBI. CER is the generation and synthesis of evidence&#xD;
      that compares the benefits and harms of alternative methods to prevent, diagnose, treat, and&#xD;
      monitor a clinical condition or to improve the delivery of care. The purpose of CER is to&#xD;
      assist consumers, clinicians, purchasers, and policy makers to make informed decisions that&#xD;
      will improve health care at both the individual and population levels.&#xD;
&#xD;
        -  Cohort:&#xD;
&#xD;
      A large core cohort of patients across the severity spectrum in TBI will be recruited at&#xD;
      approximately 77 sites in Europe and Israel (the CENTER-TBI Core Study): 5400 patients&#xD;
      differentiated into 3 equal strata of approximately 1800:&#xD;
&#xD;
        -  ER stratum: patients seen and discharged from the ER;&#xD;
&#xD;
        -  Admission stratum: patients admitted to the hospital but not to the ICU;&#xD;
&#xD;
        -  ICU stratum: patients admitted directly to the ICU. Balance in numbers between the&#xD;
           strata will be aimed for, but sites will be allowed to arrange recruitment strategies to&#xD;
           best suit their local requirements.&#xD;
&#xD;
      The core cohort will be underpinned by comparison with a larger registry (the CENTER-TBI&#xD;
      registry) based on pragmatic data collection of all patients with TBI seen in participating&#xD;
      centres (to establish the internal generalizability of our study), and by comparison with&#xD;
      national trauma registries (to establish the external generalizability of our findings).&#xD;
&#xD;
      In the core cohort, detailed data will be collected on clinical parameters, neuroimaging&#xD;
      studies, biomarker analyses, DNA analyses, and longitudinal outcome assessments. In selected&#xD;
      centres, extended studies will additionally focus on advanced magnetic resonance (MR)&#xD;
      imaging, detailed coagulation profiling and high resolution ICU monitoring.&#xD;
&#xD;
        -  Sample size assessment:&#xD;
&#xD;
      The sample size estimate (n=5400) was based on:&#xD;
&#xD;
        -  Practical logistic considerations&#xD;
&#xD;
        -  Power calculations for the different strata, targeting comparative effectiveness&#xD;
           analyses, assuming a between-centre and between-country heterogeneity as identified in&#xD;
           previous research (expressed by variance parameter from a random effects model, Tau^2 of&#xD;
           0.431)&#xD;
&#xD;
        -  Postulated odds ratios for intervention effects of approximately 5% improvement in&#xD;
           outcome.&#xD;
&#xD;
      Overall, these calculations provided a statistical power to detect odds ratios of ~1.2&#xD;
      associated with differences in process or intervention variables across the core dataset with&#xD;
      a power of 80%; and require somewhat larger odds ratios in each of the three individual&#xD;
      strata. In the registry we expect to be able to detect differences (predominantly in&#xD;
      organizational or system variables) with an odds ratio of 1.2 with a power of 82%.&#xD;
&#xD;
        -  Quality control and assurance:&#xD;
&#xD;
      Continuous monitoring of enrolment and completeness of data will be performed by ICON as&#xD;
      contract research organization (CRO). Source data verification (SDV) will be performed in 10%&#xD;
      of subjects by the CRO. The quality of data collection will be further enhanced by&#xD;
      implementing automated data entry checks for impossible/implausible values and implementing&#xD;
      data checks for consistency between variables. A task force of study personnel will evaluate&#xD;
      the completeness, consistency and validity of submitted data and function as support desk for&#xD;
      participating sites.&#xD;
&#xD;
        -  Data management:&#xD;
&#xD;
      Prior to upload to the study database, all acquired data will be stored locally. All patients&#xD;
      will be allocated a random Global Unique Personal Identification number (GUPI) which will be&#xD;
      linked locally to hospital identifiers. All uploaded data will be de-identified and images&#xD;
      will be defaced prior to upload. While blood samples and clinical data will be linked, both&#xD;
      sets of data will be kept confidential and anonymised beyond the initial stage of correlation&#xD;
      for analysis. All imaging and electronic data will be kept on individually password protected&#xD;
      servers. All clinical data will be entered into electronic Case Report Forms (eCRFs) and&#xD;
      managed by the 'QuesGen data management platform' (http://www.quesgen.com/) which will be&#xD;
      developed in collaboration with Karolinska Institutet International Neuroinformatics&#xD;
      Coordinating Faculty (KI-INCF). As data is entered into each form, the system will run data&#xD;
      validation checks that include conditionally required data, validation across fields, and&#xD;
      validation requirements based on subject type. If any validation check fails, the user is&#xD;
      alerted immediately that the data does not meet Quality Assurance (QA) criteria and the issue&#xD;
      can be addressed and corrected at that point. All de-identified electronic study data in the&#xD;
      CENTER-TBI database will be stored securely in the European data space under supervision of&#xD;
      KI-INCF for the duration of subject enrolment and follow-up and for a period afterwards for&#xD;
      data analysis and preparation of publications. We estimate that the analysis and publication&#xD;
      period will last for several years after the conclusion of subject enrolment.&#xD;
&#xD;
      Together with QuesGen Systems, KI-INCF will ensure that data standards are established for&#xD;
      the data model e.g. conformity of field formats, field codes and names to ensure consistency&#xD;
      across all datasets. Any approved changes will be fully documented with dataset updates to&#xD;
      maintain data quality and accuracy. KI-INCF will be responsible for importing cleaned&#xD;
      datasets to other analytic platforms as determined by the coordinators.&#xD;
&#xD;
      Where applicable, information relevant to the patient's care will be made available to the&#xD;
      physician responsible. Data, including blood samples collected as part of this study will be&#xD;
      shared in an anonymised form with collaborators from other European states (this is part of a&#xD;
      European Commission Framework7 funded program), and with selected collaborators in other&#xD;
      countries who form part of an emerging International Traumatic Brain Injury Research&#xD;
      initiative.&#xD;
&#xD;
        -  Computing platform and Neuroinformatics Resource:&#xD;
&#xD;
      The KI-INCF will coordinate the establishment of an informatics platform for acquisition,&#xD;
      storage and analysis of CDE-based clinical data. The goal is to develop a next generation&#xD;
      open standards-based platform to support advanced large-scale analytics and model building.&#xD;
      Such a platform also provides a model for future clinical studies on brain diseases and&#xD;
      disorders. This development will receive additional support from One Mind for Research.&#xD;
&#xD;
        -  Statistical analysis plan:&#xD;
&#xD;
      Statistical analyses for the Comparative Effectiveness Research (CER) questions will&#xD;
      primarily apply random effects modelling, in which center is included at the higher level,&#xD;
      and patients are considered clustered within centers. In some analyses, higher levels of&#xD;
      clustering will also be considered, e.g. country, or European region; or lower levels, e.g.&#xD;
      physicians within hospitals. Confounding factors as measured at the individual patient and/or&#xD;
      center level, will be considered extensively, and will be targeted to the specific research&#xD;
      question.&#xD;
&#xD;
      Statistical analyses for better characterization of TBI will be exploratory, aiming to better&#xD;
      understand the complexity of the disease and to discover new associations. In addition to&#xD;
      standard statistical descriptive and inferential techniques, we will also employ novel&#xD;
      machine learning techniques as appropriate.&#xD;
&#xD;
      Prognostic analyses will consider a range of variables, including genetic, demographic and&#xD;
      clinical data, physiological signals, imaging results, and biomarkers as predictors of early&#xD;
      endpoints and physiologic derangement (e.g. raised ICP), and late outcome, including&#xD;
      mortality, functional outcome, quality of life and neuropsychological performance. Previously&#xD;
      and newly developed prediction models will be validated by comparison of observed to&#xD;
      predicted outcome risks, with predictive performance summarized by measures for model fit,&#xD;
      discrimination, and calibration.&#xD;
&#xD;
        -  Missing data:&#xD;
&#xD;
      Every effort will be made to limit the number of missing data in the CENTER-TBI study.&#xD;
      Missing values are, however, inherent to any clinical study. Missing values may confound the&#xD;
      descriptive, prognostic and CER analyses. Thus, appropriate techniques for dealing with&#xD;
      missing values are required. First, we will evaluate the various reasons for missingness per&#xD;
      centre. Next, we will explore the use of alternative statistical approaches, including&#xD;
      inverse probability weighting and multiple imputation. We will consider missing values in&#xD;
      baseline characteristics as well as in short and long term outcomes. Based on simulation&#xD;
      studies and practical considerations we will develop standard operating procedures towards&#xD;
      the analyses with missing values, respecting the differences in multiple research questions.&#xD;
&#xD;
        -  Informed Consent:&#xD;
&#xD;
      Informed consent procedures will follow local and national requirements in all cases. We&#xD;
      anticipate that many potential patients will not be able to consent themselves to participate&#xD;
      in this project. The nature of TBI means that some patients may lack capacity to decide to&#xD;
      participate in this study especially at the earliest time point. It is important to try and&#xD;
      include these patients to ensure that representative samples of patients are included to&#xD;
      avoid bias in the study findings. Every step will be taken to ensure that a test of capacity&#xD;
      is undertaken before a decision on a person's capacity to consent or not to consent to&#xD;
      participation in research is taken. If the subject is not capable of self-consent, all&#xD;
      efforts will be made to locate a legally acceptable representative to act on behalf of the&#xD;
      subject. When a legally acceptable representative (e.g. consultee/proxy) is identified, their&#xD;
      opinion will be sought about the potential participant's wishes and feelings in relation to&#xD;
      the project, and whether he or she would have wanted to take part in the study.&#xD;
&#xD;
      Subjects are free to withdraw, or be withdrawn by their consultee/proxy if appropriate, at&#xD;
      any point in the study, and they need not state a reason.&#xD;
&#xD;
        -  Impact:&#xD;
&#xD;
      The CENTER-TBI project will contribute towards the overall goals of InTBIR, by identifying&#xD;
      more effective and efficient treatment provision, thus improving outcome and reducing costs.&#xD;
      The science in the project will provide novel information on disease processes, treatment,&#xD;
      outcome, and prognosis in TBI, identifying new therapeutic targets and therapies; while the&#xD;
      CENTER-TBI repositories will ensure opportunities for legacy research. Thus, the project has&#xD;
      the potential to improve current health care and its delivery at both population and&#xD;
      individual levels, deliver early scientific advances that could improve the care of patients&#xD;
      with TBI, and provide a rich investment for future biomedical research.&#xD;
    </textblock>
  </detailed_description>
  <overall_status>Completed</overall_status>
  <start_date type="Actual">December 19, 2014</start_date>
  <completion_date type="Actual">March 31, 2021</completion_date>
  <primary_completion_date type="Actual">September 1, 2018</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>6 Months</target_duration>
  <primary_outcome>
    <measure>Glasgow Outcome Scale - Extended (GOSE) at 6 Months</measure>
    <time_frame>6 months</time_frame>
    <description>The Extended Glasgow Outcome Scale is a global scale for functional outcome that rates patient status into 8 categories, going from dead to good recovery.&#xD;
Death&#xD;
Vegetative sate&#xD;
Lower severe disability&#xD;
Upper severe disability&#xD;
Lower moderate disability&#xD;
Upper moderate disability - some disability but can potentially return to some form of employment&#xD;
Lower good recovery - minor physical or mental defect&#xD;
Upper good recovery - full recovery&#xD;
The 6-month GOSE score is available in 3804 patients (84%).</description>
  </primary_outcome>
  <primary_outcome>
    <measure>SF-12v2 Health Survey (Short-Form Health Survey With 12 Questions) at 6 Months</measure>
    <time_frame>6 months</time_frame>
    <description>The SF-12v2 Health Survey uses 12 questions to measure functional health and well-being from the patient's point of view. The SF-12v2 at 6 months is available in 2300 patients.</description>
  </primary_outcome>
  <primary_outcome>
    <measure>6 Month Quality of Life in Brain Injury (Qolibri-OS) &lt;52 (Impaired)</measure>
    <time_frame>6 months</time_frame>
    <description>The Quality of Life in Brain Injury (Qolibri-OS) is a 6 item overall scale that provides a profile of health-related quality of life in domains typicality affected by brain injury, such as physical function, cognition, emotional status, ability to perform daily activities, personal life and social relationship, and satisfaction with current situation and future prospects.&#xD;
The QOLIBRI scores are reported on a 0-100 scale , where 0=worst possible quality of life and 100=best possible quality of life.</description>
  </primary_outcome>
  <secondary_outcome>
    <measure>6 Month Post-traumatic Stress Disorder (PTSD) Checklist for DSM-5 (PCL-5) &lt;33 (Impaired)</measure>
    <time_frame>6 months</time_frame>
    <description>The PCL-5 is a self-report rating scale intended to assess 20 DSM-5 symptoms of Posttraumatic Stress Disorder. The standard recall period for the PCL-5 is one month. For CENTER-TBI a recall period of one week was used at the 2-3 week assessment, and the standard one month recall period was used at other time points. The sum of scores can range from 0 to 80, where high scores indicate more pronounced PTSD symptoms.</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>6 Month Rivermead Post Concussion Questionnaire &lt;16 (Impaired)</measure>
    <time_frame>6 months</time_frame>
    <description>The Rivermead PCS Questionnaire (RPQ) was originally developed as a measure of severity of symptoms following MTBI. It consists of 16 post-concussion symptoms including headaches, dizziness, nausea/vomiting, noise sensitivity, sleep disturbance, fatigue, irritability, feeling depressed/tearful, feeling frustrated/ impatient, forgetfulness, poor concentration, taking longer to think, blurred vision, light sensitivity, double vision and restlessness. In the original version of the RPQ, participants are asked to rate the degree (on a scale of 0 to 4) to which a particular symptom has been absent or a mild, moderate or severe problem over the previous 7 days compared with premorbid levels. Total scores range from 0 to 64 with higher scores indicating more severe symptoms. Scores equal to or greater than 16 were considered indicative of persisting post-concussion symptoms.</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>6 Month Galveston Orientation and Amnesia Test (GOAT) &lt; 75 (Impaired)</measure>
    <time_frame>6 months</time_frame>
    <description>The GOAT is a standardised assessment used to determine whether a participant is in post-traumatic amnesia (PTA). PTA is an early phase of TBI recovery during which the person with injury shows markedly impaired memory, confusion, fluctuation in performance, disorientation, and other neurobehavioral signs and symptoms. GOAT questions assess orientation, memory for the first event that the participant can recall after the injury, and memory for the last event that the participant can recall from before the injury.&#xD;
The GOAT's total score must be achieved by subtracting from 100 the total amount of error scores (Total score = 100 - total amount of error scores). Scores lower than 75 point to the fact that the victim is still experiencing amnesia.</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>6 Month Rey Auditory Verbal Learning Test (RAVLT) - Impaired</measure>
    <time_frame>6 months</time_frame>
    <description>The Rey Auditory Verbal Learning Test (RAVLT) is a test of verbal memory that assesses the ability to acquire 15 words. Recall is assessed after each presentation of the list, after the recall of an interference list, and again following a 20-minute delay. The total score for recall of the principal list ranges from 0 to 75, with higher scores indicating better performance.&#xD;
Impairment was defined as performance that was 1.33 SDs below the mean of a reference group of healthy peers.</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>6 Month Timed up and go Test - Impaired</measure>
    <time_frame>6 months</time_frame>
    <description>In the timed up and go (TUG) test, subjects are asked to rise from a standard armchair, walk to a marker 3 m away, turn, walk back, and sit down again, for quantifying functional mobility. The presence of slowness, hesitancy, abnormal trunk or arm movements, staggering or stumbling is used to grade the patient from 1 (normal) to 5 (severely abnormal). Impaired mobility was defined as taking 14 seconds or longer to perform the TUG test.</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>6 Month JK Coma Recovery Scale - Revised &lt;23 (Impaired)</measure>
    <time_frame>6 months</time_frame>
    <description>The Coma Recovery Scale- Revised (CRS-R) is a standardized behavioral assessment instrument designed to measure neurobehavioral function in patients with disorders of consciousness (DOC). The CRS-R is comprised of six subscales addressing auditory, visual, motor, oromotor/verbal, communication and arousal functions. Subscale items are hierarchically-arranged, corresponding to brain stem, subcortical and cortically-mediated functions. Scores range between 0 (deep coma) and 23 (able to follow commands and to use objects purposefully). A total score less than 23 indicates impairment.</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>6 Month Trail Making Test (TMT) Part A - Impaired</measure>
    <time_frame>6 months</time_frame>
    <description>The Trail Making Test (TMT) is a measure of attention, speed, and mental flexibility. Part A requires the individual to draw lines to connect 25 encircled numbers distributed on a page. Part B is similar except the person must alternate between numbers and letters and is more difficult and takes longer to complete. Both sections are timed and the score represents the amount of time required to complete the task, with shorter times indicating better performance. The maximum time allowed is 100 seconds.&#xD;
Impairment cutoff: &gt; 55.9 (based on the comparison group as a whole and expressed as raw score).&#xD;
For all the cognitive tests impairment was defined as performance that was 1.33 SDs below the mean of a reference group of healthy peers. Raw scores indicating impaired performance could be &gt; or &lt; than the mean depending on the test (eg. on tests of accuracy the cut-off will be a score 1.33 SDs below the mean, while on a timed test the cut-off will be 1.33 SDs above the mean).</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>6 Month Trail Making Test (TMT) Part B - Impaired</measure>
    <time_frame>6 months</time_frame>
    <description>The TMT is a measure of attention, speed, and mental flexibility. Part A requires the individual to draw lines to connect 25 encircled numbers distributed on a page. Part B is similar except the person must alternate between numbers and letters, is more difficult, takes longer to complete. Both sections are timed, the score represents the amount of time required to complete the task, with shorter times indicating better performance.&#xD;
Impairment cutoff: &gt; 143.7 (based on the comparison group as a whole and expressed as raw score).&#xD;
For all the cognitive tests impairment was defined as performance that was 1.33 SDs below the mean of a reference group of healthy peers. Raw scores indicating impaired performance could be &gt; or &lt; than the mean depending on the test (eg. on tests of accuracy the cut-off will be a score 1.33 SDs below the mean, while on a timed test the cut-off will be 1.33 SDs above the mean).</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>6 Month Cambridge Neuropsychological Test Automated Battery (CANTAB) PAL (Paired Associate Learning Task) - Impaired</measure>
    <time_frame>6 months</time_frame>
    <description>CANTAB is a computerized neuropsychological battery examining a range of domains including attention, memory and executive functioning. Using mainly nonverbal stimuli, the test is language- and culture-independent. For CANTAB PAL, the individual must remember 1 to 8 patterns displayed in different positions on the screen. The score is the number of incorrect responses adjusted if necessary for trials that have not been completed. Scores ranged from 0-194 with lower score indicating better performance.&#xD;
Impairment cutoff: &gt; 72.3 (based on the comparison group as a whole and expressed as raw score).&#xD;
For all the cognitive tests impairment was defined as performance that was 1.33 SDs below the mean of a reference group of healthy peers. Raw scores indicating impaired performance could be &gt; or &lt; than the mean depending on the test (eg. on tests of accuracy the cut-off will be a score 1.33 SDs below the mean, while on a timed test the cut-off will be 1.33 SDs above the mean).</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>6 Month Cambridge Neuropsychological Test Automated Battery (CANTAB) RTI (Reaction Time Task) - Impaired</measure>
    <time_frame>6 months</time_frame>
    <description>The CANTAB is a computerized neuropsychological battery examining a range of domains including attention, memory and executive functioning. Using mainly nonverbal stimuli, the test is language- and culture-independent. For CANTAB RTI, the individual must respond as quickly as possible to a circle presented at one of 5 positions. The outcome measure is the median time for correct responses (ms).&#xD;
Impairment cutoff: &gt; 470.9 (based on the comparison group as a whole and expressed as raw score).&#xD;
For all the cognitive tests impairment was defined as performance that was 1.33 SDs below the mean of a reference group of healthy peers. Raw scores indicating impaired performance could be &gt; or &lt; than the mean depending on the test (eg. on tests of accuracy the cut-off will be a score 1.33 SDs below the mean, while on a timed test the cut-off will be 1.33 SDs above the mean).</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>6 Month Cambridge Neuropsychological Test Automated Battery (CANTAB) SWM (Spatial Working Memory Task) - Impaired</measure>
    <time_frame>6 months</time_frame>
    <description>The CANTAB is a computerized neuropsychological battery examining a range of domains including attention, memory and executive functioning. Using mainly nonverbal stimuli, the test is language- and culture-independent. For the CANTAB SWM, the participant searches for tokens in boxes on the screen. The between errors measure is the number of times the participant queries a box that has already been searched. Errors ranged from 0 to 151, with lower numbers indicating better performance.&#xD;
Impairment cutoff: &gt; 52.0 (based on the comparison group as a whole and expressed as raw score).&#xD;
For all the cognitive tests impairment was defined as performance that was 1.33 SDs below the mean of a reference group of healthy peers. Raw scores indicating impaired performance could be &gt; or &lt; than the mean depending on the test (eg. on tests of accuracy the cut-off will be a score 1.33 SDs below the mean, while on a timed test the cut-off will be 1.33 SDs above the mean).</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>6 Month Cambridge Neuropsychological Test Automated Battery (CANTAB) RVP (Rapid Visual Information Processing Task) - Impaired</measure>
    <time_frame>6 months</time_frame>
    <description>The CANTAB is a computerized neuropsychological battery examining a range of domains including attention, memory and executive functioning. Using mainly nonverbal stimuli, the test is language- and culture-independent. For the CANTAB RVP, sequences of numbers must be detected as they appear on the screen. The measure of accuracy is A' (A prime) which is derived from hits and correct rejections. The maximum score is 1 and, a higher A' indicates better performance.&#xD;
Impairment cutoff: &lt; 0.82 (based on the comparison group as a whole and expressed as raw score).&#xD;
For all the cognitive tests impairment was defined as performance that was 1.33 SDs below the mean of a reference group of healthy peers. Raw scores indicating impaired performance could be &gt; or &lt; than the mean depending on the test (eg. on tests of accuracy the cut-off will be a score 1.33 SDs below the mean, while on a timed test the cut-off will be 1.33 SDs above the mean).</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>6 Month Cambridge Neuropsychological Test Automated Battery (CANTAB) SOC (Stockings of Cambridge Task) - Impaired</measure>
    <time_frame>6 months</time_frame>
    <description>The CANTAB is a computerized neuropsychological battery examining a range of domains including attention, memory and executive functioning. Using mainly nonverbal stimuli, the test is language- and culture-independent. For the CANTAB SOC, the individual moves circles to match a target in this task based on the Tower of Hanoi game. The score is the number of problems solved in the minimum number of moves, with a maximum of 12. Higher scores indicate better performance.&#xD;
Impairment cutoff: &lt; 5.7(based on the comparison group as a whole and expressed as raw score).&#xD;
For all the cognitive tests impairment was defined as performance that was 1.33 SDs below the mean of a reference group of healthy peers. Raw scores indicating impaired performance could be &gt; or &lt; than the mean depending on the test (eg. on tests of accuracy the cut-off will be a score 1.33 SDs below the mean, while on a timed test the cut-off will be 1.33 SDs above the mean).</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>6 Month Cambridge Neuropsychological Test Automated Battery (CANTAB) AST (Attention Switching Task ) - Impaired</measure>
    <time_frame>6 months</time_frame>
    <description>The CANTAB is a computerized neuropsychological battery examining a range of domains including attention, memory and executive functioning. Using mainly nonverbal stimuli, the test is language- and culture-independent. For the CANTAB AST, participants respond either to the position of an arrow or the direction it is pointing, after being cued to the task on each trial. Total correct responses range from 0 to 160, where higher numbers indicate better performance.&#xD;
Impairment cutoff: &lt;135.5 (based on the comparison group as a whole and expressed as raw score).&#xD;
For all the cognitive tests impairment was defined as performance that was 1.33 SDs below the mean of a reference group of healthy peers. Raw scores indicating impaired performance could be &gt; or &lt; than the mean depending on the test (eg. on tests of accuracy the cut-off will be a score 1.33 SDs below the mean, while on a timed test the cut-off will be 1.33 SDs above the mean).</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Early (2-3 Weeks) MRI Imaging - Traumatic Intracranial Abnormalities</measure>
    <time_frame>Between 2-3 weeks after enrolment</time_frame>
    <description>A selected number of sites performed MRI follow up in a subset of patients that consented for imaging data collection. The CENTER-TBI MR protocols included a high-resolution 3D T1-weighted, a T2-weighted, a FLAIR, a DTI, a T2* sequence (gradient echo and/or SWI), and (optionally) a resting-state fMRI. Across all stratum the MRI sites performed a follow up MRI at 2-3 weeks after injury.&#xD;
Traumatic Intracranial Abnormalities were assessed according to the TBI-Common Data Elements (CDEs). It indicates whether any of the 12 following imaging abnormalities are present (Mass lesion, Extra-axial Hematoma, Epidural Hematoma, Subdural Hematoma Acute, Subdural Hematoma Subacute Chronic, Subdural Collection Mixed Density, Contusion, TAI, traumatic Subarachnoid Hemorrhage, Intraventricular Hemorrhage, Midline Shift or Cisternal Compression.</description>
  </secondary_outcome>
  <enrollment type="Actual">4559</enrollment>
  <condition>Traumatic Brain Injury</condition>
  <biospec_retention>Samples With DNA</biospec_retention>
  <biospec_descr>
    <textblock>
      whole blood samples&#xD;
    </textblock>
  </biospec_descr>
  <eligibility>
    <study_pop>
      <textblock>
        Patients presenting with traumatic brain injury.&#xD;
&#xD;
        The data collection will be stratified upon enrolment into 3 clinical groups differentiated&#xD;
        by clinical care path:&#xD;
&#xD;
          -  ER stratum: patients seen and discharged from the ER&#xD;
&#xD;
          -  Admission stratum: patients admitted to hospital but not to the ICU&#xD;
&#xD;
          -  ICU stratum: patients admitted directly to the ICU&#xD;
      </textblock>
    </study_pop>
    <sampling_method>Non-Probability Sample</sampling_method>
    <criteria>
      <textblock>
        Inclusion Criteria:&#xD;
&#xD;
          -  Clinical diagnosis of TBI&#xD;
&#xD;
          -  Clinical indication for CT scan&#xD;
&#xD;
          -  Presentation within 24 hours of injury&#xD;
&#xD;
          -  Informed consent obtained according to local and national requirements&#xD;
&#xD;
        Exclusion Criteria:&#xD;
&#xD;
          -  Severe pre-existing neurological disorder that would confound outcome assessments&#xD;
      </textblock>
    </criteria>
    <gender>All</gender>
    <minimum_age>N/A</minimum_age>
    <maximum_age>N/A</maximum_age>
    <healthy_volunteers>No</healthy_volunteers>
  </eligibility>
  <overall_official>
    <last_name>Andrew Maas, MD, PhD</last_name>
    <role>Study Chair</role>
    <affiliation>Antwerp University Hospital / University of Antwerp, Edegem, Belgium</affiliation>
  </overall_official>
  <overall_official>
    <last_name>David Menon, MD, PhD</last_name>
    <role>Study Director</role>
    <affiliation>University of Cambridge, Addenbrookes hospital, Cambridge, UK</affiliation>
  </overall_official>
  <location>
    <facility>
      <name>Innsbruck Medical University</name>
      <address>
        <city>Innsbruck</city>
        <country>Austria</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Medical University Vienna</name>
      <address>
        <city>Vienna</city>
        <country>Austria</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Antwerp University Hospital</name>
      <address>
        <city>Edegem</city>
        <country>Belgium</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>University Hospitals Leuven</name>
      <address>
        <city>Leuven</city>
        <country>Belgium</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>CHR Citadelle</name>
      <address>
        <city>Liege</city>
        <country>Belgium</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>CHU Liege</name>
      <address>
        <city>Liege</city>
        <country>Belgium</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Region Hovedstaden Rigshospitalet</name>
      <address>
        <city>Copenhagen</city>
        <country>Denmark</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Odense University Hospital</name>
      <address>
        <city>Odense</city>
        <country>Denmark</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Helsinki University Central Hospital</name>
      <address>
        <city>Helsinki</city>
        <country>Finland</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Turku University Hospital</name>
      <address>
        <city>Turku</city>
        <country>Finland</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>University Hospital of Grenoble</name>
      <address>
        <city>Grenoble</city>
        <country>France</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Lille University Hospital</name>
      <address>
        <city>Lille</city>
        <country>France</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>University Hospital Nancy</name>
      <address>
        <city>Nancy</city>
        <country>France</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>APHP</name>
      <address>
        <city>Paris</city>
        <country>France</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>CHU Poitiers</name>
      <address>
        <city>Poitiers</city>
        <country>France</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>University Hospital Aachen</name>
      <address>
        <city>Aachen</city>
        <country>Germany</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Charité Campus Virchow</name>
      <address>
        <city>Berlin</city>
        <country>Germany</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>University Hospital Heidelberg</name>
      <address>
        <city>Heidelberg</city>
        <country>Germany</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Klinikum Ludwigsburg</name>
      <address>
        <city>Ludwigsburg</city>
        <country>Germany</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>University of Pecs</name>
      <address>
        <city>Pecs</city>
        <country>Hungary</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>University of Szeged</name>
      <address>
        <city>Szeged</city>
        <country>Hungary</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Rambam Medical Center</name>
      <address>
        <city>Haifa</city>
        <country>Israel</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Hadassah-hebrew University Medical Center</name>
      <address>
        <city>Jerusalem</city>
        <country>Israel</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Bufalini Hospital</name>
      <address>
        <city>Cesena</city>
        <country>Italy</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Fondazione IRCCS Cà Granda Ospedale Maggiore Poloclinico</name>
      <address>
        <city>Milan</city>
        <country>Italy</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Niguarda Hospital</name>
      <address>
        <city>Milan</city>
        <country>Italy</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>S Raffaele University Hospital</name>
      <address>
        <city>Milan</city>
        <country>Italy</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>ASST di Monza</name>
      <address>
        <city>Monza</city>
        <country>Italy</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Maggiore Della Carità Hospital</name>
      <address>
        <city>Novara</city>
        <country>Italy</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Azienda Ospedaliera Università di Padova</name>
      <address>
        <city>Padova</city>
        <country>Italy</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>AOU Città della Salute e della Scienza di Torino</name>
      <address>
        <city>Torino</city>
        <country>Italy</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Rezekne Hospital</name>
      <address>
        <city>Rezekne</city>
        <country>Latvia</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Pauls Stradins Clinical University Hospital</name>
      <address>
        <city>Riga</city>
        <country>Latvia</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Riga Eastern Clinical University Hospital</name>
      <address>
        <city>Riga</city>
        <country>Latvia</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>University of Health Sciences</name>
      <address>
        <city>Kaunas</city>
        <country>Lithuania</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Center of neurovascular surgery, Clinic of neurology and neurosurgery, Vilnius University</name>
      <address>
        <city>Vilnius</city>
        <country>Lithuania</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Kaunas University of technology and Vilnius University</name>
      <address>
        <city>Vilnius</city>
        <country>Lithuania</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>University Medical Center Groningen</name>
      <address>
        <city>Groningen</city>
        <country>Netherlands</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Leiden University Medical Center</name>
      <address>
        <city>Leiden</city>
        <country>Netherlands</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Radboud University Medical Center</name>
      <address>
        <city>Nijmegen</city>
        <country>Netherlands</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Erasmus MC</name>
      <address>
        <city>Rotterdam</city>
        <country>Netherlands</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Medical Center Haaglanden</name>
      <address>
        <city>The Hague</city>
        <country>Netherlands</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>The HAGA Hospital</name>
      <address>
        <city>The Hague</city>
        <country>Netherlands</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>TweeSteden Ziekenhuis</name>
      <address>
        <city>Tilburg</city>
        <country>Netherlands</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Oslo University Hospital</name>
      <address>
        <city>Oslo</city>
        <country>Norway</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>University Hospital Northern Norway</name>
      <address>
        <city>Tromso</city>
        <country>Norway</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>St Olavs Hospital/Norwegian University of science and technology</name>
      <address>
        <city>Trondheim</city>
        <country>Norway</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Emergency County Hospital Timisoara</name>
      <address>
        <city>Timisoara</city>
        <country>Romania</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Clinical centre of Vojvodina</name>
      <address>
        <city>Novi Sad</city>
        <country>Serbia</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Vall d'Hebron University Hospital</name>
      <address>
        <city>Barcelona</city>
        <country>Spain</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Cruces University Hospital</name>
      <address>
        <city>Bilbao</city>
        <country>Spain</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Hospital Universitario 12 de Octubre</name>
      <address>
        <city>Madrid</city>
        <country>Spain</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Clínico Universitario de Valencia</name>
      <address>
        <city>Valencia</city>
        <country>Spain</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Karolinska University Hospital</name>
      <address>
        <city>Stockholm</city>
        <country>Sweden</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Umea University Hospital</name>
      <address>
        <city>Umea</city>
        <country>Sweden</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Centre Hospitalier Universitaire Vaudois</name>
      <address>
        <city>Lausanne</city>
        <country>Switzerland</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Queen Elizabeth Hospital</name>
      <address>
        <city>Birmingham</city>
        <country>United Kingdom</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Southmead Hospital</name>
      <address>
        <city>Bristol</city>
        <country>United Kingdom</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Addenbrookes Hospital</name>
      <address>
        <city>Cambridge</city>
        <country>United Kingdom</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Lothian Health Board</name>
      <address>
        <city>Edinburgh</city>
        <country>United Kingdom</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>The Walton centre NHS Foundation Trust</name>
      <address>
        <city>Liverpool</city>
        <country>United Kingdom</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Kings college London</name>
      <address>
        <city>London</city>
        <country>United Kingdom</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Salford Royal Hospital</name>
      <address>
        <city>Salford</city>
        <country>United Kingdom</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Sheffield Teaching Hospitals NHS Foundation Trust</name>
      <address>
        <city>Sheffield</city>
        <country>United Kingdom</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>University Hospitals Southampton NHS Trust</name>
      <address>
        <city>Southampton</city>
        <country>United Kingdom</country>
      </address>
    </facility>
  </location>
  <location_countries>
    <country>Austria</country>
    <country>Belgium</country>
    <country>Denmark</country>
    <country>Finland</country>
    <country>France</country>
    <country>Germany</country>
    <country>Hungary</country>
    <country>Israel</country>
    <country>Italy</country>
    <country>Latvia</country>
    <country>Lithuania</country>
    <country>Netherlands</country>
    <country>Norway</country>
    <country>Romania</country>
    <country>Serbia</country>
    <country>Spain</country>
    <country>Sweden</country>
    <country>Switzerland</country>
    <country>United Kingdom</country>
  </location_countries>
  <link>
    <url>https://www.center-tbi.eu/</url>
    <description>CENTER - TBI website</description>
  </link>
  <verification_date>April 2022</verification_date>
  <study_first_submitted>July 29, 2014</study_first_submitted>
  <study_first_submitted_qc>August 5, 2014</study_first_submitted_qc>
  <study_first_posted type="Estimate">August 6, 2014</study_first_posted>
  <results_first_submitted>April 6, 2020</results_first_submitted>
  <results_first_submitted_qc>September 2, 2020</results_first_submitted_qc>
  <results_first_posted type="Actual">September 25, 2020</results_first_posted>
  <last_update_submitted>April 6, 2022</last_update_submitted>
  <last_update_submitted_qc>April 6, 2022</last_update_submitted_qc>
  <last_update_posted type="Actual">November 7, 2022</last_update_posted>
  <responsible_party>
    <responsible_party_type>Principal Investigator</responsible_party_type>
    <investigator_affiliation>University Hospital, Antwerp</investigator_affiliation>
    <investigator_full_name>Andrew Maas</investigator_full_name>
    <investigator_title>M.D., PhD, Project Coordinator CENTER-TBI</investigator_title>
  </responsible_party>
  <keyword>TBI</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>
  </condition_browse>
  <patient_data>
    <sharing_ipd>Yes</sharing_ipd>
  </patient_data>
  <provided_document_section>
    <provided_document>
      <document_type>Study Protocol and Statistical Analysis Plan</document_type>
      <document_has_protocol>Yes</document_has_protocol>
      <document_has_icf>No</document_has_icf>
      <document_has_sap>Yes</document_has_sap>
      <document_date>July 3, 2014</document_date>
      <document_url>https://ClinicalTrials.gov/ProvidedDocs/21/NCT02210221/Prot_SAP_000.pdf</document_url>
    </provided_document>
  </provided_document_section>

  <clinical_results>

    <participant_flow>
      <recruitment_details>CENTER-TBI is an observational cohort study. Data from 4509 patients from 18 countries, collected between Dec 9, 2014, and Dec 17, 2017, are analysed in the core study: 848 (19%) patients were in the ER stratum, 1523 (34%) in the admission stratum, and 2138 (47%) in the ICU stratum.</recruitment_details>
      <pre_assignment_details>Of 4559 patients in the core study, 4509 patients are available for analysis.</pre_assignment_details>
      <group_list>
        <group group_id="P1">
          <title>CENTER-TBI Population</title>
          <description>Data from 4509 patients from 18 countries, collected between Dec 9, 2014, and Dec 17, 2017, were analysed in the core study and from 22 782 patients in the registry. In the core study, 848 (19%) patients were in the ER stratum, 1523 (34%) in the admission stratum, and 2138 (47%) in the ICU stratum.</description>
        </group>
      </group_list>
      <period_list>
        <period>
          <title>Overall Study</title>
          <milestone_list>
            <milestone>
              <title>STARTED</title>
              <participants_list>
                <participants group_id="P1" count="4559"/>
              </participants_list>
            </milestone>
            <milestone>
              <title>COMPLETED</title>
              <participants_list>
                <participants group_id="P1" count="4509"/>
              </participants_list>
            </milestone>
            <milestone>
              <title>NOT COMPLETED</title>
              <participants_list>
                <participants group_id="P1" count="50"/>
              </participants_list>
            </milestone>
          </milestone_list>
          <drop_withdraw_reason_list>
            <drop_withdraw_reason>
              <title>Lack of Efficacy</title>
              <participants_list>
                <participants group_id="P1" count="7"/>
              </participants_list>
            </drop_withdraw_reason>
            <drop_withdraw_reason>
              <title>Withdrawal by Subject</title>
              <participants_list>
                <participants group_id="P1" count="43"/>
              </participants_list>
            </drop_withdraw_reason>
          </drop_withdraw_reason_list>
        </period>
      </period_list>
    </participant_flow>

    <baseline>
      <group_list>
        <group group_id="B1">
          <title>CENTER-TBI Population</title>
          <description>Data from 4509 patients from 18 countries, collected between Dec 9, 2014, and Dec 17, 2017, were analysed in the core study.</description>
        </group>
      </group_list>
      <analyzed_list>
        <analyzed>
          <units>Participants</units>
          <scope>Overall</scope>
          <count_list>
            <count group_id="B1" value="4509"/>
          </count_list>
        </analyzed>
      </analyzed_list>
      <measure_list>
        <measure>
          <title>Age</title>
          <units>years</units>
          <param>Median</param>
          <dispersion>Inter-Quartile Range</dispersion>
          <class_list>
            <class>
              <analyzed_list>
                <analyzed>
                  <units>Participants</units>
                  <scope>Class</scope>
                  <count_list>
                    <count group_id="B1" value="4509"/>
                  </count_list>
                </analyzed>
              </analyzed_list>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="B1" value="50" lower_limit="30" upper_limit="66"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
          </class_list>
        </measure>
        <measure>
          <title>Sex: Female, Male</title>
          <units>Participants</units>
          <param>Count of Participants</param>
          <class_list>
            <class>
              <analyzed_list>
                <analyzed>
                  <units>Participants</units>
                  <scope>Class</scope>
                  <count_list>
                    <count group_id="B1" value="4509"/>
                  </count_list>
                </analyzed>
              </analyzed_list>
              <category_list>
                <category>
                  <title>Female</title>
                  <measurement_list>
                    <measurement group_id="B1" value="1486"/>
                  </measurement_list>
                </category>
                <category>
                  <title>Male</title>
                  <measurement_list>
                    <measurement group_id="B1" value="3023"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
          </class_list>
        </measure>
        <measure>
          <title>Race and Ethnicity Not Collected</title>
          <population>Race and Ethnicity were not collected from any participant.</population>
          <units>Participants</units>
          <param>Count of Participants</param>
          <class_list>
            <class>
              <analyzed_list>
                <analyzed>
                  <units>Participants</units>
                  <scope>Class</scope>
                  <count_list>
                    <count group_id="B1" value="0"/>
                  </count_list>
                </analyzed>
              </analyzed_list>
            </class>
          </class_list>
        </measure>
        <measure>
          <title>Region of Enrollment</title>
          <units>participants</units>
          <param>Number</param>
          <class_list>
            <class>
              <title>Europe</title>
              <analyzed_list>
                <analyzed>
                  <units>Participants</units>
                  <scope>Class</scope>
                  <count_list>
                    <count group_id="B1" value="4509"/>
                  </count_list>
                </analyzed>
              </analyzed_list>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="B1" value="4509"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
          </class_list>
        </measure>
      </measure_list>
    </baseline>

    <outcome_list>
      <outcome>
        <type>Primary</type>
        <title>Glasgow Outcome Scale - Extended (GOSE) at 6 Months</title>
        <description>The Extended Glasgow Outcome Scale is a global scale for functional outcome that rates patient status into 8 categories, going from dead to good recovery.&#xD;
Death&#xD;
Vegetative sate&#xD;
Lower severe disability&#xD;
Upper severe disability&#xD;
Lower moderate disability&#xD;
Upper moderate disability - some disability but can potentially return to some form of employment&#xD;
Lower good recovery - minor physical or mental defect&#xD;
Upper good recovery - full recovery&#xD;
The 6-month GOSE score is available in 3804 patients (84%).</description>
        <time_frame>6 months</time_frame>
        <group_list>
          <group group_id="O1">
            <title>CENTER-TBI Population</title>
            <description>Data from 4509 patients from 18 countries, collected between Dec 9, 2014, and Dec 17, 2017, were analysed in the core study.</description>
          </group>
          <group group_id="O2">
            <title>ER Stratum</title>
            <description>patients admitted to the ER</description>
          </group>
          <group group_id="O3">
            <title>Admission Stratum</title>
            <description>patients admitted but not to the ICU</description>
          </group>
          <group group_id="O4">
            <title>ICU Stratum</title>
            <description>patients admitted to the ICU</description>
          </group>
        </group_list>
        <measure>
          <title>Glasgow Outcome Scale - Extended (GOSE) at 6 Months</title>
          <description>The Extended Glasgow Outcome Scale is a global scale for functional outcome that rates patient status into 8 categories, going from dead to good recovery.&#xD;
Death&#xD;
Vegetative sate&#xD;
Lower severe disability&#xD;
Upper severe disability&#xD;
Lower moderate disability&#xD;
Upper moderate disability - some disability but can potentially return to some form of employment&#xD;
Lower good recovery - minor physical or mental defect&#xD;
Upper good recovery - full recovery&#xD;
The 6-month GOSE score is available in 3804 patients (84%).</description>
          <units>Participants</units>
          <param>Count of Participants</param>
          <analyzed_list>
            <analyzed>
              <units>Participants</units>
              <scope>Measure</scope>
              <count_list>
                <count group_id="O1" value="3804"/>
                <count group_id="O2" value="694"/>
                <count group_id="O3" value="1264"/>
                <count group_id="O4" value="1846"/>
              </count_list>
            </analyzed>
          </analyzed_list>
          <class_list>
            <class>
              <title>6-month GOSE &lt;8</title>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="O1" value="2419"/>
                    <measurement group_id="O2" value="207"/>
                    <measurement group_id="O3" value="665"/>
                    <measurement group_id="O4" value="1547"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
            <class>
              <title>6-month unfavourable outcome (GOSE &lt;5)</title>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="O1" value="966"/>
                    <measurement group_id="O2" value="31"/>
                    <measurement group_id="O3" value="140"/>
                    <measurement group_id="O4" value="795"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
          </class_list>
        </measure>
        <analysis_list>
          <analysis>
            <group_id_list>
              <group_id>O1</group_id>
            </group_id_list>
            <groups_desc>null hypothesis: no difference between ER stratum, Admission stratum and ICU stratum in 6-month mortality</groups_desc>
            <non_inferiority_type>Non-Inferiority</non_inferiority_type>
            <non_inferiority_desc>non-inferiority margin = 0</non_inferiority_desc>
            <p_value>&lt;0.0001</p_value>
            <p_value_desc>No corrections for multiple comparisons were done</p_value_desc>
            <method>ANOVA</method>
          </analysis>
          <analysis>
            <group_id_list>
              <group_id>O1</group_id>
            </group_id_list>
            <non_inferiority_type>Other</non_inferiority_type>
            <param_type>observed to expected ratio</param_type>
            <param_value>0.70</param_value>
            <ci_percent>95</ci_percent>
            <ci_n_sides>2-Sided</ci_n_sides>
            <ci_lower_limit>0.62</ci_lower_limit>
            <ci_upper_limit>0.76</ci_upper_limit>
            <estimate_desc>numerator: 6-month mortality observed denominator: 6-month mortality expected 95% CIs estimated according to a Poisson distribution</estimate_desc>
          </analysis>
        </analysis_list>
      </outcome>
      <outcome>
        <type>Primary</type>
        <title>SF-12v2 Health Survey (Short-Form Health Survey With 12 Questions) at 6 Months</title>
        <description>The SF-12v2 Health Survey uses 12 questions to measure functional health and well-being from the patient's point of view. The SF-12v2 at 6 months is available in 2300 patients.</description>
        <time_frame>6 months</time_frame>
        <group_list>
          <group group_id="O1">
            <title>CENTER-TBI Population</title>
            <description>Data from 4509 patients from 18 countries, collected between Dec 9, 2014, and Dec 17, 2017, were analysed in the core study.</description>
          </group>
          <group group_id="O2">
            <title>ER Stratum</title>
            <description>patients in the ER</description>
          </group>
          <group group_id="O3">
            <title>Admission Stratum</title>
            <description>patients admitted but not to the ICU</description>
          </group>
          <group group_id="O4">
            <title>ICU Stratum</title>
            <description>patients admitted to the ICU</description>
          </group>
        </group_list>
        <measure>
          <title>SF-12v2 Health Survey (Short-Form Health Survey With 12 Questions) at 6 Months</title>
          <description>The SF-12v2 Health Survey uses 12 questions to measure functional health and well-being from the patient's point of view. The SF-12v2 at 6 months is available in 2300 patients.</description>
          <units>Participants</units>
          <param>Count of Participants</param>
          <analyzed_list>
            <analyzed>
              <units>Participants</units>
              <scope>Measure</scope>
              <count_list>
                <count group_id="O1" value="2300"/>
                <count group_id="O2" value="480"/>
                <count group_id="O3" value="857"/>
                <count group_id="O4" value="963"/>
              </count_list>
            </analyzed>
          </analyzed_list>
          <class_list>
            <class>
              <title>6-month SF-12v2 mental component summary &lt;40 (impaired)</title>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="O1" value="551"/>
                    <measurement group_id="O2" value="101"/>
                    <measurement group_id="O3" value="184"/>
                    <measurement group_id="O4" value="266"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
            <class>
              <title>6-month SF-12v2 physical component summary &lt;40 (impaired)</title>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="O1" value="661"/>
                    <measurement group_id="O2" value="112"/>
                    <measurement group_id="O3" value="207"/>
                    <measurement group_id="O4" value="342"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
          </class_list>
        </measure>
        <analysis_list>
          <analysis>
            <group_id_list>
              <group_id>O1</group_id>
            </group_id_list>
            <groups_desc>null hypothesis: no difference between ER stratum, Admission stratum and ICU stratum in SF-12v2 mental component summary</groups_desc>
            <non_inferiority_type>Non-Inferiority</non_inferiority_type>
            <non_inferiority_desc>non-inferiority margin = 0</non_inferiority_desc>
            <p_value>&lt;0.0001</p_value>
            <p_value_desc>No corrections for multiple comparisons were done</p_value_desc>
            <method>ANOVA</method>
          </analysis>
          <analysis>
            <group_id_list>
              <group_id>O1</group_id>
            </group_id_list>
            <groups_desc>null hypothesis: no difference between ER stratum, Admission stratum and ICU stratum in SF-12v2 physical component summary</groups_desc>
            <non_inferiority_type>Non-Inferiority</non_inferiority_type>
            <non_inferiority_desc>non-inferiority margin = 0</non_inferiority_desc>
            <p_value>&lt;0.0001</p_value>
            <p_value_desc>No corrections for multiple comparisons were done</p_value_desc>
            <method>ANOVA</method>
          </analysis>
        </analysis_list>
      </outcome>
      <outcome>
        <type>Primary</type>
        <title>6 Month Quality of Life in Brain Injury (Qolibri-OS) &lt;52 (Impaired)</title>
        <description>The Quality of Life in Brain Injury (Qolibri-OS) is a 6 item overall scale that provides a profile of health-related quality of life in domains typicality affected by brain injury, such as physical function, cognition, emotional status, ability to perform daily activities, personal life and social relationship, and satisfaction with current situation and future prospects.&#xD;
The QOLIBRI scores are reported on a 0-100 scale , where 0=worst possible quality of life and 100=best possible quality of life.</description>
        <time_frame>6 months</time_frame>
        <group_list>
          <group group_id="O1">
            <title>CENTER-TBI Population</title>
            <description>Data from 4509 patients from 18 countries, collected between Dec 9, 2014, and Dec 17, 2017, were analysed in the core study.</description>
          </group>
          <group group_id="O2">
            <title>ER Stratum</title>
            <description>patients at the ER</description>
          </group>
          <group group_id="O3">
            <title>Admission Stratum</title>
            <description>patients admitted but not to the ICU</description>
          </group>
          <group group_id="O4">
            <title>ICU Stratum</title>
            <description>patients admitted to the ICU</description>
          </group>
        </group_list>
        <measure>
          <title>6 Month Quality of Life in Brain Injury (Qolibri-OS) &lt;52 (Impaired)</title>
          <description>The Quality of Life in Brain Injury (Qolibri-OS) is a 6 item overall scale that provides a profile of health-related quality of life in domains typicality affected by brain injury, such as physical function, cognition, emotional status, ability to perform daily activities, personal life and social relationship, and satisfaction with current situation and future prospects.&#xD;
The QOLIBRI scores are reported on a 0-100 scale , where 0=worst possible quality of life and 100=best possible quality of life.</description>
          <units>Participants</units>
          <param>Count of Participants</param>
          <analyzed_list>
            <analyzed>
              <units>Participants</units>
              <scope>Measure</scope>
              <count_list>
                <count group_id="O1" value="2323"/>
                <count group_id="O2" value="474"/>
                <count group_id="O3" value="866"/>
                <count group_id="O4" value="983"/>
              </count_list>
            </analyzed>
          </analyzed_list>
          <class_list>
            <class>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="O1" value="511"/>
                    <measurement group_id="O2" value="91"/>
                    <measurement group_id="O3" value="160"/>
                    <measurement group_id="O4" value="260"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
          </class_list>
        </measure>
        <analysis_list>
          <analysis>
            <group_id_list>
              <group_id>O1</group_id>
            </group_id_list>
            <groups_desc>null hypothesis: no difference between ER stratum, Admission stratum and ICU stratum in Qolibri Overall Scale</groups_desc>
            <non_inferiority_type>Non-Inferiority</non_inferiority_type>
            <non_inferiority_desc>non-inferiority margin = 0</non_inferiority_desc>
            <p_value>&lt;0.0001</p_value>
            <p_value_desc>No corrections for multiple comparisons were done</p_value_desc>
            <method>ANOVA</method>
          </analysis>
        </analysis_list>
      </outcome>
      <outcome>
        <type>Secondary</type>
        <title>6 Month Post-traumatic Stress Disorder (PTSD) Checklist for DSM-5 (PCL-5) &lt;33 (Impaired)</title>
        <description>The PCL-5 is a self-report rating scale intended to assess 20 DSM-5 symptoms of Posttraumatic Stress Disorder. The standard recall period for the PCL-5 is one month. For CENTER-TBI a recall period of one week was used at the 2-3 week assessment, and the standard one month recall period was used at other time points. The sum of scores can range from 0 to 80, where high scores indicate more pronounced PTSD symptoms.</description>
        <time_frame>6 months</time_frame>
        <group_list>
          <group group_id="O1">
            <title>CENTER-TBI Population</title>
            <description>Data from 4509 patients from 18 countries, collected between Dec 9, 2014, and Dec 17, 2017, were analysed in the core study.</description>
          </group>
          <group group_id="O2">
            <title>ER Stratum</title>
            <description>patients at the ER</description>
          </group>
          <group group_id="O3">
            <title>Admission Stratum</title>
            <description>patients admitted but not to the ICU</description>
          </group>
          <group group_id="O4">
            <title>ICU Stratum</title>
            <description>patients admitted to the ICU</description>
          </group>
        </group_list>
        <measure>
          <title>6 Month Post-traumatic Stress Disorder (PTSD) Checklist for DSM-5 (PCL-5) &lt;33 (Impaired)</title>
          <description>The PCL-5 is a self-report rating scale intended to assess 20 DSM-5 symptoms of Posttraumatic Stress Disorder. The standard recall period for the PCL-5 is one month. For CENTER-TBI a recall period of one week was used at the 2-3 week assessment, and the standard one month recall period was used at other time points. The sum of scores can range from 0 to 80, where high scores indicate more pronounced PTSD symptoms.</description>
          <units>Participants</units>
          <param>Count of Participants</param>
          <analyzed_list>
            <analyzed>
              <units>Participants</units>
              <scope>Measure</scope>
              <count_list>
                <count group_id="O1" value="2173"/>
                <count group_id="O2" value="456"/>
                <count group_id="O3" value="818"/>
                <count group_id="O4" value="899"/>
              </count_list>
            </analyzed>
          </analyzed_list>
          <class_list>
            <class>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="O1" value="201"/>
                    <measurement group_id="O2" value="40"/>
                    <measurement group_id="O3" value="77"/>
                    <measurement group_id="O4" value="84"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
          </class_list>
        </measure>
        <analysis_list>
          <analysis>
            <group_id_list>
              <group_id>O1</group_id>
            </group_id_list>
            <groups_desc>null hypothesis: no difference between ER stratum, Admission stratum and ICU stratum</groups_desc>
            <non_inferiority_type>Non-Inferiority</non_inferiority_type>
            <non_inferiority_desc>non-inferiority margin = 0</non_inferiority_desc>
            <p_value>&lt;0.0001</p_value>
            <p_value_desc>No correlations for multiple comparisons were done</p_value_desc>
            <method>ANOVA</method>
          </analysis>
        </analysis_list>
      </outcome>
      <outcome>
        <type>Secondary</type>
        <title>6 Month Rivermead Post Concussion Questionnaire &lt;16 (Impaired)</title>
        <description>The Rivermead PCS Questionnaire (RPQ) was originally developed as a measure of severity of symptoms following MTBI. It consists of 16 post-concussion symptoms including headaches, dizziness, nausea/vomiting, noise sensitivity, sleep disturbance, fatigue, irritability, feeling depressed/tearful, feeling frustrated/ impatient, forgetfulness, poor concentration, taking longer to think, blurred vision, light sensitivity, double vision and restlessness. In the original version of the RPQ, participants are asked to rate the degree (on a scale of 0 to 4) to which a particular symptom has been absent or a mild, moderate or severe problem over the previous 7 days compared with premorbid levels. Total scores range from 0 to 64 with higher scores indicating more severe symptoms. Scores equal to or greater than 16 were considered indicative of persisting post-concussion symptoms.</description>
        <time_frame>6 months</time_frame>
        <group_list>
          <group group_id="O1">
            <title>CENTER-TBI Population</title>
            <description>Data from 4509 patients from 18 countries, collected between Dec 9, 2014, and Dec 17, 2017, were analysed in the core study.</description>
          </group>
          <group group_id="O2">
            <title>ER Stratum</title>
            <description>patients at the ER</description>
          </group>
          <group group_id="O3">
            <title>Admission Stratum</title>
            <description>patients admitted but not to the ICU</description>
          </group>
          <group group_id="O4">
            <title>ICU Stratum</title>
            <description>patients admitted to the ICU</description>
          </group>
        </group_list>
        <measure>
          <title>6 Month Rivermead Post Concussion Questionnaire &lt;16 (Impaired)</title>
          <description>The Rivermead PCS Questionnaire (RPQ) was originally developed as a measure of severity of symptoms following MTBI. It consists of 16 post-concussion symptoms including headaches, dizziness, nausea/vomiting, noise sensitivity, sleep disturbance, fatigue, irritability, feeling depressed/tearful, feeling frustrated/ impatient, forgetfulness, poor concentration, taking longer to think, blurred vision, light sensitivity, double vision and restlessness. In the original version of the RPQ, participants are asked to rate the degree (on a scale of 0 to 4) to which a particular symptom has been absent or a mild, moderate or severe problem over the previous 7 days compared with premorbid levels. Total scores range from 0 to 64 with higher scores indicating more severe symptoms. Scores equal to or greater than 16 were considered indicative of persisting post-concussion symptoms.</description>
          <units>Participants</units>
          <param>Count of Participants</param>
          <analyzed_list>
            <analyzed>
              <units>Participants</units>
              <scope>Measure</scope>
              <count_list>
                <count group_id="O1" value="2259"/>
                <count group_id="O2" value="467"/>
                <count group_id="O3" value="852"/>
                <count group_id="O4" value="940"/>
              </count_list>
            </analyzed>
          </analyzed_list>
          <class_list>
            <class>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="O1" value="643"/>
                    <measurement group_id="O2" value="98"/>
                    <measurement group_id="O3" value="200"/>
                    <measurement group_id="O4" value="345"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
          </class_list>
        </measure>
        <analysis_list>
          <analysis>
            <group_id_list>
              <group_id>O1</group_id>
            </group_id_list>
            <groups_desc>null hypothesis: no difference between ER stratum, Admission stratum and ICU stratum</groups_desc>
            <non_inferiority_type>Non-Inferiority</non_inferiority_type>
            <non_inferiority_desc>non-inferiority margin = 0</non_inferiority_desc>
            <p_value>&lt;0.0001</p_value>
            <p_value_desc>No correlations for multiple comparisons were done</p_value_desc>
            <method>ANOVA</method>
          </analysis>
        </analysis_list>
      </outcome>
      <outcome>
        <type>Secondary</type>
        <title>6 Month Galveston Orientation and Amnesia Test (GOAT) &lt; 75 (Impaired)</title>
        <description>The GOAT is a standardised assessment used to determine whether a participant is in post-traumatic amnesia (PTA). PTA is an early phase of TBI recovery during which the person with injury shows markedly impaired memory, confusion, fluctuation in performance, disorientation, and other neurobehavioral signs and symptoms. GOAT questions assess orientation, memory for the first event that the participant can recall after the injury, and memory for the last event that the participant can recall from before the injury.&#xD;
The GOAT's total score must be achieved by subtracting from 100 the total amount of error scores (Total score = 100 - total amount of error scores). Scores lower than 75 point to the fact that the victim is still experiencing amnesia.</description>
        <time_frame>6 months</time_frame>
        <group_list>
          <group group_id="O1">
            <title>CENTER-TBI Population</title>
            <description>Data from 4509 patients from 18 countries, collected between Dec 9, 2014, and Dec 17, 2017, were analysed in the core study.</description>
          </group>
          <group group_id="O2">
            <title>ER Stratum</title>
            <description>patients at the ER</description>
          </group>
          <group group_id="O3">
            <title>Admission Stratum</title>
            <description>patients admitted but not to the ICU</description>
          </group>
          <group group_id="O4">
            <title>ICU Stratum</title>
            <description>patients admitted to the ICU</description>
          </group>
        </group_list>
        <measure>
          <title>6 Month Galveston Orientation and Amnesia Test (GOAT) &lt; 75 (Impaired)</title>
          <description>The GOAT is a standardised assessment used to determine whether a participant is in post-traumatic amnesia (PTA). PTA is an early phase of TBI recovery during which the person with injury shows markedly impaired memory, confusion, fluctuation in performance, disorientation, and other neurobehavioral signs and symptoms. GOAT questions assess orientation, memory for the first event that the participant can recall after the injury, and memory for the last event that the participant can recall from before the injury.&#xD;
The GOAT's total score must be achieved by subtracting from 100 the total amount of error scores (Total score = 100 - total amount of error scores). Scores lower than 75 point to the fact that the victim is still experiencing amnesia.</description>
          <units>Participants</units>
          <param>Count of Participants</param>
          <analyzed_list>
            <analyzed>
              <units>Participants</units>
              <scope>Measure</scope>
              <count_list>
                <count group_id="O1" value="1607"/>
                <count group_id="O2" value="281"/>
                <count group_id="O3" value="610"/>
                <count group_id="O4" value="716"/>
              </count_list>
            </analyzed>
          </analyzed_list>
          <class_list>
            <class>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="O1" value="67"/>
                    <measurement group_id="O2" value="6"/>
                    <measurement group_id="O3" value="8"/>
                    <measurement group_id="O4" value="53"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
          </class_list>
        </measure>
        <analysis_list>
          <analysis>
            <group_id_list>
              <group_id>O1</group_id>
            </group_id_list>
            <groups_desc>null hypothesis: no difference between ER stratum, Admission stratum and ICU stratum</groups_desc>
            <non_inferiority_type>Non-Inferiority</non_inferiority_type>
            <non_inferiority_desc>non-inferiority margin = 0</non_inferiority_desc>
            <p_value>&lt;0.0001</p_value>
            <p_value_desc>No correlations for multiple comparisons were done</p_value_desc>
            <method>ANOVA</method>
          </analysis>
        </analysis_list>
      </outcome>
      <outcome>
        <type>Secondary</type>
        <title>6 Month Rey Auditory Verbal Learning Test (RAVLT) - Impaired</title>
        <description>The Rey Auditory Verbal Learning Test (RAVLT) is a test of verbal memory that assesses the ability to acquire 15 words. Recall is assessed after each presentation of the list, after the recall of an interference list, and again following a 20-minute delay. The total score for recall of the principal list ranges from 0 to 75, with higher scores indicating better performance.&#xD;
Impairment was defined as performance that was 1.33 SDs below the mean of a reference group of healthy peers.</description>
        <time_frame>6 months</time_frame>
        <group_list>
          <group group_id="O1">
            <title>CENTER-TBI Population</title>
            <description>Data from 4509 patients from 18 countries, collected between Dec 9, 2014, and Dec 17, 2017, were analysed in the core study.</description>
          </group>
          <group group_id="O2">
            <title>ER Stratum</title>
            <description>patients at the ER</description>
          </group>
          <group group_id="O3">
            <title>Admission Stratum</title>
            <description>patients admitted but not to the ICU</description>
          </group>
          <group group_id="O4">
            <title>ICU Stratum</title>
            <description>patients admitted to the ICU</description>
          </group>
        </group_list>
        <measure>
          <title>6 Month Rey Auditory Verbal Learning Test (RAVLT) - Impaired</title>
          <description>The Rey Auditory Verbal Learning Test (RAVLT) is a test of verbal memory that assesses the ability to acquire 15 words. Recall is assessed after each presentation of the list, after the recall of an interference list, and again following a 20-minute delay. The total score for recall of the principal list ranges from 0 to 75, with higher scores indicating better performance.&#xD;
Impairment was defined as performance that was 1.33 SDs below the mean of a reference group of healthy peers.</description>
          <units>Participants</units>
          <param>Count of Participants</param>
          <analyzed_list>
            <analyzed>
              <units>Participants</units>
              <scope>Measure</scope>
              <count_list>
                <count group_id="O1" value="1823"/>
                <count group_id="O2" value="368"/>
                <count group_id="O3" value="705"/>
                <count group_id="O4" value="750"/>
              </count_list>
            </analyzed>
          </analyzed_list>
          <class_list>
            <class>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="O1" value="350"/>
                    <measurement group_id="O2" value="45"/>
                    <measurement group_id="O3" value="107"/>
                    <measurement group_id="O4" value="198"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
          </class_list>
        </measure>
        <analysis_list>
          <analysis>
            <group_id_list>
              <group_id>O1</group_id>
            </group_id_list>
            <groups_desc>null hypothesis: no difference between ER stratum, Admission stratum and ICU stratum</groups_desc>
            <non_inferiority_type>Non-Inferiority</non_inferiority_type>
            <non_inferiority_desc>non-inferiority margin = 0</non_inferiority_desc>
            <p_value>&lt;0.0001</p_value>
            <method>ANOVA</method>
          </analysis>
        </analysis_list>
      </outcome>
      <outcome>
        <type>Secondary</type>
        <title>6 Month Timed up and go Test - Impaired</title>
        <description>In the timed up and go (TUG) test, subjects are asked to rise from a standard armchair, walk to a marker 3 m away, turn, walk back, and sit down again, for quantifying functional mobility. The presence of slowness, hesitancy, abnormal trunk or arm movements, staggering or stumbling is used to grade the patient from 1 (normal) to 5 (severely abnormal). Impaired mobility was defined as taking 14 seconds or longer to perform the TUG test.</description>
        <time_frame>6 months</time_frame>
        <group_list>
          <group group_id="O1">
            <title>CENTER-TBI Population</title>
            <description>Data from 4509 patients from 18 countries, collected between Dec 9, 2014, and Dec 17, 2017, were analysed in the core study.</description>
          </group>
          <group group_id="O2">
            <title>ER Stratum</title>
            <description>patients at the ER</description>
          </group>
          <group group_id="O3">
            <title>Admission Stratum</title>
            <description>patients admitted but not to the ICU</description>
          </group>
          <group group_id="O4">
            <title>ICU Stratum</title>
            <description>patients admitted to the ICU</description>
          </group>
        </group_list>
        <measure>
          <title>6 Month Timed up and go Test - Impaired</title>
          <description>In the timed up and go (TUG) test, subjects are asked to rise from a standard armchair, walk to a marker 3 m away, turn, walk back, and sit down again, for quantifying functional mobility. The presence of slowness, hesitancy, abnormal trunk or arm movements, staggering or stumbling is used to grade the patient from 1 (normal) to 5 (severely abnormal). Impaired mobility was defined as taking 14 seconds or longer to perform the TUG test.</description>
          <units>Participants</units>
          <param>Count of Participants</param>
          <analyzed_list>
            <analyzed>
              <units>Participants</units>
              <scope>Measure</scope>
              <count_list>
                <count group_id="O1" value="1481"/>
                <count group_id="O2" value="293"/>
                <count group_id="O3" value="554"/>
                <count group_id="O4" value="634"/>
              </count_list>
            </analyzed>
          </analyzed_list>
          <class_list>
            <class>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="O1" value="342"/>
                    <measurement group_id="O2" value="62"/>
                    <measurement group_id="O3" value="108"/>
                    <measurement group_id="O4" value="172"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
          </class_list>
        </measure>
        <analysis_list>
          <analysis>
            <group_id_list>
              <group_id>O1</group_id>
            </group_id_list>
            <groups_desc>null hypothesis: no difference between ER stratum, Admission stratum and ICU stratum</groups_desc>
            <non_inferiority_type>Non-Inferiority</non_inferiority_type>
            <non_inferiority_desc>non-inferiority margin = 0</non_inferiority_desc>
            <p_value>0.169</p_value>
            <method>ANOVA</method>
          </analysis>
        </analysis_list>
      </outcome>
      <outcome>
        <type>Secondary</type>
        <title>6 Month JK Coma Recovery Scale - Revised &lt;23 (Impaired)</title>
        <description>The Coma Recovery Scale- Revised (CRS-R) is a standardized behavioral assessment instrument designed to measure neurobehavioral function in patients with disorders of consciousness (DOC). The CRS-R is comprised of six subscales addressing auditory, visual, motor, oromotor/verbal, communication and arousal functions. Subscale items are hierarchically-arranged, corresponding to brain stem, subcortical and cortically-mediated functions. Scores range between 0 (deep coma) and 23 (able to follow commands and to use objects purposefully). A total score less than 23 indicates impairment.</description>
        <time_frame>6 months</time_frame>
        <group_list>
          <group group_id="O1">
            <title>CENTER-TBI Population</title>
            <description>Data from 4509 patients from 18 countries, collected between Dec 9, 2014, and Dec 17, 2017, were analysed in the core study.</description>
          </group>
          <group group_id="O2">
            <title>ER/Admission Stratum</title>
            <description>patients at the ER or patients admitted to hospital but not to the ICU</description>
          </group>
          <group group_id="O3">
            <title>ICU Stratum</title>
            <description>patients admitted to the ICU</description>
          </group>
        </group_list>
        <measure>
          <title>6 Month JK Coma Recovery Scale - Revised &lt;23 (Impaired)</title>
          <description>The Coma Recovery Scale- Revised (CRS-R) is a standardized behavioral assessment instrument designed to measure neurobehavioral function in patients with disorders of consciousness (DOC). The CRS-R is comprised of six subscales addressing auditory, visual, motor, oromotor/verbal, communication and arousal functions. Subscale items are hierarchically-arranged, corresponding to brain stem, subcortical and cortically-mediated functions. Scores range between 0 (deep coma) and 23 (able to follow commands and to use objects purposefully). A total score less than 23 indicates impairment.</description>
          <units>Participants</units>
          <param>Count of Participants</param>
          <analyzed_list>
            <analyzed>
              <units>Participants</units>
              <scope>Measure</scope>
              <count_list>
                <count group_id="O1" value="227"/>
                <count group_id="O2" value="92"/>
                <count group_id="O3" value="135"/>
              </count_list>
            </analyzed>
          </analyzed_list>
          <class_list>
            <class>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="O1" value="17"/>
                    <measurement group_id="O2" value="0"/>
                    <measurement group_id="O3" value="17"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
          </class_list>
        </measure>
        <analysis_list>
          <analysis>
            <group_id_list>
              <group_id>O1</group_id>
            </group_id_list>
            <groups_desc>null hypothesis: no difference between ER stratum, Admission stratum and ICU stratum</groups_desc>
            <non_inferiority_type>Non-Inferiority</non_inferiority_type>
            <non_inferiority_desc>non-inferiority margin = 0</non_inferiority_desc>
            <p_value>&lt;0.0001</p_value>
            <method>Fisher Exact</method>
          </analysis>
        </analysis_list>
      </outcome>
      <outcome>
        <type>Secondary</type>
        <title>6 Month Trail Making Test (TMT) Part A - Impaired</title>
        <description>The Trail Making Test (TMT) is a measure of attention, speed, and mental flexibility. Part A requires the individual to draw lines to connect 25 encircled numbers distributed on a page. Part B is similar except the person must alternate between numbers and letters and is more difficult and takes longer to complete. Both sections are timed and the score represents the amount of time required to complete the task, with shorter times indicating better performance. The maximum time allowed is 100 seconds.&#xD;
Impairment cutoff: &gt; 55.9 (based on the comparison group as a whole and expressed as raw score).&#xD;
For all the cognitive tests impairment was defined as performance that was 1.33 SDs below the mean of a reference group of healthy peers. Raw scores indicating impaired performance could be &gt; or &lt; than the mean depending on the test (eg. on tests of accuracy the cut-off will be a score 1.33 SDs below the mean, while on a timed test the cut-off will be 1.33 SDs above the mean).</description>
        <time_frame>6 months</time_frame>
        <group_list>
          <group group_id="O1">
            <title>CENTER-TBI Population</title>
            <description>Data from 4509 patients from 18 countries, collected between Dec 9, 2014, and Dec 17, 2017, were analysed in the core study.</description>
          </group>
          <group group_id="O2">
            <title>ER Stratum</title>
            <description>patients at the ER</description>
          </group>
          <group group_id="O3">
            <title>Admission Stratum</title>
            <description>patients admitted but not to the ICU</description>
          </group>
          <group group_id="O4">
            <title>ICU Stratum</title>
            <description>patients admitted to the ICU</description>
          </group>
        </group_list>
        <measure>
          <title>6 Month Trail Making Test (TMT) Part A - Impaired</title>
          <description>The Trail Making Test (TMT) is a measure of attention, speed, and mental flexibility. Part A requires the individual to draw lines to connect 25 encircled numbers distributed on a page. Part B is similar except the person must alternate between numbers and letters and is more difficult and takes longer to complete. Both sections are timed and the score represents the amount of time required to complete the task, with shorter times indicating better performance. The maximum time allowed is 100 seconds.&#xD;
Impairment cutoff: &gt; 55.9 (based on the comparison group as a whole and expressed as raw score).&#xD;
For all the cognitive tests impairment was defined as performance that was 1.33 SDs below the mean of a reference group of healthy peers. Raw scores indicating impaired performance could be &gt; or &lt; than the mean depending on the test (eg. on tests of accuracy the cut-off will be a score 1.33 SDs below the mean, while on a timed test the cut-off will be 1.33 SDs above the mean).</description>
          <units>Participants</units>
          <param>Count of Participants</param>
          <analyzed_list>
            <analyzed>
              <units>Participants</units>
              <scope>Measure</scope>
              <count_list>
                <count group_id="O1" value="1853"/>
                <count group_id="O2" value="373"/>
                <count group_id="O3" value="720"/>
                <count group_id="O4" value="760"/>
              </count_list>
            </analyzed>
          </analyzed_list>
          <class_list>
            <class>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="O1" value="402"/>
                    <measurement group_id="O2" value="46"/>
                    <measurement group_id="O3" value="134"/>
                    <measurement group_id="O4" value="222"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
          </class_list>
        </measure>
        <analysis_list>
          <analysis>
            <group_id_list>
              <group_id>O1</group_id>
            </group_id_list>
            <groups_desc>null hypothesis: no difference between ER stratum, Admission stratum and ICU stratum</groups_desc>
            <non_inferiority_type>Non-Inferiority</non_inferiority_type>
            <non_inferiority_desc>non-inferiority margin = 0</non_inferiority_desc>
            <p_value>&lt;0.0001</p_value>
            <method>ANOVA</method>
          </analysis>
        </analysis_list>
      </outcome>
      <outcome>
        <type>Secondary</type>
        <title>6 Month Trail Making Test (TMT) Part B - Impaired</title>
        <description>The TMT is a measure of attention, speed, and mental flexibility. Part A requires the individual to draw lines to connect 25 encircled numbers distributed on a page. Part B is similar except the person must alternate between numbers and letters, is more difficult, takes longer to complete. Both sections are timed, the score represents the amount of time required to complete the task, with shorter times indicating better performance.&#xD;
Impairment cutoff: &gt; 143.7 (based on the comparison group as a whole and expressed as raw score).&#xD;
For all the cognitive tests impairment was defined as performance that was 1.33 SDs below the mean of a reference group of healthy peers. Raw scores indicating impaired performance could be &gt; or &lt; than the mean depending on the test (eg. on tests of accuracy the cut-off will be a score 1.33 SDs below the mean, while on a timed test the cut-off will be 1.33 SDs above the mean).</description>
        <time_frame>6 months</time_frame>
        <group_list>
          <group group_id="O1">
            <title>CENTER-TBI Population</title>
            <description>Data from 4509 patients from 18 countries, collected between Dec 9, 2014, and Dec 17, 2017, were analysed in the core study.</description>
          </group>
          <group group_id="O2">
            <title>ER Stratum</title>
            <description>patients at the ER</description>
          </group>
          <group group_id="O3">
            <title>Admission Stratum</title>
            <description>patients admitted but not to the ICU</description>
          </group>
          <group group_id="O4">
            <title>ICU Stratum</title>
            <description>patients admitted to the ICU</description>
          </group>
        </group_list>
        <measure>
          <title>6 Month Trail Making Test (TMT) Part B - Impaired</title>
          <description>The TMT is a measure of attention, speed, and mental flexibility. Part A requires the individual to draw lines to connect 25 encircled numbers distributed on a page. Part B is similar except the person must alternate between numbers and letters, is more difficult, takes longer to complete. Both sections are timed, the score represents the amount of time required to complete the task, with shorter times indicating better performance.&#xD;
Impairment cutoff: &gt; 143.7 (based on the comparison group as a whole and expressed as raw score).&#xD;
For all the cognitive tests impairment was defined as performance that was 1.33 SDs below the mean of a reference group of healthy peers. Raw scores indicating impaired performance could be &gt; or &lt; than the mean depending on the test (eg. on tests of accuracy the cut-off will be a score 1.33 SDs below the mean, while on a timed test the cut-off will be 1.33 SDs above the mean).</description>
          <units>Participants</units>
          <param>Count of Participants</param>
          <analyzed_list>
            <analyzed>
              <units>Participants</units>
              <scope>Measure</scope>
              <count_list>
                <count group_id="O1" value="1799"/>
                <count group_id="O2" value="365"/>
                <count group_id="O3" value="702"/>
                <count group_id="O4" value="732"/>
              </count_list>
            </analyzed>
          </analyzed_list>
          <class_list>
            <class>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="O1" value="368"/>
                    <measurement group_id="O2" value="46"/>
                    <measurement group_id="O3" value="113"/>
                    <measurement group_id="O4" value="209"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
          </class_list>
        </measure>
        <analysis_list>
          <analysis>
            <group_id_list>
              <group_id>O1</group_id>
            </group_id_list>
            <groups_desc>null hypothesis: no difference between ER stratum, Admission stratum and ICU stratum</groups_desc>
            <non_inferiority_type>Non-Inferiority</non_inferiority_type>
            <non_inferiority_desc>non-inferiority margin = 0</non_inferiority_desc>
            <p_value>&lt;0.0001</p_value>
            <method>ANOVA</method>
          </analysis>
        </analysis_list>
      </outcome>
      <outcome>
        <type>Secondary</type>
        <title>6 Month Cambridge Neuropsychological Test Automated Battery (CANTAB) PAL (Paired Associate Learning Task) - Impaired</title>
        <description>CANTAB is a computerized neuropsychological battery examining a range of domains including attention, memory and executive functioning. Using mainly nonverbal stimuli, the test is language- and culture-independent. For CANTAB PAL, the individual must remember 1 to 8 patterns displayed in different positions on the screen. The score is the number of incorrect responses adjusted if necessary for trials that have not been completed. Scores ranged from 0-194 with lower score indicating better performance.&#xD;
Impairment cutoff: &gt; 72.3 (based on the comparison group as a whole and expressed as raw score).&#xD;
For all the cognitive tests impairment was defined as performance that was 1.33 SDs below the mean of a reference group of healthy peers. Raw scores indicating impaired performance could be &gt; or &lt; than the mean depending on the test (eg. on tests of accuracy the cut-off will be a score 1.33 SDs below the mean, while on a timed test the cut-off will be 1.33 SDs above the mean).</description>
        <time_frame>6 months</time_frame>
        <group_list>
          <group group_id="O1">
            <title>CENTER-TBI Population</title>
            <description>Data from 4509 patients from 18 countries, collected between Dec 9, 2014, and Dec 17, 2017, were analysed in the core study.</description>
          </group>
          <group group_id="O2">
            <title>ER Stratum</title>
            <description>patients at the ER</description>
          </group>
          <group group_id="O3">
            <title>Admission Stratum</title>
            <description>patients admitted but not to the ICU</description>
          </group>
          <group group_id="O4">
            <title>ICU Stratum</title>
            <description>patients admitted to the ICU</description>
          </group>
        </group_list>
        <measure>
          <title>6 Month Cambridge Neuropsychological Test Automated Battery (CANTAB) PAL (Paired Associate Learning Task) - Impaired</title>
          <description>CANTAB is a computerized neuropsychological battery examining a range of domains including attention, memory and executive functioning. Using mainly nonverbal stimuli, the test is language- and culture-independent. For CANTAB PAL, the individual must remember 1 to 8 patterns displayed in different positions on the screen. The score is the number of incorrect responses adjusted if necessary for trials that have not been completed. Scores ranged from 0-194 with lower score indicating better performance.&#xD;
Impairment cutoff: &gt; 72.3 (based on the comparison group as a whole and expressed as raw score).&#xD;
For all the cognitive tests impairment was defined as performance that was 1.33 SDs below the mean of a reference group of healthy peers. Raw scores indicating impaired performance could be &gt; or &lt; than the mean depending on the test (eg. on tests of accuracy the cut-off will be a score 1.33 SDs below the mean, while on a timed test the cut-off will be 1.33 SDs above the mean).</description>
          <units>Participants</units>
          <param>Count of Participants</param>
          <analyzed_list>
            <analyzed>
              <units>Participants</units>
              <scope>Measure</scope>
              <count_list>
                <count group_id="O1" value="1546"/>
                <count group_id="O2" value="342"/>
                <count group_id="O3" value="587"/>
                <count group_id="O4" value="617"/>
              </count_list>
            </analyzed>
          </analyzed_list>
          <class_list>
            <class>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="O1" value="231"/>
                    <measurement group_id="O2" value="42"/>
                    <measurement group_id="O3" value="72"/>
                    <measurement group_id="O4" value="117"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
          </class_list>
        </measure>
        <analysis_list>
          <analysis>
            <group_id_list>
              <group_id>O1</group_id>
            </group_id_list>
            <groups_desc>null hypothesis: no difference between ER stratum, Admission stratum and ICU stratum</groups_desc>
            <non_inferiority_type>Non-Inferiority</non_inferiority_type>
            <non_inferiority_desc>non-inferiority margin = 0</non_inferiority_desc>
            <p_value>0.637</p_value>
            <method>ANOVA</method>
          </analysis>
        </analysis_list>
      </outcome>
      <outcome>
        <type>Secondary</type>
        <title>6 Month Cambridge Neuropsychological Test Automated Battery (CANTAB) RTI (Reaction Time Task) - Impaired</title>
        <description>The CANTAB is a computerized neuropsychological battery examining a range of domains including attention, memory and executive functioning. Using mainly nonverbal stimuli, the test is language- and culture-independent. For CANTAB RTI, the individual must respond as quickly as possible to a circle presented at one of 5 positions. The outcome measure is the median time for correct responses (ms).&#xD;
Impairment cutoff: &gt; 470.9 (based on the comparison group as a whole and expressed as raw score).&#xD;
For all the cognitive tests impairment was defined as performance that was 1.33 SDs below the mean of a reference group of healthy peers. Raw scores indicating impaired performance could be &gt; or &lt; than the mean depending on the test (eg. on tests of accuracy the cut-off will be a score 1.33 SDs below the mean, while on a timed test the cut-off will be 1.33 SDs above the mean).</description>
        <time_frame>6 months</time_frame>
        <group_list>
          <group group_id="O1">
            <title>CENTER-TBI Population</title>
            <description>Data from 4509 patients from 18 countries, collected between Dec 9, 2014, and Dec 17, 2017, were analysed in the core study.</description>
          </group>
          <group group_id="O2">
            <title>ER Stratum</title>
            <description>patients at the ER</description>
          </group>
          <group group_id="O3">
            <title>Admission Stratum</title>
            <description>patients admitted but not to the ICU</description>
          </group>
          <group group_id="O4">
            <title>ICU Stratum</title>
            <description>patients admitted to the ICU</description>
          </group>
        </group_list>
        <measure>
          <title>6 Month Cambridge Neuropsychological Test Automated Battery (CANTAB) RTI (Reaction Time Task) - Impaired</title>
          <description>The CANTAB is a computerized neuropsychological battery examining a range of domains including attention, memory and executive functioning. Using mainly nonverbal stimuli, the test is language- and culture-independent. For CANTAB RTI, the individual must respond as quickly as possible to a circle presented at one of 5 positions. The outcome measure is the median time for correct responses (ms).&#xD;
Impairment cutoff: &gt; 470.9 (based on the comparison group as a whole and expressed as raw score).&#xD;
For all the cognitive tests impairment was defined as performance that was 1.33 SDs below the mean of a reference group of healthy peers. Raw scores indicating impaired performance could be &gt; or &lt; than the mean depending on the test (eg. on tests of accuracy the cut-off will be a score 1.33 SDs below the mean, while on a timed test the cut-off will be 1.33 SDs above the mean).</description>
          <units>Participants</units>
          <param>Count of Participants</param>
          <analyzed_list>
            <analyzed>
              <units>Participants</units>
              <scope>Measure</scope>
              <count_list>
                <count group_id="O1" value="1462"/>
                <count group_id="O2" value="321"/>
                <count group_id="O3" value="542"/>
                <count group_id="O4" value="599"/>
              </count_list>
            </analyzed>
          </analyzed_list>
          <class_list>
            <class>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="O1" value="237"/>
                    <measurement group_id="O2" value="38"/>
                    <measurement group_id="O3" value="63"/>
                    <measurement group_id="O4" value="136"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
          </class_list>
        </measure>
        <analysis_list>
          <analysis>
            <group_id_list>
              <group_id>O1</group_id>
            </group_id_list>
            <groups_desc>null hypothesis: no difference between ER stratum, Admission stratum and ICU stratum</groups_desc>
            <non_inferiority_type>Non-Inferiority</non_inferiority_type>
            <non_inferiority_desc>non-inferiority margin = 0</non_inferiority_desc>
            <p_value>&lt;0.0001</p_value>
            <method>ANOVA</method>
          </analysis>
        </analysis_list>
      </outcome>
      <outcome>
        <type>Secondary</type>
        <title>6 Month Cambridge Neuropsychological Test Automated Battery (CANTAB) SWM (Spatial Working Memory Task) - Impaired</title>
        <description>The CANTAB is a computerized neuropsychological battery examining a range of domains including attention, memory and executive functioning. Using mainly nonverbal stimuli, the test is language- and culture-independent. For the CANTAB SWM, the participant searches for tokens in boxes on the screen. The between errors measure is the number of times the participant queries a box that has already been searched. Errors ranged from 0 to 151, with lower numbers indicating better performance.&#xD;
Impairment cutoff: &gt; 52.0 (based on the comparison group as a whole and expressed as raw score).&#xD;
For all the cognitive tests impairment was defined as performance that was 1.33 SDs below the mean of a reference group of healthy peers. Raw scores indicating impaired performance could be &gt; or &lt; than the mean depending on the test (eg. on tests of accuracy the cut-off will be a score 1.33 SDs below the mean, while on a timed test the cut-off will be 1.33 SDs above the mean).</description>
        <time_frame>6 months</time_frame>
        <group_list>
          <group group_id="O1">
            <title>CENTER-TBI Population</title>
            <description>Data from 4509 patients from 18 countries, collected between Dec 9, 2014, and Dec 17, 2017, were analysed in the core study.</description>
          </group>
          <group group_id="O2">
            <title>ER Stratum</title>
            <description>patients at the ER</description>
          </group>
          <group group_id="O3">
            <title>Admission Stratum</title>
            <description>patients admitted but not to the ICU</description>
          </group>
          <group group_id="O4">
            <title>ICU Stratum</title>
            <description>patients admitted to the ICU</description>
          </group>
        </group_list>
        <measure>
          <title>6 Month Cambridge Neuropsychological Test Automated Battery (CANTAB) SWM (Spatial Working Memory Task) - Impaired</title>
          <description>The CANTAB is a computerized neuropsychological battery examining a range of domains including attention, memory and executive functioning. Using mainly nonverbal stimuli, the test is language- and culture-independent. For the CANTAB SWM, the participant searches for tokens in boxes on the screen. The between errors measure is the number of times the participant queries a box that has already been searched. Errors ranged from 0 to 151, with lower numbers indicating better performance.&#xD;
Impairment cutoff: &gt; 52.0 (based on the comparison group as a whole and expressed as raw score).&#xD;
For all the cognitive tests impairment was defined as performance that was 1.33 SDs below the mean of a reference group of healthy peers. Raw scores indicating impaired performance could be &gt; or &lt; than the mean depending on the test (eg. on tests of accuracy the cut-off will be a score 1.33 SDs below the mean, while on a timed test the cut-off will be 1.33 SDs above the mean).</description>
          <units>Participants</units>
          <param>Count of Participants</param>
          <analyzed_list>
            <analyzed>
              <units>Participants</units>
              <scope>Measure</scope>
              <count_list>
                <count group_id="O1" value="1483"/>
                <count group_id="O2" value="334"/>
                <count group_id="O3" value="564"/>
                <count group_id="O4" value="585"/>
              </count_list>
            </analyzed>
          </analyzed_list>
          <class_list>
            <class>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="O1" value="259"/>
                    <measurement group_id="O2" value="49"/>
                    <measurement group_id="O3" value="81"/>
                    <measurement group_id="O4" value="129"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
          </class_list>
        </measure>
        <analysis_list>
          <analysis>
            <group_id_list>
              <group_id>O1</group_id>
            </group_id_list>
            <groups_desc>null hypothesis: no difference between ER stratum, Admission stratum and ICU stratum</groups_desc>
            <non_inferiority_type>Non-Inferiority</non_inferiority_type>
            <non_inferiority_desc>non-inferiority margin = 0</non_inferiority_desc>
            <p_value>0.480</p_value>
            <method>ANOVA</method>
          </analysis>
        </analysis_list>
      </outcome>
      <outcome>
        <type>Secondary</type>
        <title>6 Month Cambridge Neuropsychological Test Automated Battery (CANTAB) RVP (Rapid Visual Information Processing Task) - Impaired</title>
        <description>The CANTAB is a computerized neuropsychological battery examining a range of domains including attention, memory and executive functioning. Using mainly nonverbal stimuli, the test is language- and culture-independent. For the CANTAB RVP, sequences of numbers must be detected as they appear on the screen. The measure of accuracy is A' (A prime) which is derived from hits and correct rejections. The maximum score is 1 and, a higher A' indicates better performance.&#xD;
Impairment cutoff: &lt; 0.82 (based on the comparison group as a whole and expressed as raw score).&#xD;
For all the cognitive tests impairment was defined as performance that was 1.33 SDs below the mean of a reference group of healthy peers. Raw scores indicating impaired performance could be &gt; or &lt; than the mean depending on the test (eg. on tests of accuracy the cut-off will be a score 1.33 SDs below the mean, while on a timed test the cut-off will be 1.33 SDs above the mean).</description>
        <time_frame>6 months</time_frame>
        <group_list>
          <group group_id="O1">
            <title>CENTER-TBI Population</title>
            <description>Data from 4509 patients from 18 countries, collected between Dec 9, 2014, and Dec 17, 2017, were analysed in the core study.</description>
          </group>
          <group group_id="O2">
            <title>ER Stratum</title>
            <description>patients at the ER</description>
          </group>
          <group group_id="O3">
            <title>Admission Stratum</title>
            <description>patients admitted but not to the ICU</description>
          </group>
          <group group_id="O4">
            <title>ICU Stratum</title>
            <description>patients admitted to the ICU</description>
          </group>
        </group_list>
        <measure>
          <title>6 Month Cambridge Neuropsychological Test Automated Battery (CANTAB) RVP (Rapid Visual Information Processing Task) - Impaired</title>
          <description>The CANTAB is a computerized neuropsychological battery examining a range of domains including attention, memory and executive functioning. Using mainly nonverbal stimuli, the test is language- and culture-independent. For the CANTAB RVP, sequences of numbers must be detected as they appear on the screen. The measure of accuracy is A' (A prime) which is derived from hits and correct rejections. The maximum score is 1 and, a higher A' indicates better performance.&#xD;
Impairment cutoff: &lt; 0.82 (based on the comparison group as a whole and expressed as raw score).&#xD;
For all the cognitive tests impairment was defined as performance that was 1.33 SDs below the mean of a reference group of healthy peers. Raw scores indicating impaired performance could be &gt; or &lt; than the mean depending on the test (eg. on tests of accuracy the cut-off will be a score 1.33 SDs below the mean, while on a timed test the cut-off will be 1.33 SDs above the mean).</description>
          <units>Participants</units>
          <param>Count of Participants</param>
          <analyzed_list>
            <analyzed>
              <units>Participants</units>
              <scope>Measure</scope>
              <count_list>
                <count group_id="O1" value="1368"/>
                <count group_id="O2" value="311"/>
                <count group_id="O3" value="514"/>
                <count group_id="O4" value="543"/>
              </count_list>
            </analyzed>
          </analyzed_list>
          <class_list>
            <class>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="O1" value="225"/>
                    <measurement group_id="O2" value="33"/>
                    <measurement group_id="O3" value="46"/>
                    <measurement group_id="O4" value="146"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
          </class_list>
        </measure>
        <analysis_list>
          <analysis>
            <group_id_list>
              <group_id>O1</group_id>
            </group_id_list>
            <groups_desc>null hypothesis: no difference between ER stratum, Admission stratum and ICU stratum</groups_desc>
            <non_inferiority_type>Non-Inferiority</non_inferiority_type>
            <non_inferiority_desc>non-inferiority margin = 0</non_inferiority_desc>
            <p_value>&lt;0.0001</p_value>
            <method>ANOVA</method>
          </analysis>
        </analysis_list>
      </outcome>
      <outcome>
        <type>Secondary</type>
        <title>6 Month Cambridge Neuropsychological Test Automated Battery (CANTAB) SOC (Stockings of Cambridge Task) - Impaired</title>
        <description>The CANTAB is a computerized neuropsychological battery examining a range of domains including attention, memory and executive functioning. Using mainly nonverbal stimuli, the test is language- and culture-independent. For the CANTAB SOC, the individual moves circles to match a target in this task based on the Tower of Hanoi game. The score is the number of problems solved in the minimum number of moves, with a maximum of 12. Higher scores indicate better performance.&#xD;
Impairment cutoff: &lt; 5.7(based on the comparison group as a whole and expressed as raw score).&#xD;
For all the cognitive tests impairment was defined as performance that was 1.33 SDs below the mean of a reference group of healthy peers. Raw scores indicating impaired performance could be &gt; or &lt; than the mean depending on the test (eg. on tests of accuracy the cut-off will be a score 1.33 SDs below the mean, while on a timed test the cut-off will be 1.33 SDs above the mean).</description>
        <time_frame>6 months</time_frame>
        <group_list>
          <group group_id="O1">
            <title>CENTER-TBI Population</title>
            <description>Data from 4509 patients from 18 countries, collected between Dec 9, 2014, and Dec 17, 2017, were analysed in the core study.</description>
          </group>
          <group group_id="O2">
            <title>ER Stratum</title>
            <description>patients at the ER</description>
          </group>
          <group group_id="O3">
            <title>Admission Stratum</title>
            <description>patients admitted but not to the ICU</description>
          </group>
          <group group_id="O4">
            <title>ICU Stratum</title>
            <description>patients admitted to the ICU</description>
          </group>
        </group_list>
        <measure>
          <title>6 Month Cambridge Neuropsychological Test Automated Battery (CANTAB) SOC (Stockings of Cambridge Task) - Impaired</title>
          <description>The CANTAB is a computerized neuropsychological battery examining a range of domains including attention, memory and executive functioning. Using mainly nonverbal stimuli, the test is language- and culture-independent. For the CANTAB SOC, the individual moves circles to match a target in this task based on the Tower of Hanoi game. The score is the number of problems solved in the minimum number of moves, with a maximum of 12. Higher scores indicate better performance.&#xD;
Impairment cutoff: &lt; 5.7(based on the comparison group as a whole and expressed as raw score).&#xD;
For all the cognitive tests impairment was defined as performance that was 1.33 SDs below the mean of a reference group of healthy peers. Raw scores indicating impaired performance could be &gt; or &lt; than the mean depending on the test (eg. on tests of accuracy the cut-off will be a score 1.33 SDs below the mean, while on a timed test the cut-off will be 1.33 SDs above the mean).</description>
          <units>Participants</units>
          <param>Count of Participants</param>
          <analyzed_list>
            <analyzed>
              <units>Participants</units>
              <scope>Measure</scope>
              <count_list>
                <count group_id="O1" value="1440"/>
                <count group_id="O2" value="329"/>
                <count group_id="O3" value="548"/>
                <count group_id="O4" value="563"/>
              </count_list>
            </analyzed>
          </analyzed_list>
          <class_list>
            <class>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="O1" value="182"/>
                    <measurement group_id="O2" value="28"/>
                    <measurement group_id="O3" value="64"/>
                    <measurement group_id="O4" value="90"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
          </class_list>
        </measure>
        <analysis_list>
          <analysis>
            <group_id_list>
              <group_id>O1</group_id>
            </group_id_list>
            <groups_desc>null hypothesis: no difference between ER stratum, Admission stratum and ICU stratum</groups_desc>
            <non_inferiority_type>Non-Inferiority</non_inferiority_type>
            <non_inferiority_desc>non-inferiority margin = 0</non_inferiority_desc>
            <p_value>0.024</p_value>
            <method>ANOVA</method>
          </analysis>
        </analysis_list>
      </outcome>
      <outcome>
        <type>Secondary</type>
        <title>6 Month Cambridge Neuropsychological Test Automated Battery (CANTAB) AST (Attention Switching Task ) - Impaired</title>
        <description>The CANTAB is a computerized neuropsychological battery examining a range of domains including attention, memory and executive functioning. Using mainly nonverbal stimuli, the test is language- and culture-independent. For the CANTAB AST, participants respond either to the position of an arrow or the direction it is pointing, after being cued to the task on each trial. Total correct responses range from 0 to 160, where higher numbers indicate better performance.&#xD;
Impairment cutoff: &lt;135.5 (based on the comparison group as a whole and expressed as raw score).&#xD;
For all the cognitive tests impairment was defined as performance that was 1.33 SDs below the mean of a reference group of healthy peers. Raw scores indicating impaired performance could be &gt; or &lt; than the mean depending on the test (eg. on tests of accuracy the cut-off will be a score 1.33 SDs below the mean, while on a timed test the cut-off will be 1.33 SDs above the mean).</description>
        <time_frame>6 months</time_frame>
        <group_list>
          <group group_id="O1">
            <title>CENTER-TBI Population</title>
            <description>Data from 4509 patients from 18 countries, collected between Dec 9, 2014, and Dec 17, 2017, were analysed in the core study.</description>
          </group>
          <group group_id="O2">
            <title>ER Stratum</title>
            <description>patients at the ER</description>
          </group>
          <group group_id="O3">
            <title>Admission Stratum</title>
            <description>patients admitted but not to the ICU</description>
          </group>
          <group group_id="O4">
            <title>ICU Stratum</title>
            <description>patients admitted to the ICU</description>
          </group>
        </group_list>
        <measure>
          <title>6 Month Cambridge Neuropsychological Test Automated Battery (CANTAB) AST (Attention Switching Task ) - Impaired</title>
          <description>The CANTAB is a computerized neuropsychological battery examining a range of domains including attention, memory and executive functioning. Using mainly nonverbal stimuli, the test is language- and culture-independent. For the CANTAB AST, participants respond either to the position of an arrow or the direction it is pointing, after being cued to the task on each trial. Total correct responses range from 0 to 160, where higher numbers indicate better performance.&#xD;
Impairment cutoff: &lt;135.5 (based on the comparison group as a whole and expressed as raw score).&#xD;
For all the cognitive tests impairment was defined as performance that was 1.33 SDs below the mean of a reference group of healthy peers. Raw scores indicating impaired performance could be &gt; or &lt; than the mean depending on the test (eg. on tests of accuracy the cut-off will be a score 1.33 SDs below the mean, while on a timed test the cut-off will be 1.33 SDs above the mean).</description>
          <units>Participants</units>
          <param>Count of Participants</param>
          <analyzed_list>
            <analyzed>
              <units>Participants</units>
              <scope>Measure</scope>
              <count_list>
                <count group_id="O1" value="1488"/>
                <count group_id="O2" value="332"/>
                <count group_id="O3" value="559"/>
                <count group_id="O4" value="597"/>
              </count_list>
            </analyzed>
          </analyzed_list>
          <class_list>
            <class>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="O1" value="282"/>
                    <measurement group_id="O2" value="49"/>
                    <measurement group_id="O3" value="85"/>
                    <measurement group_id="O4" value="148"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
          </class_list>
        </measure>
        <analysis_list>
          <analysis>
            <group_id_list>
              <group_id>O1</group_id>
            </group_id_list>
            <groups_desc>null hypothesis: no difference between ER stratum, Admission stratum and ICU stratum</groups_desc>
            <non_inferiority_type>Non-Inferiority</non_inferiority_type>
            <non_inferiority_desc>non-inferiority margin = 0</non_inferiority_desc>
            <p_value>0.064</p_value>
            <method>ANOVA</method>
          </analysis>
        </analysis_list>
      </outcome>
      <outcome>
        <type>Secondary</type>
        <title>Early (2-3 Weeks) MRI Imaging - Traumatic Intracranial Abnormalities</title>
        <description>A selected number of sites performed MRI follow up in a subset of patients that consented for imaging data collection. The CENTER-TBI MR protocols included a high-resolution 3D T1-weighted, a T2-weighted, a FLAIR, a DTI, a T2* sequence (gradient echo and/or SWI), and (optionally) a resting-state fMRI. Across all stratum the MRI sites performed a follow up MRI at 2-3 weeks after injury.&#xD;
Traumatic Intracranial Abnormalities were assessed according to the TBI-Common Data Elements (CDEs). It indicates whether any of the 12 following imaging abnormalities are present (Mass lesion, Extra-axial Hematoma, Epidural Hematoma, Subdural Hematoma Acute, Subdural Hematoma Subacute Chronic, Subdural Collection Mixed Density, Contusion, TAI, traumatic Subarachnoid Hemorrhage, Intraventricular Hemorrhage, Midline Shift or Cisternal Compression.</description>
        <time_frame>Between 2-3 weeks after enrolment</time_frame>
        <group_list>
          <group group_id="O1">
            <title>CENTER-TBI Population</title>
            <description>Data from 4509 patients from 18 countries, collected between Dec 9, 2014, and Dec 17, 2017, were analysed in the core study.</description>
          </group>
          <group group_id="O2">
            <title>ER Stratum</title>
            <description>patients at the ER</description>
          </group>
          <group group_id="O3">
            <title>Admission Stratum</title>
            <description>patients admitted but not to the ICU</description>
          </group>
          <group group_id="O4">
            <title>ICU Stratum</title>
            <description>patients admitted to the ICU</description>
          </group>
        </group_list>
        <measure>
          <title>Early (2-3 Weeks) MRI Imaging - Traumatic Intracranial Abnormalities</title>
          <description>A selected number of sites performed MRI follow up in a subset of patients that consented for imaging data collection. The CENTER-TBI MR protocols included a high-resolution 3D T1-weighted, a T2-weighted, a FLAIR, a DTI, a T2* sequence (gradient echo and/or SWI), and (optionally) a resting-state fMRI. Across all stratum the MRI sites performed a follow up MRI at 2-3 weeks after injury.&#xD;
Traumatic Intracranial Abnormalities were assessed according to the TBI-Common Data Elements (CDEs). It indicates whether any of the 12 following imaging abnormalities are present (Mass lesion, Extra-axial Hematoma, Epidural Hematoma, Subdural Hematoma Acute, Subdural Hematoma Subacute Chronic, Subdural Collection Mixed Density, Contusion, TAI, traumatic Subarachnoid Hemorrhage, Intraventricular Hemorrhage, Midline Shift or Cisternal Compression.</description>
          <units>Participants</units>
          <param>Count of Participants</param>
          <analyzed_list>
            <analyzed>
              <units>Participants</units>
              <scope>Measure</scope>
              <count_list>
                <count group_id="O1" value="504"/>
                <count group_id="O2" value="123"/>
                <count group_id="O3" value="180"/>
                <count group_id="O4" value="197"/>
              </count_list>
            </analyzed>
          </analyzed_list>
          <class_list>
            <class>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="O1" value="312"/>
                    <measurement group_id="O2" value="32"/>
                    <measurement group_id="O3" value="101"/>
                    <measurement group_id="O4" value="179"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
          </class_list>
        </measure>
        <analysis_list>
          <analysis>
            <group_id_list>
              <group_id>O1</group_id>
            </group_id_list>
            <groups_desc>null hypothesis: no difference between ER stratum, Admission stratum and ICU stratum</groups_desc>
            <non_inferiority_type>Non-Inferiority</non_inferiority_type>
            <non_inferiority_desc>non-inferiority margin = 0</non_inferiority_desc>
            <p_value>&lt;0.0001</p_value>
            <method>ANOVA</method>
          </analysis>
        </analysis_list>
      </outcome>
    </outcome_list>

    <reported_events>
      <time_frame>2 years</time_frame>
      <desc>Observational study: no adverse events to be reported since there is no intervention.&#xD;
The number of patients admitted to the ICU is seen as the population at risk for all-cause mortality, due to the severity of ICU patients: 2138 patients.</desc>
      <group_list>
        <group group_id="E1">
          <title>CENTER-TBI Population</title>
          <description>Data from 4509 patients from 18 countries, collected between Dec 9, 2014, and Dec 17, 2017, were analysed in the core study.</description>
        </group>
      </group_list>
      <serious_events>
        <category_list>
          <category>
            <title>Total</title>
            <event_list>
              <event>
                <sub_title>Total, all-cause mortality</sub_title>
                <counts group_id="E1" subjects_affected="363" subjects_at_risk="2138"/>
              </event>
              <event>
                <sub_title>Total, serious adverse events</sub_title>
                <counts group_id="E1" subjects_affected="0" subjects_at_risk="0"/>
              </event>
            </event_list>
          </category>
        </category_list>
      </serious_events>
      <other_events>
        <frequency_threshold>0</frequency_threshold>
        <category_list>
          <category>
            <title>Total</title>
            <event_list>
              <event>
                <sub_title>Total, other adverse events</sub_title>
                <counts group_id="E1" subjects_affected="0" subjects_at_risk="0"/>
              </event>
            </event_list>
          </category>
        </category_list>
      </other_events>
    </reported_events>

    <certain_agreements>
      <pi_employee>Principal Investigators are NOT employed by the organization sponsoring the study.</pi_employee>
      <restrictive_agreement>The only disclosure restriction on the PI is that the sponsor can review results communications prior to public release and can embargo communications regarding trial results for a period that is less than or equal to 60 days. The sponsor cannot require changes to the communication and cannot extend the embargo.</restrictive_agreement>
    </certain_agreements>
    <point_of_contact>
      <name_or_title>Prof. Em. Dr Andrew Maas</name_or_title>
      <organization>UZA</organization>
      <phone>0032 3 821 45 37</phone>
      <email>andrew.maas@uza.be</email>
    </point_of_contact>
  </clinical_results>
</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/NCT02210221
org study id: 602150
nct id: NCT02210221
lead sponsor: 
collaborator: 
collaborator: 
collaborator: 
collaborator: 
collaborator: 
collaborator: 
collaborator: 
collaborator: 
collaborator: 
has dmc: Yes
The research aims of the CENTER-TBI study are to:

        1. better characterize Traumatic Brain Injury (TBI) as a disease and describe it in a
           European context, and

        2. identify the most effective clinical interventions for managing TBI.

      Specific aims

        1. To collect high quality clinical and epidemiological data with repositories for
           neuro-imaging, DNA, and serum from patients with TBI.

        2. To refine and improve outcome assessment and develop health utility indices for TBI.

        3. To develop multidimensional approaches to characterisation and prediction of TBI.

        4. To define patient profiles which predict efficacy of specific interventions ("Precision
           Medicine").

        5. To develop performance indicators for quality assurance and quality improvement in TBI
           care.

        6. To validate the common data elements (CDEs) for broader use in international settings,
           and to develop a user-friendly web based data entry instrument and case report form
           builder.

        7. To develop an open database compatible with Federal Interagency Traumatic Brain Injury
           Research (FITBIR).

        8. To intensify networking activities and international collaborations in TBI.

        9. To disseminate study results and management recommendations for TBI to health care
           professionals, policy makers and consumers, aiming to improve health care for TBI at
           individual and population levels.

       10. To develop a "knowledge commons" for TBI, integrating CENTER-TBI outputs into systematic
           reviews.
• Introduction:

      CENTER-TBI (Collaborative European NeuroTrauma Effectiveness Research in TBI)
      (www.center-tbi.eu) is a project embedded within the International Initiative on TBI Research
      (InTBIR) (http://intbir.nih.gov/), as a collaboration between the European Commission (EC),
      the US National Institute of Neurological Disorders and Stroke (NIH-NINDS) and the Canadian
      Institute of Health Research (CIHR).

        -  Research aims:

      The basic concept of this project is to exploit the existing heterogeneity in biology, care
      and outcome of TBI patients to discover underlying pathophysiology, to refine
      characterisation, and to identify effective clinical interventions. The key driver of our
      research plan is to collect data from a large number of European centres and sufficiently
      large cohort to enable 'Comparative effectiveness research' (CER) analyses of differences in
      clinical care and management pathways in TBI.

      Improved disease characterization will aid Precision Medicine, a concept recently enunciated
      by the US National Academy of Science. Such improved characterization and stratification will
      allow for more targeted therapies. Further, CER provides a promising framework to identify
      best practices and improve outcome after TBI. CER is the generation and synthesis of evidence
      that compares the benefits and harms of alternative methods to prevent, diagnose, treat, and
      monitor a clinical condition or to improve the delivery of care. The purpose of CER is to
      assist consumers, clinicians, purchasers, and policy makers to make informed decisions that
      will improve health care at both the individual and population levels.

        -  Cohort:

      A large core cohort of patients across the severity spectrum in TBI will be recruited at
      approximately 77 sites in Europe and Israel (the CENTER-TBI Core Study): 5400 patients
      differentiated into 3 equal strata of approximately 1800:

        -  ER stratum: patients seen and discharged from the ER;

        -  Admission stratum: patients admitted to the hospital but not to the ICU;

        -  ICU stratum: patients admitted directly to the ICU. Balance in numbers between the
           strata will be aimed for, but sites will be allowed to arrange recruitment strategies to
           best suit their local requirements.

      The core cohort will be underpinned by comparison with a larger registry (the CENTER-TBI
      registry) based on pragmatic data collection of all patients with TBI seen in participating
      centres (to establish the internal generalizability of our study), and by comparison with
      national trauma registries (to establish the external generalizability of our findings).

      In the core cohort, detailed data will be collected on clinical parameters, neuroimaging
      studies, biomarker analyses, DNA analyses, and longitudinal outcome assessments. In selected
      centres, extended studies will additionally focus on advanced magnetic resonance (MR)
      imaging, detailed coagulation profiling and high resolution ICU monitoring.

        -  Sample size assessment:

      The sample size estimate (n=5400) was based on:

        -  Practical logistic considerations

        -  Power calculations for the different strata, targeting comparative effectiveness
           analyses, assuming a between-centre and between-country heterogeneity as identified in
           previous research (expressed by variance parameter from a random effects model, Tau^2 of
           0.431)

        -  Postulated odds ratios for intervention effects of approximately 5% improvement in
           outcome.

      Overall, these calculations provided a statistical power to detect odds ratios of ~1.2
      associated with differences in process or intervention variables across the core dataset with
      a power of 80%; and require somewhat larger odds ratios in each of the three individual
      strata. In the registry we expect to be able to detect differences (predominantly in
      organizational or system variables) with an odds ratio of 1.2 with a power of 82%.

        -  Quality control and assurance:

      Continuous monitoring of enrolment and completeness of data will be performed by ICON as
      contract research organization (CRO). Source data verification (SDV) will be performed in 10%
      of subjects by the CRO. The quality of data collection will be further enhanced by
      implementing automated data entry checks for impossible/implausible values and implementing
      data checks for consistency between variables. A task force of study personnel will evaluate
      the completeness, consistency and validity of submitted data and function as support desk for
      participating sites.

        -  Data management:

      Prior to upload to the study database, all acquired data will be stored locally. All patients
      will be allocated a random Global Unique Personal Identification number (GUPI) which will be
      linked locally to hospital identifiers. All uploaded data will be de-identified and images
      will be defaced prior to upload. While blood samples and clinical data will be linked, both
      sets of data will be kept confidential and anonymised beyond the initial stage of correlation
      for analysis. All imaging and electronic data will be kept on individually password protected
      servers. All clinical data will be entered into electronic Case Report Forms (eCRFs) and
      managed by the 'QuesGen data management platform' (http://www.quesgen.com/) which will be
      developed in collaboration with Karolinska Institutet International Neuroinformatics
      Coordinating Faculty (KI-INCF). As data is entered into each form, the system will run data
      validation checks that include conditionally required data, validation across fields, and
      validation requirements based on subject type. If any validation check fails, the user is
      alerted immediately that the data does not meet Quality Assurance (QA) criteria and the issue
      can be addressed and corrected at that point. All de-identified electronic study data in the
      CENTER-TBI database will be stored securely in the European data space under supervision of
      KI-INCF for the duration of subject enrolment and follow-up and for a period afterwards for
      data analysis and preparation of publications. We estimate that the analysis and publication
      period will last for several years after the conclusion of subject enrolment.

      Together with QuesGen Systems, KI-INCF will ensure that data standards are established for
      the data model e.g. conformity of field formats, field codes and names to ensure consistency
      across all datasets. Any approved changes will be fully documented with dataset updates to
      maintain data quality and accuracy. KI-INCF will be responsible for importing cleaned
      datasets to other analytic platforms as determined by the coordinators.

      Where applicable, information relevant to the patient's care will be made available to the
      physician responsible. Data, including blood samples collected as part of this study will be
      shared in an anonymised form with collaborators from other European states (this is part of a
      European Commission Framework7 funded program), and with selected collaborators in other
      countries who form part of an emerging International Traumatic Brain Injury Research
      initiative.

        -  Computing platform and Neuroinformatics Resource:

      The KI-INCF will coordinate the establishment of an informatics platform for acquisition,
      storage and analysis of CDE-based clinical data. The goal is to develop a next generation
      open standards-based platform to support advanced large-scale analytics and model building.
      Such a platform also provides a model for future clinical studies on brain diseases and
      disorders. This development will receive additional support from One Mind for Research.

        -  Statistical analysis plan:

      Statistical analyses for the Comparative Effectiveness Research (CER) questions will
      primarily apply random effects modelling, in which center is included at the higher level,
      and patients are considered clustered within centers. In some analyses, higher levels of
      clustering will also be considered, e.g. country, or European region; or lower levels, e.g.
      physicians within hospitals. Confounding factors as measured at the individual patient and/or
      center level, will be considered extensively, and will be targeted to the specific research
      question.

      Statistical analyses for better characterization of TBI will be exploratory, aiming to better
      understand the complexity of the disease and to discover new associations. In addition to
      standard statistical descriptive and inferential techniques, we will also employ novel
      machine learning techniques as appropriate.

      Prognostic analyses will consider a range of variables, including genetic, demographic and
      clinical data, physiological signals, imaging results, and biomarkers as predictors of early
      endpoints and physiologic derangement (e.g. raised ICP), and late outcome, including
      mortality, functional outcome, quality of life and neuropsychological performance. Previously
      and newly developed prediction models will be validated by comparison of observed to
      predicted outcome risks, with predictive performance summarized by measures for model fit,
      discrimination, and calibration.

        -  Missing data:

      Every effort will be made to limit the number of missing data in the CENTER-TBI study.
      Missing values are, however, inherent to any clinical study. Missing values may confound the
      descriptive, prognostic and CER analyses. Thus, appropriate techniques for dealing with
      missing values are required. First, we will evaluate the various reasons for missingness per
      centre. Next, we will explore the use of alternative statistical approaches, including
      inverse probability weighting and multiple imputation. We will consider missing values in
      baseline characteristics as well as in short and long term outcomes. Based on simulation
      studies and practical considerations we will develop standard operating procedures towards
      the analyses with missing values, respecting the differences in multiple research questions.

        -  Informed Consent:

      Informed consent procedures will follow local and national requirements in all cases. We
      anticipate that many potential patients will not be able to consent themselves to participate
      in this project. The nature of TBI means that some patients may lack capacity to decide to
      participate in this study especially at the earliest time point. It is important to try and
      include these patients to ensure that representative samples of patients are included to
      avoid bias in the study findings. Every step will be taken to ensure that a test of capacity
      is undertaken before a decision on a person's capacity to consent or not to consent to
      participation in research is taken. If the subject is not capable of self-consent, all
      efforts will be made to locate a legally acceptable representative to act on behalf of the
      subject. When a legally acceptable representative (e.g. consultee/proxy) is identified, their
      opinion will be sought about the potential participant's wishes and feelings in relation to
      the project, and whether he or she would have wanted to take part in the study.

      Subjects are free to withdraw, or be withdrawn by their consultee/proxy if appropriate, at
      any point in the study, and they need not state a reason.

        -  Impact:

      The CENTER-TBI project will contribute towards the overall goals of InTBIR, by identifying
      more effective and efficient treatment provision, thus improving outcome and reducing costs.
      The science in the project will provide novel information on disease processes, treatment,
      outcome, and prognosis in TBI, identifying new therapeutic targets and therapies; while the
      CENTER-TBI repositories will ensure opportunities for legacy research. Thus, the project has
      the potential to improve current health care and its delivery at both population and
      individual levels, deliver early scientific advances that could improve the care of patients
      with TBI, and provide a rich investment for future biomedical research.
observational model: Cohort
time perspective: Prospective
measure: Glasgow Outcome Scale - Extended (GOSE) at 6 Months
time frame: 6 months
description: The Extended Glasgow Outcome Scale is a global scale for functional outcome that rates patient status into 8 categories, going from dead to good recovery.
Death
Vegetative sate
Lower severe disability
Upper severe disability
Lower moderate disability
Upper moderate disability - some disability but can potentially return to some form of employment
Lower good recovery - minor physical or mental defect
Upper good recovery - full recovery
The 6-month GOSE score is available in 3804 patients (84%).
measure: SF-12v2 Health Survey (Short-Form Health Survey With 12 Questions) at 6 Months
time frame: 6 months
description: The SF-12v2 Health Survey uses 12 questions to measure functional health and well-being from the patient's point of view. The SF-12v2 at 6 months is available in 2300 patients.
measure: 6 Month Quality of Life in Brain Injury (Qolibri-OS) <52 (Impaired)
time frame: 6 months
description: The Quality of Life in Brain Injury (Qolibri-OS) is a 6 item overall scale that provides a profile of health-related quality of life in domains typicality affected by brain injury, such as physical function, cognition, emotional status, ability to perform daily activities, personal life and social relationship, and satisfaction with current situation and future prospects.
The QOLIBRI scores are reported on a 0-100 scale , where 0=worst possible quality of life and 100=best possible quality of life.
measure: 6 Month Post-traumatic Stress Disorder (PTSD) Checklist for DSM-5 (PCL-5) <33 (Impaired)
time frame: 6 months
description: The PCL-5 is a self-report rating scale intended to assess 20 DSM-5 symptoms of Posttraumatic Stress Disorder. The standard recall period for the PCL-5 is one month. For CENTER-TBI a recall period of one week was used at the 2-3 week assessment, and the standard one month recall period was used at other time points. The sum of scores can range from 0 to 80, where high scores indicate more pronounced PTSD symptoms.
measure: 6 Month Rivermead Post Concussion Questionnaire <16 (Impaired)
time frame: 6 months
description: The Rivermead PCS Questionnaire (RPQ) was originally developed as a measure of severity of symptoms following MTBI. It consists of 16 post-concussion symptoms including headaches, dizziness, nausea/vomiting, noise sensitivity, sleep disturbance, fatigue, irritability, feeling depressed/tearful, feeling frustrated/ impatient, forgetfulness, poor concentration, taking longer to think, blurred vision, light sensitivity, double vision and restlessness. In the original version of the RPQ, participants are asked to rate the degree (on a scale of 0 to 4) to which a particular symptom has been absent or a mild, moderate or severe problem over the previous 7 days compared with premorbid levels. Total scores range from 0 to 64 with higher scores indicating more severe symptoms. Scores equal to or greater than 16 were considered indicative of persisting post-concussion symptoms.
measure: 6 Month Galveston Orientation and Amnesia Test (GOAT) < 75 (Impaired)
time frame: 6 months
description: The GOAT is a standardised assessment used to determine whether a participant is in post-traumatic amnesia (PTA). PTA is an early phase of TBI recovery during which the person with injury shows markedly impaired memory, confusion, fluctuation in performance, disorientation, and other neurobehavioral signs and symptoms. GOAT questions assess orientation, memory for the first event that the participant can recall after the injury, and memory for the last event that the participant can recall from before the injury.
The GOAT's total score must be achieved by subtracting from 100 the total amount of error scores (Total score = 100 - total amount of error scores). Scores lower than 75 point to the fact that the victim is still experiencing amnesia.
measure: 6 Month Rey Auditory Verbal Learning Test (RAVLT) - Impaired
time frame: 6 months
description: The Rey Auditory Verbal Learning Test (RAVLT) is a test of verbal memory that assesses the ability to acquire 15 words. Recall is assessed after each presentation of the list, after the recall of an interference list, and again following a 20-minute delay. The total score for recall of the principal list ranges from 0 to 75, with higher scores indicating better performance.
Impairment was defined as performance that was 1.33 SDs below the mean of a reference group of healthy peers.
measure: 6 Month Timed up and go Test - Impaired
time frame: 6 months
description: In the timed up and go (TUG) test, subjects are asked to rise from a standard armchair, walk to a marker 3 m away, turn, walk back, and sit down again, for quantifying functional mobility. The presence of slowness, hesitancy, abnormal trunk or arm movements, staggering or stumbling is used to grade the patient from 1 (normal) to 5 (severely abnormal). Impaired mobility was defined as taking 14 seconds or longer to perform the TUG test.
measure: 6 Month JK Coma Recovery Scale - Revised <23 (Impaired)
time frame: 6 months
description: The Coma Recovery Scale- Revised (CRS-R) is a standardized behavioral assessment instrument designed to measure neurobehavioral function in patients with disorders of consciousness (DOC). The CRS-R is comprised of six subscales addressing auditory, visual, motor, oromotor/verbal, communication and arousal functions. Subscale items are hierarchically-arranged, corresponding to brain stem, subcortical and cortically-mediated functions. Scores range between 0 (deep coma) and 23 (able to follow commands and to use objects purposefully). A total score less than 23 indicates impairment.
measure: 6 Month Trail Making Test (TMT) Part A - Impaired
time frame: 6 months
description: The Trail Making Test (TMT) is a measure of attention, speed, and mental flexibility. Part A requires the individual to draw lines to connect 25 encircled numbers distributed on a page. Part B is similar except the person must alternate between numbers and letters and is more difficult and takes longer to complete. Both sections are timed and the score represents the amount of time required to complete the task, with shorter times indicating better performance. The maximum time allowed is 100 seconds.
Impairment cutoff: > 55.9 (based on the comparison group as a whole and expressed as raw score).
For all the cognitive tests impairment was defined as performance that was 1.33 SDs below the mean of a reference group of healthy peers. Raw scores indicating impaired performance could be > or < than the mean depending on the test (eg. on tests of accuracy the cut-off will be a score 1.33 SDs below the mean, while on a timed test the cut-off will be 1.33 SDs above the mean).
measure: 6 Month Trail Making Test (TMT) Part B - Impaired
time frame: 6 months
description: The TMT is a measure of attention, speed, and mental flexibility. Part A requires the individual to draw lines to connect 25 encircled numbers distributed on a page. Part B is similar except the person must alternate between numbers and letters, is more difficult, takes longer to complete. Both sections are timed, the score represents the amount of time required to complete the task, with shorter times indicating better performance.
Impairment cutoff: > 143.7 (based on the comparison group as a whole and expressed as raw score).
For all the cognitive tests impairment was defined as performance that was 1.33 SDs below the mean of a reference group of healthy peers. Raw scores indicating impaired performance could be > or < than the mean depending on the test (eg. on tests of accuracy the cut-off will be a score 1.33 SDs below the mean, while on a timed test the cut-off will be 1.33 SDs above the mean).
measure: 6 Month Cambridge Neuropsychological Test Automated Battery (CANTAB) PAL (Paired Associate Learning Task) - Impaired
time frame: 6 months
description: CANTAB is a computerized neuropsychological battery examining a range of domains including attention, memory and executive functioning. Using mainly nonverbal stimuli, the test is language- and culture-independent. For CANTAB PAL, the individual must remember 1 to 8 patterns displayed in different positions on the screen. The score is the number of incorrect responses adjusted if necessary for trials that have not been completed. Scores ranged from 0-194 with lower score indicating better performance.
Impairment cutoff: > 72.3 (based on the comparison group as a whole and expressed as raw score).
For all the cognitive tests impairment was defined as performance that was 1.33 SDs below the mean of a reference group of healthy peers. Raw scores indicating impaired performance could be > or < than the mean depending on the test (eg. on tests of accuracy the cut-off will be a score 1.33 SDs below the mean, while on a timed test the cut-off will be 1.33 SDs above the mean).
measure: 6 Month Cambridge Neuropsychological Test Automated Battery (CANTAB) RTI (Reaction Time Task) - Impaired
time frame: 6 months
description: The CANTAB is a computerized neuropsychological battery examining a range of domains including attention, memory and executive functioning. Using mainly nonverbal stimuli, the test is language- and culture-independent. For CANTAB RTI, the individual must respond as quickly as possible to a circle presented at one of 5 positions. The outcome measure is the median time for correct responses (ms).
Impairment cutoff: > 470.9 (based on the comparison group as a whole and expressed as raw score).
For all the cognitive tests impairment was defined as performance that was 1.33 SDs below the mean of a reference group of healthy peers. Raw scores indicating impaired performance could be > or < than the mean depending on the test (eg. on tests of accuracy the cut-off will be a score 1.33 SDs below the mean, while on a timed test the cut-off will be 1.33 SDs above the mean).
measure: 6 Month Cambridge Neuropsychological Test Automated Battery (CANTAB) SWM (Spatial Working Memory Task) - Impaired
time frame: 6 months
description: The CANTAB is a computerized neuropsychological battery examining a range of domains including attention, memory and executive functioning. Using mainly nonverbal stimuli, the test is language- and culture-independent. For the CANTAB SWM, the participant searches for tokens in boxes on the screen. The between errors measure is the number of times the participant queries a box that has already been searched. Errors ranged from 0 to 151, with lower numbers indicating better performance.
Impairment cutoff: > 52.0 (based on the comparison group as a whole and expressed as raw score).
For all the cognitive tests impairment was defined as performance that was 1.33 SDs below the mean of a reference group of healthy peers. Raw scores indicating impaired performance could be > or < than the mean depending on the test (eg. on tests of accuracy the cut-off will be a score 1.33 SDs below the mean, while on a timed test the cut-off will be 1.33 SDs above the mean).
measure: 6 Month Cambridge Neuropsychological Test Automated Battery (CANTAB) RVP (Rapid Visual Information Processing Task) - Impaired
time frame: 6 months
description: The CANTAB is a computerized neuropsychological battery examining a range of domains including attention, memory and executive functioning. Using mainly nonverbal stimuli, the test is language- and culture-independent. For the CANTAB RVP, sequences of numbers must be detected as they appear on the screen. The measure of accuracy is A' (A prime) which is derived from hits and correct rejections. The maximum score is 1 and, a higher A' indicates better performance.
Impairment cutoff: < 0.82 (based on the comparison group as a whole and expressed as raw score).
For all the cognitive tests impairment was defined as performance that was 1.33 SDs below the mean of a reference group of healthy peers. Raw scores indicating impaired performance could be > or < than the mean depending on the test (eg. on tests of accuracy the cut-off will be a score 1.33 SDs below the mean, while on a timed test the cut-off will be 1.33 SDs above the mean).
measure: 6 Month Cambridge Neuropsychological Test Automated Battery (CANTAB) SOC (Stockings of Cambridge Task) - Impaired
time frame: 6 months
description: The CANTAB is a computerized neuropsychological battery examining a range of domains including attention, memory and executive functioning. Using mainly nonverbal stimuli, the test is language- and culture-independent. For the CANTAB SOC, the individual moves circles to match a target in this task based on the Tower of Hanoi game. The score is the number of problems solved in the minimum number of moves, with a maximum of 12. Higher scores indicate better performance.
Impairment cutoff: < 5.7(based on the comparison group as a whole and expressed as raw score).
For all the cognitive tests impairment was defined as performance that was 1.33 SDs below the mean of a reference group of healthy peers. Raw scores indicating impaired performance could be > or < than the mean depending on the test (eg. on tests of accuracy the cut-off will be a score 1.33 SDs below the mean, while on a timed test the cut-off will be 1.33 SDs above the mean).
measure: 6 Month Cambridge Neuropsychological Test Automated Battery (CANTAB) AST (Attention Switching Task ) - Impaired
time frame: 6 months
description: The CANTAB is a computerized neuropsychological battery examining a range of domains including attention, memory and executive functioning. Using mainly nonverbal stimuli, the test is language- and culture-independent. For the CANTAB AST, participants respond either to the position of an arrow or the direction it is pointing, after being cued to the task on each trial. Total correct responses range from 0 to 160, where higher numbers indicate better performance.
Impairment cutoff: <135.5 (based on the comparison group as a whole and expressed as raw score).
For all the cognitive tests impairment was defined as performance that was 1.33 SDs below the mean of a reference group of healthy peers. Raw scores indicating impaired performance could be > or < than the mean depending on the test (eg. on tests of accuracy the cut-off will be a score 1.33 SDs below the mean, while on a timed test the cut-off will be 1.33 SDs above the mean).
measure: Early (2-3 Weeks) MRI Imaging - Traumatic Intracranial Abnormalities
time frame: Between 2-3 weeks after enrolment
description: A selected number of sites performed MRI follow up in a subset of patients that consented for imaging data collection. The CENTER-TBI MR protocols included a high-resolution 3D T1-weighted, a T2-weighted, a FLAIR, a DTI, a T2* sequence (gradient echo and/or SWI), and (optionally) a resting-state fMRI. Across all stratum the MRI sites performed a follow up MRI at 2-3 weeks after injury.
Traumatic Intracranial Abnormalities were assessed according to the TBI-Common Data Elements (CDEs). It indicates whether any of the 12 following imaging abnormalities are present (Mass lesion, Extra-axial Hematoma, Epidural Hematoma, Subdural Hematoma Acute, Subdural Hematoma Subacute Chronic, Subdural Collection Mixed Density, Contusion, TAI, traumatic Subarachnoid Hemorrhage, Intraventricular Hemorrhage, Midline Shift or Cisternal Compression.
whole blood samples
study pop: 
sampling method: Non-Probability Sample
criteria: 
gender: All
minimum age: N/A
maximum age: N/A
healthy volunteers: No
last name: Andrew Maas, MD, PhD
role: Study Chair
affiliation: Antwerp University Hospital / University of Antwerp, Edegem, Belgium
last name: David Menon, MD, PhD
role: Study Director
affiliation: University of Cambridge, Addenbrookes hospital, Cambridge, UK
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country: Austria
country: Belgium
country: Denmark
country: Finland
country: France
country: Germany
country: Hungary
country: Israel
country: Italy
country: Latvia
country: Lithuania
country: Netherlands
country: Norway
country: Romania
country: Serbia
country: Spain
country: Sweden
country: Switzerland
country: United Kingdom
url: https://www.center-tbi.eu/
description: CENTER - TBI website
responsible party type: Principal Investigator
investigator affiliation: University Hospital, Antwerp
investigator full name: Andrew Maas
investigator title: M.D., PhD, Project Coordinator CENTER-TBI
mesh term: Brain Injuries
mesh term: Brain Injuries, Traumatic
sharing ipd: Yes
provided document: 
participant flow: 
baseline: 
outcome list: 
reported events: 
certain agreements: 
point of contact: 