<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/NCT02982122</url>
  </required_header>
  <id_info>
    <org_study_id>COGITATE</org_study_id>
    <nct_id>NCT02982122</nct_id>
  </id_info>
  <brief_title>CPPopt Guided Therapy: Assessment of Target Effectiveness</brief_title>
  <acronym>COGITATE</acronym>
  <official_title>A Randomized Clinical Trial Assessing the Effect of &quot;Optimal&quot; Cerebral Perfusion Pressure Monitoring in the Management of Severe Traumatic Brain Injury</official_title>
  <sponsors>
    <lead_sponsor>
      <agency>Maastricht University Medical Center</agency>
      <agency_class>Other</agency_class>
    </lead_sponsor>
    <collaborator>
      <agency>European Society of Intensive Care Medicine</agency>
      <agency_class>Other</agency_class>
    </collaborator>
  </sponsors>
  <source>Maastricht University Medical Center</source>
  <oversight_info>
    <has_dmc>Yes</has_dmc>
    <is_fda_regulated_drug>No</is_fda_regulated_drug>
    <is_fda_regulated_device>No</is_fda_regulated_device>
  </oversight_info>
  <brief_summary>
    <textblock>
      Despite improvements in management, mortality in severe traumatic brain injury (TBI) remains&#xD;
      25% and only 40% of patients survive without major handicap. Medical/surgical interventions&#xD;
      aim to maintain adequate brain perfusion, which is critically dependent on cerebral perfusion&#xD;
      pressure (CPP); calculated as the difference between mean arterial pressure (MAP) and&#xD;
      intracranial pressure (ICP). Current guidelines aim for a CPP above 50 mmHg, based on&#xD;
      population means. However, this 'one size fits all' approach is flawed, because the relation&#xD;
      between CPP and brain perfusion varies between individuals. Further, this approach takes no&#xD;
      account of autoregulation, a key protective mechanism that maintains cerebral perfusion&#xD;
      despite CPP fluctuations.&#xD;
&#xD;
      Autoregulation is variably preserved following TBI, and there are large between patient&#xD;
      variances in the 'optimal' CPP (CPPopt) at which autoregulation operates best. Individual&#xD;
      CPPopt can be retrieved automatically by plotting autoregulation data against the CPP over a&#xD;
      certain time window. The investigators have shown that maintenance of CPP close to CPPopt is&#xD;
      associated with improved outcomes. These data pose the hypothesis that optimisation of&#xD;
      management in individuals may be achieved by using the zone of optimal autoregulation as a&#xD;
      basis for defining individualised CPP targets.&#xD;
&#xD;
      The investigators propose, together with collaborators in the CPPopt study group (Maastricht,&#xD;
      Cambridge, Leuven and Aachen) to set up a pilot (multicenter) feasibility study to develop a&#xD;
      protocol for a definitive outcome randomized controlled trial (RCT). This study aims to&#xD;
      develop protocols for CPPopt guided critical care, and show that they maintain patients&#xD;
      closer to their optimum perfusion levels than standard protocols which keep above a&#xD;
      population CPP threshold of 60 mmHg.&#xD;
&#xD;
      Hence, the main objective is to offer clinicians monitoring and therapy algorithms that&#xD;
      achieve individualized optimal CPPopt targets and potentially improve TBI outcome.&#xD;
    </textblock>
  </brief_summary>
  <overall_status>Completed</overall_status>
  <start_date type="Actual">March 1, 2018</start_date>
  <completion_date type="Actual">February 27, 2020</completion_date>
  <primary_completion_date type="Actual">February 27, 2020</primary_completion_date>
  <phase>N/A</phase>
  <study_type>Interventional</study_type>
  <has_expanded_access>No</has_expanded_access>
  <study_design_info>
    <allocation>Randomized</allocation>
    <intervention_model>Parallel Assignment</intervention_model>
    <primary_purpose>Treatment</primary_purpose>
    <masking>None (Open Label)</masking>
  </study_design_info>
  <primary_outcome>
    <measure>Percentage of monitoring time with measured CPP within 5 mmHg of calculated CPPopt</measure>
    <time_frame>First 5 days during intensive care unit admission</time_frame>
    <description>Main feasible endpoint: In pilot studies, we showed that, on average, patients spent a mean (+SD) of 30% ( 8%) of their monitored time with measured CPP within 5 mmHg of CPPopt. The study will be powered to target an increase in this metric to 50% of monitored time.</description>
  </primary_outcome>
  <secondary_outcome>
    <measure>Treatment Intensity Level (TIL) score</measure>
    <time_frame>First 5 days during intensive care unit admission</time_frame>
    <description>Main safety secondary endpoint: A change in daily TIL score of &gt; 3 is representative of a clinical significant escalation of TBI treatment from basic ICP management to second tier therapies known to carry risk of harm and therefore is expected to represent a clinically significant potentially harmful effect of CPPopt guided management.</description>
  </secondary_outcome>
  <number_of_arms>2</number_of_arms>
  <enrollment type="Actual">60</enrollment>
  <condition>Brain Injuries, Traumatic</condition>
  <condition>Cerebrovascular Circulation</condition>
  <condition>Homeostasis</condition>
  <arm_group>
    <arm_group_label>CPPopt intervention group</arm_group_label>
    <arm_group_type>Experimental</arm_group_type>
    <description>Patients are managed according to Brain Trauma Foundation guidelines, except for CPP where the CPPopt is targeted.</description>
  </arm_group>
  <arm_group>
    <arm_group_label>CPP control group</arm_group_label>
    <arm_group_type>Active Comparator</arm_group_type>
    <description>Patients are managed according to Brain Trauma Foundation guidelines with CPP between 60 and 70 mmHg.&#xD;
CPPopt information is recorded but hidden for the treating clinicians.</description>
  </arm_group>
  <intervention>
    <intervention_type>Other</intervention_type>
    <intervention_name>For both groups, CPP targets will be achieved first by ICP control if this is raised and then by ABP support by titration (up or down) of vasopressors and fluids according to local protocols.</intervention_name>
    <description>For both groups, CPP targets will be achieved first by ICP control if this is raised and then by ABP support by titration (up or down) of vasopressors and fluids according to local protocols.</description>
    <arm_group_label>CPP control group</arm_group_label>
    <arm_group_label>CPPopt intervention group</arm_group_label>
  </intervention>
  <eligibility>
    <criteria>
      <textblock>
        Inclusion Criteria:&#xD;
&#xD;
          -  Any adult severe TBI patient requiring multimodality monitoring and ICP-directed&#xD;
             therapy for at least 24 hrs on the assessment of the recruiting team.&#xD;
&#xD;
          -  Start randomization within 24 hrs after ICU admission.&#xD;
&#xD;
          -  Deferred informed consent or deferred proxy assent from relatives/legal representative&#xD;
             (consultee).&#xD;
&#xD;
          -  Exception for enrolling a patient past the 24 hour window: A patient who is admitted&#xD;
             to the hospital and later experiences neuro-worsening that is not due to a systemic&#xD;
             insult, (e.g. myocardial infarction, arrhythmia, pulmonary embolus, systemic&#xD;
             hemorrhage) but due to a presumptive intracranial cause, and subsequently requires an&#xD;
             ICP monitor, may be screened for enrolment. Consent, randomization, and monitor&#xD;
             placement must be done within 48 hours from injury in order for the patient to&#xD;
             qualify.&#xD;
&#xD;
        Exclusion Criteria:&#xD;
&#xD;
          -  Patients &lt; 18 years old.&#xD;
&#xD;
          -  Known pregnancy.&#xD;
&#xD;
          -  Moribund at presentation (e.g. bilaterally absent pupillary responses)&#xD;
&#xD;
          -  Patients with primary decompressive craniectomy.&#xD;
&#xD;
          -  Patients already enrolled in &gt; 1 other research studies.&#xD;
      </textblock>
    </criteria>
    <gender>All</gender>
    <minimum_age>18 Years</minimum_age>
    <maximum_age>N/A</maximum_age>
    <healthy_volunteers>No</healthy_volunteers>
  </eligibility>
  <overall_official>
    <last_name>Paul Roekaerts, professor</last_name>
    <role>Study Chair</role>
    <affiliation>Maastricht University Medical Center</affiliation>
  </overall_official>
  <location>
    <facility>
      <name>Academic Hospital Leuven</name>
      <address>
        <city>Leuven</city>
        <country>Belgium</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>The Addenbrooke's Hospital</name>
      <address>
        <city>Cambridge</city>
        <country>United Kingdom</country>
      </address>
    </facility>
  </location>
  <location_countries>
    <country>Belgium</country>
    <country>United Kingdom</country>
  </location_countries>
  <results_reference>
    <citation>Aries MJ, Wesselink R, Elting JW, Donnelly J, Czosnyka M, Ercole A, Maurits NM, Smielewski P. Enhanced Visualization of Optimal Cerebral Perfusion Pressure Over Time to Support Clinical Decision Making. Crit Care Med. 2016 Oct;44(10):e996-9. doi: 10.1097/CCM.0000000000001816.</citation>
    <PMID>27270178</PMID>
  </results_reference>
  <results_reference>
    <citation>Zuercher P, Groen JL, Aries MJ, Steyerberg EW, Maas AI, Ercole A, Menon DK. Reliability and Validity of the Therapy Intensity Level Scale: Analysis of Clinimetric Properties of a Novel Approach to Assess Management of Intracranial Pressure in Traumatic Brain Injury. J Neurotrauma. 2016 Oct 1;33(19):1768-1774. doi: 10.1089/neu.2015.4266. Epub 2016 Feb 11.</citation>
    <PMID>26866876</PMID>
  </results_reference>
  <results_reference>
    <citation>Donnelly J, Aries MJ, Czosnyka M. Further understanding of cerebral autoregulation at the bedside: possible implications for future therapy. Expert Rev Neurother. 2015 Feb;15(2):169-85. doi: 10.1586/14737175.2015.996552.</citation>
    <PMID>25614952</PMID>
  </results_reference>
  <results_reference>
    <citation>Aries MJ, Czosnyka M, Budohoski KP, Steiner LA, Lavinio A, Kolias AG, Hutchinson PJ, Brady KM, Menon DK, Pickard JD, Smielewski P. Continuous determination of optimal cerebral perfusion pressure in traumatic brain injury. Crit Care Med. 2012 Aug;40(8):2456-63. doi: 10.1097/CCM.0b013e3182514eb6.</citation>
    <PMID>22622398</PMID>
  </results_reference>
  <verification_date>September 2020</verification_date>
  <study_first_submitted>November 23, 2016</study_first_submitted>
  <study_first_submitted_qc>November 30, 2016</study_first_submitted_qc>
  <study_first_posted type="Estimate">December 5, 2016</study_first_posted>
  <last_update_submitted>September 29, 2020</last_update_submitted>
  <last_update_submitted_qc>September 29, 2020</last_update_submitted_qc>
  <last_update_posted type="Actual">September 30, 2020</last_update_posted>
  <responsible_party>
    <responsible_party_type>Sponsor</responsible_party_type>
  </responsible_party>
  <condition_browse>
    <!-- CAUTION:  The following MeSH terms are assigned with an imperfect algorithm            -->
    <mesh_term>Brain Injuries</mesh_term>
    <mesh_term>Brain Injuries, Traumatic</mesh_term>
  </condition_browse>
  <intervention_browse>
    <!-- CAUTION:  The following MeSH terms are assigned with an imperfect algorithm            -->
    <mesh_term>Vasoconstrictor Agents</mesh_term>
  </intervention_browse>
  <!-- Results have not yet been posted for this study                                          -->
</clinical_study>


download date: ClinicalTrials.gov processed this data on September 20, 2023
link text: Link to the current ClinicalTrials.gov record.
url: https://clinicaltrials.gov/ct2/show/NCT02982122
org study id: COGITATE
nct id: NCT02982122
lead sponsor: 
collaborator: 
has dmc: Yes
is fda regulated drug: No
is fda regulated device: No
Despite improvements in management, mortality in severe traumatic brain injury (TBI) remains
      25% and only 40% of patients survive without major handicap. Medical/surgical interventions
      aim to maintain adequate brain perfusion, which is critically dependent on cerebral perfusion
      pressure (CPP); calculated as the difference between mean arterial pressure (MAP) and
      intracranial pressure (ICP). Current guidelines aim for a CPP above 50 mmHg, based on
      population means. However, this 'one size fits all' approach is flawed, because the relation
      between CPP and brain perfusion varies between individuals. Further, this approach takes no
      account of autoregulation, a key protective mechanism that maintains cerebral perfusion
      despite CPP fluctuations.

      Autoregulation is variably preserved following TBI, and there are large between patient
      variances in the 'optimal' CPP (CPPopt) at which autoregulation operates best. Individual
      CPPopt can be retrieved automatically by plotting autoregulation data against the CPP over a
      certain time window. The investigators have shown that maintenance of CPP close to CPPopt is
      associated with improved outcomes. These data pose the hypothesis that optimisation of
      management in individuals may be achieved by using the zone of optimal autoregulation as a
      basis for defining individualised CPP targets.

      The investigators propose, together with collaborators in the CPPopt study group (Maastricht,
      Cambridge, Leuven and Aachen) to set up a pilot (multicenter) feasibility study to develop a
      protocol for a definitive outcome randomized controlled trial (RCT). This study aims to
      develop protocols for CPPopt guided critical care, and show that they maintain patients
      closer to their optimum perfusion levels than standard protocols which keep above a
      population CPP threshold of 60 mmHg.

      Hence, the main objective is to offer clinicians monitoring and therapy algorithms that
      achieve individualized optimal CPPopt targets and potentially improve TBI outcome.
allocation: Randomized
intervention model: Parallel Assignment
primary purpose: Treatment
masking: None (Open Label)
measure: Percentage of monitoring time with measured CPP within 5 mmHg of calculated CPPopt
time frame: First 5 days during intensive care unit admission
description: Main feasible endpoint: In pilot studies, we showed that, on average, patients spent a mean (+SD) of 30% ( 8%) of their monitored time with measured CPP within 5 mmHg of CPPopt. The study will be powered to target an increase in this metric to 50% of monitored time.
measure: Treatment Intensity Level (TIL) score
time frame: First 5 days during intensive care unit admission
description: Main safety secondary endpoint: A change in daily TIL score of > 3 is representative of a clinical significant escalation of TBI treatment from basic ICP management to second tier therapies known to carry risk of harm and therefore is expected to represent a clinically significant potentially harmful effect of CPPopt guided management.
arm group label: CPPopt intervention group
arm group type: Experimental
description: Patients are managed according to Brain Trauma Foundation guidelines, except for CPP where the CPPopt is targeted.
arm group label: CPP control group
arm group type: Active Comparator
description: Patients are managed according to Brain Trauma Foundation guidelines with CPP between 60 and 70 mmHg.
CPPopt information is recorded but hidden for the treating clinicians.
intervention type: Other
intervention name: For both groups, CPP targets will be achieved first by ICP control if this is raised and then by ABP support by titration (up or down) of vasopressors and fluids according to local protocols.
description: For both groups, CPP targets will be achieved first by ICP control if this is raised and then by ABP support by titration (up or down) of vasopressors and fluids according to local protocols.
arm group label: CPP control group
arm group label: CPPopt intervention group
criteria: 
gender: All
minimum age: 18 Years
maximum age: N/A
healthy volunteers: No
last name: Paul Roekaerts, professor
role: Study Chair
affiliation: Maastricht University Medical Center
facility: 
facility: 
country: Belgium
country: United Kingdom
citation: Aries MJ, Wesselink R, Elting JW, Donnelly J, Czosnyka M, Ercole A, Maurits NM, Smielewski P. Enhanced Visualization of Optimal Cerebral Perfusion Pressure Over Time to Support Clinical Decision Making. Crit Care Med. 2016 Oct;44(10):e996-9. doi: 10.1097/CCM.0000000000001816.
PMID: 27270178
citation: Zuercher P, Groen JL, Aries MJ, Steyerberg EW, Maas AI, Ercole A, Menon DK. Reliability and Validity of the Therapy Intensity Level Scale: Analysis of Clinimetric Properties of a Novel Approach to Assess Management of Intracranial Pressure in Traumatic Brain Injury. J Neurotrauma. 2016 Oct 1;33(19):1768-1774. doi: 10.1089/neu.2015.4266. Epub 2016 Feb 11.
PMID: 26866876
citation: Donnelly J, Aries MJ, Czosnyka M. Further understanding of cerebral autoregulation at the bedside: possible implications for future therapy. Expert Rev Neurother. 2015 Feb;15(2):169-85. doi: 10.1586/14737175.2015.996552.
PMID: 25614952
citation: Aries MJ, Czosnyka M, Budohoski KP, Steiner LA, Lavinio A, Kolias AG, Hutchinson PJ, Brady KM, Menon DK, Pickard JD, Smielewski P. Continuous determination of optimal cerebral perfusion pressure in traumatic brain injury. Crit Care Med. 2012 Aug;40(8):2456-63. doi: 10.1097/CCM.0b013e3182514eb6.
PMID: 22622398
responsible party type: Sponsor
mesh term: Brain Injuries
mesh term: Brain Injuries, Traumatic
mesh term: Vasoconstrictor Agents