<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/NCT01690819</url>
  </required_header>
  <id_info>
    <org_study_id>PROLABI</org_study_id>
    <nct_id>NCT01690819</nct_id>
  </id_info>
  <brief_title>Protective Ventilatory Strategy in Severe Acute Brain Injury</brief_title>
  <acronym>PROLABI</acronym>
  <official_title>Protective Ventilatory Strategy in Severe Acute Brain Injury: Randomized Multi-center Controlled Trial</official_title>
  <sponsors>
    <lead_sponsor>
      <agency>University of Turin, Italy</agency>
      <agency_class>Other</agency_class>
    </lead_sponsor>
  </sponsors>
  <source>University of Turin, Italy</source>
  <oversight_info>
    <has_dmc>Yes</has_dmc>
  </oversight_info>
  <brief_summary>
    <textblock>
      Acute respiratory distress syndrome (ARDS) occurs in almost 20% of patients with severe acute&#xD;
      brain injury and is associated with increased morbidity and mortality. A massive increase in&#xD;
      sympathetic activity and an increased production of proinflammatory cytokines released into&#xD;
      the systemic circulation are the most important recognized mechanisms. Altered blood brain&#xD;
      barrier after injury causes spillover of inflammatory mediators from the brain into the&#xD;
      systemic circulation leading to peripheral organs damage. The adrenergic surge induces an&#xD;
      increase in vascular hydrostatic pressure and lung capillary permeability, causing an&#xD;
      alteration of alveolar capillary barrier with fluid accumulation, resulting in ARDS.&#xD;
&#xD;
      The main goal of mechanical ventilation after acute brain injury are the maintenance of&#xD;
      optimal oxygenation, and a tight control of carbon dioxide tension, although ventilatory&#xD;
      settings to be used to obtain these targets, while avoiding secondary insults to the brain,&#xD;
      are not clearly identified.&#xD;
&#xD;
      Protective ventilatory strategy has been positively evaluated first in patients with ARDS,&#xD;
      and then in those undergoing cardiopulmonary bypass or lung resection surgery, or in brain&#xD;
      death organ donors, but data on the effect of protective mechanical ventilation on patients&#xD;
      with acute brain injury are still lacking even if this is a population with recognized risk&#xD;
      factors for ARDS.&#xD;
&#xD;
      Therefore, the primary aim of this multi-center, prospective, randomized, controlled trial is&#xD;
      to investigate whether a protective ventilatory strategy, in the early phase after severe&#xD;
      acute brain injury, is associated with a lower incidence of ARDS, avoiding any further damage&#xD;
      to the brain. Secondary aim is to evaluate if a protective ventilatory strategy is associated&#xD;
      with reduced duration of mechanical ventilation, incidence of organ failure, intensive care&#xD;
      unit length of stay, and lower concentrations of plasma inflammatory cytokines, without&#xD;
      adversely affect in neurological outcome.&#xD;
    </textblock>
  </brief_summary>
  <detailed_description>
    <textblock>
      BACKGROUND Acute respiratory distress syndrome (ARDS) is described as the most common&#xD;
      non-neurologic organ dysfunction occurring in the early phase after severe acute brain&#xD;
      injury, with a reported incidence of 10-15% and increased morbidity and mortality.&#xD;
&#xD;
      A significant role has been recently proposed for neuro-inflammation in the genesis of ARDS&#xD;
      following acute brain injury. The neuro-inflammatory response represents initially a&#xD;
      coordinated effort to protect the brain after injury, but may then become altered and be&#xD;
      responsible for the activation of the secondary injury cascade leading to single or multiple&#xD;
      organ dysfunction. This preclinical event may increase the susceptibility of lungs to the&#xD;
      stress of injurious mechanical ventilation. The main targets of ventilatory management of&#xD;
      acute brain injury patients are maintenance of an optimal oxygenation, and a tight arterial&#xD;
      carbon dioxide control. Actual Guidelines for the management of severe traumatic brain&#xD;
      injury, in particular, state that hypoxia (PaO2 &lt;60 mmHg or SaO2 &lt; 90%) should be avoided and&#xD;
      PaCO2 level tightly controlled with a target of 35-38 mmHg. However, no published&#xD;
      recommendation exists on which ventilator setting, in terms of tidal volume, respiratory&#xD;
      rate, and positive end-expiratory pressure (PEEP) levels, should be used to obtain these&#xD;
      respiratory targets. In previous studies on patients with ARDS, mechanical ventilation with a&#xD;
      low tidal volume and moderate PEEP levels resulted in decreased mortality and increased&#xD;
      number of ventilatory free days, and it now represents the standard of care for these&#xD;
      patients.&#xD;
&#xD;
      Patients with acute brain injury represent a category at risk to develop ARDS both because of&#xD;
      the adrenergic cascade and the inflammatory reaction, and because of the ventilatory strategy&#xD;
      implemented to optimize gas exchange. Nevertheless, no clinical trial has been performed to&#xD;
      evaluate the effect of protective ventilatory strategies upon severe acute brain injury&#xD;
      patients.&#xD;
&#xD;
      AIMS The aim of this study is to investigate whether the application of a protective&#xD;
      ventilatory strategy, defined as low tidal volume and moderate levels of PEEP, improves the&#xD;
      combined end point of &quot;event free survival&quot; defined as survival without ventilator dependency&#xD;
      or ARDS diagnosis, without adversely affecting neurological outcome.&#xD;
&#xD;
      Secondary aim of this study is to evaluate if protective ventilatory strategy may increase&#xD;
      number of ventilator and organ failure free days, reduce intensive care unit (ICU) length of&#xD;
      stay, reduce the incidence of ventilator associated pneumonia (VAP), reduce concentrations of&#xD;
      plasma inflammatory cytokines (IL-6, TNF-alpha, TNF-RI/II, IL-8, IL-1ra, IL-1beta), without&#xD;
      adversely affecting neurological outcome as measured by the Modified Oxford Handicap scale at&#xD;
      intensive care unit discharge and the Glasgow Outcome Scale-extended (GOSe) at 6 months.&#xD;
    </textblock>
  </detailed_description>
  <overall_status>Unknown status</overall_status>
  <last_known_status>Active, not recruiting</last_known_status>
  <start_date>October 2013</start_date>
  <completion_date type="Anticipated">December 2021</completion_date>
  <primary_completion_date type="Actual">December 2018</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>Proportion of event free survival</measure>
    <time_frame>28 days</time_frame>
    <description>Combined end point of &quot;event free survival&quot; defined as survival without ventilator dependency or ARDS* diagnosis&#xD;
*ARDS will be defined according to Berlin definition criteria. If chest x-ray is not immediately available, ARDS diagnosis will be suspected and confirmed later on.&#xD;
Interpretation of bilateral infiltrates on chest x-ray and of heart failure vs. fluid overload was variable and in a large observational study (LUNGSAFE, JAMA. 2016 Feb 23;315:788-800) hypoxemic patients with new infiltrates were described as a well-defined group with outcome, risk factors, comorbidities and clinical management similar to ARDS. Therefore, in March 2016 the study protocol replaced &quot;ARDS&quot; with &quot;acute hypoxemic respiratory failure&quot; as one of the components of the composite primary endpoint. Acute hypoxemic respiratory failure was defined as PaO2/FiO2 ratio &lt; 300, with presence of infiltrates on chest x-ray, independently of lung opacities distribution and characteristics.</description>
  </primary_outcome>
  <secondary_outcome>
    <measure>Number of ventilator free days at 28 days</measure>
    <time_frame>28 days</time_frame>
  </secondary_outcome>
  <secondary_outcome>
    <measure>number of ICU free days at day 28 after randomization</measure>
    <time_frame>participants will be followed for the duration of ICU stay, an expected average of 3 weeks</time_frame>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Incidence of ventilator associated pneumonia (VAP)</measure>
    <time_frame>28 days</time_frame>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Cumulative SOFA free score from the randomization to day 28</measure>
    <time_frame>28 days</time_frame>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Concentrations of plasma inflammatory cytokines</measure>
    <time_frame>7 days</time_frame>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Modify Oxford Handicap Scale at ICU discharge</measure>
    <time_frame>participants will be followed for the duration of ICU stay, an expected average of 3 weeks</time_frame>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Glasgow Outcome Scale extended (GOSe) at 6 months</measure>
    <time_frame>at 6 months</time_frame>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Mortality at day 28 after randomization</measure>
    <time_frame>28 days</time_frame>
  </secondary_outcome>
  <secondary_outcome>
    <measure>LOS in ICU</measure>
    <time_frame>20 days (average time)</time_frame>
    <description>length of stay in intensive care unit</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Hospital length of stay (HLOS)</measure>
    <time_frame>30 days (average time)</time_frame>
    <description>length of stay in hospital</description>
  </secondary_outcome>
  <number_of_arms>2</number_of_arms>
  <enrollment type="Anticipated">524</enrollment>
  <condition>Injuries, Acute Brain</condition>
  <arm_group>
    <arm_group_label>Conventional Ventilatory Strategy</arm_group_label>
    <arm_group_type>Active Comparator</arm_group_type>
    <description>Conventional Ventilatory Strategy</description>
  </arm_group>
  <arm_group>
    <arm_group_label>Protective Ventilatory Strategy</arm_group_label>
    <arm_group_type>Experimental</arm_group_type>
    <description>Protective ventilatory strategy</description>
  </arm_group>
  <intervention>
    <intervention_type>Procedure</intervention_type>
    <intervention_name>Conventional Ventilatory Strategy</intervention_name>
    <description>The conventional strategy will be the standard of care with a lower limit of tidal volume equal to 8 ml/Kg of predicted body weight and with a PEEP of 4 cmH2O</description>
    <arm_group_label>Conventional Ventilatory Strategy</arm_group_label>
  </intervention>
  <intervention>
    <intervention_type>Procedure</intervention_type>
    <intervention_name>Protective Ventilatory Strategy</intervention_name>
    <description>The protective strategy will consist of a tidal volume of 6 ml/Kg of predicted body weight, with a PEEP of 8 cmH2O</description>
    <arm_group_label>Protective Ventilatory Strategy</arm_group_label>
  </intervention>
  <eligibility>
    <criteria>
      <textblock>
        Inclusion Criteria:&#xD;
&#xD;
          -  Patients with severe acute brain injury (traumatic brain injury, subarachnoid&#xD;
             haemorrhage, intra-cerebral haemorrhage, and ischemic stroke)&#xD;
&#xD;
          -  Patients with not obey commands and do not open eyes on GCS (Glasgow Coma Scale)&#xD;
&#xD;
          -  Less than 24 hours of mechanical ventilation (expected &gt;72 hours)&#xD;
&#xD;
        Exclusion Criteria:&#xD;
&#xD;
          -  Age &lt; 18 years&#xD;
&#xD;
          -  Diagnosis of ARDS before randomization.&#xD;
&#xD;
          -  Patients unlikely to survive for the next 24 hours in the opinion of ICU consultant.&#xD;
&#xD;
          -  Pregnancy&#xD;
&#xD;
          -  Post-anoxic coma&#xD;
&#xD;
          -  Metabolic or toxic encephalopathy&#xD;
&#xD;
          -  Lack of Informed Consent.&#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>Luciana Mascia, MD, PhD</last_name>
    <role>Principal Investigator</role>
    <affiliation>University of Turin, Italy</affiliation>
  </overall_official>
  <location>
    <facility>
      <name>University of Turin - Department of Anesthesia and Intensive care Medicine</name>
      <address>
        <city>Turin</city>
        <zip>10126</zip>
        <country>Italy</country>
      </address>
    </facility>
  </location>
  <location_countries>
    <country>Italy</country>
  </location_countries>
  <link>
    <url>http://prolabi.ddmc.unito.it</url>
    <description>Related Info</description>
  </link>
  <verification_date>April 2021</verification_date>
  <study_first_submitted>September 12, 2012</study_first_submitted>
  <study_first_submitted_qc>September 18, 2012</study_first_submitted_qc>
  <study_first_posted type="Estimate">September 24, 2012</study_first_posted>
  <last_update_submitted>April 22, 2021</last_update_submitted>
  <last_update_submitted_qc>April 22, 2021</last_update_submitted_qc>
  <last_update_posted type="Actual">April 26, 2021</last_update_posted>
  <responsible_party>
    <responsible_party_type>Principal Investigator</responsible_party_type>
    <investigator_affiliation>University of Turin, Italy</investigator_affiliation>
    <investigator_full_name>Luciana Mascia</investigator_full_name>
    <investigator_title>MD, PhD</investigator_title>
  </responsible_party>
  <keyword>Acute Respiratory Distress Syndrome</keyword>
  <keyword>Acute Brain Injury</keyword>
  <condition_browse>
    <!-- CAUTION:  The following MeSH terms are assigned with an imperfect algorithm            -->
    <mesh_term>Brain Injuries</mesh_term>
    <mesh_term>Wounds and Injuries</mesh_term>
  </condition_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/NCT01690819
org study id: PROLABI
nct id: NCT01690819
lead sponsor: 
has dmc: Yes
Acute respiratory distress syndrome (ARDS) occurs in almost 20% of patients with severe acute
      brain injury and is associated with increased morbidity and mortality. A massive increase in
      sympathetic activity and an increased production of proinflammatory cytokines released into
      the systemic circulation are the most important recognized mechanisms. Altered blood brain
      barrier after injury causes spillover of inflammatory mediators from the brain into the
      systemic circulation leading to peripheral organs damage. The adrenergic surge induces an
      increase in vascular hydrostatic pressure and lung capillary permeability, causing an
      alteration of alveolar capillary barrier with fluid accumulation, resulting in ARDS.

      The main goal of mechanical ventilation after acute brain injury are the maintenance of
      optimal oxygenation, and a tight control of carbon dioxide tension, although ventilatory
      settings to be used to obtain these targets, while avoiding secondary insults to the brain,
      are not clearly identified.

      Protective ventilatory strategy has been positively evaluated first in patients with ARDS,
      and then in those undergoing cardiopulmonary bypass or lung resection surgery, or in brain
      death organ donors, but data on the effect of protective mechanical ventilation on patients
      with acute brain injury are still lacking even if this is a population with recognized risk
      factors for ARDS.

      Therefore, the primary aim of this multi-center, prospective, randomized, controlled trial is
      to investigate whether a protective ventilatory strategy, in the early phase after severe
      acute brain injury, is associated with a lower incidence of ARDS, avoiding any further damage
      to the brain. Secondary aim is to evaluate if a protective ventilatory strategy is associated
      with reduced duration of mechanical ventilation, incidence of organ failure, intensive care
      unit length of stay, and lower concentrations of plasma inflammatory cytokines, without
      adversely affect in neurological outcome.
BACKGROUND Acute respiratory distress syndrome (ARDS) is described as the most common
      non-neurologic organ dysfunction occurring in the early phase after severe acute brain
      injury, with a reported incidence of 10-15% and increased morbidity and mortality.

      A significant role has been recently proposed for neuro-inflammation in the genesis of ARDS
      following acute brain injury. The neuro-inflammatory response represents initially a
      coordinated effort to protect the brain after injury, but may then become altered and be
      responsible for the activation of the secondary injury cascade leading to single or multiple
      organ dysfunction. This preclinical event may increase the susceptibility of lungs to the
      stress of injurious mechanical ventilation. The main targets of ventilatory management of
      acute brain injury patients are maintenance of an optimal oxygenation, and a tight arterial
      carbon dioxide control. Actual Guidelines for the management of severe traumatic brain
      injury, in particular, state that hypoxia (PaO2 <60 mmHg or SaO2 < 90%) should be avoided and
      PaCO2 level tightly controlled with a target of 35-38 mmHg. However, no published
      recommendation exists on which ventilator setting, in terms of tidal volume, respiratory
      rate, and positive end-expiratory pressure (PEEP) levels, should be used to obtain these
      respiratory targets. In previous studies on patients with ARDS, mechanical ventilation with a
      low tidal volume and moderate PEEP levels resulted in decreased mortality and increased
      number of ventilatory free days, and it now represents the standard of care for these
      patients.

      Patients with acute brain injury represent a category at risk to develop ARDS both because of
      the adrenergic cascade and the inflammatory reaction, and because of the ventilatory strategy
      implemented to optimize gas exchange. Nevertheless, no clinical trial has been performed to
      evaluate the effect of protective ventilatory strategies upon severe acute brain injury
      patients.

      AIMS The aim of this study is to investigate whether the application of a protective
      ventilatory strategy, defined as low tidal volume and moderate levels of PEEP, improves the
      combined end point of "event free survival" defined as survival without ventilator dependency
      or ARDS diagnosis, without adversely affecting neurological outcome.

      Secondary aim of this study is to evaluate if protective ventilatory strategy may increase
      number of ventilator and organ failure free days, reduce intensive care unit (ICU) length of
      stay, reduce the incidence of ventilator associated pneumonia (VAP), reduce concentrations of
      plasma inflammatory cytokines (IL-6, TNF-alpha, TNF-RI/II, IL-8, IL-1ra, IL-1beta), without
      adversely affecting neurological outcome as measured by the Modified Oxford Handicap scale at
      intensive care unit discharge and the Glasgow Outcome Scale-extended (GOSe) at 6 months.
allocation: Randomized
intervention model: Parallel Assignment
primary purpose: Treatment
masking: None (Open Label)
measure: Proportion of event free survival
time frame: 28 days
description: Combined end point of "event free survival" defined as survival without ventilator dependency or ARDS* diagnosis
*ARDS will be defined according to Berlin definition criteria. If chest x-ray is not immediately available, ARDS diagnosis will be suspected and confirmed later on.
Interpretation of bilateral infiltrates on chest x-ray and of heart failure vs. fluid overload was variable and in a large observational study (LUNGSAFE, JAMA. 2016 Feb 23;315:788-800) hypoxemic patients with new infiltrates were described as a well-defined group with outcome, risk factors, comorbidities and clinical management similar to ARDS. Therefore, in March 2016 the study protocol replaced "ARDS" with "acute hypoxemic respiratory failure" as one of the components of the composite primary endpoint. Acute hypoxemic respiratory failure was defined as PaO2/FiO2 ratio < 300, with presence of infiltrates on chest x-ray, independently of lung opacities distribution and characteristics.
measure: Number of ventilator free days at 28 days
time frame: 28 days
measure: number of ICU free days at day 28 after randomization
time frame: participants will be followed for the duration of ICU stay, an expected average of 3 weeks
measure: Incidence of ventilator associated pneumonia (VAP)
time frame: 28 days
measure: Cumulative SOFA free score from the randomization to day 28
time frame: 28 days
measure: Concentrations of plasma inflammatory cytokines
time frame: 7 days
measure: Modify Oxford Handicap Scale at ICU discharge
time frame: participants will be followed for the duration of ICU stay, an expected average of 3 weeks
measure: Glasgow Outcome Scale extended (GOSe) at 6 months
time frame: at 6 months
measure: Mortality at day 28 after randomization
time frame: 28 days
measure: LOS in ICU
time frame: 20 days (average time)
description: length of stay in intensive care unit
measure: Hospital length of stay (HLOS)
time frame: 30 days (average time)
description: length of stay in hospital
arm group label: Conventional Ventilatory Strategy
arm group type: Active Comparator
description: Conventional Ventilatory Strategy
arm group label: Protective Ventilatory Strategy
arm group type: Experimental
description: Protective ventilatory strategy
intervention type: Procedure
intervention name: Conventional Ventilatory Strategy
description: The conventional strategy will be the standard of care with a lower limit of tidal volume equal to 8 ml/Kg of predicted body weight and with a PEEP of 4 cmH2O
arm group label: Conventional Ventilatory Strategy
intervention type: Procedure
intervention name: Protective Ventilatory Strategy
description: The protective strategy will consist of a tidal volume of 6 ml/Kg of predicted body weight, with a PEEP of 8 cmH2O
arm group label: Protective Ventilatory Strategy
criteria: 
gender: All
minimum age: 18 Years
maximum age: N/A
healthy volunteers: No
last name: Luciana Mascia, MD, PhD
role: Principal Investigator
affiliation: University of Turin, Italy
facility: 
country: Italy
url: http://prolabi.ddmc.unito.it
description: Related Info
responsible party type: Principal Investigator
investigator affiliation: University of Turin, Italy
investigator full name: Luciana Mascia
investigator title: MD, PhD
mesh term: Brain Injuries
mesh term: Wounds and Injuries