<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/NCT03266016</url>
  </required_header>
  <id_info>
    <org_study_id>CHLA-17-00235</org_study_id>
    <secondary_id>5R01HL134666</secondary_id>
    <nct_id>NCT03266016</nct_id>
  </id_info>
  <brief_title>Real-time Effort Driven VENTilator Management</brief_title>
  <acronym>REDvent</acronym>
  <official_title>Identifying and Preventing Ventilator Induced Diaphragm Dysfunction in Children</official_title>
  <sponsors>
    <lead_sponsor>
      <agency>Children's Hospital Los Angeles</agency>
      <agency_class>Other</agency_class>
    </lead_sponsor>
    <collaborator>
      <agency>National Heart, Lung, and Blood Institute (NHLBI)</agency>
      <agency_class>NIH</agency_class>
    </collaborator>
    <collaborator>
      <agency>Children's Hospital of Philadelphia</agency>
      <agency_class>Other</agency_class>
    </collaborator>
  </sponsors>
  <source>Children's Hospital Los Angeles</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>
      This study is a Phase II controlled clinical trial that will obtain comprehensive, serial&#xD;
      assessments of respiratory muscle strength and architecture to understand the evolution of&#xD;
      ventilator-induced respiratory muscle weakness in critically ill children, and test whether a&#xD;
      novel computer-based approach (Real-time Effort Driven ventilator management (REDvent)) can&#xD;
      preserve respiratory muscle strength and reduce time on MV. REDvent offers systematic&#xD;
      recommendations to reduce controlled ventilation during the acute phase of MV, and uses&#xD;
      real-time measures from esophageal manometry to adjust supported ventilator pressures such&#xD;
      that patient effort of breathing remains in a normal range during the ventilator weaning&#xD;
      phase. This phase II clinical trial is expected to enroll 276 children with pulmonary&#xD;
      parenchymal disease, anticipated to be ventilated &gt; 48 hrs. Patients will be randomized to&#xD;
      REDvent-acute vs. usual care for the acute phase of MV (interval from intubation to first&#xD;
      spontaneous breathing trial (SBT)). Patients in either group who fail their first Spontaneous&#xD;
      Breathing Trial (SBT), will also be randomized to REDvent-weaning vs. usual care for the&#xD;
      weaning phase of MV (interval from first SBT to passing SBT). The primary clinical outcome is&#xD;
      length of weaning (time from first SBT until successful passage of an SBT or extubation&#xD;
      (whichever comes first)). Mechanistic outcomes surround multi-modal serial measures of&#xD;
      respiratory muscle capacity (PiMax), load (resistance, compliance), effort (esophageal&#xD;
      manometry), and architecture (ultrasound) throughout the course of MV. Upon completion, this&#xD;
      study will provide important information on the pathogenesis and timing of respiratory muscle&#xD;
      weakness during MV in children and whether this weakness can be mitigated by promoting more&#xD;
      normal patient effort during MV via the use of REDvent. This will form the basis for a&#xD;
      larger, Phase III multi-center study, powered for key clinical outcomes such as 28-day&#xD;
      Ventilator Free Days.&#xD;
    </textblock>
  </brief_summary>
  <detailed_description>
    <textblock>
      Study Aims:&#xD;
&#xD;
      SA1: To determine if REDvent acute and/or weaning phase protocols can shorten the duration of&#xD;
      weaning from MV (Primary outcome).&#xD;
&#xD;
      SA2: To determine if changes to direct measures of respiratory muscle strength, load, effort,&#xD;
      and architecture throughout the duration of MV are related to weaning outcomes.&#xD;
&#xD;
      SA3: To determine if patient effort of breathing during both acute and weaning phases of MV&#xD;
      is independently associated with the development of respiratory muscle weakness.&#xD;
&#xD;
      Study Design: Single-center randomized controlled trial (138 children per arm) using REDvent&#xD;
      (intervention arm) as compared with usual care ventilator management including a standardized&#xD;
      daily SBT (control arm). Acute phase randomization will occur upon study enrollment, and&#xD;
      patients who fail the first SBT will undergo a weaning phase randomization. The investigators&#xD;
      will obtain serial measurements of respiratory system capacity, load, effort of breathing,&#xD;
      and diaphragm architecture throughout the course of MV.&#xD;
&#xD;
      Acute Phase: The acute phase is defined as the time from intubation until the patient meets&#xD;
      weaning criteria, passes the initial oxygenation test (decrease PEEP to 5 cmH2O and FiO2 to&#xD;
      0.5, maintains SpO2 &gt; 90%), and undergoes a Spontaneous Breathing Trial (SBT).&#xD;
&#xD;
        1. Intervention Arm (REDvent-acute): Patients will be managed with pressure control plus&#xD;
           pressure support ventilation using a computerized decision support tool that will&#xD;
           recommend changes to ventilator settings approximately every 4 hr (with or without a new&#xD;
           blood gas). If the patient is spontaneously breathing, it will incorporate real-time&#xD;
           measures of effort of breathing (esophageal manometry) to keep it in a target range.&#xD;
&#xD;
        2. Control Arm (Control-acute): Ventilator management will be per usual care until the&#xD;
           patient meets weaning criteria and passes the oxygenation test.&#xD;
&#xD;
      Weaning Phase: The weaning phase is defined as the time from the first Spontaneous Breathing&#xD;
      Trial (SBT) until the patient successfully passes an SBT or is extubated (whichever comes&#xD;
      first). Patients who pass the initial SBT at the end of the acute phase will not undergo&#xD;
      weaning phase randomization.&#xD;
&#xD;
        1. Intervention Arm (REDvent-weaning): Patients will be managed in a pressure support/CPAP&#xD;
           mode of ventilation with assessments or changes to the level of pressure support every 4&#xD;
           hours, targeting maintaining effort of breathing (esophageal manometry) in a normal&#xD;
           range. An SBT will be conducted daily, and the weaning phase will continue until the&#xD;
           patient passes the SBT.&#xD;
&#xD;
        2. Control Arm (Control-weaning): Ventilator management will be per usual care. An SBT will&#xD;
           be conducted daily, and the weaning phase will continue until the patient passes the&#xD;
           SBT.&#xD;
&#xD;
      Analysis Plan and Sample Size Justification:&#xD;
&#xD;
      Aim 1: The primary outcome is weaning duration. Sample size has been determined to adequately&#xD;
      power 3 separate comparative analyses: (a) REDvent-acute versus Acute Phase control (b)&#xD;
      REDvent-weaning phase versus Weaning Phase control (c) REDvent both phases versus control&#xD;
      both phases. Power is based on 2 planned methods for analysis: cox proportional hazard ratios&#xD;
      for multivariable analysis and univariate analysis with an independent t-test using log&#xD;
      transformation (as needed) to account for the expected distribution of weaning duration. For&#xD;
      all three of the planned comparisons above, with the proposed sample size the investigators&#xD;
      would be adequately powered (&gt;0.8) to detect a difference in weaning duration of ≥ 1 day, or&#xD;
      a hazard ratio of ≥ 1.4 between groups. The secondary outcomes are ventilator free days and&#xD;
      extubation failure. Directly comparing control only patients to REDvent only patients, with&#xD;
      an expected standard deviation for VFDs between 5 to 9 days, the investigators will be able&#xD;
      to detect a 2-day change in VFDs between groups with a power between 0.35 and 0.82.&#xD;
      Re-intubation rates are expected to be 10%, allowing the investigators to confirm that&#xD;
      REDvent is not inferior to usual care in regards to re-intubation with a non-inferiority&#xD;
      margin of 0.10 with a power of 0.8 and alpha of 0.05.&#xD;
&#xD;
      Aim 2: The primary outcome of this aim is weaning duration. For respiratory muscle strength&#xD;
      the investigators will compare the first measured aPiMax (after resolution of the acute&#xD;
      phase, before the first SBT), the trajectory and value of the daily aPiMax during the weaning&#xD;
      phase prior to extubation, the lowest and highest measured aPiMax, and aPiMax on the day of&#xD;
      extubation against weaning duration. For analysis, aPiMax will be dichotomized at 30 cmH2O,&#xD;
      and weaning duration will be compared between patients with aPiMax &gt; 30 versus ≤ 30 cmH2O&#xD;
      using a t-test with or without log-transformation, or Mann-Whitney U test, depending on the&#xD;
      distribution. From preliminary data, it is anticipated at least 35% of patients (n=84) will&#xD;
      have aPiMax ≤ 30 cmH2O. Based on a similar power analysis as presented above, this would&#xD;
      allow the investigators to determine whether low aPiMax is associated with a ≥ 1-day increase&#xD;
      in weaning duration, with an alpha of 0.05 and power of 0.8. The investigators will perform&#xD;
      identical analysis for ePiMax. Diaphragm Thickness analysis will compound daily ultrasound&#xD;
      measures to detect the relative change in diaphragm thickness from study day 1 until passage&#xD;
      of an SBT. The investigators will compare the change in thickness after resolution of the&#xD;
      acute phase (on the day of the first SBT) against weaning duration, in a similar manner as&#xD;
      proposed above for aPiMax. In addition to weaning duration, the investigators will also&#xD;
      examine whether the respiratory measures taken just prior to or during each SBT are&#xD;
      associated with the patient passing the SBT. For example with aPiMax and ePiMax, the&#xD;
      investigators will examine if there is a dose response relationship between PiMax measured&#xD;
      just before the SBT and the rate of passage of the subsequent SBT.&#xD;
&#xD;
      Aim 3: The primary outcome of this aim is aPiMax &lt; 30 cmH2O.The analysis will focus on&#xD;
      determining whether the degree of patient effort of breathing is independently associated&#xD;
      with the development of respiratory muscle weakness. For the acute phase, the investigators&#xD;
      will generate a time-weighted average PRP during the acute phase and graph it against aPiMax&#xD;
      at the first SBT. They will subsequently dichotomize aPiMax at the first SBT and compare mean&#xD;
      time weighted average PRP in the acute phase between aPiMax groups (&gt; 30 vs. ≤ 30 cmH2O). For&#xD;
      the weaning phase, the investigators will graph the changes in aPiMax throughout the weaning&#xD;
      phase (from first failed SBT until successful SBT) against time-weighted average PRP, with&#xD;
      the anticipation that low PRP will be associated with either further reductions in aPiMax, or&#xD;
      no improvement, while PRP in the physiologic range of 150-400 will be associated with&#xD;
      improvement in aPiMax. The investigators will subsequently dichotomize aPiMax (at 30 cm H2O)&#xD;
      at the time of successful passage of an SBT and compare time-weighted average PRP in the&#xD;
      weaning phase between aPiMax groups. Subsequently, the investigators will build a&#xD;
      multivariable logistic regression model on the outcome of aPiMax ≤ 30 cmH2O to determine if&#xD;
      time-weighted PRP in the acute phase, weaning phase or both have an independent association&#xD;
      with preserving aPiMax, after controlling for confounding variables.&#xD;
    </textblock>
  </detailed_description>
  <overall_status>Recruiting</overall_status>
  <start_date type="Actual">October 21, 2017</start_date>
  <completion_date type="Anticipated">June 30, 2025</completion_date>
  <primary_completion_date type="Anticipated">May 31, 2024</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>
    <intervention_model_description>Randomized Controlled Trial</intervention_model_description>
    <primary_purpose>Prevention</primary_purpose>
    <masking>Single (Outcomes Assessor)</masking>
    <masking_description>Analysis Blinded</masking_description>
  </study_design_info>
  <primary_outcome>
    <measure>Median Duration of Weaning</measure>
    <time_frame>First 28 days of Mechanical Ventilation</time_frame>
    <description>Time from first attempted SBT until SBT passage or extubation [whichever comes first]</description>
  </primary_outcome>
  <secondary_outcome>
    <measure>Median Ventilator Free Days</measure>
    <time_frame>28 and 60 days</time_frame>
    <description>Days alive and not on mechanical ventilation</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Number of Participants with Extubation Failure</measure>
    <time_frame>7 days after extubation</time_frame>
    <description>re-intubation or use of non invasive ventilation</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Number of Participants with Mortality</measure>
    <time_frame>Through study completion up to maximum of 90 Days</time_frame>
    <description>Death</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Median Maximal Inspiratory Airway Pressure During Airway Occlusion (aPiMax)</measure>
    <time_frame>Each day after passing oxygenation test through extubation up to a maximum of 28 days</time_frame>
    <description>Measured during standardized airway occlusion maneuvers</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Median Maximal Inspiratory Esophageal Pressure During Airway Occlusion (ePiMax)</measure>
    <time_frame>Each day after passing oxygenation test through extubation up to a maximum of 28 days</time_frame>
    <description>Measured during standardized airway occlusion maneuvers</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Median Change in diaphragm thickness on Exhalation (Dte) from baseline</measure>
    <time_frame>Each day from study initiation until extubation up to a maximum of 28 days</time_frame>
    <description>From daily ultrasound measurement</description>
  </secondary_outcome>
  <number_of_arms>4</number_of_arms>
  <enrollment type="Anticipated">276</enrollment>
  <condition>Ventilation Therapy; Complications</condition>
  <condition>Diaphragm Disease</condition>
  <condition>Pediatric Respiratory Diseases</condition>
  <arm_group>
    <arm_group_label>REDvent-acute</arm_group_label>
    <arm_group_type>Experimental</arm_group_type>
    <description>Acute Phase: The acute phase is defined as the time from intubation until the patient meets weaning criteria, passes the initial oxygenation test (decrease PEEP to 5 cmH2O and FiO2 to 0.5, maintains SpO2 &gt; 90%), and undergoes a Spontaneous Breathing Trial (SBT). Patients will be managed with pressure control plus pressure support ventilation using a computerized decision support tool that will recommend changes to ventilator settings approximately every 4 hr (with or without a new blood gas). If the patient is spontaneously breathing, it will incorporate real-time measures of effort of breathing (esophageal manometry) to keep it in a target range.</description>
  </arm_group>
  <arm_group>
    <arm_group_label>Control-acute</arm_group_label>
    <arm_group_type>Placebo Comparator</arm_group_type>
    <description>Acute Phase: The acute phase is defined as the time from intubation until the patient meets weaning criteria, passes the initial oxygenation test (decrease PEEP to 5 cmH2O and FiO2 to 0.5, maintains SpO2 &gt; 90%), and undergoes a Spontaneous Breathing Trial (SBT). Ventilator management will be per usual care until the patient meets weaning criteria and passes the oxygenation test.</description>
  </arm_group>
  <arm_group>
    <arm_group_label>REDvent-weaning</arm_group_label>
    <arm_group_type>Experimental</arm_group_type>
    <description>Weaning Phase: The weaning phase is defined as the time from the first Spontaneous Breathing Trial (SBT) until the patient successfully passes an SBT or is extubated (whichever comes first). Patients who pass the initial SBT at the end of the acute phase will not undergo weaning phase randomization. Patients will be managed in a pressure support/CPAP mode of ventilation with assessments or changes to the level of pressure support every 4 hours, targeting maintaining effort of breathing (esophageal manometry) in a normal range. An SBT will be conducted daily, and the weaning phase will continue until the patient passes the SBT.</description>
  </arm_group>
  <arm_group>
    <arm_group_label>Control-weaning</arm_group_label>
    <arm_group_type>Placebo Comparator</arm_group_type>
    <description>Weaning Phase: The weaning phase is defined as the time from the first Spontaneous Breathing Trial (SBT) until the patient successfully passes an SBT or is extubated (whichever comes first). Patients who pass the initial SBT at the end of the acute phase will not undergo weaning phase randomization. Ventilator management will be per usual care. An SBT will be conducted daily, and the weaning phase will continue until the patient passes the SBT.</description>
  </arm_group>
  <intervention>
    <intervention_type>Other</intervention_type>
    <intervention_name>Computerized Ventilator Protocol</intervention_name>
    <description>Computerized Decision Support System which recommends changes to ventilator settings to promote physiologic levels of patient effort of breathing.</description>
    <arm_group_label>REDvent-acute</arm_group_label>
    <arm_group_label>REDvent-weaning</arm_group_label>
  </intervention>
  <intervention>
    <intervention_type>Diagnostic Test</intervention_type>
    <intervention_name>Esophageal Manometry</intervention_name>
    <description>Esophageal Manometry Catheter to measure effort of breathing an transpulmonary pressure</description>
    <arm_group_label>Control-acute</arm_group_label>
    <arm_group_label>Control-weaning</arm_group_label>
    <arm_group_label>REDvent-acute</arm_group_label>
    <arm_group_label>REDvent-weaning</arm_group_label>
  </intervention>
  <intervention>
    <intervention_type>Diagnostic Test</intervention_type>
    <intervention_name>Respiratory Inductance Plethysmography (RIP)</intervention_name>
    <description>RIP bands to measure thoraco-abdominal synchrony during spontaneous breathing trials</description>
    <arm_group_label>Control-acute</arm_group_label>
    <arm_group_label>Control-weaning</arm_group_label>
    <arm_group_label>REDvent-acute</arm_group_label>
    <arm_group_label>REDvent-weaning</arm_group_label>
  </intervention>
  <intervention>
    <intervention_type>Diagnostic Test</intervention_type>
    <intervention_name>Diaphragm Ultrasound</intervention_name>
    <description>Daily measurement of diaphragm thickness and diaphragm contractile activity</description>
    <arm_group_label>Control-acute</arm_group_label>
    <arm_group_label>Control-weaning</arm_group_label>
    <arm_group_label>REDvent-acute</arm_group_label>
    <arm_group_label>REDvent-weaning</arm_group_label>
  </intervention>
  <intervention>
    <intervention_type>Diagnostic Test</intervention_type>
    <intervention_name>Maximal Inspiratory Pressure</intervention_name>
    <description>Prior to Spontaneous breathing trials, measurement of airway and esophageal maximal inspiratory pressure during airway occlusion</description>
    <arm_group_label>Control-acute</arm_group_label>
    <arm_group_label>Control-weaning</arm_group_label>
    <arm_group_label>REDvent-acute</arm_group_label>
    <arm_group_label>REDvent-weaning</arm_group_label>
  </intervention>
  <eligibility>
    <criteria>
      <textblock>
        Inclusion Criteria:&#xD;
&#xD;
          -  Children &gt; 1 month (&gt;44 weeks CGA) and ≤ 18 years of age AND&#xD;
&#xD;
          -  Supported on mechanical ventilation with pulmonary parenchymal disease (i.e.,&#xD;
             pneumonia, bronchiolitis, Pediatric Acute Respiratory Distress Syndrome (PARDS)) with&#xD;
             Oxygen Saturation Index (OSI) ≥ 5 or Oxygenation Index (OI) ≥) AND&#xD;
&#xD;
          -  Who are within 48 hours of initiation of invasive mechanical ventilation (allow for up&#xD;
             to 72 hours for those transferred from another institution)&#xD;
&#xD;
        Exclusion Criteria:&#xD;
&#xD;
          -  Contraindications to use of an esophageal catheter (i.e. severe mucosal bleeding,&#xD;
             nasal encephalocele, transphenoidal surgery) OR&#xD;
&#xD;
          -  Contraindications to use of RIP bands (i.e. omphalocele, chest immobilizer or cast) OR&#xD;
&#xD;
          -  Conditions precluding diaphragm ultrasound measurement (i.e. abdominal wall defects,&#xD;
             pregnancy) OR&#xD;
&#xD;
          -  Conditions on enrollment that preclude conventional methods of weaning (i.e., status&#xD;
             asthmaticus, severe lower airway obstruction, critical airway, intracranial&#xD;
             hypertension, Extra Corporeal Life Support (ECLS), intubation for UAO, DNR, severe&#xD;
             chronic respiratory failure, spinal cord injury above lumbar region, cyanotic heart&#xD;
             disease (unrepaired or palliated)) OR&#xD;
&#xD;
          -  Primary Attending physician refuses (will be cleared with primary attending before&#xD;
             approaching the patient).&#xD;
      </textblock>
    </criteria>
    <gender>All</gender>
    <minimum_age>30 Days</minimum_age>
    <maximum_age>18 Years</maximum_age>
    <healthy_volunteers>No</healthy_volunteers>
  </eligibility>
  <overall_official>
    <last_name>Robinder G Khemani, MD, MsCI</last_name>
    <role>Principal Investigator</role>
    <affiliation>Children's Hospital Los Angeles</affiliation>
  </overall_official>
  <overall_contact>
    <last_name>Robinder G Khemani, MD,MsCI</last_name>
    <phone>3233612557</phone>
    <email>rkhemani@chla.usc.edu</email>
  </overall_contact>
  <location>
    <facility>
      <name>Children's Hospital Los Angeles</name>
      <address>
        <city>Los Angeles</city>
        <state>California</state>
        <zip>90027</zip>
        <country>United States</country>
      </address>
    </facility>
    <status>Recruiting</status>
  </location>
  <location_countries>
    <country>United States</country>
  </location_countries>
  <verification_date>February 2023</verification_date>
  <study_first_submitted>August 23, 2017</study_first_submitted>
  <study_first_submitted_qc>August 28, 2017</study_first_submitted_qc>
  <study_first_posted type="Actual">August 29, 2017</study_first_posted>
  <last_update_submitted>August 28, 2023</last_update_submitted>
  <last_update_submitted_qc>August 28, 2023</last_update_submitted_qc>
  <last_update_posted type="Actual">August 30, 2023</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>Respiratory Tract Diseases</mesh_term>
    <mesh_term>Respiration Disorders</mesh_term>
  </condition_browse>
  <patient_data>
    <sharing_ipd>Yes</sharing_ipd>
    <ipd_description>De-Identified IPD will be made available as per NIH guidelines.</ipd_description>
    <ipd_info_type>Study Protocol</ipd_info_type>
    <ipd_info_type>Statistical Analysis Plan (SAP)</ipd_info_type>
    <ipd_time_frame>Within 5 years of publication of primary manuscript</ipd_time_frame>
    <ipd_access_criteria>Will be made available through biolinc</ipd_access_criteria>
    <ipd_url>https://biolincc.nhlbi.nih.gov/home/</ipd_url>
  </patient_data>
  <!-- Results have not yet been posted for this study                                          -->
</clinical_study>


download date: ClinicalTrials.gov processed this data on September 20, 2023
link text: Link to the current ClinicalTrials.gov record.
url: https://clinicaltrials.gov/ct2/show/NCT03266016
org study id: CHLA-17-00235
secondary id: 5R01HL134666
nct id: NCT03266016
lead sponsor: 
collaborator: 
collaborator: 
has dmc: Yes
is fda regulated drug: No
is fda regulated device: No
This study is a Phase II controlled clinical trial that will obtain comprehensive, serial
      assessments of respiratory muscle strength and architecture to understand the evolution of
      ventilator-induced respiratory muscle weakness in critically ill children, and test whether a
      novel computer-based approach (Real-time Effort Driven ventilator management (REDvent)) can
      preserve respiratory muscle strength and reduce time on MV. REDvent offers systematic
      recommendations to reduce controlled ventilation during the acute phase of MV, and uses
      real-time measures from esophageal manometry to adjust supported ventilator pressures such
      that patient effort of breathing remains in a normal range during the ventilator weaning
      phase. This phase II clinical trial is expected to enroll 276 children with pulmonary
      parenchymal disease, anticipated to be ventilated > 48 hrs. Patients will be randomized to
      REDvent-acute vs. usual care for the acute phase of MV (interval from intubation to first
      spontaneous breathing trial (SBT)). Patients in either group who fail their first Spontaneous
      Breathing Trial (SBT), will also be randomized to REDvent-weaning vs. usual care for the
      weaning phase of MV (interval from first SBT to passing SBT). The primary clinical outcome is
      length of weaning (time from first SBT until successful passage of an SBT or extubation
      (whichever comes first)). Mechanistic outcomes surround multi-modal serial measures of
      respiratory muscle capacity (PiMax), load (resistance, compliance), effort (esophageal
      manometry), and architecture (ultrasound) throughout the course of MV. Upon completion, this
      study will provide important information on the pathogenesis and timing of respiratory muscle
      weakness during MV in children and whether this weakness can be mitigated by promoting more
      normal patient effort during MV via the use of REDvent. This will form the basis for a
      larger, Phase III multi-center study, powered for key clinical outcomes such as 28-day
      Ventilator Free Days.
Study Aims:

      SA1: To determine if REDvent acute and/or weaning phase protocols can shorten the duration of
      weaning from MV (Primary outcome).

      SA2: To determine if changes to direct measures of respiratory muscle strength, load, effort,
      and architecture throughout the duration of MV are related to weaning outcomes.

      SA3: To determine if patient effort of breathing during both acute and weaning phases of MV
      is independently associated with the development of respiratory muscle weakness.

      Study Design: Single-center randomized controlled trial (138 children per arm) using REDvent
      (intervention arm) as compared with usual care ventilator management including a standardized
      daily SBT (control arm). Acute phase randomization will occur upon study enrollment, and
      patients who fail the first SBT will undergo a weaning phase randomization. The investigators
      will obtain serial measurements of respiratory system capacity, load, effort of breathing,
      and diaphragm architecture throughout the course of MV.

      Acute Phase: The acute phase is defined as the time from intubation until the patient meets
      weaning criteria, passes the initial oxygenation test (decrease PEEP to 5 cmH2O and FiO2 to
      0.5, maintains SpO2 > 90%), and undergoes a Spontaneous Breathing Trial (SBT).

        1. Intervention Arm (REDvent-acute): Patients will be managed with pressure control plus
           pressure support ventilation using a computerized decision support tool that will
           recommend changes to ventilator settings approximately every 4 hr (with or without a new
           blood gas). If the patient is spontaneously breathing, it will incorporate real-time
           measures of effort of breathing (esophageal manometry) to keep it in a target range.

        2. Control Arm (Control-acute): Ventilator management will be per usual care until the
           patient meets weaning criteria and passes the oxygenation test.

      Weaning Phase: The weaning phase is defined as the time from the first Spontaneous Breathing
      Trial (SBT) until the patient successfully passes an SBT or is extubated (whichever comes
      first). Patients who pass the initial SBT at the end of the acute phase will not undergo
      weaning phase randomization.

        1. Intervention Arm (REDvent-weaning): Patients will be managed in a pressure support/CPAP
           mode of ventilation with assessments or changes to the level of pressure support every 4
           hours, targeting maintaining effort of breathing (esophageal manometry) in a normal
           range. An SBT will be conducted daily, and the weaning phase will continue until the
           patient passes the SBT.

        2. Control Arm (Control-weaning): Ventilator management will be per usual care. An SBT will
           be conducted daily, and the weaning phase will continue until the patient passes the
           SBT.

      Analysis Plan and Sample Size Justification:

      Aim 1: The primary outcome is weaning duration. Sample size has been determined to adequately
      power 3 separate comparative analyses: (a) REDvent-acute versus Acute Phase control (b)
      REDvent-weaning phase versus Weaning Phase control (c) REDvent both phases versus control
      both phases. Power is based on 2 planned methods for analysis: cox proportional hazard ratios
      for multivariable analysis and univariate analysis with an independent t-test using log
      transformation (as needed) to account for the expected distribution of weaning duration. For
      all three of the planned comparisons above, with the proposed sample size the investigators
      would be adequately powered (>0.8) to detect a difference in weaning duration of ≥ 1 day, or
      a hazard ratio of ≥ 1.4 between groups. The secondary outcomes are ventilator free days and
      extubation failure. Directly comparing control only patients to REDvent only patients, with
      an expected standard deviation for VFDs between 5 to 9 days, the investigators will be able
      to detect a 2-day change in VFDs between groups with a power between 0.35 and 0.82.
      Re-intubation rates are expected to be 10%, allowing the investigators to confirm that
      REDvent is not inferior to usual care in regards to re-intubation with a non-inferiority
      margin of 0.10 with a power of 0.8 and alpha of 0.05.

      Aim 2: The primary outcome of this aim is weaning duration. For respiratory muscle strength
      the investigators will compare the first measured aPiMax (after resolution of the acute
      phase, before the first SBT), the trajectory and value of the daily aPiMax during the weaning
      phase prior to extubation, the lowest and highest measured aPiMax, and aPiMax on the day of
      extubation against weaning duration. For analysis, aPiMax will be dichotomized at 30 cmH2O,
      and weaning duration will be compared between patients with aPiMax > 30 versus ≤ 30 cmH2O
      using a t-test with or without log-transformation, or Mann-Whitney U test, depending on the
      distribution. From preliminary data, it is anticipated at least 35% of patients (n=84) will
      have aPiMax ≤ 30 cmH2O. Based on a similar power analysis as presented above, this would
      allow the investigators to determine whether low aPiMax is associated with a ≥ 1-day increase
      in weaning duration, with an alpha of 0.05 and power of 0.8. The investigators will perform
      identical analysis for ePiMax. Diaphragm Thickness analysis will compound daily ultrasound
      measures to detect the relative change in diaphragm thickness from study day 1 until passage
      of an SBT. The investigators will compare the change in thickness after resolution of the
      acute phase (on the day of the first SBT) against weaning duration, in a similar manner as
      proposed above for aPiMax. In addition to weaning duration, the investigators will also
      examine whether the respiratory measures taken just prior to or during each SBT are
      associated with the patient passing the SBT. For example with aPiMax and ePiMax, the
      investigators will examine if there is a dose response relationship between PiMax measured
      just before the SBT and the rate of passage of the subsequent SBT.

      Aim 3: The primary outcome of this aim is aPiMax < 30 cmH2O.The analysis will focus on
      determining whether the degree of patient effort of breathing is independently associated
      with the development of respiratory muscle weakness. For the acute phase, the investigators
      will generate a time-weighted average PRP during the acute phase and graph it against aPiMax
      at the first SBT. They will subsequently dichotomize aPiMax at the first SBT and compare mean
      time weighted average PRP in the acute phase between aPiMax groups (> 30 vs. ≤ 30 cmH2O). For
      the weaning phase, the investigators will graph the changes in aPiMax throughout the weaning
      phase (from first failed SBT until successful SBT) against time-weighted average PRP, with
      the anticipation that low PRP will be associated with either further reductions in aPiMax, or
      no improvement, while PRP in the physiologic range of 150-400 will be associated with
      improvement in aPiMax. The investigators will subsequently dichotomize aPiMax (at 30 cm H2O)
      at the time of successful passage of an SBT and compare time-weighted average PRP in the
      weaning phase between aPiMax groups. Subsequently, the investigators will build a
      multivariable logistic regression model on the outcome of aPiMax ≤ 30 cmH2O to determine if
      time-weighted PRP in the acute phase, weaning phase or both have an independent association
      with preserving aPiMax, after controlling for confounding variables.
allocation: Randomized
intervention model: Parallel Assignment
intervention model description: Randomized Controlled Trial
primary purpose: Prevention
masking: Single (Outcomes Assessor)
masking description: Analysis Blinded
measure: Median Duration of Weaning
time frame: First 28 days of Mechanical Ventilation
description: Time from first attempted SBT until SBT passage or extubation [whichever comes first]
measure: Median Ventilator Free Days
time frame: 28 and 60 days
description: Days alive and not on mechanical ventilation
measure: Number of Participants with Extubation Failure
time frame: 7 days after extubation
description: re-intubation or use of non invasive ventilation
measure: Number of Participants with Mortality
time frame: Through study completion up to maximum of 90 Days
description: Death
measure: Median Maximal Inspiratory Airway Pressure During Airway Occlusion (aPiMax)
time frame: Each day after passing oxygenation test through extubation up to a maximum of 28 days
description: Measured during standardized airway occlusion maneuvers
measure: Median Maximal Inspiratory Esophageal Pressure During Airway Occlusion (ePiMax)
time frame: Each day after passing oxygenation test through extubation up to a maximum of 28 days
description: Measured during standardized airway occlusion maneuvers
measure: Median Change in diaphragm thickness on Exhalation (Dte) from baseline
time frame: Each day from study initiation until extubation up to a maximum of 28 days
description: From daily ultrasound measurement
arm group label: REDvent-acute
arm group type: Experimental
description: Acute Phase: The acute phase is defined as the time from intubation until the patient meets weaning criteria, passes the initial oxygenation test (decrease PEEP to 5 cmH2O and FiO2 to 0.5, maintains SpO2 > 90%), and undergoes a Spontaneous Breathing Trial (SBT). Patients will be managed with pressure control plus pressure support ventilation using a computerized decision support tool that will recommend changes to ventilator settings approximately every 4 hr (with or without a new blood gas). If the patient is spontaneously breathing, it will incorporate real-time measures of effort of breathing (esophageal manometry) to keep it in a target range.
arm group label: Control-acute
arm group type: Placebo Comparator
description: Acute Phase: The acute phase is defined as the time from intubation until the patient meets weaning criteria, passes the initial oxygenation test (decrease PEEP to 5 cmH2O and FiO2 to 0.5, maintains SpO2 > 90%), and undergoes a Spontaneous Breathing Trial (SBT). Ventilator management will be per usual care until the patient meets weaning criteria and passes the oxygenation test.
arm group label: REDvent-weaning
arm group type: Experimental
description: Weaning Phase: The weaning phase is defined as the time from the first Spontaneous Breathing Trial (SBT) until the patient successfully passes an SBT or is extubated (whichever comes first). Patients who pass the initial SBT at the end of the acute phase will not undergo weaning phase randomization. Patients will be managed in a pressure support/CPAP mode of ventilation with assessments or changes to the level of pressure support every 4 hours, targeting maintaining effort of breathing (esophageal manometry) in a normal range. An SBT will be conducted daily, and the weaning phase will continue until the patient passes the SBT.
arm group label: Control-weaning
arm group type: Placebo Comparator
description: Weaning Phase: The weaning phase is defined as the time from the first Spontaneous Breathing Trial (SBT) until the patient successfully passes an SBT or is extubated (whichever comes first). Patients who pass the initial SBT at the end of the acute phase will not undergo weaning phase randomization. Ventilator management will be per usual care. An SBT will be conducted daily, and the weaning phase will continue until the patient passes the SBT.
intervention type: Other
intervention name: Computerized Ventilator Protocol
description: Computerized Decision Support System which recommends changes to ventilator settings to promote physiologic levels of patient effort of breathing.
arm group label: REDvent-acute
arm group label: REDvent-weaning
intervention type: Diagnostic Test
intervention name: Esophageal Manometry
description: Esophageal Manometry Catheter to measure effort of breathing an transpulmonary pressure
arm group label: Control-acute
arm group label: Control-weaning
arm group label: REDvent-acute
arm group label: REDvent-weaning
intervention type: Diagnostic Test
intervention name: Respiratory Inductance Plethysmography (RIP)
description: RIP bands to measure thoraco-abdominal synchrony during spontaneous breathing trials
arm group label: Control-acute
arm group label: Control-weaning
arm group label: REDvent-acute
arm group label: REDvent-weaning
intervention type: Diagnostic Test
intervention name: Diaphragm Ultrasound
description: Daily measurement of diaphragm thickness and diaphragm contractile activity
arm group label: Control-acute
arm group label: Control-weaning
arm group label: REDvent-acute
arm group label: REDvent-weaning
intervention type: Diagnostic Test
intervention name: Maximal Inspiratory Pressure
description: Prior to Spontaneous breathing trials, measurement of airway and esophageal maximal inspiratory pressure during airway occlusion
arm group label: Control-acute
arm group label: Control-weaning
arm group label: REDvent-acute
arm group label: REDvent-weaning
criteria: 
gender: All
minimum age: 30 Days
maximum age: 18 Years
healthy volunteers: No
last name: Robinder G Khemani, MD, MsCI
role: Principal Investigator
affiliation: Children's Hospital Los Angeles
last name: Robinder G Khemani, MD,MsCI
phone: 3233612557
email: rkhemani@chla.usc.edu
facility: 
status: Recruiting
country: United States
responsible party type: Sponsor
mesh term: Respiratory Tract Diseases
mesh term: Respiration Disorders
sharing ipd: Yes
ipd description: De-Identified IPD will be made available as per NIH guidelines.
ipd info type: Study Protocol
ipd info type: Statistical Analysis Plan (SAP)
ipd time frame: Within 5 years of publication of primary manuscript
ipd access criteria: Will be made available through biolinc
ipd url: https://biolincc.nhlbi.nih.gov/home/