<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/NCT01667146</url>
  </required_header>
  <id_info>
    <org_study_id>ANZIC-RC/AD002 Version 8</org_study_id>
    <nct_id>NCT01667146</nct_id>
  </id_info>
  <brief_title>A Multi-centre Trial of an Open Lung Strategy Including Permissive Hypercapnia, Alveolar Recruitment and Low Airway Pressure in Patients With Acute Respiratory Distress Syndrome</brief_title>
  <acronym>PHARLAP</acronym>
  <official_title>A Multi-centre Randomised Controlled Trial of an Open Lung Strategy Including Permissive Hypercapnia, Alveolar Recruitment and Low Airway Pressure in Patients With Acute Respiratory Distress Syndrome.</official_title>
  <sponsors>
    <lead_sponsor>
      <agency>Australian and New Zealand Intensive Care Research Centre</agency>
      <agency_class>Other</agency_class>
    </lead_sponsor>
  </sponsors>
  <source>Australian and New Zealand Intensive Care Research Centre</source>
  <oversight_info>
    <has_dmc>No</has_dmc>
  </oversight_info>
  <brief_summary>
    <textblock>
      Some people develop the condition called acute respiratory distress syndrome (ARDS). This is&#xD;
      a condition where the lungs have become injured from one of a number of various causes, and&#xD;
      do not work as they normally do to provide oxygen and remove carbon dioxide from the body.&#xD;
      This can lead to a reduced amount of oxygen in the patient's bloodstream. Patients with ARDS&#xD;
      are admitted to the intensive care unit (ICU) and need help with their breathing by being&#xD;
      connected to a ventilator (breathing machine). ARDS can lead to injury in other organs of the&#xD;
      body causing other problems but also death.&#xD;
&#xD;
      Over the past few years, reducing the size of each breath delivered by the ventilator in&#xD;
      conjunction with the use of an occasional sustained deep breath called a &quot;recruitment&#xD;
      manoeuvre&quot; have been used to try to prevent further damage to the lungs in people with ARDS.&#xD;
      This ventilator strategy (termed the PHARLAP strategy) has been shown in a small research&#xD;
      study to have some beneficial effects without causing any obvious harm, when compared to a&#xD;
      current best practice ventilator strategy. The main beneficial effects of the PHARLAP&#xD;
      strategy were to increase the amount of oxygen in the blood and to reduce markers of&#xD;
      inflammation (the body reacting to a disease process) in the body. This study was too small&#xD;
      to make a strong conclusion, so this study will be much larger and will assess whether&#xD;
      patients who have developed ARDS are better off when we use the PHARLAP strategy. Three&#xD;
      hundred and forty patients will be enrolled into this study in multiple ICUs across Australia&#xD;
      and New Zealand.&#xD;
&#xD;
      The study hypothesis is that the PHARLAP strategy group will have a higher number of&#xD;
      ventilator free days at day 28 than the control group.&#xD;
    </textblock>
  </brief_summary>
  <overall_status>Terminated</overall_status>
  <why_stopped>
    Halted by the Management Committee after the publication of the ART Trial&#xD;
  </why_stopped>
  <start_date>October 2012</start_date>
  <completion_date type="Actual">March 2018</completion_date>
  <primary_completion_date type="Actual">October 2017</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>Number of ventilator free days at day 28 post randomisation</measure>
    <time_frame>28 days post randomisation</time_frame>
  </primary_outcome>
  <secondary_outcome>
    <measure>PaO2/FiO2 ratio and static lung compliance</measure>
    <time_frame>Up to day 28 post randomisation</time_frame>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Baseline to day 3 change in IL-8 and IL-6 concentrations in broncho-alveolar lavage and plasma</measure>
    <time_frame>Day 3 post randomisation</time_frame>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Incidence of severe hypotension</measure>
    <time_frame>Up to 90 days post randomisation</time_frame>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Incidence of barotrauma</measure>
    <time_frame>Up to 90 days post randomisation</time_frame>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Use of rescue therapies for severe hypoxaemia - inhaled nitric oxide, inhaled prostacyclin, prone positioning, high frequency oscillatory ventilation and extracorporeal membrane oxygenation (ECMO)</measure>
    <time_frame>Within hospital admission</time_frame>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Mortality</measure>
    <time_frame>Up to 6 months post randomisation</time_frame>
    <description>At timepoints: ICU discharge, hospital discharge, 28 days, 90 days and 6 months</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>ICU and hospital length of stay</measure>
    <time_frame>Up to 6 months</time_frame>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Incidence of AKI</measure>
    <time_frame>Within hospital admission</time_frame>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Quality of life assessment</measure>
    <time_frame>6 months post randomisation</time_frame>
    <description>SF36v2</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Cost effectiveness analysis</measure>
    <time_frame>6 months post randomisation</time_frame>
    <description>Based on EQ-5D</description>
  </secondary_outcome>
  <number_of_arms>2</number_of_arms>
  <enrollment type="Actual">115</enrollment>
  <condition>Acute Respiratory Distress Syndrome</condition>
  <arm_group>
    <arm_group_label>PHARLAP ventilation group</arm_group_label>
    <arm_group_type>Experimental</arm_group_type>
    <description>PHARLAP mechanical ventilation strategy</description>
  </arm_group>
  <arm_group>
    <arm_group_label>Control group ventilation</arm_group_label>
    <arm_group_type>Active Comparator</arm_group_type>
    <description>Control group mechanical ventilation strategy</description>
  </arm_group>
  <intervention>
    <intervention_type>Other</intervention_type>
    <intervention_name>PHARLAP mechanical ventilation strategy</intervention_name>
    <description>Pressure control ventilation to maintain tidal volume 4-6 ml/kg and plateau pressure ≤ 30 cmH2O while tolerating respiratory acidosis if pH &gt; 7.15; daily staircase recruitment manoeuvre and individualised PEEP titration.</description>
    <arm_group_label>PHARLAP ventilation group</arm_group_label>
  </intervention>
  <intervention>
    <intervention_type>Other</intervention_type>
    <intervention_name>Control group mechanical ventilation strategy</intervention_name>
    <description>Mechanical ventilation based on the ARDSnet protocol using volume control ventilation with tidal volume 6 ml/kg, plateau pressure ≤ 30 cmH2O and FiO2/PEEP titration according to a FiO2/PEEP/oxygen saturation combination chart. This has been modified for Australian and New Zealand practice to allow pressure control and pressure support ventilation.</description>
    <arm_group_label>Control group ventilation</arm_group_label>
  </intervention>
  <eligibility>
    <criteria>
      <textblock>
        Inclusion Criteria:&#xD;
&#xD;
        Adult ICU patients who met all of the following criteria:&#xD;
&#xD;
          -  Currently intubated and receiving mechanical ventilation&#xD;
&#xD;
          -  Within 72 Hours of a diagnosis of ARDS (moderate and severe) based on the following&#xD;
             Berlin definition:&#xD;
&#xD;
          -  Within 1 week of a known clinical insult or new or worsening respiratory symptoms&#xD;
&#xD;
          -  Bilateral opacities on CXR which are not fully explained by effusions, lobar/lung&#xD;
             collapse or nodules&#xD;
&#xD;
          -  Respiratory failure not fully explained by cardiac failure or fluid overload&#xD;
&#xD;
          -  PaO2/FiO2 &lt; 200mmHg with PEEP ≥ 5cmH2O&#xD;
&#xD;
        Exclusion Criteria:&#xD;
&#xD;
          -  &gt; 72 hours since diagnosis of ARDS&#xD;
&#xD;
          -  &gt; 10 days of continuous mechanical ventilation&#xD;
&#xD;
          -  Barotrauma (pneumothorax, pneumomediastinum, subcutaneous emphysema or any intercostal&#xD;
             catheter for the treatment of air leak)&#xD;
&#xD;
          -  Significant chest trauma i.e. multiple rib fractures&#xD;
&#xD;
          -  Active bronchospasm or a history of significant chronic obstructive pulmonary disease&#xD;
             or asthma&#xD;
&#xD;
          -  Clinical suspicion for significant restrictive lung disease (history of pulmonary&#xD;
             fibrosis or suggestive pulmonary function tests)&#xD;
&#xD;
          -  Moderate or severe traumatic brain injury, the presence of an intracranial pressure&#xD;
             monitor, or any medical condition associated with a clinical suspicion of raised&#xD;
             intracranial pressure&#xD;
&#xD;
          -  Unstable cardiovascular status defined as sustained heart rate &lt; 40 or &gt; 140 bpm,&#xD;
             ventricular tachycardia, or SBP &lt; 80mmHg&#xD;
&#xD;
          -  Pregnancy&#xD;
&#xD;
          -  Receiving ECMO&#xD;
&#xD;
          -  Receiving high frequency oscillatory ventilation&#xD;
&#xD;
          -  Death is deemed imminent and inevitable&#xD;
&#xD;
          -  The treating physician believes it is not in the best interest of the patient to be&#xD;
             enrolled in the trial&#xD;
&#xD;
          -  Consent not obtained or refused by patient's legal surrogate&#xD;
      </textblock>
    </criteria>
    <gender>All</gender>
    <minimum_age>16 Years</minimum_age>
    <maximum_age>N/A</maximum_age>
    <healthy_volunteers>No</healthy_volunteers>
  </eligibility>
  <overall_official>
    <last_name>Carol Hodgson, PhD, FACP, BAppSc (Physio)</last_name>
    <role>Study Chair</role>
    <affiliation>Australian and New Zealand Intensive Care Research Centre (ANZIC-RC)</affiliation>
  </overall_official>
  <overall_official>
    <last_name>Alistair Nichol, PhD, FCICM</last_name>
    <role>Study Chair</role>
    <affiliation>Australian and New Zealand Intensive Care Research Centre (ANZIC-RC)</affiliation>
  </overall_official>
  <location>
    <facility>
      <name>Albury/Wodonga</name>
      <address>
        <city>Albury</city>
        <state>New South Wales</state>
        <country>Australia</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Nepean Hospital</name>
      <address>
        <city>Kingswood</city>
        <state>New South Wales</state>
        <zip>2747</zip>
        <country>Australia</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Royal Prince Alfred</name>
      <address>
        <city>Sydney</city>
        <state>New South Wales</state>
        <country>Australia</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Wollongong Hospital</name>
      <address>
        <city>Wollongong</city>
        <state>New South Wales</state>
        <zip>2500</zip>
        <country>Australia</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>The Prince Charles Hospital</name>
      <address>
        <city>Brisbane</city>
        <state>Queensland</state>
        <country>Australia</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Flinders Medical Centre</name>
      <address>
        <city>Adelaide</city>
        <state>South Australia</state>
        <country>Australia</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Geelong Hospital</name>
      <address>
        <city>Geelong</city>
        <state>Victoria</state>
        <zip>3220</zip>
        <country>Australia</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>The Alfred Hosptial</name>
      <address>
        <city>Melbourne</city>
        <state>Victoria</state>
        <zip>3004</zip>
        <country>Australia</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Adelaide and Meath (Tallaght) Hospital</name>
      <address>
        <city>Dublin</city>
        <country>Ireland</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Beaumont Hospital</name>
      <address>
        <city>Dublin</city>
        <country>Ireland</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Mater Misericordiae University Hospital</name>
      <address>
        <city>Dublin</city>
        <country>Ireland</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>St Vincents Hospital</name>
      <address>
        <city>Dublin</city>
        <country>Ireland</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>University Hospital Limerick</name>
      <address>
        <city>Limerick</city>
        <country>Ireland</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Middlemore Hospital</name>
      <address>
        <city>Otahuhu</city>
        <state>Auckland</state>
        <zip>1640</zip>
        <country>New Zealand</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Auckland City Hospital (DCCM)</name>
      <address>
        <city>Auckland</city>
        <zip>1142</zip>
        <country>New Zealand</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Auckland City Hospital CVICU</name>
      <address>
        <city>Auckland</city>
        <zip>1142</zip>
        <country>New Zealand</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>King Abdulaziz Medical City</name>
      <address>
        <city>Riyadh</city>
        <country>Saudi Arabia</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Peterborough City Hospital</name>
      <address>
        <city>Peterborough</city>
        <state>Cambridgeshire</state>
        <country>United Kingdom</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Derriford Hospital</name>
      <address>
        <city>Plymouth</city>
        <state>Devon</state>
        <country>United Kingdom</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Princess Royal University Hospital</name>
      <address>
        <city>Orpington</city>
        <state>Kent</state>
        <country>United Kingdom</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Royal Surrey County Hospital</name>
      <address>
        <city>Guildford</city>
        <state>Surrey</state>
        <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>Hull Royal Infirmary</name>
      <address>
        <city>Hull</city>
        <country>United Kingdom</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>King's College Hospital</name>
      <address>
        <city>London</city>
        <country>United Kingdom</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>North Middlesex University Hospital</name>
      <address>
        <city>London</city>
        <country>United Kingdom</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>University Hospital, Lewisham</name>
      <address>
        <city>London</city>
        <country>United Kingdom</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>James Cook University Hospital</name>
      <address>
        <city>Middlesbrough</city>
        <country>United Kingdom</country>
      </address>
    </facility>
  </location>
  <location_countries>
    <country>Australia</country>
    <country>Ireland</country>
    <country>New Zealand</country>
    <country>Saudi Arabia</country>
    <country>United Kingdom</country>
  </location_countries>
  <verification_date>November 2018</verification_date>
  <study_first_submitted>August 12, 2012</study_first_submitted>
  <study_first_submitted_qc>August 15, 2012</study_first_submitted_qc>
  <study_first_posted type="Estimate">August 17, 2012</study_first_posted>
  <last_update_submitted>November 26, 2018</last_update_submitted>
  <last_update_submitted_qc>November 26, 2018</last_update_submitted_qc>
  <last_update_posted type="Actual">November 28, 2018</last_update_posted>
  <responsible_party>
    <responsible_party_type>Principal Investigator</responsible_party_type>
    <investigator_affiliation>Australian and New Zealand Intensive Care Research Centre</investigator_affiliation>
    <investigator_full_name>Carol Hodgson</investigator_full_name>
    <investigator_title>Dr Carol Hodgson</investigator_title>
  </responsible_party>
  <condition_browse>
    <!-- CAUTION:  The following MeSH terms are assigned with an imperfect algorithm            -->
    <mesh_term>Respiratory Distress Syndrome</mesh_term>
    <mesh_term>Respiratory Distress Syndrome, Newborn</mesh_term>
    <mesh_term>Acute Lung Injury</mesh_term>
    <mesh_term>Syndrome</mesh_term>
    <mesh_term>Hypercapnia</mesh_term>
  </condition_browse>
  <pending_results>
    <submitted>April 10, 2022</submitted>
    <returned>January 6, 2023</returned>
    <submitted>February 19, 2023</submitted>
  </pending_results>
  <!-- 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/NCT01667146
org study id: ANZIC-RC/AD002 Version 8
nct id: NCT01667146
lead sponsor: 
has dmc: No
Some people develop the condition called acute respiratory distress syndrome (ARDS). This is
      a condition where the lungs have become injured from one of a number of various causes, and
      do not work as they normally do to provide oxygen and remove carbon dioxide from the body.
      This can lead to a reduced amount of oxygen in the patient's bloodstream. Patients with ARDS
      are admitted to the intensive care unit (ICU) and need help with their breathing by being
      connected to a ventilator (breathing machine). ARDS can lead to injury in other organs of the
      body causing other problems but also death.

      Over the past few years, reducing the size of each breath delivered by the ventilator in
      conjunction with the use of an occasional sustained deep breath called a "recruitment
      manoeuvre" have been used to try to prevent further damage to the lungs in people with ARDS.
      This ventilator strategy (termed the PHARLAP strategy) has been shown in a small research
      study to have some beneficial effects without causing any obvious harm, when compared to a
      current best practice ventilator strategy. The main beneficial effects of the PHARLAP
      strategy were to increase the amount of oxygen in the blood and to reduce markers of
      inflammation (the body reacting to a disease process) in the body. This study was too small
      to make a strong conclusion, so this study will be much larger and will assess whether
      patients who have developed ARDS are better off when we use the PHARLAP strategy. Three
      hundred and forty patients will be enrolled into this study in multiple ICUs across Australia
      and New Zealand.

      The study hypothesis is that the PHARLAP strategy group will have a higher number of
      ventilator free days at day 28 than the control group.
allocation: Randomized
intervention model: Parallel Assignment
primary purpose: Treatment
masking: None (Open Label)
measure: Number of ventilator free days at day 28 post randomisation
time frame: 28 days post randomisation
measure: PaO2/FiO2 ratio and static lung compliance
time frame: Up to day 28 post randomisation
measure: Baseline to day 3 change in IL-8 and IL-6 concentrations in broncho-alveolar lavage and plasma
time frame: Day 3 post randomisation
measure: Incidence of severe hypotension
time frame: Up to 90 days post randomisation
measure: Incidence of barotrauma
time frame: Up to 90 days post randomisation
measure: Use of rescue therapies for severe hypoxaemia - inhaled nitric oxide, inhaled prostacyclin, prone positioning, high frequency oscillatory ventilation and extracorporeal membrane oxygenation (ECMO)
time frame: Within hospital admission
measure: Mortality
time frame: Up to 6 months post randomisation
description: At timepoints: ICU discharge, hospital discharge, 28 days, 90 days and 6 months
measure: ICU and hospital length of stay
time frame: Up to 6 months
measure: Incidence of AKI
time frame: Within hospital admission
measure: Quality of life assessment
time frame: 6 months post randomisation
description: SF36v2
measure: Cost effectiveness analysis
time frame: 6 months post randomisation
description: Based on EQ-5D
arm group label: PHARLAP ventilation group
arm group type: Experimental
description: PHARLAP mechanical ventilation strategy
arm group label: Control group ventilation
arm group type: Active Comparator
description: Control group mechanical ventilation strategy
intervention type: Other
intervention name: PHARLAP mechanical ventilation strategy
description: Pressure control ventilation to maintain tidal volume 4-6 ml/kg and plateau pressure ≤ 30 cmH2O while tolerating respiratory acidosis if pH > 7.15; daily staircase recruitment manoeuvre and individualised PEEP titration.
arm group label: PHARLAP ventilation group
intervention type: Other
intervention name: Control group mechanical ventilation strategy
description: Mechanical ventilation based on the ARDSnet protocol using volume control ventilation with tidal volume 6 ml/kg, plateau pressure ≤ 30 cmH2O and FiO2/PEEP titration according to a FiO2/PEEP/oxygen saturation combination chart. This has been modified for Australian and New Zealand practice to allow pressure control and pressure support ventilation.
arm group label: Control group ventilation
criteria: 
gender: All
minimum age: 16 Years
maximum age: N/A
healthy volunteers: No
last name: Carol Hodgson, PhD, FACP, BAppSc (Physio)
role: Study Chair
affiliation: Australian and New Zealand Intensive Care Research Centre (ANZIC-RC)
last name: Alistair Nichol, PhD, FCICM
role: Study Chair
affiliation: Australian and New Zealand Intensive Care Research Centre (ANZIC-RC)
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country: Australia
country: Ireland
country: New Zealand
country: Saudi Arabia
country: United Kingdom
responsible party type: Principal Investigator
investigator affiliation: Australian and New Zealand Intensive Care Research Centre
investigator full name: Carol Hodgson
investigator title: Dr Carol Hodgson
mesh term: Respiratory Distress Syndrome
mesh term: Respiratory Distress Syndrome, Newborn
mesh term: Acute Lung Injury
mesh term: Syndrome
mesh term: Hypercapnia
submitted: April 10, 2022
returned: January 6, 2023
submitted: February 19, 2023