<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/NCT03033251</url>
  </required_header>
  <id_info>
    <org_study_id>REB# 16-389</org_study_id>
    <nct_id>NCT03033251</nct_id>
  </id_info>
  <brief_title>High Flow Nasal Cannula Versus Non-Invasive Ventilation in Exacerbations of Chronic Obstructive Pulmonary Disease</brief_title>
  <acronym>HiFOLD</acronym>
  <official_title>High Flow Nasal Cannula Versus Non-Invasive Ventilation in Exacerbations of Chronic Obstructive Pulmonary Disease</official_title>
  <sponsors>
    <lead_sponsor>
      <agency>Unity Health Toronto</agency>
      <agency_class>Other</agency_class>
    </lead_sponsor>
  </sponsors>
  <source>Unity Health Toronto</source>
  <oversight_info>
    <has_dmc>No</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>
      Chronic obstructive lung disease is a disabling disease that affects people usually after&#xD;
      several years of smoke tobacco exposure and affects millions of patients worldwide. The&#xD;
      disease is marked by multiples episode of worsening, termed exacerbations necessitating&#xD;
      frequent hospitalizations. During these exacerbations, patients present breathless, and in&#xD;
      the most severe cases, are admitted to an Intensive Care Unit (ICU) for respiratory&#xD;
      assistance. Currently, respiratory assistance is provided by a ventilator via a oronasal mask&#xD;
      (referred to non-invasive ventilation, NIV), that helps patients to cope with their&#xD;
      breathless. The mask is not always well tolerated and the ventilator sessions are delivered&#xD;
      intermittently. In the past decade, a new technique that provides air-oxygen with high flow&#xD;
      has been developed. This technique, called High Flow via Nasal Cannula (HFNC) can deliver&#xD;
      from 21 to 100% heated and humidified air-oxygen at a high flow of gas via simple nasal&#xD;
      cannula. Recent studies have shown that the technique is very efficient to treat patients&#xD;
      presenting with acute respiratory failure who don't have any underlying chronic pulmonary&#xD;
      disease. Whether the technique would be also efficient in patients with COLD presenting with&#xD;
      severe exacerbations has not yet been demonstrated. Since HFNC does not require any mask, it&#xD;
      is thought that the comfort of the patient would be much better in comparison to NIV and&#xD;
      could potentially help to treat many patients with the disease. The objective of the present&#xD;
      study is to study the physiological effect of HFNC as compared to NIV in patients with severe&#xD;
      exacerbations of COPD and to show that it is non-inferior to NIV.&#xD;
    </textblock>
  </brief_summary>
  <detailed_description>
    <textblock>
      Design: Prospective, observational, cross-over, clinical physiologic study of HFNC and NIV in&#xD;
      patients with COPD and hypercapnic respiratory failure Intervention: Participants will be&#xD;
      consecutively ventilated with the two devices, i.e., HFNC and NIV. HFNC 30 and 50 L/min will&#xD;
      be applied in a random order (sealed, opaque envelope). HFNC will be set with a temperature&#xD;
      at 37°C or 34°C if perceived as too warm. NIV settings will be adjusted based on the clinical&#xD;
      assessment of the Respiratory Therapist as per standard practice and will not be modified&#xD;
      during the test. In both groups, FiO2 will be adjusted to achieve a SpO2 of at least 92%.&#xD;
&#xD;
      Setting: The intervention will be applied in the Medical-Surgical ICU of St. Michael's&#xD;
      Hospital.&#xD;
&#xD;
      Duration: Each device will be studied for 30 minutes. The entire study will take place over&#xD;
      approximately 3 hours. There is no additional follow-up thereafter.&#xD;
&#xD;
      Procedures: The study will start first by recording patients under spontaneous breathing&#xD;
      considered as a baseline (sequence #1). Under spontaneous breathing, patients will be&#xD;
      receiving oxygen therapy as it is usually done between 2 NIV sessions. Then, the patient will&#xD;
      have 20 -30 minutes to acclimatize to HFNC and select his/her preferred flow rate (sequence&#xD;
      #2). NIV will be applied (sequence #3). The NIV settings will be adjusted based on the&#xD;
      clinical assessment of the Respiratory Therapist and will not be modified throughout the&#xD;
      study. Then, according to randomization order (sealed envelopes), patients will receive a&#xD;
      flow corresponding to the preferred flow selected by the patient and a second flow, either&#xD;
      HFNC 30 L/min or HFNC 50 L/min depending on the initial choice (sequences #4 and #5) (see&#xD;
      flow diagram). FiO2 will be adjusted to achieve a SpO2 of 90 to 94%. Each condition will be&#xD;
      studied for 30 minutes and will be separated by a 5-minute washout period during which&#xD;
      patients will be receiving oxygen therapy. The measurements will be collected at baseline&#xD;
      (under spontaneous breathing) and during the last five minutes of each condition. In case of&#xD;
      clinical intolerance as considered by the attending physician, the study will stop. In case&#xD;
      the patient is considered dependent of NIV by clinicians, we will still enroll the patient&#xD;
      without doing baseline period after discussion with clinicians.&#xD;
&#xD;
      The pulse oximeter (SpO2) and transcutaneous CO2 monitor (SenTec Digital Monitoring System&#xD;
      (SDMS)) will be continuously monitored throughout the study period. Exspiron device will be&#xD;
      calibrated to measure minute ventilation. Four surface electrodes will be placed bilaterally&#xD;
      to record each hemidiaphragm activity using a specific recording system (Acqknowledge&#xD;
      software, Biopac Systems) A bedside ultrasound examination will be performed, using a&#xD;
      SonoSite system (Fujifilm) equipped with a 10-15 MHz ultrasound linear probe. Diaphragm&#xD;
      thickness will be measured both at end-inspiration and end-expiration. This technique will be&#xD;
      applied at the end of each sequence (before ventilatory assist under conventional O2&#xD;
      therapy). In patients becoming rapidly intolerant to NIV disconnection, we will limit this&#xD;
      &quot;baseline&quot; period under O2 to a minimum (5 minutes). The thickness and contraction of the&#xD;
      intercostal muscles and abdominal muscles will also be assessed.&#xD;
&#xD;
      Interpretation of the ultrasound results to determine diaphragm and other muscle thickness&#xD;
      will be read at a later time by an individual blinded to the intervention.&#xD;
    </textblock>
  </detailed_description>
  <overall_status>Unknown status</overall_status>
  <last_known_status>Recruiting</last_known_status>
  <start_date type="Actual">September 2, 2018</start_date>
  <completion_date type="Anticipated">July 1, 2022</completion_date>
  <primary_completion_date type="Anticipated">July 1, 2022</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>Crossover Assignment</intervention_model>
    <intervention_model_description>Participants will receive 2 treatments (non invasive ventilation and high flow nasal cannula). The high flow nasal cannula will be applied with 2 flows (50 L/min and 30 L/min). The order of application of the 2 high flow sequences will be randomized (sealed opaque enveloppes).</intervention_model_description>
    <primary_purpose>Treatment</primary_purpose>
    <masking>None (Open Label)</masking>
  </study_design_info>
  <primary_outcome>
    <measure>Change in work of breathing between NIV and HFNC</measure>
    <time_frame>30 minutes</time_frame>
    <description>The primary endpoint is to compare the decrease in work of breathing under HFNC to the decrease in work of breathing under NIV.&#xD;
The work of breathing will be assessed with diaphragm ultrasound (measurement of the diaphragm thickening fraction).</description>
  </primary_outcome>
  <secondary_outcome>
    <measure>Change in Work of breathing between HFNC 50 and 30 L/min</measure>
    <time_frame>30 minutes</time_frame>
    <description>The secondary endpoints include comparison of the work of breathing under HFNC (50L/min vs 30 L/min).&#xD;
The work of breathing will be assessed with diaphragm ultrasound (measurement of the diaphragm thickening fraction).</description>
  </secondary_outcome>
  <number_of_arms>3</number_of_arms>
  <enrollment type="Anticipated">30</enrollment>
  <condition>Exacerbation Copd</condition>
  <condition>Acute Respiratory Distress</condition>
  <arm_group>
    <arm_group_label>Non invasive ventilation</arm_group_label>
    <arm_group_type>Active Comparator</arm_group_type>
    <description>Patients will receive non invasive ventilation with setting decided by the attending physician.</description>
  </arm_group>
  <arm_group>
    <arm_group_label>High Flow 50 L/min</arm_group_label>
    <arm_group_type>Active Comparator</arm_group_type>
    <description>High Flow Oxygen Cannula with a flow set at 50 L/min.</description>
  </arm_group>
  <arm_group>
    <arm_group_label>High Flow 30 L/min</arm_group_label>
    <arm_group_type>Active Comparator</arm_group_type>
    <description>High Flow Oxygen Cannula with a flow set at 30 L/min.</description>
  </arm_group>
  <intervention>
    <intervention_type>Device</intervention_type>
    <intervention_name>Non Invasive Ventilation</intervention_name>
    <description>Patients will receive non invasive ventilation as a standard of care.</description>
    <arm_group_label>Non invasive ventilation</arm_group_label>
    <other_name>Standard of Care</other_name>
  </intervention>
  <intervention>
    <intervention_type>Device</intervention_type>
    <intervention_name>High Flow Oxygen Cannula 50</intervention_name>
    <description>Patients will receive High Flow Oxygen Cannula with a flow set at 50 L/min</description>
    <arm_group_label>High Flow 50 L/min</arm_group_label>
    <other_name>HFNO 50</other_name>
  </intervention>
  <intervention>
    <intervention_type>Device</intervention_type>
    <intervention_name>High Flow Oxygen Cannula 30</intervention_name>
    <description>Patients will receive High Flow Oxygen Cannula with a flow set at 30 L/min</description>
    <arm_group_label>High Flow 30 L/min</arm_group_label>
    <other_name>HFNO 30</other_name>
  </intervention>
  <eligibility>
    <criteria>
      <textblock>
        Inclusion Criteria:&#xD;
&#xD;
          1. COPD exacerbation with acute respiratory failure defined by&#xD;
&#xD;
               -  Respiratory acidosis (pH ≤7.35 and PaCO2 ≥45 mmHg);&#xD;
&#xD;
               -  Respiratory rate≥20 breaths/min;&#xD;
&#xD;
               -  Activation of accessory respiratory muscles;&#xD;
&#xD;
          2. Undergone at least 1 hour of NIV since their admission&#xD;
&#xD;
          3. English speaking&#xD;
&#xD;
          4. Adult patient with age &gt; 40 year old.&#xD;
&#xD;
        Exclusion Criteria:&#xD;
&#xD;
          1. Severe respiratory acidosis defined by pH&lt;7.25&#xD;
&#xD;
          2. Decreased level of consciousness (Glasgow Coma Score Scale &lt; 11)&#xD;
&#xD;
          3. Urgent intubation required&#xD;
&#xD;
          4. Pneumothorax with pleural drainage and persistent air leak&#xD;
&#xD;
          5. Hemodynamic instability requiring vasopressors&#xD;
&#xD;
          6. Uncooperative&#xD;
&#xD;
          7. Patients with skin or chest wall or abdominal trauma (potentially worsened by&#xD;
             placement of a surface sensor)&#xD;
&#xD;
          8. Clinical judgement of the attending physician&#xD;
&#xD;
          9. Body mass index &gt; 35 kg/m2&#xD;
      </textblock>
    </criteria>
    <gender>All</gender>
    <minimum_age>40 Years</minimum_age>
    <maximum_age>N/A</maximum_age>
    <healthy_volunteers>No</healthy_volunteers>
  </eligibility>
  <overall_contact>
    <last_name>Laurent Brochard, MD</last_name>
    <phone>+1 416 864 5686</phone>
    <email>BrochardL@smh.ca</email>
  </overall_contact>
  <overall_contact_backup>
    <last_name>Martin Dres, MD</last_name>
    <phone>+1 416 692 7420</phone>
    <email>DresM@smh.ca</email>
  </overall_contact_backup>
  <location>
    <facility>
      <name>St. Michael's Hospital</name>
      <address>
        <city>Toronto</city>
        <state>Ontario</state>
        <zip>M5B 1W8</zip>
        <country>Canada</country>
      </address>
    </facility>
    <status>Recruiting</status>
    <contact>
      <last_name>Laurent Brochard</last_name>
      <email>brochardl@smh.ca</email>
    </contact>
  </location>
  <location_countries>
    <country>Canada</country>
  </location_countries>
  <verification_date>June 2021</verification_date>
  <study_first_submitted>January 19, 2017</study_first_submitted>
  <study_first_submitted_qc>January 24, 2017</study_first_submitted_qc>
  <study_first_posted type="Estimate">January 26, 2017</study_first_posted>
  <last_update_submitted>June 28, 2021</last_update_submitted>
  <last_update_submitted_qc>June 28, 2021</last_update_submitted_qc>
  <last_update_posted type="Actual">June 29, 2021</last_update_posted>
  <responsible_party>
    <responsible_party_type>Sponsor</responsible_party_type>
  </responsible_party>
  <keyword>COPD exacerbation</keyword>
  <keyword>Work of breathing</keyword>
  <keyword>Non invasive ventilation</keyword>
  <keyword>High Flow Oxygen Cannula</keyword>
  <condition_browse>
    <!-- CAUTION:  The following MeSH terms are assigned with an imperfect algorithm            -->
    <mesh_term>Lung Diseases, Obstructive</mesh_term>
    <mesh_term>Pulmonary Disease, Chronic Obstructive</mesh_term>
  </condition_browse>
  <patient_data>
    <sharing_ipd>No</sharing_ipd>
  </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/NCT03033251
org study id: REB# 16-389
nct id: NCT03033251
lead sponsor: 
has dmc: No
is fda regulated drug: No
is fda regulated device: No
Chronic obstructive lung disease is a disabling disease that affects people usually after
      several years of smoke tobacco exposure and affects millions of patients worldwide. The
      disease is marked by multiples episode of worsening, termed exacerbations necessitating
      frequent hospitalizations. During these exacerbations, patients present breathless, and in
      the most severe cases, are admitted to an Intensive Care Unit (ICU) for respiratory
      assistance. Currently, respiratory assistance is provided by a ventilator via a oronasal mask
      (referred to non-invasive ventilation, NIV), that helps patients to cope with their
      breathless. The mask is not always well tolerated and the ventilator sessions are delivered
      intermittently. In the past decade, a new technique that provides air-oxygen with high flow
      has been developed. This technique, called High Flow via Nasal Cannula (HFNC) can deliver
      from 21 to 100% heated and humidified air-oxygen at a high flow of gas via simple nasal
      cannula. Recent studies have shown that the technique is very efficient to treat patients
      presenting with acute respiratory failure who don't have any underlying chronic pulmonary
      disease. Whether the technique would be also efficient in patients with COLD presenting with
      severe exacerbations has not yet been demonstrated. Since HFNC does not require any mask, it
      is thought that the comfort of the patient would be much better in comparison to NIV and
      could potentially help to treat many patients with the disease. The objective of the present
      study is to study the physiological effect of HFNC as compared to NIV in patients with severe
      exacerbations of COPD and to show that it is non-inferior to NIV.
Design: Prospective, observational, cross-over, clinical physiologic study of HFNC and NIV in
      patients with COPD and hypercapnic respiratory failure Intervention: Participants will be
      consecutively ventilated with the two devices, i.e., HFNC and NIV. HFNC 30 and 50 L/min will
      be applied in a random order (sealed, opaque envelope). HFNC will be set with a temperature
      at 37°C or 34°C if perceived as too warm. NIV settings will be adjusted based on the clinical
      assessment of the Respiratory Therapist as per standard practice and will not be modified
      during the test. In both groups, FiO2 will be adjusted to achieve a SpO2 of at least 92%.

      Setting: The intervention will be applied in the Medical-Surgical ICU of St. Michael's
      Hospital.

      Duration: Each device will be studied for 30 minutes. The entire study will take place over
      approximately 3 hours. There is no additional follow-up thereafter.

      Procedures: The study will start first by recording patients under spontaneous breathing
      considered as a baseline (sequence #1). Under spontaneous breathing, patients will be
      receiving oxygen therapy as it is usually done between 2 NIV sessions. Then, the patient will
      have 20 -30 minutes to acclimatize to HFNC and select his/her preferred flow rate (sequence
      #2). NIV will be applied (sequence #3). The NIV settings will be adjusted based on the
      clinical assessment of the Respiratory Therapist and will not be modified throughout the
      study. Then, according to randomization order (sealed envelopes), patients will receive a
      flow corresponding to the preferred flow selected by the patient and a second flow, either
      HFNC 30 L/min or HFNC 50 L/min depending on the initial choice (sequences #4 and #5) (see
      flow diagram). FiO2 will be adjusted to achieve a SpO2 of 90 to 94%. Each condition will be
      studied for 30 minutes and will be separated by a 5-minute washout period during which
      patients will be receiving oxygen therapy. The measurements will be collected at baseline
      (under spontaneous breathing) and during the last five minutes of each condition. In case of
      clinical intolerance as considered by the attending physician, the study will stop. In case
      the patient is considered dependent of NIV by clinicians, we will still enroll the patient
      without doing baseline period after discussion with clinicians.

      The pulse oximeter (SpO2) and transcutaneous CO2 monitor (SenTec Digital Monitoring System
      (SDMS)) will be continuously monitored throughout the study period. Exspiron device will be
      calibrated to measure minute ventilation. Four surface electrodes will be placed bilaterally
      to record each hemidiaphragm activity using a specific recording system (Acqknowledge
      software, Biopac Systems) A bedside ultrasound examination will be performed, using a
      SonoSite system (Fujifilm) equipped with a 10-15 MHz ultrasound linear probe. Diaphragm
      thickness will be measured both at end-inspiration and end-expiration. This technique will be
      applied at the end of each sequence (before ventilatory assist under conventional O2
      therapy). In patients becoming rapidly intolerant to NIV disconnection, we will limit this
      "baseline" period under O2 to a minimum (5 minutes). The thickness and contraction of the
      intercostal muscles and abdominal muscles will also be assessed.

      Interpretation of the ultrasound results to determine diaphragm and other muscle thickness
      will be read at a later time by an individual blinded to the intervention.
allocation: Randomized
intervention model: Crossover Assignment
intervention model description: Participants will receive 2 treatments (non invasive ventilation and high flow nasal cannula). The high flow nasal cannula will be applied with 2 flows (50 L/min and 30 L/min). The order of application of the 2 high flow sequences will be randomized (sealed opaque enveloppes).
primary purpose: Treatment
masking: None (Open Label)
measure: Change in work of breathing between NIV and HFNC
time frame: 30 minutes
description: The primary endpoint is to compare the decrease in work of breathing under HFNC to the decrease in work of breathing under NIV.
The work of breathing will be assessed with diaphragm ultrasound (measurement of the diaphragm thickening fraction).
measure: Change in Work of breathing between HFNC 50 and 30 L/min
time frame: 30 minutes
description: The secondary endpoints include comparison of the work of breathing under HFNC (50L/min vs 30 L/min).
The work of breathing will be assessed with diaphragm ultrasound (measurement of the diaphragm thickening fraction).
arm group label: Non invasive ventilation
arm group type: Active Comparator
description: Patients will receive non invasive ventilation with setting decided by the attending physician.
arm group label: High Flow 50 L/min
arm group type: Active Comparator
description: High Flow Oxygen Cannula with a flow set at 50 L/min.
arm group label: High Flow 30 L/min
arm group type: Active Comparator
description: High Flow Oxygen Cannula with a flow set at 30 L/min.
intervention type: Device
intervention name: Non Invasive Ventilation
description: Patients will receive non invasive ventilation as a standard of care.
arm group label: Non invasive ventilation
other name: Standard of Care
intervention type: Device
intervention name: High Flow Oxygen Cannula 50
description: Patients will receive High Flow Oxygen Cannula with a flow set at 50 L/min
arm group label: High Flow 50 L/min
other name: HFNO 50
intervention type: Device
intervention name: High Flow Oxygen Cannula 30
description: Patients will receive High Flow Oxygen Cannula with a flow set at 30 L/min
arm group label: High Flow 30 L/min
other name: HFNO 30
criteria: 
gender: All
minimum age: 40 Years
maximum age: N/A
healthy volunteers: No
last name: Laurent Brochard, MD
phone: +1 416 864 5686
email: BrochardL@smh.ca
last name: Martin Dres, MD
phone: +1 416 692 7420
email: DresM@smh.ca
facility: 
status: Recruiting
contact: 
country: Canada
responsible party type: Sponsor
mesh term: Lung Diseases, Obstructive
mesh term: Pulmonary Disease, Chronic Obstructive
sharing ipd: No