<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/NCT04497090</url>
  </required_header>
  <id_info>
    <org_study_id>Polimi</org_study_id>
    <nct_id>NCT04497090</nct_id>
  </id_info>
  <brief_title>Adaptive Non-invasive Ventilation to Abolish Tidal Flow Limitation</brief_title>
  <official_title>Non-invasive Ventilation With Automatic Expiratory Positive Airway Pressure Titration to Abolish Tidal Expiratory Flow Limitation in COPD Patients With Chronic Hypercapnia</official_title>
  <sponsors>
    <lead_sponsor>
      <agency>Politecnico di Milano</agency>
      <agency_class>Other</agency_class>
    </lead_sponsor>
    <collaborator>
      <agency>Istituti Clinici Scientifici Maugeri SpA</agency>
      <agency_class>Other</agency_class>
    </collaborator>
    <collaborator>
      <agency>Philips Healthcare</agency>
      <agency_class>Industry</agency_class>
    </collaborator>
  </sponsors>
  <source>Politecnico di Milano</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>
      This study aimed to evaluate the effects of a novel automatic non-invasive ventilation (NIV)&#xD;
      mode that continuously adjusts expiratory positive airway pressure (EPAP) to the lowest value&#xD;
      that abolishes tidal expiratory flow limitation. The investigators conducted a prospective,&#xD;
      randomized, cross-over study on stable chronic obstructive pulmonary disease (COPD) patients.&#xD;
      Patients were studied in the hospital during two non-consecutive nights while using either&#xD;
      fixed or adaptive EPAP. The primary outcome was the transcutaneous partial pressure of carbon&#xD;
      dioxide. Secondary outcomes were: oxygen saturation, breathing pattern, oscillatory&#xD;
      mechanics, patient-ventilation asynchronies, sleep quality and sleep-related respiratory&#xD;
      events.&#xD;
    </textblock>
  </brief_summary>
  <detailed_description>
    <textblock>
      Study design: prospective, randomized, cross-over study. Study population: moderate to severe&#xD;
      COPD patients, long-term users of nocturnal non-invasive ventilation for chronic hypercapnic&#xD;
      respiratory failure. Inclusion criteria: age&lt;85 years; presence of tidal expiratory flow&#xD;
      limitation in the supine position at an expiratory positive airway pressure of 4 cmH2O.&#xD;
      Exclusion criteria: COPD exacerbation within the past two months; acute illness; clinical&#xD;
      instability.&#xD;
&#xD;
      Study protocol: Patients were studied in the hospital over 2 non-consecutive nights while&#xD;
      using either fixed or automatic EPAP.&#xD;
&#xD;
      Ventilation strategy: pressure-controlled NIV was delivered using a non-commercial version of&#xD;
      BiPAP Synchrony Ventilator (Philips-Respironics) via an unvented facial mask (AMARA,&#xD;
      Philips-Respironics). The ventilator evaluated the presence of tidal expiratory flow&#xD;
      limitation by the forced oscillation technique. In the automatic-EPAP mode, the ventilator&#xD;
      continuously adjusted EPAP to the minimum level able to abolish tidal expiratory flow&#xD;
      limitation, with a minimum EPAP of 4 cmH2O and keeping the pressure support constant.&#xD;
&#xD;
      Measurements: During each study night, the investigators recorded transcutaneous partial&#xD;
      pressure of carbon dioxide and oxygen saturation (TOSCA, Radiometer) continuously. Airway&#xD;
      opening pressure, flow and volume tracings were exported from the ventilator. Full laboratory&#xD;
      polysomnography (Alice5, Philips-Respironics) was performed according to the American Academy&#xD;
      of Sleep Medicine recommendations.&#xD;
&#xD;
      Data analysis: the investigators compared parameters from the two nights using Wilcoxon&#xD;
      signed-rank test. P-values &lt;0.05 were considered statistically significant.&#xD;
    </textblock>
  </detailed_description>
  <overall_status>Completed</overall_status>
  <start_date type="Actual">October 23, 2014</start_date>
  <completion_date type="Actual">May 15, 2018</completion_date>
  <primary_completion_date type="Actual">May 15, 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>Crossover Assignment</intervention_model>
    <primary_purpose>Supportive Care</primary_purpose>
    <masking>None (Open Label)</masking>
  </study_design_info>
  <primary_outcome>
    <measure>Mean transcutaneous partial pressure of carbon dioxide (PtcCO2)</measure>
    <time_frame>Overnight (about 8 hours)</time_frame>
    <description>The partial pressure of carbon dioxide measures the efficacy of ventilation. Reducing PCO2 is the aim of nocturnal non-invasive ventilation in stable COPD patients with chronic hypercapnia. PCO2 is normally measured non-invasively using a transcutaneous probe during overnight studies.</description>
  </primary_outcome>
  <primary_outcome>
    <measure>Percent of night time spent in hypercapnia</measure>
    <time_frame>Overnight (about 8 hours)</time_frame>
    <description>Hypercapnia is defined as PtcCO2 &gt; 45 mm Hg. The aim of non-invasive ventilation in stable COPD patients is to reduce the time spent with PCO2 levels above the physiological range.</description>
  </primary_outcome>
  <secondary_outcome>
    <measure>Mean peripheral oxygen saturation (SpO2)</measure>
    <time_frame>Through study completion, an average of 8 hours</time_frame>
    <description>Peripheral oxygen saturation in a non-invasive measure of oxygenation, which is routinely evaluated in sleep and ventilation trials.</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Desaturation</measure>
    <time_frame>Through study completion, an average of 8 hours</time_frame>
    <description>Desaturations are common complications in respiratory disorders. A desaturation is commonly defined by a reduction in SpO2 &lt; 90%. The investigators computed the percent of night time in which SpO2 was &lt; 90% and the Oxygen Desaturation Index (number of desaturations per hour).</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Number of ineffective efforts per hour (IE)</measure>
    <time_frame>Through study completion, an average of 8 hours</time_frame>
    <description>Ineffective efforts are defined as inspiratory efforts that are not supported by the ventilator. They are indicative of patient-ventilator asynchrony, they may be associated with tidal expiratory flow limitation and they increase work of breathing and cause discomfort.</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Sleep quality</measure>
    <time_frame>Through study completion, an average of 8 hours</time_frame>
    <description>Sleep quality is a key outcome during overnight studies. Nocturnal non-invasive ventilation may affect sleep quality in two ways: 1) it may improve it by reducing sleep-related respiratory problems; 2) it may worsen it if the ventilation mode causes discomfort to the patient. Sleep quality was evaluated by full laboratory polysomnography. Sleep stages were identified on epochs lasting 30 seconds by a trained operator blind to the study arms. Sleep quality was quantified using the following parameters: Sleep efficiency (percent of night time asleep), percentage of sleep time spent in phase 3 sleep and in REM sleep, number of awakenings per hour.</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>EPAP</measure>
    <time_frame>Through study completion, an average of 8 hours</time_frame>
    <description>The expiratory positive airway pressure (EPAP) is the parameter that is adjusted in the experimental arm. The ventilator automatically titrates EPAP to the minimum value able to abolish expiratory flow limitation.</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Breathing pattern</measure>
    <time_frame>Through study completion, an average of 8 hours</time_frame>
    <description>Tidal volume, respiratory rate, minute ventilation, and inspiratory to expiratory time ratio are the breathing pattern parameters that the respiratory control system adjusts to achieve an adequate gas exchange while minimizing work of breathing. Non-invasive ventilation interacts with and supports breathing pattern.</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Difference between mean inspiratory and expiatory reactance</measure>
    <time_frame>Through study completion, an average of 8 hours</time_frame>
    <description>The difference between mean inspiratory and expiatory reactance is measured using the forced oscillation technique. The difference between mean inspiratory and expiratory reactance is an index of tidal expiratory flow limitation. Values &gt; 2.8 cmH2O*s/L are indicative of tidal expiratory flow limitation.</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Mean inspiratory resistance</measure>
    <time_frame>Through study completion, an average of 8 hours</time_frame>
    <description>Mean inspiratory resistance is measured using the forced oscillation technique. Inspiratory resistance is an index of airway obstruction, which increases work of breathing and contributes to the development of flow limitation.</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Mean inspiratory reactance</measure>
    <time_frame>Through study completion, an average of 8 hours</time_frame>
    <description>Mean inspiratory reactance is measured using the forced oscillation technique.</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Sleep related respiratory event</measure>
    <time_frame>Through study completion, an average of 8 hours</time_frame>
    <description>During full laboratory polysomnography the respiratory activity is monitored and sleep related respiratory events are analysed, such as apneas, hypopnea, with a breakdown into central, peripheral or mixed events.</description>
  </secondary_outcome>
  <number_of_arms>2</number_of_arms>
  <enrollment type="Actual">12</enrollment>
  <condition>Pulmonary Disease, Chronic Obstructive</condition>
  <condition>Hypercapnia</condition>
  <condition>Ventilator Lung</condition>
  <arm_group>
    <arm_group_label>Fixed-EPAP</arm_group_label>
    <arm_group_type>Active Comparator</arm_group_type>
    <description>EPAP was kept fixed at the prescribed level throughout the night</description>
  </arm_group>
  <arm_group>
    <arm_group_label>Auto-EPAP</arm_group_label>
    <arm_group_type>Experimental</arm_group_type>
    <description>EPAP was continuously adjusted using the experimental approach aimed at abolishing tidal expiratory flow limitation</description>
  </arm_group>
  <intervention>
    <intervention_type>Device</intervention_type>
    <intervention_name>fixed-EPAP</intervention_name>
    <description>In the fixed-EPAP mode, the device kept EPAP fixed at the prescribed value</description>
    <arm_group_label>Fixed-EPAP</arm_group_label>
  </intervention>
  <intervention>
    <intervention_type>Device</intervention_type>
    <intervention_name>auto-EPAP</intervention_name>
    <description>In the Auto-EPAP mode, the device automatically adjusted EPAP to the minimum level able to abolish tidal expiratory flow limitation.</description>
    <arm_group_label>Auto-EPAP</arm_group_label>
  </intervention>
  <eligibility>
    <criteria>
      <textblock>
        Inclusion Criteria:&#xD;
&#xD;
          -  moderate to severe COPD (GOLD 2017);&#xD;
&#xD;
          -  long-term users of nocturnal non-invasive ventilation for chronic hypercapnic&#xD;
             respiratory failure;&#xD;
&#xD;
          -  presence of tidal expiratory flow limitation in the supine position at an expiratory&#xD;
             positive airway pressure of 4 cmH2O.&#xD;
&#xD;
        Exclusion Criteria:&#xD;
&#xD;
          -  COPD exacerbation within the past two months;&#xD;
&#xD;
          -  acute illness;&#xD;
&#xD;
          -  clinical instability.&#xD;
      </textblock>
    </criteria>
    <gender>All</gender>
    <minimum_age>18 Years</minimum_age>
    <maximum_age>84 Years</maximum_age>
    <healthy_volunteers>No</healthy_volunteers>
  </eligibility>
  <overall_official>
    <last_name>Raffaele L Dellacà, Prof.</last_name>
    <role>Principal Investigator</role>
    <affiliation>Politecnico di Milano</affiliation>
  </overall_official>
  <location>
    <facility>
      <name>Divisione di Pneumologia, Fondazione S. Maugeri, IRCCS</name>
      <address>
        <city>Lumezzane</city>
        <state>BS</state>
        <country>Italy</country>
      </address>
    </facility>
  </location>
  <location_countries>
    <country>Italy</country>
  </location_countries>
  <reference>
    <citation>Milesi I, Porta R, Barbano L, Cacciatore S, Vitacca M, Dellaca RL. Automatic tailoring of the lowest PEEP to abolish tidal expiratory flow limitation in seated and supine COPD patients. Respir Med. 2019 Aug;155:13-18. doi: 10.1016/j.rmed.2019.06.022. Epub 2019 Jun 23.</citation>
    <PMID>31276979</PMID>
  </reference>
  <verification_date>July 2020</verification_date>
  <study_first_submitted>July 25, 2020</study_first_submitted>
  <study_first_submitted_qc>July 29, 2020</study_first_submitted_qc>
  <study_first_posted type="Actual">August 4, 2020</study_first_posted>
  <last_update_submitted>July 29, 2020</last_update_submitted>
  <last_update_submitted_qc>July 29, 2020</last_update_submitted_qc>
  <last_update_posted type="Actual">August 4, 2020</last_update_posted>
  <responsible_party>
    <responsible_party_type>Principal Investigator</responsible_party_type>
    <investigator_affiliation>Politecnico di Milano</investigator_affiliation>
    <investigator_full_name>Raffaele Dellaca</investigator_full_name>
    <investigator_title>Prof</investigator_title>
  </responsible_party>
  <condition_browse>
    <!-- CAUTION:  The following MeSH terms are assigned with an imperfect algorithm            -->
    <mesh_term>Pulmonary Disease, Chronic Obstructive</mesh_term>
    <mesh_term>Hypercapnia</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/NCT04497090
org study id: Polimi
nct id: NCT04497090
lead sponsor: 
collaborator: 
collaborator: 
has dmc: No
is fda regulated drug: No
is fda regulated device: No
This study aimed to evaluate the effects of a novel automatic non-invasive ventilation (NIV)
      mode that continuously adjusts expiratory positive airway pressure (EPAP) to the lowest value
      that abolishes tidal expiratory flow limitation. The investigators conducted a prospective,
      randomized, cross-over study on stable chronic obstructive pulmonary disease (COPD) patients.
      Patients were studied in the hospital during two non-consecutive nights while using either
      fixed or adaptive EPAP. The primary outcome was the transcutaneous partial pressure of carbon
      dioxide. Secondary outcomes were: oxygen saturation, breathing pattern, oscillatory
      mechanics, patient-ventilation asynchronies, sleep quality and sleep-related respiratory
      events.
Study design: prospective, randomized, cross-over study. Study population: moderate to severe
      COPD patients, long-term users of nocturnal non-invasive ventilation for chronic hypercapnic
      respiratory failure. Inclusion criteria: age<85 years; presence of tidal expiratory flow
      limitation in the supine position at an expiratory positive airway pressure of 4 cmH2O.
      Exclusion criteria: COPD exacerbation within the past two months; acute illness; clinical
      instability.

      Study protocol: Patients were studied in the hospital over 2 non-consecutive nights while
      using either fixed or automatic EPAP.

      Ventilation strategy: pressure-controlled NIV was delivered using a non-commercial version of
      BiPAP Synchrony Ventilator (Philips-Respironics) via an unvented facial mask (AMARA,
      Philips-Respironics). The ventilator evaluated the presence of tidal expiratory flow
      limitation by the forced oscillation technique. In the automatic-EPAP mode, the ventilator
      continuously adjusted EPAP to the minimum level able to abolish tidal expiratory flow
      limitation, with a minimum EPAP of 4 cmH2O and keeping the pressure support constant.

      Measurements: During each study night, the investigators recorded transcutaneous partial
      pressure of carbon dioxide and oxygen saturation (TOSCA, Radiometer) continuously. Airway
      opening pressure, flow and volume tracings were exported from the ventilator. Full laboratory
      polysomnography (Alice5, Philips-Respironics) was performed according to the American Academy
      of Sleep Medicine recommendations.

      Data analysis: the investigators compared parameters from the two nights using Wilcoxon
      signed-rank test. P-values <0.05 were considered statistically significant.
allocation: Randomized
intervention model: Crossover Assignment
primary purpose: Supportive Care
masking: None (Open Label)
measure: Mean transcutaneous partial pressure of carbon dioxide (PtcCO2)
time frame: Overnight (about 8 hours)
description: The partial pressure of carbon dioxide measures the efficacy of ventilation. Reducing PCO2 is the aim of nocturnal non-invasive ventilation in stable COPD patients with chronic hypercapnia. PCO2 is normally measured non-invasively using a transcutaneous probe during overnight studies.
measure: Percent of night time spent in hypercapnia
time frame: Overnight (about 8 hours)
description: Hypercapnia is defined as PtcCO2 > 45 mm Hg. The aim of non-invasive ventilation in stable COPD patients is to reduce the time spent with PCO2 levels above the physiological range.
measure: Mean peripheral oxygen saturation (SpO2)
time frame: Through study completion, an average of 8 hours
description: Peripheral oxygen saturation in a non-invasive measure of oxygenation, which is routinely evaluated in sleep and ventilation trials.
measure: Desaturation
time frame: Through study completion, an average of 8 hours
description: Desaturations are common complications in respiratory disorders. A desaturation is commonly defined by a reduction in SpO2 < 90%. The investigators computed the percent of night time in which SpO2 was < 90% and the Oxygen Desaturation Index (number of desaturations per hour).
measure: Number of ineffective efforts per hour (IE)
time frame: Through study completion, an average of 8 hours
description: Ineffective efforts are defined as inspiratory efforts that are not supported by the ventilator. They are indicative of patient-ventilator asynchrony, they may be associated with tidal expiratory flow limitation and they increase work of breathing and cause discomfort.
measure: Sleep quality
time frame: Through study completion, an average of 8 hours
description: Sleep quality is a key outcome during overnight studies. Nocturnal non-invasive ventilation may affect sleep quality in two ways: 1) it may improve it by reducing sleep-related respiratory problems; 2) it may worsen it if the ventilation mode causes discomfort to the patient. Sleep quality was evaluated by full laboratory polysomnography. Sleep stages were identified on epochs lasting 30 seconds by a trained operator blind to the study arms. Sleep quality was quantified using the following parameters: Sleep efficiency (percent of night time asleep), percentage of sleep time spent in phase 3 sleep and in REM sleep, number of awakenings per hour.
measure: EPAP
time frame: Through study completion, an average of 8 hours
description: The expiratory positive airway pressure (EPAP) is the parameter that is adjusted in the experimental arm. The ventilator automatically titrates EPAP to the minimum value able to abolish expiratory flow limitation.
measure: Breathing pattern
time frame: Through study completion, an average of 8 hours
description: Tidal volume, respiratory rate, minute ventilation, and inspiratory to expiratory time ratio are the breathing pattern parameters that the respiratory control system adjusts to achieve an adequate gas exchange while minimizing work of breathing. Non-invasive ventilation interacts with and supports breathing pattern.
measure: Difference between mean inspiratory and expiatory reactance
time frame: Through study completion, an average of 8 hours
description: The difference between mean inspiratory and expiatory reactance is measured using the forced oscillation technique. The difference between mean inspiratory and expiratory reactance is an index of tidal expiratory flow limitation. Values > 2.8 cmH2O*s/L are indicative of tidal expiratory flow limitation.
measure: Mean inspiratory resistance
time frame: Through study completion, an average of 8 hours
description: Mean inspiratory resistance is measured using the forced oscillation technique. Inspiratory resistance is an index of airway obstruction, which increases work of breathing and contributes to the development of flow limitation.
measure: Mean inspiratory reactance
time frame: Through study completion, an average of 8 hours
description: Mean inspiratory reactance is measured using the forced oscillation technique.
measure: Sleep related respiratory event
time frame: Through study completion, an average of 8 hours
description: During full laboratory polysomnography the respiratory activity is monitored and sleep related respiratory events are analysed, such as apneas, hypopnea, with a breakdown into central, peripheral or mixed events.
arm group label: Fixed-EPAP
arm group type: Active Comparator
description: EPAP was kept fixed at the prescribed level throughout the night
arm group label: Auto-EPAP
arm group type: Experimental
description: EPAP was continuously adjusted using the experimental approach aimed at abolishing tidal expiratory flow limitation
intervention type: Device
intervention name: fixed-EPAP
description: In the fixed-EPAP mode, the device kept EPAP fixed at the prescribed value
arm group label: Fixed-EPAP
intervention type: Device
intervention name: auto-EPAP
description: In the Auto-EPAP mode, the device automatically adjusted EPAP to the minimum level able to abolish tidal expiratory flow limitation.
arm group label: Auto-EPAP
criteria: 
gender: All
minimum age: 18 Years
maximum age: 84 Years
healthy volunteers: No
last name: Raffaele L Dellacà, Prof.
role: Principal Investigator
affiliation: Politecnico di Milano
facility: 
country: Italy
citation: Milesi I, Porta R, Barbano L, Cacciatore S, Vitacca M, Dellaca RL. Automatic tailoring of the lowest PEEP to abolish tidal expiratory flow limitation in seated and supine COPD patients. Respir Med. 2019 Aug;155:13-18. doi: 10.1016/j.rmed.2019.06.022. Epub 2019 Jun 23.
PMID: 31276979
responsible party type: Principal Investigator
investigator affiliation: Politecnico di Milano
investigator full name: Raffaele Dellaca
investigator title: Prof
mesh term: Pulmonary Disease, Chronic Obstructive
mesh term: Hypercapnia
sharing ipd: No