<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/NCT02201875</url>
  </required_header>
  <id_info>
    <org_study_id>PERHYP1</org_study_id>
    <nct_id>NCT02201875</nct_id>
  </id_info>
  <brief_title>Intrinsic Periodic Pattern of Breathing</brief_title>
  <acronym>PERHYP1</acronym>
  <official_title>Study of Periodic Breathing in Healthy Humans</official_title>
  <sponsors>
    <lead_sponsor>
      <agency>Association pour la Recherche en Physiologie de l'Environnement</agency>
      <agency_class>Other</agency_class>
    </lead_sponsor>
  </sponsors>
  <source>Association pour la Recherche en Physiologie de l'Environnement</source>
  <oversight_info>
    <has_dmc>No</has_dmc>
  </oversight_info>
  <brief_summary>
    <textblock>
      We made a fortuitous observation of periodic breathing in a healthy subject coming to our&#xD;
      outpatient mountain medicine consultation at Avicenne hospital in Bobigny (France). During&#xD;
      this consultation, subjects perform a hypoxia exercise test, which allows a good prediction&#xD;
      of their risk factors for severe high altitude illnesses. Surprisingly, breath-by-breath&#xD;
      recording of the ventilation signal showed a periodic breathing pattern, which increased when&#xD;
      the subject started to exercise in hypoxic conditions and was maintained during normoxic&#xD;
      exercise.&#xD;
&#xD;
      Therefore, our objective was to confirm this observation in a retrospective study led in 82&#xD;
      subjects who passed this test. We tested the hypothesis that subjects with a brisk&#xD;
      ventilatory response to hypoxia might show a more pronounced periodic pattern of ventilation,&#xD;
      due to a higher gain of the chemoreceptor feedback loop. Then, our objective is to&#xD;
      investigate the mechanisms involved in the periodic pattern in healthy subjects, as a&#xD;
      function of exercise intensity, altitude intensity, role of peripheral and central&#xD;
      chemoreceptors to O2 and CO2. Finally, we want to investigate the possible role of this&#xD;
      ventilatory instability in patients with obstructive or central apneas.&#xD;
    </textblock>
  </brief_summary>
  <detailed_description>
    <textblock>
      In a preliminary study, among the population coming to the outpatient consultation of&#xD;
      mountain medicine at Avicenne hospital in 2012, 82 subjects (38 females and 44 males) were&#xD;
      randomly selected and separated in two groups of 41 high and 41 low responders to hypoxia&#xD;
      according to the median value of the hypoxic ventilatory response to hypoxia at exercise&#xD;
      (HVRe &gt; or &lt; 0.84 L/min/kg) derived from the hypoxic exercise test (inspired fraction of O2:&#xD;
      0.115, exercise intensity of 30% of maximal aerobic power), as previously described.&#xD;
&#xD;
      The hypoxic exercise test consists in 4 successive phases of 3 to 4 minutes each with the&#xD;
      following sequence: rest in normoxia (RN), rest in hypoxia (RH), exercise in hypoxia (EH) and&#xD;
      exercise in normoxia (EN). Minute ventilation ( E, L.min-1) is measured through a metabograph&#xD;
      (Vmax Encore, SensorMedics, Yorba Linda, CA). Pulse O2 saturation (SpO2, %) is measured by&#xD;
      transcutaneous oximetry (Nellcor N-595, Nellcor, Pleasanton, CA) on a pre-warmed ear lobe.&#xD;
      End tidal PCO2 (PETCO2) is measured by infrared thermopile (Vmax Encore, SensorMedics, Yorba&#xD;
      Linda, CA). During the whole test, VE, SpO2 and PETCO2 were recorded breath-by-breath.&#xD;
      Continuous blood pressure is measured by a Finapres system. Data are transferred to a&#xD;
      computer for further spectrum analysis. A Fast Fourier Transform (FFT) is then applied to the&#xD;
      ventilation signal in sequences of 128 points in each phase of the test. This method will&#xD;
      allow us to detect the presence of peaks in the frequency domain of the ventilation signal.&#xD;
      Two main parameters are derived from the FFT: the frequency in hertz (or period in seconds)&#xD;
      of the larger peak and its power estimated as the area under the peak at ± 0.02 Hz around the&#xD;
      peak (in L2.s-2).&#xD;
&#xD;
      The main study will be designed in order to unravel the mechanisms and role of these&#xD;
      oscillations in ventilation. An overall population of 90 healthy subjects and 30 patients&#xD;
      will be included in the study.&#xD;
&#xD;
      Step 1. Effect of exercise intensity.&#xD;
&#xD;
      Step 2. Effect of altitude level.&#xD;
&#xD;
      Step 3. Effect of the stimulation of central chemoreceptors by acetazolamide.&#xD;
&#xD;
      Step 4. Effect of inhibiting the peripheral chemoreceptors by hyperoxia.&#xD;
&#xD;
      Step 5. Effect of inhibiting the peripheral chemoreceptors by hyperoxia and stimulating the&#xD;
      central chemoreceptors by hypercapnia.&#xD;
&#xD;
      Step 6. Evaluating the presence of these oscillations in patients with sleep apneas.&#xD;
&#xD;
      Step 7. Evaluating the presence of these oscillations in patients with cardiac failure.&#xD;
    </textblock>
  </detailed_description>
  <overall_status>Unknown status</overall_status>
  <last_known_status>Not yet recruiting</last_known_status>
  <start_date>September 2014</start_date>
  <completion_date type="Anticipated">December 2015</completion_date>
  <primary_completion_date type="Anticipated">June 2015</primary_completion_date>
  <study_type>Observational</study_type>
  <has_expanded_access>No</has_expanded_access>
  <study_design_info>
    <observational_model>Cohort</observational_model>
  </study_design_info>
  <primary_outcome>
    <measure>Periodic pattern of ventilation</measure>
    <time_frame>The measure is made at the end of the 6-min exercise period, only once in each condition (normoxia, hypoxia, hyperoxia, hypercapnia),</time_frame>
    <description>Presence of oscillation in the ventilation signal</description>
  </primary_outcome>
  <secondary_outcome>
    <measure>Oscillations in heart rate</measure>
    <time_frame>The measure is made at the end of the 6-min exercise period, only once in each condition (normoxia, hypoxia, hyperoxia, hypercapnia)</time_frame>
    <description>Presence of oscillations in the beat-by-beat ECG signal with a specific peak in the frequency spectrum</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Oscillations in arterial blood pressure</measure>
    <time_frame>The measure is made at the end of the 6-min exercise period, only once in each condition (normoxia, hypoxia, hyperoxia, hypercapnia)</time_frame>
    <description>Presence of oscillations in the systolic/diastolic value of instant arterial blood pressure, measured non-invasively.</description>
  </secondary_outcome>
  <number_of_groups>3</number_of_groups>
  <enrollment type="Anticipated">120</enrollment>
  <condition>Normoxia</condition>
  <condition>Hypoxia</condition>
  <condition>Hyperoxia</condition>
  <condition>Hypercapnia</condition>
  <arm_group>
    <arm_group_label>Healthy subjects</arm_group_label>
    <description>male, aged 18-65 moderately trained healthy, no treatment</description>
  </arm_group>
  <arm_group>
    <arm_group_label>obstructive sleep apneas</arm_group_label>
    <description>patients with apnea/hypopnea index &gt; 15 BMI &lt; 30 Age &lt; 50 yrs</description>
  </arm_group>
  <arm_group>
    <arm_group_label>cardiac failure</arm_group_label>
    <description>NYHA class I to III ejection fraction &lt; 40% age &lt; 65 yrs BMI &lt; 30</description>
  </arm_group>
  <eligibility>
    <study_pop>
      <textblock>
        Healthy subjects Patients with obstructive sleep apneas Patients with cardiac failure&#xD;
      </textblock>
    </study_pop>
    <sampling_method>Probability Sample</sampling_method>
    <criteria>
      <textblock>
        Inclusion Criteria:&#xD;
&#xD;
          -  depending on the group: see definition of groups&#xD;
&#xD;
        Exclusion Criteria:&#xD;
&#xD;
          -  BMI &gt; 30&#xD;
&#xD;
          -  history of severe cardiac arrhythmia&#xD;
&#xD;
          -  pulmonary hypertension&#xD;
&#xD;
          -  history of coronary disease&#xD;
      </textblock>
    </criteria>
    <gender>All</gender>
    <minimum_age>18 Years</minimum_age>
    <maximum_age>65 Years</maximum_age>
    <healthy_volunteers>Accepts Healthy Volunteers</healthy_volunteers>
  </eligibility>
  <overall_contact>
    <last_name>Jean-Paul Richalet, MD, PhD</last_name>
    <phone>33148387758</phone>
    <email>richalet@univ-paris13.fr</email>
  </overall_contact>
  <location>
    <facility>
      <name>Physiology Department</name>
      <address>
        <city>Bobigny</city>
        <zip>93009</zip>
        <country>France</country>
      </address>
    </facility>
    <contact>
      <last_name>Jean-Paul Richalet, MD, PhD</last_name>
      <phone>33148387758</phone>
      <email>richalet@univ-paris13.fr</email>
    </contact>
    <investigator>
      <last_name>Jean-Paul Richalet, MD, PhD</last_name>
      <role>Principal Investigator</role>
    </investigator>
    <investigator>
      <last_name>François J Lhuissier, MD, PhD</last_name>
      <role>Sub-Investigator</role>
    </investigator>
    <investigator>
      <last_name>Carole Planès, MD, PhD</last_name>
      <role>Sub-Investigator</role>
    </investigator>
    <investigator>
      <last_name>Christophe Meune, MD, PhD</last_name>
      <role>Sub-Investigator</role>
    </investigator>
  </location>
  <location_countries>
    <country>France</country>
  </location_countries>
  <reference>
    <citation>Richalet JP, Larmignat P, Poitrine E, Letournel M, Canoui-Poitrine F. Physiological risk factors for severe high-altitude illness: a prospective cohort study. Am J Respir Crit Care Med. 2012 Jan 15;185(2):192-8. doi: 10.1164/rccm.201108-1396OC. Epub 2011 Oct 27.</citation>
    <PMID>22071330</PMID>
  </reference>
  <verification_date>July 2014</verification_date>
  <study_first_submitted>January 22, 2014</study_first_submitted>
  <study_first_submitted_qc>July 24, 2014</study_first_submitted_qc>
  <study_first_posted type="Estimate">July 28, 2014</study_first_posted>
  <last_update_submitted>July 24, 2014</last_update_submitted>
  <last_update_submitted_qc>July 24, 2014</last_update_submitted_qc>
  <last_update_posted type="Estimate">July 28, 2014</last_update_posted>
  <responsible_party>
    <responsible_party_type>Principal Investigator</responsible_party_type>
    <investigator_affiliation>Association pour la Recherche en Physiologie de l'Environnement</investigator_affiliation>
    <investigator_full_name>Pr. Jean Paul RICHALET</investigator_full_name>
    <investigator_title>Director of Department</investigator_title>
  </responsible_party>
  <keyword>hypoxia</keyword>
  <keyword>exercise</keyword>
  <keyword>periodic breathing</keyword>
  <keyword>hypercapnia</keyword>
  <keyword>apneas</keyword>
  <keyword>cardiac failure</keyword>
  <condition_browse>
    <!-- CAUTION:  The following MeSH terms are assigned with an imperfect algorithm            -->
    <mesh_term>Hypoxia</mesh_term>
    <mesh_term>Hypercapnia</mesh_term>
    <mesh_term>Hyperoxia</mesh_term>
  </condition_browse>
  <!-- Results have not yet been posted for this study                                          -->
</clinical_study>


download date: ClinicalTrials.gov processed this data on September 20, 2023
link text: Link to the current ClinicalTrials.gov record.
url: https://clinicaltrials.gov/ct2/show/NCT02201875
org study id: PERHYP1
nct id: NCT02201875
lead sponsor: 
has dmc: No
We made a fortuitous observation of periodic breathing in a healthy subject coming to our
      outpatient mountain medicine consultation at Avicenne hospital in Bobigny (France). During
      this consultation, subjects perform a hypoxia exercise test, which allows a good prediction
      of their risk factors for severe high altitude illnesses. Surprisingly, breath-by-breath
      recording of the ventilation signal showed a periodic breathing pattern, which increased when
      the subject started to exercise in hypoxic conditions and was maintained during normoxic
      exercise.

      Therefore, our objective was to confirm this observation in a retrospective study led in 82
      subjects who passed this test. We tested the hypothesis that subjects with a brisk
      ventilatory response to hypoxia might show a more pronounced periodic pattern of ventilation,
      due to a higher gain of the chemoreceptor feedback loop. Then, our objective is to
      investigate the mechanisms involved in the periodic pattern in healthy subjects, as a
      function of exercise intensity, altitude intensity, role of peripheral and central
      chemoreceptors to O2 and CO2. Finally, we want to investigate the possible role of this
      ventilatory instability in patients with obstructive or central apneas.
In a preliminary study, among the population coming to the outpatient consultation of
      mountain medicine at Avicenne hospital in 2012, 82 subjects (38 females and 44 males) were
      randomly selected and separated in two groups of 41 high and 41 low responders to hypoxia
      according to the median value of the hypoxic ventilatory response to hypoxia at exercise
      (HVRe > or < 0.84 L/min/kg) derived from the hypoxic exercise test (inspired fraction of O2:
      0.115, exercise intensity of 30% of maximal aerobic power), as previously described.

      The hypoxic exercise test consists in 4 successive phases of 3 to 4 minutes each with the
      following sequence: rest in normoxia (RN), rest in hypoxia (RH), exercise in hypoxia (EH) and
      exercise in normoxia (EN). Minute ventilation ( E, L.min-1) is measured through a metabograph
      (Vmax Encore, SensorMedics, Yorba Linda, CA). Pulse O2 saturation (SpO2, %) is measured by
      transcutaneous oximetry (Nellcor N-595, Nellcor, Pleasanton, CA) on a pre-warmed ear lobe.
      End tidal PCO2 (PETCO2) is measured by infrared thermopile (Vmax Encore, SensorMedics, Yorba
      Linda, CA). During the whole test, VE, SpO2 and PETCO2 were recorded breath-by-breath.
      Continuous blood pressure is measured by a Finapres system. Data are transferred to a
      computer for further spectrum analysis. A Fast Fourier Transform (FFT) is then applied to the
      ventilation signal in sequences of 128 points in each phase of the test. This method will
      allow us to detect the presence of peaks in the frequency domain of the ventilation signal.
      Two main parameters are derived from the FFT: the frequency in hertz (or period in seconds)
      of the larger peak and its power estimated as the area under the peak at ± 0.02 Hz around the
      peak (in L2.s-2).

      The main study will be designed in order to unravel the mechanisms and role of these
      oscillations in ventilation. An overall population of 90 healthy subjects and 30 patients
      will be included in the study.

      Step 1. Effect of exercise intensity.

      Step 2. Effect of altitude level.

      Step 3. Effect of the stimulation of central chemoreceptors by acetazolamide.

      Step 4. Effect of inhibiting the peripheral chemoreceptors by hyperoxia.

      Step 5. Effect of inhibiting the peripheral chemoreceptors by hyperoxia and stimulating the
      central chemoreceptors by hypercapnia.

      Step 6. Evaluating the presence of these oscillations in patients with sleep apneas.

      Step 7. Evaluating the presence of these oscillations in patients with cardiac failure.
observational model: Cohort
measure: Periodic pattern of ventilation
time frame: The measure is made at the end of the 6-min exercise period, only once in each condition (normoxia, hypoxia, hyperoxia, hypercapnia),
description: Presence of oscillation in the ventilation signal
measure: Oscillations in heart rate
time frame: The measure is made at the end of the 6-min exercise period, only once in each condition (normoxia, hypoxia, hyperoxia, hypercapnia)
description: Presence of oscillations in the beat-by-beat ECG signal with a specific peak in the frequency spectrum
measure: Oscillations in arterial blood pressure
time frame: The measure is made at the end of the 6-min exercise period, only once in each condition (normoxia, hypoxia, hyperoxia, hypercapnia)
description: Presence of oscillations in the systolic/diastolic value of instant arterial blood pressure, measured non-invasively.
arm group label: Healthy subjects
description: male, aged 18-65 moderately trained healthy, no treatment
arm group label: obstructive sleep apneas
description: patients with apnea/hypopnea index > 15 BMI < 30 Age < 50 yrs
arm group label: cardiac failure
description: NYHA class I to III ejection fraction < 40% age < 65 yrs BMI < 30
study pop: 
sampling method: Probability Sample
criteria: 
gender: All
minimum age: 18 Years
maximum age: 65 Years
healthy volunteers: Accepts Healthy Volunteers
last name: Jean-Paul Richalet, MD, PhD
phone: 33148387758
email: richalet@univ-paris13.fr
facility: 
contact: 
investigator: 
investigator: 
investigator: 
investigator: 
country: France
citation: Richalet JP, Larmignat P, Poitrine E, Letournel M, Canoui-Poitrine F. Physiological risk factors for severe high-altitude illness: a prospective cohort study. Am J Respir Crit Care Med. 2012 Jan 15;185(2):192-8. doi: 10.1164/rccm.201108-1396OC. Epub 2011 Oct 27.
PMID: 22071330
responsible party type: Principal Investigator
investigator affiliation: Association pour la Recherche en Physiologie de l'Environnement
investigator full name: Pr. Jean Paul RICHALET
investigator title: Director of Department
mesh term: Hypoxia
mesh term: Hypercapnia
mesh term: Hyperoxia