<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/NCT03029559</url>
  </required_header>
  <id_info>
    <org_study_id>IRB201601878</org_study_id>
    <nct_id>NCT03029559</nct_id>
  </id_info>
  <brief_title>Intermittent Hypoxia and Inspiratory Threshold Loading to Enhance Inspiratory Muscle Function</brief_title>
  <official_title>Intermittent Hypoxia and Inspiratory Threshold Loading as Strategies to Enhance Inspiratory Muscle Function</official_title>
  <sponsors>
    <lead_sponsor>
      <agency>University of Florida</agency>
      <agency_class>Other</agency_class>
    </lead_sponsor>
  </sponsors>
  <source>University of Florida</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>
      Rehabilitation approaches introduce a stimulus to a motor system, with the goal to enhance&#xD;
      motor function to patients. For example, exposure to brief and intermittent episodes of mild&#xD;
      hypoxia has shown to strengthen synaptic pathways to respiratory and skeletal muscle motor&#xD;
      neurons. In humans with spinal cord injury, exposure to intermittent hypoxia (IH) alone or in&#xD;
      combination with rehabilitative strategies has shown enhanced motor function. Another&#xD;
      strategy known as inspiratory threshold loading, which involves breathing against pressure&#xD;
      threshold loads, results in improved inspiratory muscle strength. Although there is evidence&#xD;
      supporting the use of IH alone or in combination with other rehabilitative strategies in&#xD;
      improving motor function in humans, the impact of exposure to IH or IH with inspiratory&#xD;
      threshold loading on inspiratory muscle function and ventilation in humans is unknown.&#xD;
    </textblock>
  </brief_summary>
  <detailed_description>
    <textblock>
      Investigators will test whether exposure to IH alone and in combination with inspiratory&#xD;
      threshold loading (ITL) will result in increased inspiratory muscle strength and ventilation.&#xD;
&#xD;
      Investigators will use a Latin square, repeated measures design which will consist of 12&#xD;
      subjects participating in four experimental conditions.There will be an interval of 1 week&#xD;
      between each of the four conditions, which will serve as a washout period.&#xD;
&#xD;
      At the end of each of the 5 sessions, the subjects will rest in a reclining chair for 15&#xD;
      minutes while their heart rate, blood pressure, oxygen saturation and breathing are&#xD;
      monitored. Subjects that have a blood systolic blood pressure &gt; 140 or diastolic pressure &gt;&#xD;
      90 or SPO2 &lt; 92% will be asked to remain in the laboratory for 15 additional minutes and the&#xD;
      vital signs will be repeated. If the blood pressure and/or peripheral capillary oxygen&#xD;
      saturation (SPO2) remain outside of the criteria mentioned above, the subject will be&#xD;
      instructed to seek assessment by their health provider and the incident will be reported to&#xD;
      the Institutional Review Board. Subjects will also be asked to report any discomfort.&#xD;
    </textblock>
  </detailed_description>
  <overall_status>Completed</overall_status>
  <start_date type="Actual">February 17, 2017</start_date>
  <completion_date type="Actual">February 19, 2018</completion_date>
  <primary_completion_date type="Actual">February 19, 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>Factorial Assignment</intervention_model>
    <intervention_model_description>Latin square, repeated measures design to study the effects of IH administered alone and in combination with inspiratory threshold loading on the above stated respiratory parameters.</intervention_model_description>
    <primary_purpose>Treatment</primary_purpose>
    <masking>Single (Participant)</masking>
    <masking_description>We will use a Latin square, repeated measures design which will consist of 12 subjects participating in the following four experimental conditions: There will be an interval of 1 week between each of the four conditions, which will serve as a washout period.&#xD;
IH+ITL: Subjects will be exposed to a session of IH (45 minutes, 2 minutes of hypoxia alternating with 1 minute of hyperoxia) followed by 5 sets of ITL at 80%MIP (10 breaths per set).&#xD;
IH: Subjects will only be exposed to a session of intermittent hypoxia.&#xD;
Sham IH +ITL: Subjects will be exposed to a single 45-minute session of sham IH (normoxia). This will consist of the subject breathing room air (FiO2=21%) through a 4 way valve connected to the hypoxicator. Exposure to normoxia will be followed by 5 sets of ITL at 80%MIP (10 breaths per set).&#xD;
Sham IH: Subjects will be exposed to a single 45-minute session of sham IH (normoxia) alone.</masking_description>
  </study_design_info>
  <primary_outcome>
    <measure>Maximal Inspiratory Pressure will be measured across all groups</measure>
    <time_frame>Change between 15, 30, and 60 minutes</time_frame>
    <description>Maximal Inspiratory Pressure(MIP) which is a measure of inspiratory muscle strength will be measured as the MIP recorded at the mouth by a pressure manometer. Subjects will be seated upright in a comfortable chair and the nose occluded with clips. After exhaling to residual volume (RV), subjects place their lips around the mouthpiece and inspire as forcefully as possible for at least three seconds. Repeated measurements will be taken, with a 1- to 2-min rest between trials, until three measurements are obtained within 5% variability. Of these three values, the best MIP will be recorded.</description>
  </primary_outcome>
  <primary_outcome>
    <measure>Ventilatory responses to inspiratory loading will be measured across all groups</measure>
    <time_frame>Change between 15, 30, and 60 minutes</time_frame>
    <description>Subjects will be asked to breathe as forcefully as possible against a inspiratory load( 2-4 sets of 5 repetitions) of either 40% of their maximal inspiratory pressure(MIP) or at 41CmH2O (lowest of the two as the maximum resistance offered by the device is 41CmH2O) using a inspiratory muscle training (IMT) device. During this task, a respiratory monitor will be connected to the IMT device. Parameters such as the inspiratory flow, volume and pressure generated by the subjects while breathing against the load will be recorded. Imposed work of breathing (WOBi) will be calculated as a product of the pressure generated and the inspired tidal volume when breathing against a fixed load (40%MIP).</description>
  </primary_outcome>
  <primary_outcome>
    <measure>Mouth occlusion pressure (P0.1) will be measured across all groups</measure>
    <time_frame>Change between 15, 30, and 60 minutes</time_frame>
    <description>To record P0.1, the subjects will breathe through a mouth piece connected to a 2 way respiratory valve in a closed circuit. As the subjects breathe through the circuit, the inspiratory valve will be manually occluded during the expiratory phase and the occlusion will be maintained till the end of next inspiration. Occlusion will be random in order to prevent the subjects from getting conscious about the occlusions. The circuit is connected to the respiratory monitor and the negative pressure recorded in the first 100 milliseconds of the occluded breath will be recorded as the subject's P0.1.&#xD;
3 such recordings will be obtained and the highest pressure amongst the 3 trials will be considered for analysis.</description>
  </primary_outcome>
  <secondary_outcome>
    <measure>Heart Rate Variability (HRV) will be measured across all groups</measure>
    <time_frame>Change between 15, 30, and 60 minutes</time_frame>
    <description>Heart Rate Variability (HRV): HRV will be assessed to determine the autonomic response to intermittent hypoxia. HRV will be measured using a 3 lead ECG and HRV recording kit.</description>
  </secondary_outcome>
  <number_of_arms>4</number_of_arms>
  <enrollment type="Actual">20</enrollment>
  <condition>Intermittent Hypoxia</condition>
  <arm_group>
    <arm_group_label>IH + ITL</arm_group_label>
    <arm_group_type>Experimental</arm_group_type>
    <description>Subjects will be exposed to a session of Intermittent hypoxia (IH) (45 minutes, 2 minutes of hypoxia alternating with 1 minute of hyperoxia) followed by 5 sets of Inspiratory threshold loading (ITL) at 80%MIP (10 breaths per set).</description>
  </arm_group>
  <arm_group>
    <arm_group_label>Intermittent hypoxia (IH)</arm_group_label>
    <arm_group_type>Experimental</arm_group_type>
    <description>Subjects will only be exposed to a session of intermittent hypoxia.</description>
  </arm_group>
  <arm_group>
    <arm_group_label>Sham IH + ITL</arm_group_label>
    <arm_group_type>Experimental</arm_group_type>
    <description>Sham Intermittent Hypoxia + Inspiratory threshold loading (ITL) subjects will be exposed to a single 45-minute session of sham IH (normoxia). This will consist of the subject breathing room air (FiO2=21%) through a 4 way valve connected to the hypoxicator. Exposure to normoxia will be followed by 5 sets of ITL at 80%MIP (10 breaths per set).</description>
  </arm_group>
  <arm_group>
    <arm_group_label>Sham IH</arm_group_label>
    <arm_group_type>Sham Comparator</arm_group_type>
    <description>Sham intermittent hypoxia subjects will be exposed to a single 45-minute session of sham IH alone.</description>
  </arm_group>
  <intervention>
    <intervention_type>Other</intervention_type>
    <intervention_name>Intermittent Hypoxia</intervention_name>
    <description>A single session of IH will last for 45 minutes and will consist of alternating phases of hypoxia(FiO2 :9%-11%) and hyperoxia (FiO2 :22%-38%).&#xD;
Each hypoxic interval will last for 2 minutes whereas the hyperoxic interval lasts for 1 minute each (15, two-minute episodes of hypoxia and 15, one-minute episodes of hyperoxia).</description>
    <arm_group_label>IH + ITL</arm_group_label>
    <arm_group_label>Intermittent hypoxia (IH)</arm_group_label>
    <other_name>IH</other_name>
  </intervention>
  <intervention>
    <intervention_type>Other</intervention_type>
    <intervention_name>Inspiratory Threshold Loading</intervention_name>
    <description>Subjects will undergo inspiratory threshold loading using a commercially available Threshold IMT device (Power breathe®). ITL will be administered at an intensity of 80% of the individual's maximal inspiratory pressure (MIP). The subjects will be instructed to take 10 deep, forceful breaths through the threshold device followed by at least 2 minutes of rest. The process will be repeated 4 more times for a total of 5 sets of 10 breaths each.</description>
    <arm_group_label>IH + ITL</arm_group_label>
    <arm_group_label>Sham IH + ITL</arm_group_label>
    <other_name>ITL</other_name>
  </intervention>
  <intervention>
    <intervention_type>Other</intervention_type>
    <intervention_name>Sham Intermittent Hypoxia</intervention_name>
    <description>Subjects will be exposed to a session of sham Intermittent hypoxia.This will consist of breathing room air for 45 minutes through a hypoxicator.</description>
    <arm_group_label>Sham IH</arm_group_label>
    <arm_group_label>Sham IH + ITL</arm_group_label>
    <other_name>Normoxia</other_name>
  </intervention>
  <eligibility>
    <criteria>
      <textblock>
        Inclusion Criteria:&#xD;
&#xD;
          -  Participating in three or fewer musculoskeletal strength training sessions per week at&#xD;
             an intensity equivalent to 7-10 on the Modified Borg's scale&#xD;
&#xD;
          -  Participating in three or fewer cardiovascular endurance training sessions per week at&#xD;
             an intensity equivalent to 7-10 on the Modified Borg's scale&#xD;
&#xD;
        Exclusion Criteria:&#xD;
&#xD;
          -  Diagnosis of cardiovascular disease (Hypertension, arrhythmias, coronary artery&#xD;
             disease, congenital and valvar heart diseases)&#xD;
&#xD;
          -  Diagnosis of neuromuscular disease&#xD;
&#xD;
          -  Diagnosis of any neurological disease&#xD;
&#xD;
          -  Presence of concurrent medical illness including infection, fractures&#xD;
&#xD;
          -  Diagnosis of obstructive sleep apnea&#xD;
&#xD;
          -  Diagnosis of obstructive/restrictive lung disease&#xD;
&#xD;
          -  Diagnosis of exercise induced asthma&#xD;
&#xD;
          -  Forced expiratory volume at one second/forced vital capacity (FVC) &lt;80% and/or FVC&lt;80%&#xD;
             of predicted value indicating airway obstruction&#xD;
&#xD;
          -  Subjects on prednisolone therapy or selective serotonin reuptake inhibitor (SSRI)&#xD;
             therapy will be excluded from the study.&#xD;
&#xD;
          -  Diagnosis of epilepsy or history of seizures and attention deficit disorders&#xD;
&#xD;
          -  Pregnancy&#xD;
&#xD;
          -  Diabetes&#xD;
&#xD;
          -  History of coagulation disorders&#xD;
&#xD;
          -  History of chronic pain&#xD;
&#xD;
          -  Body mass index(BMI)&gt; 35kg/m2&#xD;
&#xD;
          -  Subjects on prescription medicines such as beta blockers and other drugs that are&#xD;
             prescribed in any of the exclusionary disorders listed above.&#xD;
&#xD;
          -  Any other factor that in the investigators' opinions would prevent response to&#xD;
             training or create an unsafe condition for the subject.&#xD;
      </textblock>
    </criteria>
    <gender>All</gender>
    <minimum_age>18 Years</minimum_age>
    <maximum_age>40 Years</maximum_age>
    <healthy_volunteers>Accepts Healthy Volunteers</healthy_volunteers>
  </eligibility>
  <overall_official>
    <last_name>Daniel Martin, PhD</last_name>
    <role>Principal Investigator</role>
    <affiliation>University of Florida</affiliation>
  </overall_official>
  <location>
    <facility>
      <name>University of Florida</name>
      <address>
        <city>Gainesville</city>
        <state>Florida</state>
        <zip>32611</zip>
        <country>United States</country>
      </address>
    </facility>
  </location>
  <location_countries>
    <country>United States</country>
  </location_countries>
  <verification_date>June 2019</verification_date>
  <study_first_submitted>January 17, 2017</study_first_submitted>
  <study_first_submitted_qc>January 19, 2017</study_first_submitted_qc>
  <study_first_posted type="Estimate">January 24, 2017</study_first_posted>
  <last_update_submitted>June 19, 2019</last_update_submitted>
  <last_update_submitted_qc>June 19, 2019</last_update_submitted_qc>
  <last_update_posted type="Actual">June 20, 2019</last_update_posted>
  <responsible_party>
    <responsible_party_type>Sponsor</responsible_party_type>
  </responsible_party>
  <keyword>Inspiratory threshold loading</keyword>
  <condition_browse>
    <!-- CAUTION:  The following MeSH terms are assigned with an imperfect algorithm            -->
    <mesh_term>Respiratory Aspiration</mesh_term>
    <mesh_term>Hypoxia</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/NCT03029559
org study id: IRB201601878
nct id: NCT03029559
lead sponsor: 
has dmc: No
is fda regulated drug: No
is fda regulated device: No
Rehabilitation approaches introduce a stimulus to a motor system, with the goal to enhance
      motor function to patients. For example, exposure to brief and intermittent episodes of mild
      hypoxia has shown to strengthen synaptic pathways to respiratory and skeletal muscle motor
      neurons. In humans with spinal cord injury, exposure to intermittent hypoxia (IH) alone or in
      combination with rehabilitative strategies has shown enhanced motor function. Another
      strategy known as inspiratory threshold loading, which involves breathing against pressure
      threshold loads, results in improved inspiratory muscle strength. Although there is evidence
      supporting the use of IH alone or in combination with other rehabilitative strategies in
      improving motor function in humans, the impact of exposure to IH or IH with inspiratory
      threshold loading on inspiratory muscle function and ventilation in humans is unknown.
Investigators will test whether exposure to IH alone and in combination with inspiratory
      threshold loading (ITL) will result in increased inspiratory muscle strength and ventilation.

      Investigators will use a Latin square, repeated measures design which will consist of 12
      subjects participating in four experimental conditions.There will be an interval of 1 week
      between each of the four conditions, which will serve as a washout period.

      At the end of each of the 5 sessions, the subjects will rest in a reclining chair for 15
      minutes while their heart rate, blood pressure, oxygen saturation and breathing are
      monitored. Subjects that have a blood systolic blood pressure > 140 or diastolic pressure >
      90 or SPO2 < 92% will be asked to remain in the laboratory for 15 additional minutes and the
      vital signs will be repeated. If the blood pressure and/or peripheral capillary oxygen
      saturation (SPO2) remain outside of the criteria mentioned above, the subject will be
      instructed to seek assessment by their health provider and the incident will be reported to
      the Institutional Review Board. Subjects will also be asked to report any discomfort.
allocation: Randomized
intervention model: Factorial Assignment
intervention model description: Latin square, repeated measures design to study the effects of IH administered alone and in combination with inspiratory threshold loading on the above stated respiratory parameters.
primary purpose: Treatment
masking: Single (Participant)
masking description: We will use a Latin square, repeated measures design which will consist of 12 subjects participating in the following four experimental conditions: There will be an interval of 1 week between each of the four conditions, which will serve as a washout period.
IH+ITL: Subjects will be exposed to a session of IH (45 minutes, 2 minutes of hypoxia alternating with 1 minute of hyperoxia) followed by 5 sets of ITL at 80%MIP (10 breaths per set).
IH: Subjects will only be exposed to a session of intermittent hypoxia.
Sham IH +ITL: Subjects will be exposed to a single 45-minute session of sham IH (normoxia). This will consist of the subject breathing room air (FiO2=21%) through a 4 way valve connected to the hypoxicator. Exposure to normoxia will be followed by 5 sets of ITL at 80%MIP (10 breaths per set).
Sham IH: Subjects will be exposed to a single 45-minute session of sham IH (normoxia) alone.
measure: Maximal Inspiratory Pressure will be measured across all groups
time frame: Change between 15, 30, and 60 minutes
description: Maximal Inspiratory Pressure(MIP) which is a measure of inspiratory muscle strength will be measured as the MIP recorded at the mouth by a pressure manometer. Subjects will be seated upright in a comfortable chair and the nose occluded with clips. After exhaling to residual volume (RV), subjects place their lips around the mouthpiece and inspire as forcefully as possible for at least three seconds. Repeated measurements will be taken, with a 1- to 2-min rest between trials, until three measurements are obtained within 5% variability. Of these three values, the best MIP will be recorded.
measure: Ventilatory responses to inspiratory loading will be measured across all groups
time frame: Change between 15, 30, and 60 minutes
description: Subjects will be asked to breathe as forcefully as possible against a inspiratory load( 2-4 sets of 5 repetitions) of either 40% of their maximal inspiratory pressure(MIP) or at 41CmH2O (lowest of the two as the maximum resistance offered by the device is 41CmH2O) using a inspiratory muscle training (IMT) device. During this task, a respiratory monitor will be connected to the IMT device. Parameters such as the inspiratory flow, volume and pressure generated by the subjects while breathing against the load will be recorded. Imposed work of breathing (WOBi) will be calculated as a product of the pressure generated and the inspired tidal volume when breathing against a fixed load (40%MIP).
measure: Mouth occlusion pressure (P0.1) will be measured across all groups
time frame: Change between 15, 30, and 60 minutes
description: To record P0.1, the subjects will breathe through a mouth piece connected to a 2 way respiratory valve in a closed circuit. As the subjects breathe through the circuit, the inspiratory valve will be manually occluded during the expiratory phase and the occlusion will be maintained till the end of next inspiration. Occlusion will be random in order to prevent the subjects from getting conscious about the occlusions. The circuit is connected to the respiratory monitor and the negative pressure recorded in the first 100 milliseconds of the occluded breath will be recorded as the subject's P0.1.
3 such recordings will be obtained and the highest pressure amongst the 3 trials will be considered for analysis.
measure: Heart Rate Variability (HRV) will be measured across all groups
time frame: Change between 15, 30, and 60 minutes
description: Heart Rate Variability (HRV): HRV will be assessed to determine the autonomic response to intermittent hypoxia. HRV will be measured using a 3 lead ECG and HRV recording kit.
arm group label: IH + ITL
arm group type: Experimental
description: Subjects will be exposed to a session of Intermittent hypoxia (IH) (45 minutes, 2 minutes of hypoxia alternating with 1 minute of hyperoxia) followed by 5 sets of Inspiratory threshold loading (ITL) at 80%MIP (10 breaths per set).
arm group label: Intermittent hypoxia (IH)
arm group type: Experimental
description: Subjects will only be exposed to a session of intermittent hypoxia.
arm group label: Sham IH + ITL
arm group type: Experimental
description: Sham Intermittent Hypoxia + Inspiratory threshold loading (ITL) subjects will be exposed to a single 45-minute session of sham IH (normoxia). This will consist of the subject breathing room air (FiO2=21%) through a 4 way valve connected to the hypoxicator. Exposure to normoxia will be followed by 5 sets of ITL at 80%MIP (10 breaths per set).
arm group label: Sham IH
arm group type: Sham Comparator
description: Sham intermittent hypoxia subjects will be exposed to a single 45-minute session of sham IH alone.
intervention type: Other
intervention name: Intermittent Hypoxia
description: A single session of IH will last for 45 minutes and will consist of alternating phases of hypoxia(FiO2 :9%-11%) and hyperoxia (FiO2 :22%-38%).
Each hypoxic interval will last for 2 minutes whereas the hyperoxic interval lasts for 1 minute each (15, two-minute episodes of hypoxia and 15, one-minute episodes of hyperoxia).
arm group label: IH + ITL
arm group label: Intermittent hypoxia (IH)
other name: IH
intervention type: Other
intervention name: Inspiratory Threshold Loading
description: Subjects will undergo inspiratory threshold loading using a commercially available Threshold IMT device (Power breathe®). ITL will be administered at an intensity of 80% of the individual's maximal inspiratory pressure (MIP). The subjects will be instructed to take 10 deep, forceful breaths through the threshold device followed by at least 2 minutes of rest. The process will be repeated 4 more times for a total of 5 sets of 10 breaths each.
arm group label: IH + ITL
arm group label: Sham IH + ITL
other name: ITL
intervention type: Other
intervention name: Sham Intermittent Hypoxia
description: Subjects will be exposed to a session of sham Intermittent hypoxia.This will consist of breathing room air for 45 minutes through a hypoxicator.
arm group label: Sham IH
arm group label: Sham IH + ITL
other name: Normoxia
criteria: 
gender: All
minimum age: 18 Years
maximum age: 40 Years
healthy volunteers: Accepts Healthy Volunteers
last name: Daniel Martin, PhD
role: Principal Investigator
affiliation: University of Florida
facility: 
country: United States
responsible party type: Sponsor
mesh term: Respiratory Aspiration
mesh term: Hypoxia