<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/NCT03800017</url>
  </required_header>
  <id_info>
    <org_study_id>H18-02059</org_study_id>
    <nct_id>NCT03800017</nct_id>
  </id_info>
  <brief_title>Skeletal Muscle Function in Interstitial Lung Disease</brief_title>
  <official_title>Investigating the Role of Skeletal Muscle Dysfunction on Dyspnea and Exercise Intolerance in Interstitial Lung Disease</official_title>
  <sponsors>
    <lead_sponsor>
      <agency>University of British Columbia</agency>
      <agency_class>Other</agency_class>
    </lead_sponsor>
  </sponsors>
  <source>University of British Columbia</source>
  <oversight_info>
    <is_fda_regulated_drug>No</is_fda_regulated_drug>
    <is_fda_regulated_device>No</is_fda_regulated_device>
  </oversight_info>
  <brief_summary>
    <textblock>
      Dyspnea (i.e. breathlessness) and exercise intolerance are common symptoms for patients with&#xD;
      interstitial lung disease (ILD), yet it is not known why. It has been suggested that muscle&#xD;
      dysfunction may contribute to dyspnea and exercise intolerance in ILD. Our study aims to: i)&#xD;
      examine differences in the structure and function of the leg muscles in ILD patients, ii)&#xD;
      determine if leg muscle fatigue contributes to dyspnea and exercise limitation in patients&#xD;
      with ILD, and iii) determine the effects of breathing extra oxygen on leg muscle fatigue, as&#xD;
      well as ability to exercise in ILD patients.&#xD;
    </textblock>
  </brief_summary>
  <detailed_description>
    <textblock>
      PURPOSE:&#xD;
&#xD;
      The primary purpose of the proposed work is to characterize skeletal muscle function in&#xD;
      patients with interstitial lung disease (ILD), and to determine the physiological and sensory&#xD;
      consequences of impaired skeletal muscle function in ILD during exercise.&#xD;
&#xD;
      HYPOTHESES:&#xD;
&#xD;
      The hypotheses are threefold; i) patients with ILD will have impaired skeletal muscle&#xD;
      function when compared to healthy controls, ii) impairments in skeletal muscle function&#xD;
      predispose ILD patients to exercise-induced quadriceps muscle fatigue, increase the&#xD;
      perception of exertional dyspnea, as well as reduce exercise tolerance, and iii) delivery of&#xD;
      supplemental oxygen during exercise mitigates exercise-induced quadriceps muscle fatigue,&#xD;
      attenuates the perceived intensity of dyspnea, and improves exercise tolerance.&#xD;
&#xD;
      OBJECTIVE:&#xD;
&#xD;
      The objective of the proposed study is to comprehensively investigate skeletal muscle&#xD;
      dysfunction in patients with ILD and characterize its impact on dyspnea and exercise&#xD;
      tolerance. In doing so, the proposed work will be the first to comprehensively assess&#xD;
      skeletal muscle function in patients with ILD as well as determine its functional&#xD;
      consequences. The results will provide important insight into the putative role of skeletal&#xD;
      muscle dysfunction on exercise limitation in patient with ILD.&#xD;
&#xD;
      JUSTIFICATION:&#xD;
&#xD;
      ILD refers to a diverse group of diseases that share common physiological characteristics&#xD;
      resulting from inflammation and/or fibrosis of the lung parenchyma. ILD has an estimated&#xD;
      prevalence of approximately 67-81 cases per 100 000 individuals. Given the heterogeneity of&#xD;
      disease sub-types, it is difficult to determine a precise median survival for patients with&#xD;
      ILD, however; in patients with idiopathic pulmonary fibrosis, the most common ILD sub-type,&#xD;
      have a median survival of only 2-3 years from the time of diagnosis. For patients with ILD,&#xD;
      dyspnea (i.e. breathlessness) is the most common symptom. Dyspnea can be extremely&#xD;
      debilitating, particularly during physical exertion. The clinical significance of dyspnea in&#xD;
      ILD is underscored by its strong correlation with quality of life and mortality. Patients&#xD;
      attempt to minimize dyspnea by avoiding physical activity, resulting in deconditioning and an&#xD;
      associated reduction in functional capacity. The importance of maintaining functional&#xD;
      capacity is highlighted by the fact that ILD patients with the lowest physical activity&#xD;
      levels have the lowest quality of life and the highest mortality. The effective management of&#xD;
      dyspnea and exercise intolerance is therefore of critical importance when considering the&#xD;
      management of patients with ILD.&#xD;
&#xD;
      The pathophysiological mechanisms of dyspnea and exercise intolerance in ILD are complex,&#xD;
      multifactorial, and poorly understood. Indeed, relatively few studies that have adequately&#xD;
      investigated the mechanistic basis of dyspnea and exercise intolerance in patients with ILD.&#xD;
      It is generally agreed upon that exercise limitation in ILD is related to the combination of&#xD;
      altered respiratory mechanics, gas exchange impairment, and circulatory limitation. However,&#xD;
      it is assumed that dyspnea and exercise intolerance are exclusively related to the&#xD;
      respiratory and circulatory impairment associated with the pathogenesis of ILD. While this&#xD;
      assumption is reasonable, it ignores the potentially crucial role of skeletal muscle&#xD;
      dysfunction as a source of dyspnea and exercise intolerance. Recent experimental evidence&#xD;
      indicates that skeletal muscle dysfunction contributes to both dyspnea and exercise&#xD;
      intolerance in COPD.&#xD;
&#xD;
      A growing body of literature supports the notion that skeletal muscle dysfunction is common&#xD;
      in ILD. While the precise mechanisms remain unclear, several well-established skeletal muscle&#xD;
      dysfunction-promoting factors are present in many ILD patients, including: chronic&#xD;
      hypoxaemia, oxidative stress, pulmonary and systemic inflammation, physical deconditioning,&#xD;
      malnutrition, and corticosteroid use. These factors may act individually or synergistically&#xD;
      to impair skeletal muscle function by causing muscle atrophy, mitochondrial dysfunction, a&#xD;
      reduction in type I muscle fibre proportion, and increases in intramuscular fat. To our&#xD;
      knowledge, there is limited imaging data of skeletal muscle morphology in ILD, and&#xD;
      assessments of skeletal muscle oxidative capacity, and contractile function have not been&#xD;
      concurrently obtained. If present, skeletal muscle dysfunction likely reduces locomotor&#xD;
      muscle oxidative capacity, leading to premature fatigue, increased dyspnea, and diminished&#xD;
      exercise tolerance. Most importantly, there is no data on the physiological effects of&#xD;
      skeletal muscle fatigue and dysfunction on dyspnea and exercise capacity nor whether targeted&#xD;
      treatment options such as supplemental oxygen (O2) delivery can attenuate muscle fatigue.&#xD;
&#xD;
      Accordingly, the aims of the proposed research are threefold: i) to characterize skeletal&#xD;
      muscle function in patients with ILD compared to healthy controls, ii) to determine the&#xD;
      influence of skeletal muscle dysfunction on dyspnea, fatigue, and exercise intolerance in&#xD;
      patients with ILD compared to healthy controls, and iii) to determine if improving exercise&#xD;
      tolerance using supplemental oxygen relieves exercise-induce skeletal muscle fatigue in ILD&#xD;
      patients.&#xD;
&#xD;
      RESEARCH DESIGN:&#xD;
&#xD;
      Experimental hypotheses tested using combination of research designs. To test the hypotheses&#xD;
      i) and ii), the investigators will use a cross sectional design. To test hypothesis iii), the&#xD;
      investigators will use a single-blind placebo-controlled study design.&#xD;
&#xD;
      METHODS Participants will report to the laboratory on four separate occasions separated by a&#xD;
      minimum of 48 hours, and each visit will last ~2-3 hours.&#xD;
&#xD;
      Visit 1:&#xD;
&#xD;
      Participants will complete medical history screening, complete a series of questionnaires&#xD;
      concerning chronic activity-related dyspnea, quality of life, and physical activity.&#xD;
      Participants will then have their height and weight measured and perform pulmonary function&#xD;
      testing. Finally, participants will perform a symptom limited incremental cycle exercise&#xD;
      test. Detailed physiological and sensory measurements will be obtained immediately before and&#xD;
      throughout the incremental cycle exercise test.&#xD;
&#xD;
      Visit 1 will be intended to characterize participant's pulmonary function and exercise&#xD;
      capacity.&#xD;
&#xD;
      Visit 2:&#xD;
&#xD;
      Participants will undergo a magnetic resonance imaging scan to assess the volume and the fat&#xD;
      percentage of their quadriceps muscles They will then perform a series of tests aimed at&#xD;
      evaluating their quadriceps muscle function, including: i) assessment of maximum voluntary&#xD;
      quadriceps muscles strength, and ii) the non-invasive assessment of the oxidative capacity of&#xD;
      their quadriceps muscle using near-infrared spectroscopy.&#xD;
&#xD;
      Data from visit 2 will be used to address hypothesis 1 by characterizing participant's&#xD;
      quadriceps muscle function.&#xD;
&#xD;
      Visits 3:&#xD;
&#xD;
      Participants will perform a constant-load exercise test to exhaustion while breathing ambient&#xD;
      air (i.e., 20.93% oxygen). The work load will be set at 75% of the highest work rate achieved&#xD;
      during the incremental exercise test performed during visit 1.&#xD;
&#xD;
      Data from visits 3 and 4 will be used to address hypothesis 2 by characterizing the effect of&#xD;
      exercise on skeletal muscle fatigue in patients with ILD and healthy controls.&#xD;
&#xD;
      Visit 4:&#xD;
&#xD;
      Participants will perform a constant-load exercise test while breathing supplemental oxygen&#xD;
      (i.e., 60% oxygen). The work load will be set at 75% of the highest work rate achieved during&#xD;
      the incremental exercise test performed during visit 1 and the test will be terminated once&#xD;
      participants reach the same time that they achieved during the constant-load exercise test on&#xD;
      Day 3.&#xD;
&#xD;
      Data from visit 4 will be used to address hypothesis 3 by determining if supplemental oxygen&#xD;
      can be used to alleviate exercise-induced skeletal muscle fatigue in patients with ILD and&#xD;
      healthy controls.&#xD;
    </textblock>
  </detailed_description>
  <overall_status>Not yet recruiting</overall_status>
  <start_date type="Anticipated">January 1, 2023</start_date>
  <completion_date type="Anticipated">December 31, 2024</completion_date>
  <primary_completion_date type="Anticipated">December 31, 2024</primary_completion_date>
  <phase>N/A</phase>
  <study_type>Interventional</study_type>
  <has_expanded_access>No</has_expanded_access>
  <study_design_info>
    <allocation>Non-Randomized</allocation>
    <intervention_model>Parallel Assignment</intervention_model>
    <primary_purpose>Basic Science</primary_purpose>
    <masking>Single (Participant)</masking>
  </study_design_info>
  <primary_outcome>
    <measure>Change in standardized dyspnea score during the constant load exercise test (visit 3)</measure>
    <time_frame>Dyspnea will be measured once every minute during exercise on visit 3 (up to 7 weeks after baseline) until participants reach volitional exhaustion (assessed for up to 30 minutes)</time_frame>
    <description>Dyspnea rating, measured using the Borg 0-10 category ratio scale, will be assessed every 1 minute during the constant-load exercise test on visit 3.</description>
  </primary_outcome>
  <primary_outcome>
    <measure>Change in standardized dyspnea score during the constant load exercise test (visit 4)</measure>
    <time_frame>Dyspnea will be measured once every minute during exercise on visit 4 (up to 8 weeks after baseline) until participants reach volitional exhaustion (assessed for up to 30 minutes)</time_frame>
    <description>Dyspnea rating, measured using the Borg 0-10 category ratio scale, will be assessed every 1 minute during the constant-load exercise test on visit 4.</description>
  </primary_outcome>
  <primary_outcome>
    <measure>Change in leg muscle strength measured following the constant load exercise test (visit 3)</measure>
    <time_frame>Leg muscle strength will be measured before and after exercise (assessed for up to 40 minutes) on visit 3 (up to 8 weeks after baseline)</time_frame>
    <description>Leg muscle strength will be measured before (at rest) and 3 min after the constant-load exercise test on visit 3 using the femoral magnetic stimulation technique.</description>
  </primary_outcome>
  <primary_outcome>
    <measure>Change in leg muscle strength measured following the constant load exercise test (visit 4)</measure>
    <time_frame>Leg muscle strength will be measured before and after exercise (assessed for up to 40 minutes) on visit 4 (up to 8 weeks after baseline)</time_frame>
    <description>Leg muscle strength will be measured before (at rest) and 3 min after the constant-load exercise test on visit 4 using the femoral magnetic stimulation technique.</description>
  </primary_outcome>
  <secondary_outcome>
    <measure>Quadriceps muscle oxidative capacity measured using near-infrared spectroscopy</measure>
    <time_frame>On visit 2, approximately 3 weeks post-baseline (visit 1)</time_frame>
    <description>Quadriceps muscle oxidative capacity will measured using near-infrared spectroscopy. Parameters will be measured over 5 minutes once on visit 2</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Quadriceps muscle volume measured using magnetic resonance imaging</measure>
    <time_frame>On visit 2, approximately 3 weeks post-baseline (visit 1)</time_frame>
    <description>Quadriceps muscle volume will be measured using magnetic resonance imaging. Parameters will be measured over 15 minutes once on visit 2</description>
  </secondary_outcome>
  <number_of_arms>2</number_of_arms>
  <enrollment type="Anticipated">40</enrollment>
  <condition>Interstitial Lung Disease</condition>
  <condition>Idiopathic Pulmonary Fibrosis</condition>
  <condition>Hypersensitivity Pneumonitis</condition>
  <condition>Scleroderma</condition>
  <condition>Nonspecific Interstitial Pneumonia</condition>
  <arm_group>
    <arm_group_label>Hyperoxia</arm_group_label>
    <arm_group_type>Experimental</arm_group_type>
    <description>During exercise on visit 4, participants in both groups (i.e., ILD patients and controls) will breathe supplemental oxygen (i.e., 60% oxygen) during constant-load exercise.</description>
  </arm_group>
  <arm_group>
    <arm_group_label>Healthy Controls</arm_group_label>
    <arm_group_type>Placebo Comparator</arm_group_type>
    <description>During exercise on visit 3, participants in both groups (i.e., ILD patients and controls) will breathe ambient air (i.e., 20.93% oxygen) during constant-load exercise.</description>
  </arm_group>
  <intervention>
    <intervention_type>Biological</intervention_type>
    <intervention_name>Hyperoxia</intervention_name>
    <description>Participants breathe 60% oxygen during exercise</description>
    <arm_group_label>Healthy Controls</arm_group_label>
    <arm_group_label>Hyperoxia</arm_group_label>
  </intervention>
  <eligibility>
    <criteria>
      <textblock>
        Inclusion Criteria for ILD Patients:&#xD;
&#xD;
          -  Age 40-80 years (inclusive)&#xD;
&#xD;
          -  A multidisciplinary diagnosis of idiopathic pulmonary fibrosis (IPF), idiopathic&#xD;
             fibrotic nonspecific interstitial pneumonia (NSIP), chronic hypersensitivity&#xD;
             pneumonitis (HP), or unclassifiable ILD with a differential diagnosis that consists of&#xD;
             the above diagnoses&#xD;
&#xD;
          -  Fibrosis on high resolution computed tomography (HRCT): honeycombing, reticulation, or&#xD;
             traction bronchiectasis&#xD;
&#xD;
          -  Appropriate candidate for pulmonary rehabilitation&#xD;
&#xD;
          -  6 minute walk distance 50m or more&#xD;
&#xD;
          -  Oxygen saturation ≥ 92% by pulse oximetry at rest while breathing room air&#xD;
&#xD;
          -  Clinically stable for the preceding 6 weeks&#xD;
&#xD;
          -  Can fluently read and write in English&#xD;
&#xD;
        Inclusion Criteria for Healthy Controls:&#xD;
&#xD;
          -  Age 40-80 (inclusive)&#xD;
&#xD;
          -  Normal pulmonary function (80-120% predicted)&#xD;
&#xD;
          -  No lung or cardiovascular disease&#xD;
&#xD;
          -  Can fluently read and write in English&#xD;
&#xD;
        Exclusion Criteria for the ILD patients:&#xD;
&#xD;
          -  Contraindication to exercise testing (e.g. significant cardiovascular,&#xD;
             musculoskeletal, neurological disease)&#xD;
&#xD;
          -  Other significant extra-pulmonary disease that, based on clinical assessment, could&#xD;
             impair exercise capacity and/or oxygenation&#xD;
&#xD;
          -  Forced vital capacity (FVC) less than 50% or Diffusion capacity for carbon monoxide&#xD;
             (DLCO) less than 25%&#xD;
&#xD;
          -  Concurrent or recent participation (less than 6 months) in a pulmonary rehabilitation&#xD;
             program&#xD;
&#xD;
          -  Use of prednisone greater than 10 mg/day for more than 2 weeks within 3 months of the&#xD;
             first study visit&#xD;
&#xD;
          -  Significant emphysema (less than 10% volume on HRCT or FEV1/FVC less than 0.70)&#xD;
&#xD;
        Exclusion Criteria for Healthy Controls:&#xD;
&#xD;
          -  Currently smoking or previously smoked more than 10 pack-years&#xD;
&#xD;
          -  Any medical conditions that prevents them for exercising safely&#xD;
&#xD;
          -  Cardiac pacemaker or any metal or electronic inside the body&#xD;
      </textblock>
    </criteria>
    <gender>All</gender>
    <minimum_age>40 Years</minimum_age>
    <maximum_age>80 Years</maximum_age>
    <healthy_volunteers>Accepts Healthy Volunteers</healthy_volunteers>
  </eligibility>
  <overall_official>
    <last_name>Jordan A Guenette, PhD</last_name>
    <role>Principal Investigator</role>
    <affiliation>University of British Columbia</affiliation>
  </overall_official>
  <overall_contact>
    <last_name>Yannick Molgat-seon, PhD</last_name>
    <phone>1-604-682-2344</phone>
    <phone_ext>63258</phone_ext>
    <email>yannick.molgat-seon@hli.ubc.ca</email>
  </overall_contact>
  <overall_contact_backup>
    <last_name>Satvir S Dhillon, MSc</last_name>
    <phone>1-604-806-8835</phone>
    <email>Satvir.Dhillon@hli.ubc.ca</email>
  </overall_contact_backup>
  <verification_date>November 2022</verification_date>
  <study_first_submitted>November 21, 2018</study_first_submitted>
  <study_first_submitted_qc>January 9, 2019</study_first_submitted_qc>
  <study_first_posted type="Actual">January 10, 2019</study_first_posted>
  <last_update_submitted>November 1, 2022</last_update_submitted>
  <last_update_submitted_qc>November 1, 2022</last_update_submitted_qc>
  <last_update_posted type="Actual">November 3, 2022</last_update_posted>
  <responsible_party>
    <responsible_party_type>Principal Investigator</responsible_party_type>
    <investigator_affiliation>University of British Columbia</investigator_affiliation>
    <investigator_full_name>Jordan Guenette</investigator_full_name>
    <investigator_title>Associate Professor</investigator_title>
  </responsible_party>
  <condition_browse>
    <!-- CAUTION:  The following MeSH terms are assigned with an imperfect algorithm            -->
    <mesh_term>Pneumonia</mesh_term>
    <mesh_term>Lung Diseases</mesh_term>
    <mesh_term>Pulmonary Fibrosis</mesh_term>
    <mesh_term>Idiopathic Pulmonary Fibrosis</mesh_term>
    <mesh_term>Lung Diseases, Interstitial</mesh_term>
    <mesh_term>Alveolitis, Extrinsic Allergic</mesh_term>
    <mesh_term>Hypersensitivity</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/NCT03800017
org study id: H18-02059
nct id: NCT03800017
lead sponsor: 
is fda regulated drug: No
is fda regulated device: No
Dyspnea (i.e. breathlessness) and exercise intolerance are common symptoms for patients with
      interstitial lung disease (ILD), yet it is not known why. It has been suggested that muscle
      dysfunction may contribute to dyspnea and exercise intolerance in ILD. Our study aims to: i)
      examine differences in the structure and function of the leg muscles in ILD patients, ii)
      determine if leg muscle fatigue contributes to dyspnea and exercise limitation in patients
      with ILD, and iii) determine the effects of breathing extra oxygen on leg muscle fatigue, as
      well as ability to exercise in ILD patients.
PURPOSE:

      The primary purpose of the proposed work is to characterize skeletal muscle function in
      patients with interstitial lung disease (ILD), and to determine the physiological and sensory
      consequences of impaired skeletal muscle function in ILD during exercise.

      HYPOTHESES:

      The hypotheses are threefold; i) patients with ILD will have impaired skeletal muscle
      function when compared to healthy controls, ii) impairments in skeletal muscle function
      predispose ILD patients to exercise-induced quadriceps muscle fatigue, increase the
      perception of exertional dyspnea, as well as reduce exercise tolerance, and iii) delivery of
      supplemental oxygen during exercise mitigates exercise-induced quadriceps muscle fatigue,
      attenuates the perceived intensity of dyspnea, and improves exercise tolerance.

      OBJECTIVE:

      The objective of the proposed study is to comprehensively investigate skeletal muscle
      dysfunction in patients with ILD and characterize its impact on dyspnea and exercise
      tolerance. In doing so, the proposed work will be the first to comprehensively assess
      skeletal muscle function in patients with ILD as well as determine its functional
      consequences. The results will provide important insight into the putative role of skeletal
      muscle dysfunction on exercise limitation in patient with ILD.

      JUSTIFICATION:

      ILD refers to a diverse group of diseases that share common physiological characteristics
      resulting from inflammation and/or fibrosis of the lung parenchyma. ILD has an estimated
      prevalence of approximately 67-81 cases per 100 000 individuals. Given the heterogeneity of
      disease sub-types, it is difficult to determine a precise median survival for patients with
      ILD, however; in patients with idiopathic pulmonary fibrosis, the most common ILD sub-type,
      have a median survival of only 2-3 years from the time of diagnosis. For patients with ILD,
      dyspnea (i.e. breathlessness) is the most common symptom. Dyspnea can be extremely
      debilitating, particularly during physical exertion. The clinical significance of dyspnea in
      ILD is underscored by its strong correlation with quality of life and mortality. Patients
      attempt to minimize dyspnea by avoiding physical activity, resulting in deconditioning and an
      associated reduction in functional capacity. The importance of maintaining functional
      capacity is highlighted by the fact that ILD patients with the lowest physical activity
      levels have the lowest quality of life and the highest mortality. The effective management of
      dyspnea and exercise intolerance is therefore of critical importance when considering the
      management of patients with ILD.

      The pathophysiological mechanisms of dyspnea and exercise intolerance in ILD are complex,
      multifactorial, and poorly understood. Indeed, relatively few studies that have adequately
      investigated the mechanistic basis of dyspnea and exercise intolerance in patients with ILD.
      It is generally agreed upon that exercise limitation in ILD is related to the combination of
      altered respiratory mechanics, gas exchange impairment, and circulatory limitation. However,
      it is assumed that dyspnea and exercise intolerance are exclusively related to the
      respiratory and circulatory impairment associated with the pathogenesis of ILD. While this
      assumption is reasonable, it ignores the potentially crucial role of skeletal muscle
      dysfunction as a source of dyspnea and exercise intolerance. Recent experimental evidence
      indicates that skeletal muscle dysfunction contributes to both dyspnea and exercise
      intolerance in COPD.

      A growing body of literature supports the notion that skeletal muscle dysfunction is common
      in ILD. While the precise mechanisms remain unclear, several well-established skeletal muscle
      dysfunction-promoting factors are present in many ILD patients, including: chronic
      hypoxaemia, oxidative stress, pulmonary and systemic inflammation, physical deconditioning,
      malnutrition, and corticosteroid use. These factors may act individually or synergistically
      to impair skeletal muscle function by causing muscle atrophy, mitochondrial dysfunction, a
      reduction in type I muscle fibre proportion, and increases in intramuscular fat. To our
      knowledge, there is limited imaging data of skeletal muscle morphology in ILD, and
      assessments of skeletal muscle oxidative capacity, and contractile function have not been
      concurrently obtained. If present, skeletal muscle dysfunction likely reduces locomotor
      muscle oxidative capacity, leading to premature fatigue, increased dyspnea, and diminished
      exercise tolerance. Most importantly, there is no data on the physiological effects of
      skeletal muscle fatigue and dysfunction on dyspnea and exercise capacity nor whether targeted
      treatment options such as supplemental oxygen (O2) delivery can attenuate muscle fatigue.

      Accordingly, the aims of the proposed research are threefold: i) to characterize skeletal
      muscle function in patients with ILD compared to healthy controls, ii) to determine the
      influence of skeletal muscle dysfunction on dyspnea, fatigue, and exercise intolerance in
      patients with ILD compared to healthy controls, and iii) to determine if improving exercise
      tolerance using supplemental oxygen relieves exercise-induce skeletal muscle fatigue in ILD
      patients.

      RESEARCH DESIGN:

      Experimental hypotheses tested using combination of research designs. To test the hypotheses
      i) and ii), the investigators will use a cross sectional design. To test hypothesis iii), the
      investigators will use a single-blind placebo-controlled study design.

      METHODS Participants will report to the laboratory on four separate occasions separated by a
      minimum of 48 hours, and each visit will last ~2-3 hours.

      Visit 1:

      Participants will complete medical history screening, complete a series of questionnaires
      concerning chronic activity-related dyspnea, quality of life, and physical activity.
      Participants will then have their height and weight measured and perform pulmonary function
      testing. Finally, participants will perform a symptom limited incremental cycle exercise
      test. Detailed physiological and sensory measurements will be obtained immediately before and
      throughout the incremental cycle exercise test.

      Visit 1 will be intended to characterize participant's pulmonary function and exercise
      capacity.

      Visit 2:

      Participants will undergo a magnetic resonance imaging scan to assess the volume and the fat
      percentage of their quadriceps muscles They will then perform a series of tests aimed at
      evaluating their quadriceps muscle function, including: i) assessment of maximum voluntary
      quadriceps muscles strength, and ii) the non-invasive assessment of the oxidative capacity of
      their quadriceps muscle using near-infrared spectroscopy.

      Data from visit 2 will be used to address hypothesis 1 by characterizing participant's
      quadriceps muscle function.

      Visits 3:

      Participants will perform a constant-load exercise test to exhaustion while breathing ambient
      air (i.e., 20.93% oxygen). The work load will be set at 75% of the highest work rate achieved
      during the incremental exercise test performed during visit 1.

      Data from visits 3 and 4 will be used to address hypothesis 2 by characterizing the effect of
      exercise on skeletal muscle fatigue in patients with ILD and healthy controls.

      Visit 4:

      Participants will perform a constant-load exercise test while breathing supplemental oxygen
      (i.e., 60% oxygen). The work load will be set at 75% of the highest work rate achieved during
      the incremental exercise test performed during visit 1 and the test will be terminated once
      participants reach the same time that they achieved during the constant-load exercise test on
      Day 3.

      Data from visit 4 will be used to address hypothesis 3 by determining if supplemental oxygen
      can be used to alleviate exercise-induced skeletal muscle fatigue in patients with ILD and
      healthy controls.
allocation: Non-Randomized
intervention model: Parallel Assignment
primary purpose: Basic Science
masking: Single (Participant)
measure: Change in standardized dyspnea score during the constant load exercise test (visit 3)
time frame: Dyspnea will be measured once every minute during exercise on visit 3 (up to 7 weeks after baseline) until participants reach volitional exhaustion (assessed for up to 30 minutes)
description: Dyspnea rating, measured using the Borg 0-10 category ratio scale, will be assessed every 1 minute during the constant-load exercise test on visit 3.
measure: Change in standardized dyspnea score during the constant load exercise test (visit 4)
time frame: Dyspnea will be measured once every minute during exercise on visit 4 (up to 8 weeks after baseline) until participants reach volitional exhaustion (assessed for up to 30 minutes)
description: Dyspnea rating, measured using the Borg 0-10 category ratio scale, will be assessed every 1 minute during the constant-load exercise test on visit 4.
measure: Change in leg muscle strength measured following the constant load exercise test (visit 3)
time frame: Leg muscle strength will be measured before and after exercise (assessed for up to 40 minutes) on visit 3 (up to 8 weeks after baseline)
description: Leg muscle strength will be measured before (at rest) and 3 min after the constant-load exercise test on visit 3 using the femoral magnetic stimulation technique.
measure: Change in leg muscle strength measured following the constant load exercise test (visit 4)
time frame: Leg muscle strength will be measured before and after exercise (assessed for up to 40 minutes) on visit 4 (up to 8 weeks after baseline)
description: Leg muscle strength will be measured before (at rest) and 3 min after the constant-load exercise test on visit 4 using the femoral magnetic stimulation technique.
measure: Quadriceps muscle oxidative capacity measured using near-infrared spectroscopy
time frame: On visit 2, approximately 3 weeks post-baseline (visit 1)
description: Quadriceps muscle oxidative capacity will measured using near-infrared spectroscopy. Parameters will be measured over 5 minutes once on visit 2
measure: Quadriceps muscle volume measured using magnetic resonance imaging
time frame: On visit 2, approximately 3 weeks post-baseline (visit 1)
description: Quadriceps muscle volume will be measured using magnetic resonance imaging. Parameters will be measured over 15 minutes once on visit 2
arm group label: Hyperoxia
arm group type: Experimental
description: During exercise on visit 4, participants in both groups (i.e., ILD patients and controls) will breathe supplemental oxygen (i.e., 60% oxygen) during constant-load exercise.
arm group label: Healthy Controls
arm group type: Placebo Comparator
description: During exercise on visit 3, participants in both groups (i.e., ILD patients and controls) will breathe ambient air (i.e., 20.93% oxygen) during constant-load exercise.
intervention type: Biological
intervention name: Hyperoxia
description: Participants breathe 60% oxygen during exercise
arm group label: Healthy Controls
arm group label: Hyperoxia
criteria: 
gender: All
minimum age: 40 Years
maximum age: 80 Years
healthy volunteers: Accepts Healthy Volunteers
last name: Jordan A Guenette, PhD
role: Principal Investigator
affiliation: University of British Columbia
last name: Yannick Molgat-seon, PhD
phone: 1-604-682-2344
phone ext: 63258
email: yannick.molgat-seon@hli.ubc.ca
last name: Satvir S Dhillon, MSc
phone: 1-604-806-8835
email: Satvir.Dhillon@hli.ubc.ca
responsible party type: Principal Investigator
investigator affiliation: University of British Columbia
investigator full name: Jordan Guenette
investigator title: Associate Professor
mesh term: Pneumonia
mesh term: Lung Diseases
mesh term: Pulmonary Fibrosis
mesh term: Idiopathic Pulmonary Fibrosis
mesh term: Lung Diseases, Interstitial
mesh term: Alveolitis, Extrinsic Allergic
mesh term: Hypersensitivity
sharing ipd: No