<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/NCT04484948</url>
  </required_header>
  <id_info>
    <org_study_id>H-2006-054-1131</org_study_id>
    <nct_id>NCT04484948</nct_id>
  </id_info>
  <brief_title>Utility of Breath-holding Test in Systemic Sclerosis</brief_title>
  <official_title>Utility of Breath-holding Test for Assessment of Pulmonary Disease Severity in Patients With Systemic Sclerosis</official_title>
  <sponsors>
    <lead_sponsor>
      <agency>Seoul National University Hospital</agency>
      <agency_class>Other</agency_class>
    </lead_sponsor>
  </sponsors>
  <source>Seoul National University Hospital</source>
  <oversight_info>
    <has_dmc>Yes</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 aims to evaluate the utility of breath-holding test as a marker of pulmonary&#xD;
      disease severity in patients with systemic sclerosis.&#xD;
    </textblock>
  </brief_summary>
  <detailed_description>
    <textblock>
      Systemic sclerosis (SSc) is a chronic autoimmune disease of unknown etiology with high&#xD;
      morbidity and mortality. SSc manifests by fibrosis of skin and internal organs. Although the&#xD;
      underlying mechanisms are still subject to investigation, endothelial dysfunction and&#xD;
      abnormal immune response are thought to contribute to vascular dysfunction and fibrosis in&#xD;
      SSc.&#xD;
&#xD;
      Pulmonary involvement, such as pulmonary arterial hypertension (PAH) and interstitial lung&#xD;
      disease (ILD) is a major cause of death in SSc. Although the 6MWT is generally used for&#xD;
      evaluating PAH and ILD, the utility in SSc is undetermined. Several investigators have found&#xD;
      weak or moderate correlations of 6MWT in pulmonary involvement in SSc. The 6MWT is influenced&#xD;
      by the status of all organ systems involved in exercise (pulmonary, cardiac, peripheral&#xD;
      vascular, neuromuscular unit and muscle metabolism) as well as by specifics of test&#xD;
      conditions. There is a pressing need for new, practical method which corroborates the current&#xD;
      6MWT for the evaluation of pulmonary disease severity in SSc.&#xD;
&#xD;
      Breath-holding test (BHT) is one of the most useful methods for assessing the sensitivity of&#xD;
      peripheral chemoreflex. Recent studies have demonstrated that BHT was correlated to pulmonary&#xD;
      function test. BHT can be safely conducted and doctors handle a medical emergency during test&#xD;
      easily as well. Therefore, this study evaluates the utility of BHT as surrogate marker of&#xD;
      pulmonary involvement in patients with SSc.&#xD;
    </textblock>
  </detailed_description>
  <overall_status>Completed</overall_status>
  <start_date type="Actual">August 12, 2020</start_date>
  <completion_date type="Actual">May 31, 2023</completion_date>
  <primary_completion_date type="Actual">January 29, 2021</primary_completion_date>
  <phase>N/A</phase>
  <study_type>Interventional</study_type>
  <has_expanded_access>No</has_expanded_access>
  <study_design_info>
    <allocation>N/A</allocation>
    <intervention_model>Single Group Assignment</intervention_model>
    <primary_purpose>Other</primary_purpose>
    <masking>None (Open Label)</masking>
  </study_design_info>
  <primary_outcome>
    <measure>Correlation of breath-holding test with Borg Dyspnea Index</measure>
    <time_frame>Day 1 at inclusion</time_frame>
    <description>Borg Scale on a 0-10 point</description>
  </primary_outcome>
  <secondary_outcome>
    <measure>Correlation of breath-holding time with 6 minute walk test (6MWT) distance</measure>
    <time_frame>Day 1 at inclusion</time_frame>
    <description>6MWT distance measured in meters according to American Thoracic Society guidelines</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Correlation of breath-holding time with oxygen saturation during 6MWT</measure>
    <time_frame>Day 1 at inclusion</time_frame>
    <description>Oxygen saturation monitored by wearable pulse oximeter (Radius PPG™ Tetherless Pulse Oximetry, Masimo Corp., Irvine, CA, USA)</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Correlation of breath-holding time with pulmonary function indices</measure>
    <time_frame>Day 1 at inclusion</time_frame>
    <description>Pulmonary function indices including FVC (%) and DLCO (%)</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Correlation of breath-holding time with data on the echocardiography</measure>
    <time_frame>Day 1 at inclusion</time_frame>
    <description>Echocardiography including left ventricular ejection fraction and pulmonary arterial systolic pressure (mmHg)</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Correlation of breath-holding time with scleroderma health assessment questionnaire (SHAQ)</measure>
    <time_frame>Day 1 at inclusion</time_frame>
    <description>SHAQ ranging from 0 to 3</description>
  </secondary_outcome>
  <other_outcome>
    <measure>Changes of oxygen saturation during breath-holding test</measure>
    <time_frame>Day 1 at inclusion</time_frame>
    <description>Oxygen saturation monitored by radius or forehead pulse oximeter (Masimo Corp., Irvine, CA, USA)</description>
  </other_outcome>
  <other_outcome>
    <measure>Changes of oxygen saturation during of 6MWT</measure>
    <time_frame>Day 1 at inclusion</time_frame>
    <description>Oxygen saturation monitored by wearable pulse oximeter (Radius PPG™ Tetherless Pulse Oximetry, Masimo Corp., Irvine, CA, USA)</description>
  </other_outcome>
  <other_outcome>
    <measure>Responsiveness of breath-holding test</measure>
    <time_frame>Month 6 at inclusion</time_frame>
    <description>Correlation of Δbreath-holding test and ΔPulmonary function indices after 6months</description>
  </other_outcome>
  <other_outcome>
    <measure>Reliability of breath-holding test</measure>
    <time_frame>Day 1, and Day 7~Day14 at inclusion</time_frame>
    <description>Additional 30 patients collection for test-retest reliability</description>
  </other_outcome>
  <other_outcome>
    <measure>Development of the machine learning model to predict pulmonary parameters</measure>
    <time_frame>Year 2 at inclusion</time_frame>
    <description>Developing two cohorts: Cohort 1 for training a ML model and internal validation; and Cohort 2 for external validation</description>
  </other_outcome>
  <number_of_arms>1</number_of_arms>
  <enrollment type="Actual">120</enrollment>
  <condition>Systemic Sclerosis</condition>
  <arm_group>
    <arm_group_label>Systemic sclerosis group</arm_group_label>
    <arm_group_type>Experimental</arm_group_type>
    <description>Systemic sclerosis diagnosis according to 2013 American College of Rheumatology(ACR)/European League Against Rheumatism(EULAR) classification criteria</description>
  </arm_group>
  <intervention>
    <intervention_type>Other</intervention_type>
    <intervention_name>scleroderma health assessment questionnaire (SHAQ), BHT, and 6MWT</intervention_name>
    <description>Participants will perform the SHAQ.&#xD;
BHT and 6MWT will be performed in the randomized way for each participant.&#xD;
For BHT, the participants will be told to sit comfortably on a chair, and breath normally. After 1 minute, they were required to make a maximum expiration followed by a maximum inspiration and to hold the breath as long as possible at maximum inspiratory level. This procedure was repeated three times, with 5-minute intervals between the tests.&#xD;
6MWT will be performed according to the ATS guidelines.&#xD;
Information on CXR, TTE, and PFT (FVC%, DLCO%) will be obtained from the medical record if the data was obtained within 3 months. If not, the tests will be performed.&#xD;
BHT and PFT will be followed by six months after the first breath-holding test to confirm the responsiveness.&#xD;
Additional 30 patients with systemic sclerosis will be collected to perform the test-retest reliability of BHT.</description>
    <arm_group_label>Systemic sclerosis group</arm_group_label>
  </intervention>
  <eligibility>
    <criteria>
      <textblock>
        Inclusion Criteria:&#xD;
&#xD;
          -  A diagnosis of systemic sclerosis according to 2013 ACR/EULAR criteria&#xD;
&#xD;
          -  Must understand and voluntarily sign an informed consent form including writing&#xD;
             consent for data protection&#xD;
&#xD;
        Exclusion Criteria:&#xD;
&#xD;
          -  The resting oxygen saturation by pulse oximetry &lt; 90% in room air&#xD;
&#xD;
          -  Unstable angina or myocardial infarction during the previous month&#xD;
&#xD;
          -  Patients considered unable to the breath-holding test or 6 minute walk test&#xD;
      </textblock>
    </criteria>
    <gender>All</gender>
    <minimum_age>19 Years</minimum_age>
    <maximum_age>N/A</maximum_age>
    <healthy_volunteers>No</healthy_volunteers>
  </eligibility>
  <overall_official>
    <last_name>Eun Bong Lee, MD PhD</last_name>
    <role>Principal Investigator</role>
    <affiliation>Seoul National University College of Medicine</affiliation>
  </overall_official>
  <overall_official>
    <last_name>Jina Yeo, MD</last_name>
    <role>Study Director</role>
    <affiliation>Seoul National University College of Medicine</affiliation>
  </overall_official>
  <location>
    <facility>
      <name>Seoul National University Hospital</name>
      <address>
        <city>Seoul</city>
        <zip>03080</zip>
        <country>Korea, Republic of</country>
      </address>
    </facility>
  </location>
  <location_countries>
    <country>Korea, Republic of</country>
  </location_countries>
  <link>
    <url>https://erj.ersjournals.com/content/52/suppl_62/PA4053</url>
    <description>Azza Slim, Abir Hedhli, Sana Cheikh Rouhou, et al. Maximal voluntary inspiratory breath holding time test in patients with chronic obstructive pulmonary disease. European Respiratory Journal 2018 52:PA4053</description>
  </link>
  <reference>
    <citation>Hachulla E, Launay D. Diagnosis and classification of systemic sclerosis. Clin Rev Allergy Immunol. 2011 Apr;40(2):78-83. doi: 10.1007/s12016-010-8198-y.</citation>
    <PMID>20143182</PMID>
  </reference>
  <reference>
    <citation>Morelli S, Ferrante L, Sgreccia A, Eleuteri ML, Perrone C, De Marzio P, Balsano F. Pulmonary hypertension is associated with impaired exercise performance in patients with systemic sclerosis. Scand J Rheumatol. 2000;29(4):236-42. doi: 10.1080/030097400750041389.</citation>
    <PMID>11028845</PMID>
  </reference>
  <reference>
    <citation>Vandecasteele E, De Pauw M, De Keyser F, Decuman S, Deschepper E, Piette Y, Brusselle G, Smith V. Six-minute walk test in systemic sclerosis: A systematic review and meta-analysis. Int J Cardiol. 2016 Jun 1;212:265-73. doi: 10.1016/j.ijcard.2016.03.084. Epub 2016 Mar 25.</citation>
    <PMID>27057932</PMID>
  </reference>
  <reference>
    <citation>Impens AJ, Wangkaew S, Seibold JR. The 6-minute walk test in scleroderma--how measuring everything measures nothing. Rheumatology (Oxford). 2008 Oct;47 Suppl 5:v68-9. doi: 10.1093/rheumatology/ken273.</citation>
    <PMID>18784152</PMID>
  </reference>
  <reference>
    <citation>ATS Committee on Proficiency Standards for Clinical Pulmonary Function Laboratories. ATS statement: guidelines for the six-minute walk test. Am J Respir Crit Care Med. 2002 Jul 1;166(1):111-7. doi: 10.1164/ajrccm.166.1.at1102. No abstract available. Erratum In: Am J Respir Crit Care Med. 2016 May 15;193(10):1185.</citation>
    <PMID>12091180</PMID>
  </reference>
  <verification_date>May 2023</verification_date>
  <study_first_submitted>July 21, 2020</study_first_submitted>
  <study_first_submitted_qc>July 23, 2020</study_first_submitted_qc>
  <study_first_posted type="Actual">July 24, 2020</study_first_posted>
  <last_update_submitted>May 31, 2023</last_update_submitted>
  <last_update_submitted_qc>May 31, 2023</last_update_submitted_qc>
  <last_update_posted type="Actual">June 2, 2023</last_update_posted>
  <responsible_party>
    <responsible_party_type>Principal Investigator</responsible_party_type>
    <investigator_affiliation>Seoul National University Hospital</investigator_affiliation>
    <investigator_full_name>Eun Bong Lee</investigator_full_name>
    <investigator_title>Professor</investigator_title>
  </responsible_party>
  <keyword>Breath-holding test</keyword>
  <keyword>Six minute walk test</keyword>
  <keyword>Systemic sclerosis</keyword>
  <condition_browse>
    <!-- CAUTION:  The following MeSH terms are assigned with an imperfect algorithm            -->
    <mesh_term>Scleroderma, Systemic</mesh_term>
    <mesh_term>Scleroderma, Diffuse</mesh_term>
    <mesh_term>Sclerosis</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/NCT04484948
org study id: H-2006-054-1131
nct id: NCT04484948
lead sponsor: 
has dmc: Yes
is fda regulated drug: No
is fda regulated device: No
This study aims to evaluate the utility of breath-holding test as a marker of pulmonary
      disease severity in patients with systemic sclerosis.
Systemic sclerosis (SSc) is a chronic autoimmune disease of unknown etiology with high
      morbidity and mortality. SSc manifests by fibrosis of skin and internal organs. Although the
      underlying mechanisms are still subject to investigation, endothelial dysfunction and
      abnormal immune response are thought to contribute to vascular dysfunction and fibrosis in
      SSc.

      Pulmonary involvement, such as pulmonary arterial hypertension (PAH) and interstitial lung
      disease (ILD) is a major cause of death in SSc. Although the 6MWT is generally used for
      evaluating PAH and ILD, the utility in SSc is undetermined. Several investigators have found
      weak or moderate correlations of 6MWT in pulmonary involvement in SSc. The 6MWT is influenced
      by the status of all organ systems involved in exercise (pulmonary, cardiac, peripheral
      vascular, neuromuscular unit and muscle metabolism) as well as by specifics of test
      conditions. There is a pressing need for new, practical method which corroborates the current
      6MWT for the evaluation of pulmonary disease severity in SSc.

      Breath-holding test (BHT) is one of the most useful methods for assessing the sensitivity of
      peripheral chemoreflex. Recent studies have demonstrated that BHT was correlated to pulmonary
      function test. BHT can be safely conducted and doctors handle a medical emergency during test
      easily as well. Therefore, this study evaluates the utility of BHT as surrogate marker of
      pulmonary involvement in patients with SSc.
allocation: N/A
intervention model: Single Group Assignment
primary purpose: Other
masking: None (Open Label)
measure: Correlation of breath-holding test with Borg Dyspnea Index
time frame: Day 1 at inclusion
description: Borg Scale on a 0-10 point
measure: Correlation of breath-holding time with 6 minute walk test (6MWT) distance
time frame: Day 1 at inclusion
description: 6MWT distance measured in meters according to American Thoracic Society guidelines
measure: Correlation of breath-holding time with oxygen saturation during 6MWT
time frame: Day 1 at inclusion
description: Oxygen saturation monitored by wearable pulse oximeter (Radius PPG™ Tetherless Pulse Oximetry, Masimo Corp., Irvine, CA, USA)
measure: Correlation of breath-holding time with pulmonary function indices
time frame: Day 1 at inclusion
description: Pulmonary function indices including FVC (%) and DLCO (%)
measure: Correlation of breath-holding time with data on the echocardiography
time frame: Day 1 at inclusion
description: Echocardiography including left ventricular ejection fraction and pulmonary arterial systolic pressure (mmHg)
measure: Correlation of breath-holding time with scleroderma health assessment questionnaire (SHAQ)
time frame: Day 1 at inclusion
description: SHAQ ranging from 0 to 3
measure: Changes of oxygen saturation during breath-holding test
time frame: Day 1 at inclusion
description: Oxygen saturation monitored by radius or forehead pulse oximeter (Masimo Corp., Irvine, CA, USA)
measure: Changes of oxygen saturation during of 6MWT
time frame: Day 1 at inclusion
description: Oxygen saturation monitored by wearable pulse oximeter (Radius PPG™ Tetherless Pulse Oximetry, Masimo Corp., Irvine, CA, USA)
measure: Responsiveness of breath-holding test
time frame: Month 6 at inclusion
description: Correlation of Δbreath-holding test and ΔPulmonary function indices after 6months
measure: Reliability of breath-holding test
time frame: Day 1, and Day 7~Day14 at inclusion
description: Additional 30 patients collection for test-retest reliability
measure: Development of the machine learning model to predict pulmonary parameters
time frame: Year 2 at inclusion
description: Developing two cohorts: Cohort 1 for training a ML model and internal validation; and Cohort 2 for external validation
arm group label: Systemic sclerosis group
arm group type: Experimental
description: Systemic sclerosis diagnosis according to 2013 American College of Rheumatology(ACR)/European League Against Rheumatism(EULAR) classification criteria
intervention type: Other
intervention name: scleroderma health assessment questionnaire (SHAQ), BHT, and 6MWT
description: Participants will perform the SHAQ.
BHT and 6MWT will be performed in the randomized way for each participant.
For BHT, the participants will be told to sit comfortably on a chair, and breath normally. After 1 minute, they were required to make a maximum expiration followed by a maximum inspiration and to hold the breath as long as possible at maximum inspiratory level. This procedure was repeated three times, with 5-minute intervals between the tests.
6MWT will be performed according to the ATS guidelines.
Information on CXR, TTE, and PFT (FVC%, DLCO%) will be obtained from the medical record if the data was obtained within 3 months. If not, the tests will be performed.
BHT and PFT will be followed by six months after the first breath-holding test to confirm the responsiveness.
Additional 30 patients with systemic sclerosis will be collected to perform the test-retest reliability of BHT.
arm group label: Systemic sclerosis group
criteria: 
gender: All
minimum age: 19 Years
maximum age: N/A
healthy volunteers: No
last name: Eun Bong Lee, MD PhD
role: Principal Investigator
affiliation: Seoul National University College of Medicine
last name: Jina Yeo, MD
role: Study Director
affiliation: Seoul National University College of Medicine
facility: 
country: Korea, Republic of
url: https://erj.ersjournals.com/content/52/suppl_62/PA4053
description: Azza Slim, Abir Hedhli, Sana Cheikh Rouhou, et al. Maximal voluntary inspiratory breath holding time test in patients with chronic obstructive pulmonary disease. European Respiratory Journal 2018 52:PA4053
citation: Hachulla E, Launay D. Diagnosis and classification of systemic sclerosis. Clin Rev Allergy Immunol. 2011 Apr;40(2):78-83. doi: 10.1007/s12016-010-8198-y.
PMID: 20143182
citation: Morelli S, Ferrante L, Sgreccia A, Eleuteri ML, Perrone C, De Marzio P, Balsano F. Pulmonary hypertension is associated with impaired exercise performance in patients with systemic sclerosis. Scand J Rheumatol. 2000;29(4):236-42. doi: 10.1080/030097400750041389.
PMID: 11028845
citation: Vandecasteele E, De Pauw M, De Keyser F, Decuman S, Deschepper E, Piette Y, Brusselle G, Smith V. Six-minute walk test in systemic sclerosis: A systematic review and meta-analysis. Int J Cardiol. 2016 Jun 1;212:265-73. doi: 10.1016/j.ijcard.2016.03.084. Epub 2016 Mar 25.
PMID: 27057932
citation: Impens AJ, Wangkaew S, Seibold JR. The 6-minute walk test in scleroderma--how measuring everything measures nothing. Rheumatology (Oxford). 2008 Oct;47 Suppl 5:v68-9. doi: 10.1093/rheumatology/ken273.
PMID: 18784152
citation: ATS Committee on Proficiency Standards for Clinical Pulmonary Function Laboratories. ATS statement: guidelines for the six-minute walk test. Am J Respir Crit Care Med. 2002 Jul 1;166(1):111-7. doi: 10.1164/ajrccm.166.1.at1102. No abstract available. Erratum In: Am J Respir Crit Care Med. 2016 May 15;193(10):1185.
PMID: 12091180
responsible party type: Principal Investigator
investigator affiliation: Seoul National University Hospital
investigator full name: Eun Bong Lee
investigator title: Professor
mesh term: Scleroderma, Systemic
mesh term: Scleroderma, Diffuse
mesh term: Sclerosis