<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/NCT02220387</url>
  </required_header>
  <id_info>
    <org_study_id>01201463369/1</org_study_id>
    <secondary_id>01201463369</secondary_id>
    <nct_id>NCT02220387</nct_id>
  </id_info>
  <brief_title>Molecular, Cytological Features and Genetic Susceptibility of COPD Attributable to Different Environmental Exposures</brief_title>
  <official_title>Molecular, Cytological Features and Genetic Susceptibility of Occupational Chronic Obstructive Pulmonary Disease Attributable to Different Environmental Exposures</official_title>
  <sponsors>
    <lead_sponsor>
      <agency>Novosibirsk City Hospital #2</agency>
      <agency_class>Other</agency_class>
    </lead_sponsor>
    <collaborator>
      <agency>Siberian Branch of the Russian Academy of Medical Sciences</agency>
      <agency_class>Other</agency_class>
    </collaborator>
  </sponsors>
  <source>Novosibirsk City Hospital #2</source>
  <oversight_info>
    <has_dmc>No</has_dmc>
  </oversight_info>
  <brief_summary>
    <textblock>
      The objective of this study is to investigate molecular, cytological and genetic features of&#xD;
      occupational chronic obstructive pulmonary disease (COPD) in conditions of different&#xD;
      occupational exposures. In order to achieve this goal serum pro-inflammatory cytokines and&#xD;
      standard inflammation markers level, hemostasis, cytological analysis of bronchoalveolar&#xD;
      lavage and associations of single nucleotide polymorphisms (SNPs) rs1800470 transforming&#xD;
      growing factor β1 (TGF β1) gene, rs1828591 hedgehog interacting protein (HHIP) gene,&#xD;
      rs4129267 interleukin 6 receptor (IL-6R) gene, rs1051730 nicotinic acetylcholine receptor 3&#xD;
      (CHRNA3) gene with COPD in subjects exposed to silica dust and in those exposed to polycyclic&#xD;
      aromatic hydrocarbons exhaust will be investigated. The relationship between genotype and&#xD;
      phenotype characteristics, such as an inflammation activity, assessed by C-reactive protein&#xD;
      (hsCRP) and tumor necrosis factor-α (TNF α) serum concentration, in different occupational&#xD;
      COPD groups will be studied. The hypothesis is that the mechanisms underlying disease&#xD;
      development and progression are different due to environmental risk factor that reflex in&#xD;
      differs in disease attributes - molecular biomarkers, cytology results and genetic&#xD;
      susceptibility between COPD due to dust, COPD due to chemicals and COPD in smokers therefore&#xD;
      COPD can be subdivided into ecological phenotypes according to environmental risk factor.&#xD;
    </textblock>
  </brief_summary>
  <detailed_description>
    <textblock>
      Study rationale: The main risk factors of COPD are tobacco smoking, biomass smoking and&#xD;
      occupational factors. Tobacco smoking is well-known risk factor so tobacco induced COPD is&#xD;
      completely established. Nevertheless the meaning of occupational factors which are less&#xD;
      famous are equally important. Based on comprehensive literature review American Thoracic&#xD;
      Society (ATS) endorsed the notion that strong evidence implicates occupational factors as&#xD;
      cause of COPD [Eisner MD et al., 2010]. Occupational COPD takes 19.2 % of all COPD patients&#xD;
      and 31.1 % of never smokers as resulted NHANESIII study [Hnizdo E. et al., 2004]. A&#xD;
      considerable number of work-related factors have evidence for a causal association with COPD&#xD;
      including (and of course not limited) silica and silicates and polycyclic aromatic&#xD;
      hydrocarbons. Individuals in a variety of occupations and industries such as coal miners,&#xD;
      coke workers, tunnel workers, metallurgists, welding workers, transportation workers,&#xD;
      builders, farmers are exposed to factors cited above. Despite this the clinical and&#xD;
      pathophysiological features of COPD caused by occupational factors are still unclear.&#xD;
&#xD;
      Occupational factors leading airflow limitation are various entities - vapors, dusts, gases&#xD;
      and fumes with different physical, chemical, biological and other features, so the mechanisms&#xD;
      underlying disease development and progression may be different attributable to risk factor.&#xD;
&#xD;
      An environmental risk factors exposure as well as tobacco smoking results in COPD only in&#xD;
      part of the subjects which indicates the significant genome and gene environmental&#xD;
      interactions role. COPD develops in predisposed subjects undergoing risk factors exposure.&#xD;
      Therefore the risk of COPD is individual and depends on both genetic and environments. There&#xD;
      are few data concerning the effects of genetic on COPD risk in this specific subgroup -&#xD;
      people who are exposed to occupational risk factors related to the certain environmental&#xD;
      factor.&#xD;
&#xD;
      Statistical analysis: Statistical analysis will be carried out by Statistica 9.0 software.&#xD;
      Significance level will be considered p = 0.05. The qualitative variables will be expressed&#xD;
      as counts and percentages. The quantitative continuous variables will be expressed as means&#xD;
      and standard error of means (M ± m) for variables that meet the criteria of normality and&#xD;
      minimum and maximum, median for those that do not meet the criteria of normality.&#xD;
      Kruskal-Wallis test will be used for comparing multiply independent samples and Mann-Whitney&#xD;
      U test for comparing two independent samples if variable under consideration will continuous&#xD;
      and that it will be measured on an ordinal scale. For comparisons of proportions, the&#xD;
      Chi-square will be used.&#xD;
&#xD;
      For associations assessment logistic regression method will be used. The odds ratio (OR) and&#xD;
      95% confidence interval (CI) will be calculated for each professional group. Multiple&#xD;
      regression model will be used to explore the relationships between demographic&#xD;
      characteristics, cytokine concentrations, hemostasis and airflow limitation in professional&#xD;
      groups.&#xD;
    </textblock>
  </detailed_description>
  <overall_status>Completed</overall_status>
  <start_date>August 2014</start_date>
  <completion_date type="Actual">September 2014</completion_date>
  <primary_completion_date type="Actual">September 2014</primary_completion_date>
  <study_type>Observational</study_type>
  <has_expanded_access>No</has_expanded_access>
  <study_design_info>
    <observational_model>Case-Control</observational_model>
    <time_perspective>Cross-Sectional</time_perspective>
  </study_design_info>
  <primary_outcome>
    <measure>Association of SNPs rs1800470 TGF β1 gene, rs1828591 HHIP gene, rs4129267 IL-6R gene, rs1051730 CHRNA3 gene with COPD in subjects exposed to dust and in those exposed to chemicals.</measure>
    <time_frame>1 day (a single measurement)</time_frame>
    <description>Odds ratio and 95% confidence interval will be calculated for each occupational group. Controls - healthy people.</description>
  </primary_outcome>
  <primary_outcome>
    <measure>Difference in cytological analysis of bronchoalveolar lavage fluid results between COPD patients exposed to dust, chemicals and tobacco smoke</measure>
    <time_frame>1 day (a single measurement)</time_frame>
    <description>Comparison of groups.</description>
  </primary_outcome>
  <primary_outcome>
    <measure>Difference in serum interleukin 1 beta (IL-1β) level between COPD patients exposed to dust, chemicals and tobacco smoke.</measure>
    <time_frame>1 day (a single measurement)</time_frame>
    <description>Comparison of groups.</description>
  </primary_outcome>
  <primary_outcome>
    <measure>Difference in serum TNFα level between COPD patients exposed to dust, chemicals and tobacco smoke</measure>
    <time_frame>1 day (a single measurement)</time_frame>
    <description>Comparison of groups.</description>
  </primary_outcome>
  <primary_outcome>
    <measure>Difference in spontaneous thrombocyte aggregation between COPD patients exposed to dust, chemicals and tobacco smoke</measure>
    <time_frame>1 day (a single measurement)</time_frame>
    <description>Comparison of groups.</description>
  </primary_outcome>
  <primary_outcome>
    <measure>Difference in collagen induced thrombocyte aggregation between COPD patients exposed to dust, chemicals and tobacco smoke</measure>
    <time_frame>1 day (a single measurement)</time_frame>
    <description>Comparison of groups.</description>
  </primary_outcome>
  <primary_outcome>
    <measure>Difference in epinephrine induced thrombocyte aggregation between COPD patients exposed to dust, chemicals and tobacco smoke</measure>
    <time_frame>1 day (a single measurement)</time_frame>
    <description>Comparison of groups.</description>
  </primary_outcome>
  <primary_outcome>
    <measure>Difference in adenosine diphosphate induced thrombocyte aggregation between COPD patients exposed to dust, chemicals and tobacco smoke</measure>
    <time_frame>1 day (a single measurement)</time_frame>
    <description>Comparison of groups.</description>
  </primary_outcome>
  <primary_outcome>
    <measure>Difference in fibrinogen level between COPD patients exposed to dust, chemicals and tobacco smoke</measure>
    <time_frame>1 day (a single measurement)</time_frame>
    <description>Comparison of groups.</description>
  </primary_outcome>
  <primary_outcome>
    <measure>Difference in fibrinogen degradation products level between COPD patients exposed to dust, chemicals and tobacco smoke</measure>
    <time_frame>1 day (a single measurement)</time_frame>
    <description>Comparison of groups.</description>
  </primary_outcome>
  <primary_outcome>
    <measure>Difference in D-dimer level between COPD patients exposed to dust, chemicals and tobacco smoke</measure>
    <time_frame>1 day (a single measurement)</time_frame>
    <description>Comparison of groups.</description>
  </primary_outcome>
  <primary_outcome>
    <measure>Difference in serum endothelin1 level between COPD patients exposed to dust, chemicals and tobacco smoke</measure>
    <time_frame>1 day (a single measurement)</time_frame>
    <description>Comparison of groups.</description>
  </primary_outcome>
  <primary_outcome>
    <measure>Difference in serum nitric oxide level between COPD patients exposed to dust, chemicals and tobacco smoke</measure>
    <time_frame>1 day (a single measurement)</time_frame>
    <description>Comparison of groups.</description>
  </primary_outcome>
  <secondary_outcome>
    <measure>Relationship between genotype and phenotype characteristics, such as an inflammation activity, assessed by hsCRP and TNF α serum concentration, in different occupational COPD groups.</measure>
    <time_frame>1 day (a single measurement)</time_frame>
    <description>For SNPs that will occur associated with occupational COPD differences in hsCRP and TNFα serum concentration between subjects with different genotypes will be established separately for exposed to dust COPD group and for exposed to chemicals COPD group.</description>
  </secondary_outcome>
  <number_of_groups>2</number_of_groups>
  <enrollment type="Actual">352</enrollment>
  <condition>Chronic Obstructive Pulmonary Disease</condition>
  <arm_group>
    <arm_group_label>occupational COPD</arm_group_label>
    <description>Consists of 2 subgroups&#xD;
COPD patients with history of exposure to respirable silica dust&#xD;
COPD patients with history of exposure to polycyclic aromatic hydrocarbons exhaust</description>
  </arm_group>
  <arm_group>
    <arm_group_label>smokers with COPD and healthy control</arm_group_label>
    <description>Consists of 2 subgroups&#xD;
patients with COPD, history of tobacco smoke and no history of occupational exposure&#xD;
healthy subjects</description>
  </arm_group>
  <intervention>
    <intervention_type>Other</intervention_type>
    <intervention_name>exposure to respirable silica dust</intervention_name>
    <description>History of exposure to respirable silica dust due to job</description>
    <arm_group_label>occupational COPD</arm_group_label>
  </intervention>
  <intervention>
    <intervention_type>Other</intervention_type>
    <intervention_name>exposure to polycyclic aromatic hydrocarbons exhaust</intervention_name>
    <description>history of exposure to polycyclic aromatic hydrocarbons exhaust due to job</description>
    <arm_group_label>occupational COPD</arm_group_label>
  </intervention>
  <biospec_retention>Samples With DNA</biospec_retention>
  <biospec_descr>
    <textblock>
      whole blood, serum,bronchoalveolar lavage fluid&#xD;
    </textblock>
  </biospec_descr>
  <eligibility>
    <study_pop>
      <textblock>
        Residents of a certain town (Novosibirsk, Russian Federation)&#xD;
      </textblock>
    </study_pop>
    <sampling_method>Probability Sample</sampling_method>
    <criteria>
      <textblock>
        Inclusion Criteria:&#xD;
&#xD;
          -  Post- bronchodilator forced Expiratory Volume in 1 second (FEV1)/Forced Vital Capacity&#xD;
             (FVC) ratio less than 0.7&#xD;
&#xD;
          -  Stable phase of COPD&#xD;
&#xD;
          -  History of exposure to respirable silica dust, nonsmokers with absence of passive&#xD;
             exposure to tobacco smoke or history of exposure to polycyclic aromatic hydrocarbons&#xD;
             exhaust, nonsmokers with absence of passive exposure to tobacco smoke or current&#xD;
             tobacco smokers without history of occupational exposure&#xD;
&#xD;
          -  COPD risk factor exposure (occupational or tobacco smoke) duration not less than 12&#xD;
             months&#xD;
&#xD;
          -  Male&#xD;
&#xD;
          -  Caucasian&#xD;
&#xD;
          -  Age of 40 - 75 years old&#xD;
&#xD;
          -  Control group - healthy people&#xD;
&#xD;
        Exclusion Criteria:&#xD;
&#xD;
          -  history of biomass smoke exposure&#xD;
&#xD;
          -  age less than 40 and above 75 years old&#xD;
&#xD;
          -  current COPD exacerbation&#xD;
&#xD;
          -  concomitant asthma&#xD;
&#xD;
          -  tuberculosis and other pulmonary diseases&#xD;
&#xD;
          -  allergic and autoimmune disorders&#xD;
&#xD;
          -  active infections&#xD;
&#xD;
          -  immunodeficiency, including HIV infection&#xD;
&#xD;
          -  parasitological diseases&#xD;
&#xD;
          -  malignancies&#xD;
&#xD;
          -  lack of informed consent&#xD;
      </textblock>
    </criteria>
    <gender>Male</gender>
    <minimum_age>40 Years</minimum_age>
    <maximum_age>75 Years</maximum_age>
    <healthy_volunteers>No</healthy_volunteers>
  </eligibility>
  <overall_official>
    <last_name>Liubov Shpagina, PhD</last_name>
    <role>Principal Investigator</role>
    <affiliation>Novosibirsk Citi Hospital #2, Novosibirsk State Medical University</affiliation>
  </overall_official>
  <location>
    <facility>
      <name>Novosibirsk City Hospital #2</name>
      <address>
        <city>Novosibirsk</city>
        <zip>630084</zip>
        <country>Russian Federation</country>
      </address>
    </facility>
  </location>
  <location_countries>
    <country>Russian Federation</country>
  </location_countries>
  <verification_date>October 2015</verification_date>
  <study_first_submitted>August 11, 2014</study_first_submitted>
  <study_first_submitted_qc>August 16, 2014</study_first_submitted_qc>
  <study_first_posted type="Estimate">August 19, 2014</study_first_posted>
  <last_update_submitted>October 5, 2015</last_update_submitted>
  <last_update_submitted_qc>October 5, 2015</last_update_submitted_qc>
  <last_update_posted type="Estimate">October 6, 2015</last_update_posted>
  <responsible_party>
    <responsible_party_type>Principal Investigator</responsible_party_type>
    <investigator_affiliation>Novosibirsk City Hospital #2</investigator_affiliation>
    <investigator_full_name>Liubov A Shpagina</investigator_full_name>
    <investigator_title>Prof., Dr</investigator_title>
  </responsible_party>
  <keyword>occupational COPD</keyword>
  <keyword>phenotype</keyword>
  <keyword>genetic</keyword>
  <condition_browse>
    <!-- CAUTION:  The following MeSH terms are assigned with an imperfect algorithm            -->
    <mesh_term>Lung Diseases</mesh_term>
    <mesh_term>Lung Diseases, Obstructive</mesh_term>
    <mesh_term>Pulmonary Disease, Chronic Obstructive</mesh_term>
    <mesh_term>Genetic Predisposition to Disease</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/NCT02220387
org study id: 01201463369/1
secondary id: 01201463369
nct id: NCT02220387
lead sponsor: 
collaborator: 
has dmc: No
The objective of this study is to investigate molecular, cytological and genetic features of
      occupational chronic obstructive pulmonary disease (COPD) in conditions of different
      occupational exposures. In order to achieve this goal serum pro-inflammatory cytokines and
      standard inflammation markers level, hemostasis, cytological analysis of bronchoalveolar
      lavage and associations of single nucleotide polymorphisms (SNPs) rs1800470 transforming
      growing factor β1 (TGF β1) gene, rs1828591 hedgehog interacting protein (HHIP) gene,
      rs4129267 interleukin 6 receptor (IL-6R) gene, rs1051730 nicotinic acetylcholine receptor 3
      (CHRNA3) gene with COPD in subjects exposed to silica dust and in those exposed to polycyclic
      aromatic hydrocarbons exhaust will be investigated. The relationship between genotype and
      phenotype characteristics, such as an inflammation activity, assessed by C-reactive protein
      (hsCRP) and tumor necrosis factor-α (TNF α) serum concentration, in different occupational
      COPD groups will be studied. The hypothesis is that the mechanisms underlying disease
      development and progression are different due to environmental risk factor that reflex in
      differs in disease attributes - molecular biomarkers, cytology results and genetic
      susceptibility between COPD due to dust, COPD due to chemicals and COPD in smokers therefore
      COPD can be subdivided into ecological phenotypes according to environmental risk factor.
Study rationale: The main risk factors of COPD are tobacco smoking, biomass smoking and
      occupational factors. Tobacco smoking is well-known risk factor so tobacco induced COPD is
      completely established. Nevertheless the meaning of occupational factors which are less
      famous are equally important. Based on comprehensive literature review American Thoracic
      Society (ATS) endorsed the notion that strong evidence implicates occupational factors as
      cause of COPD [Eisner MD et al., 2010]. Occupational COPD takes 19.2 % of all COPD patients
      and 31.1 % of never smokers as resulted NHANESIII study [Hnizdo E. et al., 2004]. A
      considerable number of work-related factors have evidence for a causal association with COPD
      including (and of course not limited) silica and silicates and polycyclic aromatic
      hydrocarbons. Individuals in a variety of occupations and industries such as coal miners,
      coke workers, tunnel workers, metallurgists, welding workers, transportation workers,
      builders, farmers are exposed to factors cited above. Despite this the clinical and
      pathophysiological features of COPD caused by occupational factors are still unclear.

      Occupational factors leading airflow limitation are various entities - vapors, dusts, gases
      and fumes with different physical, chemical, biological and other features, so the mechanisms
      underlying disease development and progression may be different attributable to risk factor.

      An environmental risk factors exposure as well as tobacco smoking results in COPD only in
      part of the subjects which indicates the significant genome and gene environmental
      interactions role. COPD develops in predisposed subjects undergoing risk factors exposure.
      Therefore the risk of COPD is individual and depends on both genetic and environments. There
      are few data concerning the effects of genetic on COPD risk in this specific subgroup -
      people who are exposed to occupational risk factors related to the certain environmental
      factor.

      Statistical analysis: Statistical analysis will be carried out by Statistica 9.0 software.
      Significance level will be considered p = 0.05. The qualitative variables will be expressed
      as counts and percentages. The quantitative continuous variables will be expressed as means
      and standard error of means (M ± m) for variables that meet the criteria of normality and
      minimum and maximum, median for those that do not meet the criteria of normality.
      Kruskal-Wallis test will be used for comparing multiply independent samples and Mann-Whitney
      U test for comparing two independent samples if variable under consideration will continuous
      and that it will be measured on an ordinal scale. For comparisons of proportions, the
      Chi-square will be used.

      For associations assessment logistic regression method will be used. The odds ratio (OR) and
      95% confidence interval (CI) will be calculated for each professional group. Multiple
      regression model will be used to explore the relationships between demographic
      characteristics, cytokine concentrations, hemostasis and airflow limitation in professional
      groups.
observational model: Case-Control
time perspective: Cross-Sectional
measure: Association of SNPs rs1800470 TGF β1 gene, rs1828591 HHIP gene, rs4129267 IL-6R gene, rs1051730 CHRNA3 gene with COPD in subjects exposed to dust and in those exposed to chemicals.
time frame: 1 day (a single measurement)
description: Odds ratio and 95% confidence interval will be calculated for each occupational group. Controls - healthy people.
measure: Difference in cytological analysis of bronchoalveolar lavage fluid results between COPD patients exposed to dust, chemicals and tobacco smoke
time frame: 1 day (a single measurement)
description: Comparison of groups.
measure: Difference in serum interleukin 1 beta (IL-1β) level between COPD patients exposed to dust, chemicals and tobacco smoke.
time frame: 1 day (a single measurement)
description: Comparison of groups.
measure: Difference in serum TNFα level between COPD patients exposed to dust, chemicals and tobacco smoke
time frame: 1 day (a single measurement)
description: Comparison of groups.
measure: Difference in spontaneous thrombocyte aggregation between COPD patients exposed to dust, chemicals and tobacco smoke
time frame: 1 day (a single measurement)
description: Comparison of groups.
measure: Difference in collagen induced thrombocyte aggregation between COPD patients exposed to dust, chemicals and tobacco smoke
time frame: 1 day (a single measurement)
description: Comparison of groups.
measure: Difference in epinephrine induced thrombocyte aggregation between COPD patients exposed to dust, chemicals and tobacco smoke
time frame: 1 day (a single measurement)
description: Comparison of groups.
measure: Difference in adenosine diphosphate induced thrombocyte aggregation between COPD patients exposed to dust, chemicals and tobacco smoke
time frame: 1 day (a single measurement)
description: Comparison of groups.
measure: Difference in fibrinogen level between COPD patients exposed to dust, chemicals and tobacco smoke
time frame: 1 day (a single measurement)
description: Comparison of groups.
measure: Difference in fibrinogen degradation products level between COPD patients exposed to dust, chemicals and tobacco smoke
time frame: 1 day (a single measurement)
description: Comparison of groups.
measure: Difference in D-dimer level between COPD patients exposed to dust, chemicals and tobacco smoke
time frame: 1 day (a single measurement)
description: Comparison of groups.
measure: Difference in serum endothelin1 level between COPD patients exposed to dust, chemicals and tobacco smoke
time frame: 1 day (a single measurement)
description: Comparison of groups.
measure: Difference in serum nitric oxide level between COPD patients exposed to dust, chemicals and tobacco smoke
time frame: 1 day (a single measurement)
description: Comparison of groups.
measure: Relationship between genotype and phenotype characteristics, such as an inflammation activity, assessed by hsCRP and TNF α serum concentration, in different occupational COPD groups.
time frame: 1 day (a single measurement)
description: For SNPs that will occur associated with occupational COPD differences in hsCRP and TNFα serum concentration between subjects with different genotypes will be established separately for exposed to dust COPD group and for exposed to chemicals COPD group.
arm group label: occupational COPD
description: Consists of 2 subgroups
COPD patients with history of exposure to respirable silica dust
COPD patients with history of exposure to polycyclic aromatic hydrocarbons exhaust
arm group label: smokers with COPD and healthy control
description: Consists of 2 subgroups
patients with COPD, history of tobacco smoke and no history of occupational exposure
healthy subjects
intervention type: Other
intervention name: exposure to respirable silica dust
description: History of exposure to respirable silica dust due to job
arm group label: occupational COPD
intervention type: Other
intervention name: exposure to polycyclic aromatic hydrocarbons exhaust
description: history of exposure to polycyclic aromatic hydrocarbons exhaust due to job
arm group label: occupational COPD
whole blood, serum,bronchoalveolar lavage fluid
study pop: 
sampling method: Probability Sample
criteria: 
gender: Male
minimum age: 40 Years
maximum age: 75 Years
healthy volunteers: No
last name: Liubov Shpagina, PhD
role: Principal Investigator
affiliation: Novosibirsk Citi Hospital #2, Novosibirsk State Medical University
facility: 
country: Russian Federation
responsible party type: Principal Investigator
investigator affiliation: Novosibirsk City Hospital #2
investigator full name: Liubov A Shpagina
investigator title: Prof., Dr
mesh term: Lung Diseases
mesh term: Lung Diseases, Obstructive
mesh term: Pulmonary Disease, Chronic Obstructive
mesh term: Genetic Predisposition to Disease