<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/NCT03234790</url>
  </required_header>
  <id_info>
    <org_study_id>H16-03053</org_study_id>
    <nct_id>NCT03234790</nct_id>
  </id_info>
  <brief_title>Human Study to Develop a Signature of Occupational Diesel Exhaust Exposure</brief_title>
  <acronym>DICE</acronym>
  <official_title>A Controlled Dose-Response Human Study to Develop a Signature of Occupational Diesel Exhaust Exposure</official_title>
  <sponsors>
    <lead_sponsor>
      <agency>University of British Columbia</agency>
      <agency_class>Other</agency_class>
    </lead_sponsor>
    <collaborator>
      <agency>Government of Alberta</agency>
      <agency_class>Other</agency_class>
    </collaborator>
    <collaborator>
      <agency>Ottawa Hospital Research Institute</agency>
      <agency_class>Other</agency_class>
    </collaborator>
  </sponsors>
  <source>University of British Columbia</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>
      Strong scientific understanding of how emissions from diesel engines impact the lungs could&#xD;
      improve policies and regulations protecting workers exposed to diesel exhaust. Accordingly,&#xD;
      we are recruiting healthy volunteers who are non-smokers to participate in our study.&#xD;
      Volunteers sit in a room for four hours and breathe either clean filtered air or air that&#xD;
      contains pollution at various concentrations similar to occupational settings such as bus and&#xD;
      ferry terminals where diesel engines are used. A respirologist assesses the volunteer's lung&#xD;
      health and clinical samples are taken. We are equipped with advanced molecular biology tools&#xD;
      to measure different molecules and compare samples from our volunteer subjects following&#xD;
      exposure to clean air or diesel exhaust. Our research aim is to find a simple, clinically&#xD;
      relevant strategy that can be used to measure the impact of diesel exhaust on workers' lung&#xD;
      health. This knowledge will empower regulators, companies, and ultimately workers to better&#xD;
      manage their health risks. Our research aims to provide specific data to help regulators to&#xD;
      make informed decisions about the risks of diesel exhaust exposure.&#xD;
    </textblock>
  </brief_summary>
  <detailed_description>
    <textblock>
      1. Purpose: Over 100,000 employees in Alberta are inadvertently exposed to diesel exhaust&#xD;
           at work because of wide use of diesel engines in vehicles and machines used in road&#xD;
           construction, trucking, forestry, oil extraction and mineral mining. Although ambient&#xD;
           air monitoring of DE exposure exists in some occupational settings, ambient air&#xD;
           monitoring depends heavily on surrogate models and may yield a distorted picture of past&#xD;
           exhaust exposure. Thus, a clear exposure limit based on bio-monitoring is needed to&#xD;
           adequately protect the workers.&#xD;
&#xD;
        2. Objective: Our research aims to establish the relationship between exposure&#xD;
           concentration and biological effect as an aid to determination of reference ranges for&#xD;
           acceptable exposure.&#xD;
&#xD;
        3. Hypotheses and Aims:&#xD;
&#xD;
           Hypothesis 1: Diesel exhaust (DE) inhalation elicits a characteristic protein output, in&#xD;
           a dose-dependent manner.&#xD;
&#xD;
           Aim 1. Demonstrate, using a proteomic analysis of serum and urine, a signature that&#xD;
           acutely increases in response to a range of occupationally relevant DE concentrations.&#xD;
&#xD;
           Hypothesis 2: DE inhalation increases concentrations of metabolites of polyaromatic&#xD;
           hydrocarbons (PAH) in urine, in a dose-dependent manner.&#xD;
&#xD;
           Aim 2. Ascertain the range of PAH metabolites accumulation in urine following acute&#xD;
           exposure to a range of occupationally relevant DE concentrations.&#xD;
&#xD;
           Hypothesis 3: DE inhalation alters the airway responsiveness to a contractile stimulus,&#xD;
           in a dose-dependent manner, and that alteration is associated with changes in a combined&#xD;
           proteomic/PAH-metabolomic signature.&#xD;
&#xD;
           Aim 3: Determine the dose-response slope to methacholine, in response to a range of&#xD;
           occupationally relevant DE concentrations, and correlate changes in this slope to&#xD;
           changes in proteins and metabolites.&#xD;
&#xD;
           Additionally, we aim to establish the relationship between a range of controlled DE&#xD;
           exposure concentrations and sleep quality and breathing in sleep through the sub-study&#xD;
           component.&#xD;
&#xD;
        4. Justification:&#xD;
&#xD;
           Our work will inform decision makers and stakeholders in creating evidence-based&#xD;
           policies to limit occupational diesel exhaust exposure based on relevant biology.&#xD;
&#xD;
        5. Research Method:&#xD;
&#xD;
           This is an order-randomized, double-blinded, crossover human exposure study.&#xD;
&#xD;
           This project aims to determine markers of DE exposure that can be used in an&#xD;
           occupational setting. Therefore, we will use a range of occupational exposure levels to&#xD;
           appropriately contextualize our results. For this, 20 healthy participants will be&#xD;
           exposed to a control condition and 3 different levels of DE concentration, each for a&#xD;
           period of 4 hours, in a randomized order. Each exposure will be separated by a washout&#xD;
           period of two weeks. The levels will be DE titrated to 20, 50 and 150 ug/m3 PM2.5, and&#xD;
           the control exposure will be filtered air (FA).&#xD;
&#xD;
           Participants will undergo a methacholine challenge and will provide urine and blood&#xD;
           samples before and after exposures to analyze lung function and biological responses.&#xD;
&#xD;
           If participants consent to participation in the sleep sub-study, they will be provided&#xD;
           with additional questionnaires throughout their visits pertaining to their sleep&#xD;
           quality. The participants will be provided with an Alice NightOne sleep monitor and&#xD;
           instructions on how to operate the equipment. The sleep monitor will be hooked up by the&#xD;
           participant at home when they are about to sleep, following an exposure, and will&#xD;
           monitor their sleep patterns for that night.&#xD;
&#xD;
        6. Statistical Analysis:&#xD;
&#xD;
      First, the changes in clinical parameters (methacholine PC20 and dose response slope) and&#xD;
      serum blood protein abundance between pre- and post-exposure will be determined. These&#xD;
      'delta' values will be statistically compared across exposures using linear mixed effects&#xD;
      models using R program, as outlined in our previous publications from similarly-designed&#xD;
      protocols from our group. Values of p&lt;0.05 will be considered significant throughout, with&#xD;
      adjustments for multiple comparisons. Although the 2-week washout period is intended to&#xD;
      minimize the likelihood of carryover effects, we will formally assess for this by including a&#xD;
      term for order of exposures in the models.&#xD;
&#xD;
      Analyses for the sleep component will be performed at the Hospital of Ottawa and will be&#xD;
      completed through a linear or logistic mixed effects model, as applicable using the R&#xD;
      program. Similar methods to data collected from the main study. Data interpretation will be&#xD;
      completed through a software algorithm on the local server.&#xD;
    </textblock>
  </detailed_description>
  <overall_status>Completed</overall_status>
  <start_date type="Actual">September 27, 2017</start_date>
  <completion_date type="Actual">July 16, 2021</completion_date>
  <primary_completion_date type="Actual">July 16, 2021</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>Crossover Assignment</intervention_model>
    <primary_purpose>Screening</primary_purpose>
    <masking>Triple (Participant, Investigator, Outcomes Assessor)</masking>
  </study_design_info>
  <primary_outcome>
    <measure>Serum proteome in response to DE exposure</measure>
    <time_frame>4 hours &amp; 24 hours</time_frame>
    <description>Serum from each experimental condition will be analyzed by liquid chromatography-mass spectrometry (LC-MS/MS) to observe any changes between the baseline and listed time points</description>
  </primary_outcome>
  <secondary_outcome>
    <measure>Urine proteins in response to DE exposure</measure>
    <time_frame>4 hours &amp; 24 hours</time_frame>
    <description>Urine from each experimental condition will be analyzed by liquid mass chromatography to observe any changes between the baseline and listed time points.</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Polycyclic Aromatic Hydrocarbons (PAH) metabolites in response to DE exposure</measure>
    <time_frame>4 hours &amp; 24 hours</time_frame>
    <description>PAH metabolites in urine samples will be analyzed by HPLC to observe any changes between the baseline and listed time points.</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Sleep quality</measure>
    <time_frame>baseline versus 24 hours post-exposure</time_frame>
    <description>Sleep quality will be assessed by level 3 overnight monitor and questionnaires</description>
  </secondary_outcome>
  <number_of_arms>2</number_of_arms>
  <enrollment type="Actual">20</enrollment>
  <condition>Experimental</condition>
  <arm_group>
    <arm_group_label>Filtered Air Exposure</arm_group_label>
    <arm_group_type>Active Comparator</arm_group_type>
    <description>Exposure for 4 hours to filtered air</description>
  </arm_group>
  <arm_group>
    <arm_group_label>Diesel Exhaust Exposure</arm_group_label>
    <arm_group_type>Experimental</arm_group_type>
    <description>Volunteers exposed to different concentrations of diesel exhaust</description>
  </arm_group>
  <intervention>
    <intervention_type>Other</intervention_type>
    <intervention_name>Filtered Air Exposure</intervention_name>
    <description>Exposure to Filtered air</description>
    <arm_group_label>Filtered Air Exposure</arm_group_label>
  </intervention>
  <intervention>
    <intervention_type>Other</intervention_type>
    <intervention_name>Diesel Exhaust Exposure</intervention_name>
    <description>Diesel exposure to different concentrations at different times: 20, 50 and 150ug/m3</description>
    <arm_group_label>Diesel Exhaust Exposure</arm_group_label>
  </intervention>
  <eligibility>
    <criteria>
      <textblock>
        Inclusion Criteria:&#xD;
&#xD;
          1. 19-49 years&#xD;
&#xD;
          2. Non-smokers&#xD;
&#xD;
          3. No physician diagnosed asthma&#xD;
&#xD;
        Exclusion Criteria:&#xD;
&#xD;
          1. Pregnant/breastfeeding&#xD;
&#xD;
          2. Using inhaled corticosteroids&#xD;
&#xD;
          3. Co-existing medical conditions (as assessed by the primary investigator)&#xD;
&#xD;
          4. Taking part in another study that involves taking medications.&#xD;
&#xD;
          5. Abnormal lung function based on screening spirometry&#xD;
&#xD;
          6. Cardiac diagnosis or arrhythmia is discovered during the screening process&#xD;
      </textblock>
    </criteria>
    <gender>All</gender>
    <minimum_age>19 Years</minimum_age>
    <maximum_age>49 Years</maximum_age>
    <healthy_volunteers>Accepts Healthy Volunteers</healthy_volunteers>
  </eligibility>
  <overall_official>
    <last_name>Christopher Carlsten, MD, MPH</last_name>
    <role>Principal Investigator</role>
    <affiliation>University of British Columbia</affiliation>
  </overall_official>
  <location>
    <facility>
      <name>University of British Columbia - VGH site</name>
      <address>
        <city>Vancouver</city>
        <state>British Columbia</state>
        <zip>V5Z 1M9</zip>
        <country>Canada</country>
      </address>
    </facility>
  </location>
  <location_countries>
    <country>Canada</country>
  </location_countries>
  <reference>
    <citation>Guest PC, Gottschalk MG, Bahn S. Proteomics: improving biomarker translation to modern medicine? Genome Med. 2013 Feb 27;5(2):17. doi: 10.1186/gm421. eCollection 2013. No abstract available.</citation>
    <PMID>23445684</PMID>
  </reference>
  <reference>
    <citation>Huang W, Smith TJ, Ngo L, Wang T, Chen H, Wu F, Herrick RF, Christiani DC, Ding H. Characterizing and biological monitoring of polycyclic aromatic hydrocarbons in exposures to diesel exhaust. Environ Sci Technol. 2007 Apr 15;41(8):2711-6. doi: 10.1021/es062863j.</citation>
    <PMID>17533828</PMID>
  </reference>
  <reference>
    <citation>Morgott DA. Factors and Trends Affecting the Identification of a Reliable Biomarker for Diesel Exhaust Exposure. Crit Rev Environ Sci Technol. 2014 Aug;44(16):1795-1864. doi: 10.1080/10643389.2013.790748.</citation>
    <PMID>25170242</PMID>
  </reference>
  <verification_date>October 2021</verification_date>
  <study_first_submitted>July 25, 2017</study_first_submitted>
  <study_first_submitted_qc>July 26, 2017</study_first_submitted_qc>
  <study_first_posted type="Actual">July 31, 2017</study_first_posted>
  <last_update_submitted>October 29, 2021</last_update_submitted>
  <last_update_submitted_qc>October 29, 2021</last_update_submitted_qc>
  <last_update_posted type="Actual">November 2, 2021</last_update_posted>
  <responsible_party>
    <responsible_party_type>Principal Investigator</responsible_party_type>
    <investigator_affiliation>University of British Columbia</investigator_affiliation>
    <investigator_full_name>Christopher Carlsten</investigator_full_name>
    <investigator_title>Principal Investigator</investigator_title>
  </responsible_party>
  <keyword>Diesel Exhaust</keyword>
  <keyword>Air Pollution</keyword>
  <keyword>Airway Responsiveness</keyword>
  <keyword>Proteomics</keyword>
  <keyword>Urine PAH Metabolites</keyword>
  <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/NCT03234790
org study id: H16-03053
nct id: NCT03234790
lead sponsor: 
collaborator: 
collaborator: 
has dmc: No
is fda regulated drug: No
is fda regulated device: No
Strong scientific understanding of how emissions from diesel engines impact the lungs could
      improve policies and regulations protecting workers exposed to diesel exhaust. Accordingly,
      we are recruiting healthy volunteers who are non-smokers to participate in our study.
      Volunteers sit in a room for four hours and breathe either clean filtered air or air that
      contains pollution at various concentrations similar to occupational settings such as bus and
      ferry terminals where diesel engines are used. A respirologist assesses the volunteer's lung
      health and clinical samples are taken. We are equipped with advanced molecular biology tools
      to measure different molecules and compare samples from our volunteer subjects following
      exposure to clean air or diesel exhaust. Our research aim is to find a simple, clinically
      relevant strategy that can be used to measure the impact of diesel exhaust on workers' lung
      health. This knowledge will empower regulators, companies, and ultimately workers to better
      manage their health risks. Our research aims to provide specific data to help regulators to
      make informed decisions about the risks of diesel exhaust exposure.
1. Purpose: Over 100,000 employees in Alberta are inadvertently exposed to diesel exhaust
           at work because of wide use of diesel engines in vehicles and machines used in road
           construction, trucking, forestry, oil extraction and mineral mining. Although ambient
           air monitoring of DE exposure exists in some occupational settings, ambient air
           monitoring depends heavily on surrogate models and may yield a distorted picture of past
           exhaust exposure. Thus, a clear exposure limit based on bio-monitoring is needed to
           adequately protect the workers.

        2. Objective: Our research aims to establish the relationship between exposure
           concentration and biological effect as an aid to determination of reference ranges for
           acceptable exposure.

        3. Hypotheses and Aims:

           Hypothesis 1: Diesel exhaust (DE) inhalation elicits a characteristic protein output, in
           a dose-dependent manner.

           Aim 1. Demonstrate, using a proteomic analysis of serum and urine, a signature that
           acutely increases in response to a range of occupationally relevant DE concentrations.

           Hypothesis 2: DE inhalation increases concentrations of metabolites of polyaromatic
           hydrocarbons (PAH) in urine, in a dose-dependent manner.

           Aim 2. Ascertain the range of PAH metabolites accumulation in urine following acute
           exposure to a range of occupationally relevant DE concentrations.

           Hypothesis 3: DE inhalation alters the airway responsiveness to a contractile stimulus,
           in a dose-dependent manner, and that alteration is associated with changes in a combined
           proteomic/PAH-metabolomic signature.

           Aim 3: Determine the dose-response slope to methacholine, in response to a range of
           occupationally relevant DE concentrations, and correlate changes in this slope to
           changes in proteins and metabolites.

           Additionally, we aim to establish the relationship between a range of controlled DE
           exposure concentrations and sleep quality and breathing in sleep through the sub-study
           component.

        4. Justification:

           Our work will inform decision makers and stakeholders in creating evidence-based
           policies to limit occupational diesel exhaust exposure based on relevant biology.

        5. Research Method:

           This is an order-randomized, double-blinded, crossover human exposure study.

           This project aims to determine markers of DE exposure that can be used in an
           occupational setting. Therefore, we will use a range of occupational exposure levels to
           appropriately contextualize our results. For this, 20 healthy participants will be
           exposed to a control condition and 3 different levels of DE concentration, each for a
           period of 4 hours, in a randomized order. Each exposure will be separated by a washout
           period of two weeks. The levels will be DE titrated to 20, 50 and 150 ug/m3 PM2.5, and
           the control exposure will be filtered air (FA).

           Participants will undergo a methacholine challenge and will provide urine and blood
           samples before and after exposures to analyze lung function and biological responses.

           If participants consent to participation in the sleep sub-study, they will be provided
           with additional questionnaires throughout their visits pertaining to their sleep
           quality. The participants will be provided with an Alice NightOne sleep monitor and
           instructions on how to operate the equipment. The sleep monitor will be hooked up by the
           participant at home when they are about to sleep, following an exposure, and will
           monitor their sleep patterns for that night.

        6. Statistical Analysis:

      First, the changes in clinical parameters (methacholine PC20 and dose response slope) and
      serum blood protein abundance between pre- and post-exposure will be determined. These
      'delta' values will be statistically compared across exposures using linear mixed effects
      models using R program, as outlined in our previous publications from similarly-designed
      protocols from our group. Values of p<0.05 will be considered significant throughout, with
      adjustments for multiple comparisons. Although the 2-week washout period is intended to
      minimize the likelihood of carryover effects, we will formally assess for this by including a
      term for order of exposures in the models.

      Analyses for the sleep component will be performed at the Hospital of Ottawa and will be
      completed through a linear or logistic mixed effects model, as applicable using the R
      program. Similar methods to data collected from the main study. Data interpretation will be
      completed through a software algorithm on the local server.
allocation: Randomized
intervention model: Crossover Assignment
primary purpose: Screening
masking: Triple (Participant, Investigator, Outcomes Assessor)
measure: Serum proteome in response to DE exposure
time frame: 4 hours & 24 hours
description: Serum from each experimental condition will be analyzed by liquid chromatography-mass spectrometry (LC-MS/MS) to observe any changes between the baseline and listed time points
measure: Urine proteins in response to DE exposure
time frame: 4 hours & 24 hours
description: Urine from each experimental condition will be analyzed by liquid mass chromatography to observe any changes between the baseline and listed time points.
measure: Polycyclic Aromatic Hydrocarbons (PAH) metabolites in response to DE exposure
time frame: 4 hours & 24 hours
description: PAH metabolites in urine samples will be analyzed by HPLC to observe any changes between the baseline and listed time points.
measure: Sleep quality
time frame: baseline versus 24 hours post-exposure
description: Sleep quality will be assessed by level 3 overnight monitor and questionnaires
arm group label: Filtered Air Exposure
arm group type: Active Comparator
description: Exposure for 4 hours to filtered air
arm group label: Diesel Exhaust Exposure
arm group type: Experimental
description: Volunteers exposed to different concentrations of diesel exhaust
intervention type: Other
intervention name: Filtered Air Exposure
description: Exposure to Filtered air
arm group label: Filtered Air Exposure
intervention type: Other
intervention name: Diesel Exhaust Exposure
description: Diesel exposure to different concentrations at different times: 20, 50 and 150ug/m3
arm group label: Diesel Exhaust Exposure
criteria: 
gender: All
minimum age: 19 Years
maximum age: 49 Years
healthy volunteers: Accepts Healthy Volunteers
last name: Christopher Carlsten, MD, MPH
role: Principal Investigator
affiliation: University of British Columbia
facility: 
country: Canada
citation: Guest PC, Gottschalk MG, Bahn S. Proteomics: improving biomarker translation to modern medicine? Genome Med. 2013 Feb 27;5(2):17. doi: 10.1186/gm421. eCollection 2013. No abstract available.
PMID: 23445684
citation: Huang W, Smith TJ, Ngo L, Wang T, Chen H, Wu F, Herrick RF, Christiani DC, Ding H. Characterizing and biological monitoring of polycyclic aromatic hydrocarbons in exposures to diesel exhaust. Environ Sci Technol. 2007 Apr 15;41(8):2711-6. doi: 10.1021/es062863j.
PMID: 17533828
citation: Morgott DA. Factors and Trends Affecting the Identification of a Reliable Biomarker for Diesel Exhaust Exposure. Crit Rev Environ Sci Technol. 2014 Aug;44(16):1795-1864. doi: 10.1080/10643389.2013.790748.
PMID: 25170242
responsible party type: Principal Investigator
investigator affiliation: University of British Columbia
investigator full name: Christopher Carlsten
investigator title: Principal Investigator
sharing ipd: No