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Diesel Exhaust Induces Glucocorticoid Resistance (DIGR)

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ClinicalTrials.gov Identifier: NCT03615742
Recruitment Status : Recruiting
First Posted : August 6, 2018
Last Update Posted : December 7, 2018
Sponsor:
Collaborators:
Canadian Institutes of Health Research (CIHR)
AllerGen NCE Inc.
Information provided by (Responsible Party):
Christopher Carlsten, University of British Columbia

Brief Summary:

The investigators are studying the effects of exposure to diesel exhaust on lung inflammation in the presence and absence of an inhaled corticosteroid. Although data is mixed, studies show that asthmatics have increased lung inflammation and worse symptoms during periods of higher air pollution despite taking their anti-inflammatory corticosteroid medication. One possible reason is that air pollution exposure may decrease the ability of corticosteroids to combat inflammation.

To test this volunteers will inhale either a placebo or a corticosteroid, before sitting in an exposure booth for 2 hours breathing either filtered air or diluted diesel exhaust. Samples will be collected before and after exposure to analyze the effects of budesonide and diesel exhaust exposure.


Condition or disease Intervention/treatment Phase
Exposure to Pollution Glucocorticoid Resistance Other: Placebo Drug: Budesonide Other: Filtered Air Other: Diesel Exhaust Phase 4

Detailed Description:

1) Purpose Inhalation of air pollutants leads to both airway inflammation, with increased cytokine expression and inflammatory cell recruitment to the airways, and to airway hyperresponsiveness, which together contribute to airway resistance and breathing difficulties. Correlational data indicate that exposure to air pollution increases inhaled corticosteroids (ICS) use in asthmatics, suggesting that steroidal anti-inflammatory medications are suboptimally effective under these conditions. However, a major issue is that no study has yet been performed specifically to determine the effects of controlled diesel exhaust (DE) exposure on responses to ICS. Furthermore, investigators need better insight into mechanisms, including the effects of epigenetic modifications and polymorphisms in oxidative stress response genes, which remain under explored. Investigators anticipate that an improved understanding of air pollution-induced ICS hyporesponsiveness (reduced effectiveness) could underpin preventative guidelines, guide ICS usage in response to environmental exposures, and inform rational pharmaceutical development. Ultimately this could lead to fewer exacerbations in asthmatic and other susceptible populations.

Hypothesis:

Acute exposure to DE reduces ICS-inducible gene expression in vivo in asthmatics, in part through effects on epigenetic processes.

Justification:

Air pollution exposure correlates with increased use of ICS inhalers in asthmatics, suggesting that ICS offer less control during periods of higher air pollution. As genes induced by ICS are critical in reducing inflammatory messenger ribonucleic acid (mRNA) and protein expression, the investigators have chosen to focus on the effects of DE on ICS-inducible gene expression as our primary endpoint.

Research Method:

To test this the effects of air pollution exposure on a corticosteroid, volunteers will inhale either a placebo (inhaler containing no medication) or budesonide (1.6mg), before sitting in our exposure booth for 2 hours breathing either filtered air (as a control) or diluted diesel exhaust (standardized to 300µg/m³ of particulate matter with a diameter of 2.5 micrometers or less).

Volunteers will visit our lab four different times to be exposed to: 1) placebo & filtered air, 2) placebo & diesel exhaust, 3) corticosteroid and filtered air, and 4) corticosteroid and diesel exhaust. Investigators can then compare responses to each of these combinations of exposures.

Investigators will take blood samples before and after volunteers complete each of these exposures to track how they affect the body. Six hours after placebo or budesonide inhalation a research bronchoscopy will be performed during which a very thin flexible tube will be inserted through the mouth and down into lungs to collect samples from each volunteer.

Bronchoalveolar lavage, bronchial washes, bronchial brushes and tissue biopsies will be obtained for analysis of gene expression and epigenetic endpoints. Nasal lavage samples will also be collected to examine responses in the upper airways and blood and urine will be studied to examine systemic responses. Spirometry will be used to assess effects on airway function.


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Study Type : Interventional  (Clinical Trial)
Estimated Enrollment : 30 participants
Allocation: Randomized
Intervention Model: Crossover Assignment
Intervention Model Description: Volunteers will visit our lab four different times to be exposed to: 1) placebo & filtered air, 2) placebo & diesel exhaust, 3) budesonide and filtered air, and 4) budesonide and diesel exhaust
Masking: Triple (Participant, Investigator, Outcomes Assessor)
Masking Description: Blinding of exposures will be performed by the air pollution exposure laboratory (APEL) engineer, who will not interact with volunteers. Visually indistinguishable placebo and budesonide inhalers will be coded by research pharmacy staff. All assays will be performed by personnel who do not know the exposure conditions of individual samples.
Primary Purpose: Prevention
Official Title: Diesel Exhaust Induces Glucocorticoid Resistance
Actual Study Start Date : December 1, 2018
Estimated Primary Completion Date : December 31, 2020
Estimated Study Completion Date : December 31, 2021

Resource links provided by the National Library of Medicine

Drug Information available for: Budesonide

Arm Intervention/treatment
Placebo Comparator: Placebo and Filtered Air
Volunteers will use an inhaler that does not contain any medication, before sitting in a booth and being exposed to high-efficiency particulate air (HEPA) filtered air for 2 hours.
Other: Placebo
Inhalation of air through a Turbuhaler that contains no medication, as a control.

Other: Filtered Air
Exposure to HEPA filtered air, as a control.

Active Comparator: Budesonide and Filtered Air
Volunteers will inhale 1.6mg of budesonide before sitting in a booth and being exposed to HEPA filtered air for 2 hours.
Drug: Budesonide
1.6mg of budesonide from a Turbuhaler.
Other Name: Pulmicort

Other: Filtered Air
Exposure to HEPA filtered air, as a control.

Active Comparator: Placebo and Diesel Exhaust
Volunteers will use an inhaler that does not contain any medication, before sitting in a booth and being exposed to 300µg/m³ concentration of diesel exhaust for 2 hours.
Other: Placebo
Inhalation of air through a Turbuhaler that contains no medication, as a control.

Other: Diesel Exhaust
Diesel exhaust standardized to 300µg/m³ of particulate matter with a diameter of 2.5 micrometers or less (PM2.5).
Other Name: Traffic Related Air Pollution

Experimental: Budesonide and Diesel Exhaust
Volunteers will inhale 1.6mg of budesonide before sitting in a booth and being exposed to 300µg/m³ concentration of diesel exhaust for 2 hours.
Drug: Budesonide
1.6mg of budesonide from a Turbuhaler.
Other Name: Pulmicort

Other: Diesel Exhaust
Diesel exhaust standardized to 300µg/m³ of particulate matter with a diameter of 2.5 micrometers or less (PM2.5).
Other Name: Traffic Related Air Pollution




Primary Outcome Measures :
  1. Change in DNA methylation, mRNA and protein expression attributable to diesel exhaust and inhaled corticosteroid [ Time Frame: Baseline versus 6 hours ]
    EPIC arrays and RNA Seq will be used to determine effect of exposure(s)


Secondary Outcome Measures :
  1. Modification by variants in genes governing inflammation and responses to oxidative stress after DE exposure and ICS. [ Time Frame: Baseline versus 6 hours ]
    genotypes will be assessed by polymerase chain reaction assay (PCR) and a gene score created for statistical interaction analysis



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Ages Eligible for Study:   19 Years to 49 Years   (Adult)
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   No
Criteria

Inclusion Criteria:

  1. Aged 19-49
  2. Have physician-diagnosed asthma confirmed by the study physician examination, spirometry, methacholine challenge provocative concentration causing a 20% fall (PC20) of <16 mg/mL, and questionnaires during a screening visit

Exclusion Criteria:

  1. Smoking of any kind (0.5 pack-years ever, or any current) or use of vape/vaporizing devices
  2. Regular anti-histamine, NSAID, corticosteroid or other controller medication use
  3. Pregnancy or breastfeeding
  4. Methacholine PC20 >16
  5. Relevant cardiac condition or arrhythmia
  6. Body mass index of >35
  7. Currently participating in another study that may interfere with this study
  8. Use of either inhaled or oral corticosteroids in preceding 6 months
  9. Substantial comorbidities on study physician's examination or other concerns
  10. Surgery scheduled before anticipated study completion

Information from the National Library of Medicine

To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.

Please refer to this study by its ClinicalTrials.gov identifier (NCT number): NCT03615742


Contacts
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Contact: Ryan D Huff, MSc 6048755132 rhuff@mail.ubc.ca
Contact: Agnes CY Yuen, BSc 6048754111 ext 66455 agnes.yuen@ubc.ca

Locations
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Canada, British Columbia
University of British Columbia Recruiting
Vancouver, British Columbia, Canada, V5Z1M9
Contact: Chris Carlsten, MD MPH    604-875-4729    carlsten@mail.ubc.ca   
Contact: Ryan D Huff, MSc    604-875-5132    digr.study@ubc.ca   
Sub-Investigator: Christopher F Rider, PhD         
Sub-Investigator: Robert Newton, PhD         
Sponsors and Collaborators
University of British Columbia
Canadian Institutes of Health Research (CIHR)
AllerGen NCE Inc.
Investigators
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Principal Investigator: Chris Carlsten, MD University of British Columbia
Study Director: Christopher F Rider, PhD University of British Columbia
Study Director: Robert Newton, PhD University of Calgary

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Responsible Party: Christopher Carlsten, Principal Investigator, University of British Columbia
ClinicalTrials.gov Identifier: NCT03615742     History of Changes
Other Study ID Numbers: H17-01336
First Posted: August 6, 2018    Key Record Dates
Last Update Posted: December 7, 2018
Last Verified: December 2018
Individual Participant Data (IPD) Sharing Statement:
Plan to Share IPD: No

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Studies a U.S. FDA-regulated Drug Product: No
Studies a U.S. FDA-regulated Device Product: No
Product Manufactured in and Exported from the U.S.: No
Keywords provided by Christopher Carlsten, University of British Columbia:
Diesel Exhaust
Air Pollution
Inhaled Corticosteroids
Gene Expression
Asthma
Controlled Human Exposure Study
Additional relevant MeSH terms:
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Metabolism, Inborn Errors
Genetic Diseases, Inborn
Metabolic Diseases
Budesonide
Glucocorticoids
Anti-Inflammatory Agents
Bronchodilator Agents
Autonomic Agents
Peripheral Nervous System Agents
Physiological Effects of Drugs
Anti-Asthmatic Agents
Respiratory System Agents
Hormones
Hormones, Hormone Substitutes, and Hormone Antagonists