Ignite Creation Date:
2024-05-06 @ 8:10 AM
Last Modification Date:
2024-10-26 @ 11:57 AM
Study NCT ID:
NCT02688478
Status:
UNKNOWN
Last Update Posted:
2019-08-02
First Post:
2016-01-06
Brief Title:
The Phthalate-Allergen Immune Response Study
Sponsor:
University of British Columbia
Organization:
University of British Columbia
Study Overview
Official Title:
Effects of Phthalate Inhalation on Airway Immunology A Controlled Human Exposure Study
Status:
UNKNOWN
Status Verified Date:
2019-07
Last Known Status:
ACTIVE_NOT_RECRUITING
Delayed Posting:
No
If Stopped, Why?:
Not Stopped
Has Expanded Access:
False
If Expanded Access, NCT#:
N/A
Has Expanded Access, NCT# Status:
N/A
Acronym:
PAIR
Brief Summary:
Phthalates are commonly used plasticizers that have been linked to asthma in epidemiological studies The investigators are researching effects of phthalates on airway immunology and lung function and on allergic responses by doing an inhaled allergen challenge After exposing participants to either filtered air or carefully controlled levels of phthalate in our exposure chamber we will collect samples from the nose and the upper airways by rinsing the nose with saltwater or performing small brushings The investigators will also collect a bronchial samples by bronchoscopy after each exposure After 2 weeks the entire procedure will be repeated with the alternate exposure
Detailed Description:
1 Purpose
To study the effects of phthalates on airway immunology lung function and nasal allergic responses
2 Hypotheses
Phthalate inhalation increases recruitment of immune cells to the upper airways and affects the functionality of immune and epithelial cells
Hypothesis 2 Phthalate inhalation alters the cellular response to an inhalation allergen challenge
3 Justification
Phthalates are plasticizers or softeners used in PVC and other plastics and a range of consumer products Since phthalates are not chemically bound to the plastic they leak out from these products causing routine human exposure through air dust and food Exposure to phthalates has been linked to worsening or development of airway diseases in epidemiological studies but the effects of phthalates on our airways and immune responses are largely unknown In this study we would like to investigate how one particular phthalate dibutyl phthalate DBP can affect the human respiratory and immune systems The investigators are not expecting that the responses will be noticeable to the subjects they are expecting that any responses that may occur will only be detectable through careful examination of cells and tissues eg nasal lavage and brushes fluid from the nose bronchial samples blood urine Nasal samples will be used for measurement of nasal inflammatory responses in terms of cell recruitment and levels of inflammatory mediators Bronchial samples will allow for a refined examination of an inflammatory responses in the lung and thus provide a much more detailed information concerning the phthalate-induced responses due to allergen challenge Understanding these subtle changes will help us prevent health problems associated with phthalate exposure in the future
4 Objectives
To establish that phthalates alter the cellular immune response in the upper airways
5 Research Method
This is a blinded crossover experiment between two conditions dibutyl phthalate DBP or filtered air FA randomized and counter-balanced to order
After each exposure of DBP or FA we will deliver an inhaled allergen challenge Data collection for each condition will be separated by a 2-week washout period
To evaluate the effects of the exposure on the immune response and lung function the investigators will collect and perform the following on the day of the exposure or the following day
Before each exposure 3h and 24h post-exposure we will collect urine and blood samples perform NAL and measure forced expiratory volume FEV1 by spirometry and FeNO
Methacholine challenge will be performed 24h after exposure
Nasal brushing NAB will be performed at 3h pre-exposure on the left nostril and 3h post-exposure in the right nostril
A fraction of the subjects enrolled will have a bronchoscopy performed 24h post-exposure where bronchoalveolar samples and endobronchial biopsies will be collected
The literature provides conflicting data for phthalates with regard to some of the analytical endpoints Therefore to facilitate the choice of endpoints for the principal study as well as to validate some study procedures a Method optimization sub-study will be performed prior to the start of the principal study A maximum of 25 healthy subjects will be recruited for this sub-study who will sign a modified consent that reflects their limited participation These subjects will not be exposed to DBP or CA but will only be recruited for collection of blood nasal lavage and nasal brushing or a subset of these samples They will only attend one visit to the Vancouver General Hospital dedicating 1 - 3 hours of their time when participating in the sub-study Moreover prior starting the principal study above up to four healthy subjects may be recruited for a Pilot study to optimize the logistics of the exposures and the experimental procedures of the principal study These subjects will be subjected to CA exposure only and have all procedures and samples collected as described for the actual study with the exception of the bronchoscopy
Samples collected during the Method optimization sub-study and the Pilot study will be used to establish analytical methods to measure immune cellular responses such as white blood or nasal epithelial cell responses to bacterial components Toll Like Receptor TLR agonists and phagocytosis assays after in vitro phthalate exposure as described under study procedures
6 Statistical Analysis
A mixed effects model will be used to estimate all effects and pertinent contrasts will be used to test the hypotheses Specifically models will include exposure CA or DBP order CA before DBP or DBP before CA and gene variant status eg GSTM1 present or GSTM1 null as fixed effects and subject identifying number as a random effect The inhalation allergen challenge is given during both DBP and CA exposures and will therefore not be included in the statistical analyses
The influence of the general phthalate exposure level for 6 commonly measured phthalates assessed in urine samples Day 1 and 2 on FeNObloodlung function will be analyzed by mixed effects model including exposure DBP CA sampling period Day 1 Day 2 and phthalate level Day 1 Day 2 A one-way ANOVA will be used to compare pre- and post-exposure urinary MnBP levels for various time-points to verify phthalate exposure
To study the effects of phthalates on airway immunology lung function and nasal allergic responses
2 Hypotheses
Phthalate inhalation increases recruitment of immune cells to the upper airways and affects the functionality of immune and epithelial cells
Hypothesis 2 Phthalate inhalation alters the cellular response to an inhalation allergen challenge
3 Justification
Phthalates are plasticizers or softeners used in PVC and other plastics and a range of consumer products Since phthalates are not chemically bound to the plastic they leak out from these products causing routine human exposure through air dust and food Exposure to phthalates has been linked to worsening or development of airway diseases in epidemiological studies but the effects of phthalates on our airways and immune responses are largely unknown In this study we would like to investigate how one particular phthalate dibutyl phthalate DBP can affect the human respiratory and immune systems The investigators are not expecting that the responses will be noticeable to the subjects they are expecting that any responses that may occur will only be detectable through careful examination of cells and tissues eg nasal lavage and brushes fluid from the nose bronchial samples blood urine Nasal samples will be used for measurement of nasal inflammatory responses in terms of cell recruitment and levels of inflammatory mediators Bronchial samples will allow for a refined examination of an inflammatory responses in the lung and thus provide a much more detailed information concerning the phthalate-induced responses due to allergen challenge Understanding these subtle changes will help us prevent health problems associated with phthalate exposure in the future
4 Objectives
To establish that phthalates alter the cellular immune response in the upper airways
5 Research Method
This is a blinded crossover experiment between two conditions dibutyl phthalate DBP or filtered air FA randomized and counter-balanced to order
After each exposure of DBP or FA we will deliver an inhaled allergen challenge Data collection for each condition will be separated by a 2-week washout period
To evaluate the effects of the exposure on the immune response and lung function the investigators will collect and perform the following on the day of the exposure or the following day
Before each exposure 3h and 24h post-exposure we will collect urine and blood samples perform NAL and measure forced expiratory volume FEV1 by spirometry and FeNO
Methacholine challenge will be performed 24h after exposure
Nasal brushing NAB will be performed at 3h pre-exposure on the left nostril and 3h post-exposure in the right nostril
A fraction of the subjects enrolled will have a bronchoscopy performed 24h post-exposure where bronchoalveolar samples and endobronchial biopsies will be collected
The literature provides conflicting data for phthalates with regard to some of the analytical endpoints Therefore to facilitate the choice of endpoints for the principal study as well as to validate some study procedures a Method optimization sub-study will be performed prior to the start of the principal study A maximum of 25 healthy subjects will be recruited for this sub-study who will sign a modified consent that reflects their limited participation These subjects will not be exposed to DBP or CA but will only be recruited for collection of blood nasal lavage and nasal brushing or a subset of these samples They will only attend one visit to the Vancouver General Hospital dedicating 1 - 3 hours of their time when participating in the sub-study Moreover prior starting the principal study above up to four healthy subjects may be recruited for a Pilot study to optimize the logistics of the exposures and the experimental procedures of the principal study These subjects will be subjected to CA exposure only and have all procedures and samples collected as described for the actual study with the exception of the bronchoscopy
Samples collected during the Method optimization sub-study and the Pilot study will be used to establish analytical methods to measure immune cellular responses such as white blood or nasal epithelial cell responses to bacterial components Toll Like Receptor TLR agonists and phagocytosis assays after in vitro phthalate exposure as described under study procedures
6 Statistical Analysis
A mixed effects model will be used to estimate all effects and pertinent contrasts will be used to test the hypotheses Specifically models will include exposure CA or DBP order CA before DBP or DBP before CA and gene variant status eg GSTM1 present or GSTM1 null as fixed effects and subject identifying number as a random effect The inhalation allergen challenge is given during both DBP and CA exposures and will therefore not be included in the statistical analyses
The influence of the general phthalate exposure level for 6 commonly measured phthalates assessed in urine samples Day 1 and 2 on FeNObloodlung function will be analyzed by mixed effects model including exposure DBP CA sampling period Day 1 Day 2 and phthalate level Day 1 Day 2 A one-way ANOVA will be used to compare pre- and post-exposure urinary MnBP levels for various time-points to verify phthalate exposure
Study Oversight
Has Oversight DMC:
None
Is a FDA Regulated Drug?:
False
Is a FDA Regulated Device?:
False
Is an Unapproved Device?:
None
Is a PPSD?:
None
Is a US Export?:
None
Is an FDA AA801 Violation?:
None