BronchitisNCT00729131
Functional Implications of TNF
An observational study of Bronchitis, run by National Institute of Environmental Health Sciences (NIEHS) at 1 site in United States.
Trial summary
The research plan proposes to develop translational studies in humans that will identify host susceptibility factors that confer vulnerability to the prototypal air pollutant, ozone. Read more about this study
- Who is it for?
- Ages 18 to 35 yearsHealthy volunteers can take part
- Conditions the study is for
- Bronchitis
- What is being tested?
- Etanercept inhibition of ozone-induced airway hyper-responsiveness.
- Type of treatment
- Injection or infusion
- How many people
- 10 participants
- Where
- 1 siteUnited States
- Study dates
- Aug 2008to Feb 2012
- Phase
- Observational
- Are there results?
- None posted in the registry
Key requirements
Who can take part, as listed by the sponsor. Only the study team can confirm whether you are eligible, so take this list to your doctor.
- Ages 18 to 35 years
- All sexes
- Healthy volunteers accepted
- Adult
Study population: Healthy non-smokers (18-35 yr) will be recruited from the Duke campus and local community; 50% will be women. Subjects will have a clinical history and lung function screening at protocol entry. Female subjects of childbearing age will have pregnancy testing. We will only recruit subjects with a normal body habitus as an increased BMI may modify sensitivity to O3. Subjects will have lung volumes within predicted normal, and FEV1, and FEF25-75, within range of predicted, and methacholine response less than the mean Mch PC20 dose for non-asthmatic population in our human inhalation laboratory. Atopic status of study subjects will be determined by lack of positive skin test by prick technique (using panel of antigens common to central NC) and without seasonal or perennial allergic symptoms.
Who may be able to join
- -
Who cannot join
- subjects with current or past smoking history, acute respiratory illness within six weeks of the study, and significant non-pulmonary disease as determined by the investigator, pregnancy, age <18 or >35 yr, or inability to understand the protocol. Subjects will be requested to refrain from anti-histamines, nonsteroidal anti-inflammatory agents, and supplemental vitamins, e.g. C and E, for 1 week prior to, and during lab visits for exposures and follow-up measures.
Trial locations and contacts
1 site in 1 country.
United States1 site
Duke University Medical Center
Durham, North Carolina, 27710
About this study
The research plan proposes to develop translational studies in humans that will identify host susceptibility factors that confer vulnerability to the prototypal air pollutant, ozone. Ozone is a ubiquitous urban air pollutant and associated with increased emergency room visits, and co-associates with other air pollutants, to increase mortality in high risk groups (cardio-pulmonary disease) of the population.The results will have significant impact upon and aid in understanding mechanisms of pro-oxidant lung injury, airway hyperresponsiveness, and adverse health effects, that occur during and following exposure to inhalable airborne irritants.
Read the detailed description
Exposure of the airways to air toxins initiates transient and reversible airway injury to both adults and young children. Repetitive exposures of children residing within high oxidant communities leads to impairment of lung growth and pulmonary function, and remodeling of airway epithelial tissues is also suggested to occur. In the completely normal/healthy airway, exposure to ozone (O3), a ubiquitous urban air pollutant, induces an inflammatory response that is characterized by increases in epithelial permeability, neutrophilic infiltration, and bronchial hyperreactivity. Inhalation by humans of the pleiotropic pro-inflammatory cytokine tumor necrosis factor (Tnf) leads to the development of nearly identical responses: hyperresponsiveness of the bronchial airway (AHR), and neutrophil influx. Using controlled exposure to O3 in a laboratory setting, we have recently established a link between a genetic single nucleotide polymorphism (SNP) of TNF gene (-308) and the development of AHR to methacholine within a 24 h time frame, post exposure to O3. In a healthy human study group (n=137) the presence of a common TNF (-308) SNP was found to confer susceptibility to an ambient concentration of O3 (220 ppb, and frequently attained in many cities of the US during the summer months): stratified for ethnicity, Caucasian subjects who were homozygotic (A/A) or heterozygotic (G/A) for the minor allele of the TNF (-308) SNP were 2-times as likely to develop sensitivity to methacholine after O3 as compared to subjects with the wild-type, major allele (G/G) haplotype.
Literature reports suggest that the TNF(-308) polymorphism associates with increased TNF gene transcription and increased Tnf cytokine production. However, the functional significance of this common TNF polymorphism remains uncertain; and moreover, the functional implications of the TNF(-308) polymorphism in the lung remain undeveloped. We hypothesize that subjects either homozygotic (A/A) or heterozygotic (G/A) for the minor allele of the TNF(-308) promoter polymorphism, will demonstrate enhancement in phenotypic responses to O3 including: increased cellular inflammation and secretion of pre-inflammation cytokines, enhanced activation of resident alveolar macrophages, and altered bronchial sensitivity, leading to AHR.
Our research plan is designed to mechanistically investigate the interaction between host factors of humans and exposure to the prototypal air pollutant, ozone. The research plan will expand upon, and enable, a clear assignment of the functional contribution of a common SNP of TNF gene to the initiation of airway hyperresponsiveness, a cardinal feature of inflammatory airway disease.
- Conditions
- Bronchitis
- Being tested
- Etanercept inhibition of ozone-induced airway hyper-responsiveness.
- Keywords
- Ozone, TNF, TNF promoter polymorphism, airway hyperresponsiveness.
- Medical subject headings
- Bronchitis, Respiratory Hypersensitivity
What participants receive
What participants receive. In a randomised study each person is assigned to one group by chance.
Etanercept inhibition of ozone-induced airway hyper-responsiveness.Drug
Also called Only a single group of subjects, known to demonstrate airway hyperresponsiveness at 20 hr post exposure to ozone will be studied in the, intervention.
Single dosage of etanercept(50 mg, subcutaneous) given 2 days prior to a laboratory ozone exposure.
| Study group | Role | What they receive |
|---|---|---|
| A | Control group: subjects are homozygotic for major allele for TNF-308 promoter polymorphism. Receives: Drug: Etanercept inhibition of ozone-induced airway hyper-responsiveness. | |
| B | Case Group: subjects are homozygotic or heterozygotic for minor allele of TNF-308 promoter polymorphism. |
What is being measured
The primary outcome is the main question the study is designed to answer.
biologic response to ozone exposure: bronchoalveolar lavage fluid analyzed for inflammatory cytokines, cell differentials, and activated alveolar macrophages.
Measured: Lung lavage evaluated 20 hr post-exposure to ozone.
Secondary outcomes (1)
Alveolar macrophages (collected in lung lavage fluid) will be studied ex vivo for activation state and pro-inflammatory cytokine secretion.
Measured: 20 hr post-exposure to ozone.
Timeline
From the start of the study to its completion; the mark is today. Estimated dates are the sponsor’s plan.
- First posted7 Aug 2008 (estimated)
- Study startAug 2008
- Primary completionJan 2010
- Study completionFeb 2012
Resources
- Official record on ClinicalTrials.govThe registry entry this page is built from, with its full change history.
- Other trials for BronchitisStudies of the same condition, open and under way.
- What the trial phases meanHow a treatment moves from first tests in people to approval.
More details
For doctors and researchers: how the study is designed, who runs it, and its registry IDs.
Study design
- Study type
- Observational
- Observational model
- Case-control
- Time perspective
- Prospective
- Enrolment
- 10 participants (actual)
Sponsor and investigators
- Lead sponsor
- National Institute of Environmental Health Sciences (NIEHS)
- Sponsor type
- US National Institutes of Health
- Responsible party
- Principal investigator, Michael Foster, National Institute of Environmental Health Sciences (NIEHS)
IDs, dates and publications
- ClinicalTrials.gov ID
- NCT00729131
- Sponsor's protocol ID
- 00008547
- Status last verified
- Sep 2014
- First submitted
- 6 Aug 2008
- Last updated
- 29 Sep 2014
- Results posted
- No
- Data monitoring committee
- No
Study at a glance
From the registry record, last updated by the sponsor on 29 Sep 2014. Recruitment status is as the sponsor reported it: confirm with the study team.
- Official title
- Functional Implications of TNF
- ClinicalTrials.gov ID
- NCT00729131
- Acronym / sponsor ID
- 00008547
- Conditions
- Bronchitis
- Keywords
- Ozone, TNF, TNF promoter polymorphism, airway hyperresponsiveness.
- Study type
- Observational
- Recruitment status
- Completed
- Enrolment
- 10 participants (actual)
- Lead sponsor
- National Institute of Environmental Health Sciences (NIEHS)US National Institutes of Health
- Study start
- Aug 2008
- Primary completion
- Jan 2010 (actual)
- Study completion
- Feb 2012 (actual)
- First posted
- 7 Aug 2008 (estimated)
- Results
- Not posted in the source record
Clinical summary
The research question as the sponsor registered it. This describes what the study plans to test, not what it found.
The research plan proposes to develop translational studies in humans that will identify host susceptibility factors that confer vulnerability to the prototypal air pollutant, ozone. Ozone is a ubiquitous urban air pollutant and associated with increased emergency room visits, and co-associates with other air pollutants, to increase mortality in high risk groups (cardio-pulmonary disease) of the population.The results will have significant impact upon and aid in understanding mechanisms of pro-oxidant lung injury, airway hyperresponsiveness, and adverse health effects, that occur during and following exposure to inhalable airborne irritants.
Detailed description
Exposure of the airways to air toxins initiates transient and reversible airway injury to both adults and young children. Repetitive exposures of children residing within high oxidant communities leads to impairment of lung growth and pulmonary function, and remodeling of airway epithelial tissues is also suggested to occur. In the completely normal/healthy airway, exposure to ozone (O3), a ubiquitous urban air pollutant, induces an inflammatory response that is characterized by increases in epithelial permeability, neutrophilic infiltration, and bronchial hyperreactivity. Inhalation by humans of the pleiotropic pro-inflammatory cytokine tumor necrosis factor (Tnf) leads to the development of nearly identical responses: hyperresponsiveness of the bronchial airway (AHR), and neutrophil influx. Using controlled exposure to O3 in a laboratory setting, we have recently established a link between a genetic single nucleotide polymorphism (SNP) of TNF gene (-308) and the development of AHR to methacholine within a 24 h time frame, post exposure to O3. In a healthy human study group (n=137) the presence of a common TNF (-308) SNP was found to confer susceptibility to an ambient concentration of O3 (220 ppb, and frequently attained in many cities of the US during the summer months): stratified for ethnicity, Caucasian subjects who were homozygotic (A/A) or heterozygotic (G/A) for the minor allele of the TNF (-308) SNP were 2-times as likely to develop sensitivity to methacholine after O3 as compared to subjects with the wild-type, major allele (G/G) haplotype.
Literature reports suggest that the TNF(-308) polymorphism associates with increased TNF gene transcription and increased Tnf cytokine production. However, the functional significance of this common TNF polymorphism remains uncertain; and moreover, the functional implications of the TNF(-308) polymorphism in the lung remain undeveloped. We hypothesize that subjects either homozygotic (A/A) or heterozygotic (G/A) for the minor allele of the TNF(-308) promoter polymorphism, will demonstrate enhancement in phenotypic responses to O3 including: increased cellular inflammation and secretion of pre-inflammation cytokines, enhanced activation of resident alveolar macrophages, and altered bronchial sensitivity, leading to AHR.
Our research plan is designed to mechanistically investigate the interaction between host factors of humans and exposure to the prototypal air pollutant, ozone. The research plan will expand upon, and enable, a clear assignment of the functional contribution of a common SNP of TNF gene to the initiation of airway hyperresponsiveness, a cardinal feature of inflammatory airway disease.
Study design
- Observational model
- Case-control
- Time perspective
- Prospective
- Number of arms
- 2
| Arm | Type | Receives |
|---|---|---|
| A | – | Drug: Etanercept inhibition of ozone-induced airway hyper-responsiveness.Control group: subjects are homozygotic for major allele for TNF-308 promoter polymorphism. |
| B | – | –Case Group: subjects are homozygotic or heterozygotic for minor allele of TNF-308 promoter polymorphism. |
Who may qualify
- Ages
- 18 to 35 years
- Sex
- All
- Healthy volunteers
- Accepted
- Age groups
- Adult
- Study population
- Healthy non-smokers (18-35 yr) will be recruited from the Duke campus and local community; 50% will be women. Subjects will have a clinical history and lung function screening at protocol entry. Female subjects of childbearing age will have pregnancy testing. We will only recruit subjects with a normal body habitus as an increased BMI may modify sensitivity to O3. Subjects will have lung volumes within predicted normal, and FEV1, and FEF25-75, within range of predicted, and methacholine response less than the mean Mch PC20 dose for non-asthmatic population in our human inhalation laboratory. Atopic status of study subjects will be determined by lack of positive skin test by prick technique (using panel of antigens common to central NC) and without seasonal or perennial allergic symptoms.
Key inclusion criteria (1 listed)
- -
Key exclusion criteria (1 listed)
- subjects with current or past smoking history, acute respiratory illness within six weeks of the study, and significant non-pulmonary disease as determined by the investigator, pregnancy, age <18 or >35 yr, or inability to understand the protocol. Subjects will be requested to refrain from anti-histamines, nonsteroidal anti-inflammatory agents, and supplemental vitamins, e.g. C and E, for 1 week prior to, and during lab visits for exposures and follow-up measures.
Eligibility is decided by the study team after screening; this overview does not establish that a patient qualifies. Full inclusion and exclusion criteria.
Interventions
| Intervention | Type | Arms |
|---|---|---|
| Etanercept inhibition of ozone-induced airway hyper-responsiveness.Also: Only a single group of subjects, known to demonstrate airway hyperresponsiveness at 20 hr post exposure to ozone will be studied in the, intervention.Single dosage of etanercept(50 mg, subcutaneous) given 2 days prior to a laboratory ozone exposure. | Drug | A |
Primary outcome
biologic response to ozone exposure: bronchoalveolar lavage fluid analyzed for inflammatory cytokines, cell differentials, and activated alveolar macrophages.
Time frame: Lung lavage evaluated 20 hr post-exposure to ozone.
1 secondary outcome
Alveolar macrophages (collected in lung lavage fluid) will be studied ex vivo for activation state and pro-inflammatory cytokine secretion.
Time frame: 20 hr post-exposure to ozone.
Results and safety
The study is completed, but results are not available in the source record. That does not mean the treatment did or did not work.
Research links
- Official record on ClinicalTrials.govLast updated by the sponsor 29 Sep 2014.
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Referral and contact
AzTrials does not enrol participants or take referrals. Contact the study team or a site listed below; they decide who can take part. This study is not recruiting at the moment.
The record lists no contact. Use the official record to reach the sponsor.
1 site in 1 country: see every site and its status.
Questions about this trial
What is this clinical trial studying?
An observational study of Bronchitis, run by National Institute of Environmental Health Sciences (NIEHS) at 1 site in United States.
The full registered description is in the About this study section and the official record.
Who may be eligible to take part?
The sponsor lists 1 inclusion and 1 exclusion criteria. Eligibility is decided by the study team after screening, so read the full criteria and contact a listed site.
Is this clinical trial currently recruiting?
The record says: finished, as of the sponsor's last update on 29 Sep 2014. Status can change between updates, so confirm with the study contact before making plans.
Where is the study taking place?
The record lists 1 site in United States. Whether a site is taking part right now should be confirmed with that site. See every site.
What are the possible benefits and risks?
They depend on the study and the treatment, and no study can promise a benefit. The study team explains the known risks during informed consent, before anyone joins; the record itself does not list them.
Are results available for this study?
The study is completed, but results are not available in the source record. That does not mean the treatment did or did not work.
How can a doctor refer a patient or contact the research team?
The record lists no contact. The official record names the sponsor, who can be asked directly. AzTrials does not enrol participants or take referrals.
What does the primary outcome measure?
biologic response to ozone exposure: bronchoalveolar lavage fluid analyzed for inflammatory cytokines, cell differentials, and activated alveolar macrophages. (time frame: Lung lavage evaluated 20 hr post-exposure to ozone.). It is what the study was designed to measure, not a finding.
Where can I read the original study information?
Does a listing mean the treatment is approved or proven to work?
No. A listing means the study is registered. It does not show that the treatment is safe, works, or is approved by a regulator.
How often is this information updated?
AzTrials copies changed records from ClinicalTrials.gov every night and reloads the whole registry every week. The sponsor last updated this record on 29 Sep 2014.