AsthmaPhase 1NCT00671892
Role of TLR4 in Environmental Asthma
A Phase 1 study testing Lipopolysaccharide endotoxin in people with Asthma, run by John Sundy at 1 site in United States.
Trial summary
The overall goal of this project is to identify genes that are involved in the development of airflow obstruction and airway inflammation in asthmatics, and to determine whether polymorphisms in these differentially expressed genes predispose individuals to develop asthma. Read more about this study
- Who is it for?
- Ages 18 to 40 yearsHealthy volunteers can take part
- Conditions the study is for
- Asthma
- What is being tested?
- Lipopolysaccharide endotoxin
- Could I receive a placebo?
- No, everyone receives an active treatment
- How many people
- 855 participants
- Where
- 1 siteUnited States
- Study dates
- Sep 2001to Apr 2008
- Phase
- Phase 1
- 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 40 years
- All sexes
- Healthy volunteers accepted
- Adult
Who may be able to join
- vital signs within normal limits
- negative methacholine challenge (non asthmatic)
- normal PFT's, CXR, EKG
- negative allergy skin tests (non atopic)
- never cigarette smoker
- no chronic illness
Show all 9Show fewer
- no daily meds except contraceptives
- able and willing to sign informed consent
- not an employee working for,or a student under the authority of the PI's
Who cannot join
- allergic rhinitis past or present
- chronic illness resulting in altered lung function
- chronic daily medications
- cigarette smoking
- allergy to acetaminophen or albuterol
- pregnant or nursing females
Show all 14Show fewer
- PFT results below cut off
- Positive allergy skin test
- Abnormal CXR or EKG
- Positive methacholine challenge
- Infection in the previous 2 weeks
- Past or present allergen immunotherapy
- Occupational exposure to hay or grain
- Other medical or psychological conditions which, in the opinion of the PI, may create undue risk to the subject or interfere with the subject's ability to comply with protocol requirements.
Trial locations and contacts
1 site in 1 country.
United States1 site
Duke University Medical Center
Durham, North Carolina, 27710
About this study
The overall goal of this project is to identify genes that are involved in the development of airflow obstruction and airway inflammation in asthmatics, and to determine whether polymorphisms in these differentially expressed genes predispose individuals to develop asthma. In this project, we hypothesize that polymorphisms of genes expressed by the airway epithelia in asthmatics following specific airway challenges predispose individuals to the development of asthma.
Read the detailed description
The overall goal of this project is to identify genes that are involved in the development of airflow obstruction and airway inflammation in asthmatics, and to determine whether polymorphisms in these differentially expressed genes predispose individuals to develop asthma. Asthma is a complex genetic disorder that is caused by a number of unique gene-gene and gene-environment interactions. The search for asthma susceptibility genes has been complicated by the broad clinical phenotype of asthma, the polygenic inheritance pattern of this disease, and the substantial role of environmental exposures in the development and progression of asthma. Inhaled environmental agents induce several biologic responses in asthmatics; including the induction of acquired and innate immunity that leads to acute and chronic forms of airway inflammation and airway remodeling. Acquired immune responses to protein antigens, such as house dust mite allergen, often induce type 2 T lymphocyte-driven responses (Th2) which appear to be important in atopic asthma. Recent studies by our group and others demonstrate that innate immunity, initiated by inhalation of bacterial and viral pathogens, organic dusts, endotoxin or lipopolysaccharide (LPS), air pollution particulate matter, and ozone, can also cause acute and chronic forms of airflow obstruction, airway inflammation, and even airway remodeling. Emerging evidence indicates that both acquired and innate immune responses in the lung may be influenced by polymorphic genes. For instance, functional polymorphisms in the IL-4 receptor gene are thought to preferentially stimulate acquired Th2 immune responses to inhaled allergens, and we have recently shown that common co-segregating mutations in TLR4 (a transmembrane receptor for LPS) are associated with diminished airway responsiveness to inhaled LPS. These observations suggest that environmental challenges can be used to narrow the phenotype of asthma and investigate genetic susceptibility in biologically specific forms of asthma.
In this project, we hypothesize that polymorphisms of genes expressed by the airway epithelia in asthmatics following specific airway challenges predispose individuals to the development of asthma. To test this hypothesis, we plan to identify the genes that are differentially expressed by airway epithelial cells following challenge with stimuli that induce acquired (house dust mite) or innate (LPS) immune responses, and then determine whether polymorphisms in these genes are associated with the development of asthma in a separate, well characterized, familial cohort of asthmatics. This is a powerful approach that is designed to identify novel genes that are associated with both asthma pathogenesis (differentially expressed in the exposure-response study) and asthma susceptibility (genetically associated with asthma in a linkage/association study).
We hypothesize that individuals with the co-segregating Asp299Gly and Thr399Ile mutations in the TLR4 gene will exhibit a defective immune response to LPS, and that specific components of altered immunity in these individuals are linked to characteristic airway responses to LPS.
Specific Aim 1: Approximately 1000 individuals will be genotyped in order to establish 3 study groups: 10 subjects homozygous for the TLR4 299/399 mutation; 10 subjects heterozygous for the TLR4 299/399 mutation; and 10 subjects homozygous for wild type TLR 4.
Specific Aim 2: Ten individuals with wild type TLR4, 10 individuals heterozygous for mutant TLR4 and 10 individuals homozygous for mutant TLR4 will be phenotyped for airway responsiveness to inhaled LPS.
Specific Aim 3: In vitro immune responses to LPS will be measured in peripheral blood monocytes and PMNs from 10 individuals with wild type TLR4, 10 individuals heterozygous for mutant TLR4 and 10 individuals homozygous for mutant TLR4.
Specific Aim 4: The in vivo immune response to inhaled LPS will be assessed in bronchoalveolar lavage (BAL) fluid and cells, and airway endobronchial brush biopsy cells in 10 individuals with wild type TLR4, 10 individuals heterozygous for mutant TLR4 and 10 individuals homozygous for mutant TLR4.
- Conditions
- Asthma
- Being tested
- Lipopolysaccharide endotoxin
- Keywords
- LPS endotoxin, asthma
- Medical subject headings
- Asthma
What participants receive
What participants receive. In a randomised study each person is assigned to one group by chance.
Lipopolysaccharide endotoxinBiological
Also called (CCRE)LPS endotoxin from E. Coli 0:113 maintained by NIH
Delivered in nebulized form expressed in activity units(endotoxin units -EU).
Subjects receive each dose 30 min after completing the previous dose, dose duration is approximately 10 minutes:
Challenge One first saline then 5000 EU 10,000 EU 20,000 EU
Challenge 1 and 2 must be at least 2 weeks apart.
Challenge 2 Saline 40,000 EU 80,000 EU
| Study group | Role | What they receive |
|---|---|---|
| Challenge | Experimental | Experimental Challenge Challenge 1 saline 5000EU 10,000EU 20,000EU
Challenge 2 Saline 40,000EU 80,000EU Receives: Biological: Lipopolysaccharide endotoxin |
What is being measured
The primary outcome is the main question the study is designed to answer.
Ascertain individuals homozygous, and heterozygous for mutant TLR4 genotype, along with wild types by recruitment of healthy screening subjects in the community.
Measured: completed
Secondary outcomes (1)
Assess the effect of TLR4 genotype on LPS endotoxin induced immune responses and assess the association of the LPS-induced immune response with LPS-induced airway responses.
Measured: 24 hours
Timeline
From the start of the study to its completion; the mark is today. Estimated dates are the sponsor’s plan.
- First posted5 May 2008 (estimated)
- Study startSep 2001
- Primary completionAug 2006
- Study completionApr 2008
Resources
- Official record on ClinicalTrials.govThe registry entry this page is built from, with its full change history.
- Other trials for AsthmaStudies 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
- Interventional
- Phase
- Phase 1
- Primary purpose
- Basic science
- Allocation
- Not applicable
- Intervention model
- Single group
- Masking
- None (open label)
- Enrolment
- 855 participants (actual)
Sponsor and investigators
- Lead sponsor
- John Sundy
- Sponsor type
- University, hospital or other
- Responsible party
- Sponsor-investigator, John Sundy, Duke University
- Investigators
- John S Sundy, M.D., PhD., Principal investigator, Duke University
IDs, dates and publications
- ClinicalTrials.gov ID
- NCT00671892
- Sponsor's protocol ID
- 3030-07-8R5
- Other IDs
- 12496-CP-007
- Status last verified
- Jul 2013
- First submitted
- 2 May 2008
- Last updated
- 16 Jul 2013
- Results posted
- No
- Data monitoring committee
- No
Study at a glance
From the registry record, last updated by the sponsor on 16 Jul 2013. Recruitment status is as the sponsor reported it: confirm with the study team.
- Official title
- Role of TLR4 in Environmental Asthma
- ClinicalTrials.gov ID
- NCT00671892
- Acronym / sponsor ID
- 3030-07-8R5
- Conditions
- Asthma
- Keywords
- LPS endotoxin, asthma
- Phase
- Phase 1
- Study type
- Interventional
- Recruitment status
- Completed
- Enrolment
- 855 participants (actual)
- Lead sponsor
- John SundyUniversity, hospital or other
- Study start
- Sep 2001
- Primary completion
- Aug 2006 (actual)
- Study completion
- Apr 2008 (actual)
- First posted
- 5 May 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 overall goal of this project is to identify genes that are involved in the development of airflow obstruction and airway inflammation in asthmatics, and to determine whether polymorphisms in these differentially expressed genes predispose individuals to develop asthma. In this project, we hypothesize that polymorphisms of genes expressed by the airway epithelia in asthmatics following specific airway challenges predispose individuals to the development of asthma.
Detailed description
The overall goal of this project is to identify genes that are involved in the development of airflow obstruction and airway inflammation in asthmatics, and to determine whether polymorphisms in these differentially expressed genes predispose individuals to develop asthma. Asthma is a complex genetic disorder that is caused by a number of unique gene-gene and gene-environment interactions. The search for asthma susceptibility genes has been complicated by the broad clinical phenotype of asthma, the polygenic inheritance pattern of this disease, and the substantial role of environmental exposures in the development and progression of asthma. Inhaled environmental agents induce several biologic responses in asthmatics; including the induction of acquired and innate immunity that leads to acute and chronic forms of airway inflammation and airway remodeling. Acquired immune responses to protein antigens, such as house dust mite allergen, often induce type 2 T lymphocyte-driven responses (Th2) which appear to be important in atopic asthma. Recent studies by our group and others demonstrate that innate immunity, initiated by inhalation of bacterial and viral pathogens, organic dusts, endotoxin or lipopolysaccharide (LPS), air pollution particulate matter, and ozone, can also cause acute and chronic forms of airflow obstruction, airway inflammation, and even airway remodeling. Emerging evidence indicates that both acquired and innate immune responses in the lung may be influenced by polymorphic genes. For instance, functional polymorphisms in the IL-4 receptor gene are thought to preferentially stimulate acquired Th2 immune responses to inhaled allergens, and we have recently shown that common co-segregating mutations in TLR4 (a transmembrane receptor for LPS) are associated with diminished airway responsiveness to inhaled LPS. These observations suggest that environmental challenges can be used to narrow the phenotype of asthma and investigate genetic susceptibility in biologically specific forms of asthma.
In this project, we hypothesize that polymorphisms of genes expressed by the airway epithelia in asthmatics following specific airway challenges predispose individuals to the development of asthma. To test this hypothesis, we plan to identify the genes that are differentially expressed by airway epithelial cells following challenge with stimuli that induce acquired (house dust mite) or innate (LPS) immune responses, and then determine whether polymorphisms in these genes are associated with the development of asthma in a separate, well characterized, familial cohort of asthmatics. This is a powerful approach that is designed to identify novel genes that are associated with both asthma pathogenesis (differentially expressed in the exposure-response study) and asthma susceptibility (genetically associated with asthma in a linkage/association study).
We hypothesize that individuals with the co-segregating Asp299Gly and Thr399Ile mutations in the TLR4 gene will exhibit a defective immune response to LPS, and that specific components of altered immunity in these individuals are linked to characteristic airway responses to LPS.
Specific Aim 1: Approximately 1000 individuals will be genotyped in order to establish 3 study groups: 10 subjects homozygous for the TLR4 299/399 mutation; 10 subjects heterozygous for the TLR4 299/399 mutation; and 10 subjects homozygous for wild type TLR 4.
Specific Aim 2: Ten individuals with wild type TLR4, 10 individuals heterozygous for mutant TLR4 and 10 individuals homozygous for mutant TLR4 will be phenotyped for airway responsiveness to inhaled LPS.
Specific Aim 3: In vitro immune responses to LPS will be measured in peripheral blood monocytes and PMNs from 10 individuals with wild type TLR4, 10 individuals heterozygous for mutant TLR4 and 10 individuals homozygous for mutant TLR4.
Specific Aim 4: The in vivo immune response to inhaled LPS will be assessed in bronchoalveolar lavage (BAL) fluid and cells, and airway endobronchial brush biopsy cells in 10 individuals with wild type TLR4, 10 individuals heterozygous for mutant TLR4 and 10 individuals homozygous for mutant TLR4.
Study design
- Primary purpose
- Basic science
- Allocation
- Not applicable
- Intervention model
- Single group
- Masking
- None (open label)
- Number of arms
- 1
| Arm | Type | Receives |
|---|---|---|
| Challenge | Experimental | Biological: Lipopolysaccharide endotoxinExperimental Challenge Challenge 1 saline 5000EU 10,000EU 20,000EU Challenge 2 Saline 40,000EU 80,000EU |
Who may qualify
- Ages
- 18 to 40 years
- Sex
- All
- Healthy volunteers
- Accepted
- Age groups
- Adult
Key inclusion criteria (9 listed)
- vital signs within normal limits
- negative methacholine challenge (non asthmatic)
- normal PFT's, CXR, EKG
- negative allergy skin tests (non atopic)
- never cigarette smoker
Key exclusion criteria (14 listed)
- allergic rhinitis past or present
- chronic illness resulting in altered lung function
- chronic daily medications
- cigarette smoking
- allergy to acetaminophen or albuterol
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 |
|---|---|---|
| Lipopolysaccharide endotoxinAlso: (CCRE)LPS endotoxin from E. Coli 0:113 maintained by NIHDelivered in nebulized form expressed in activity units(endotoxin units -EU). Subjects receive each dose 30 min after completing the previous dose, dose duration is approximately 10 minutes: Challenge One first saline then 5000 EU 10,000 EU 20,000 EU Challenge 1 and 2 must be at least 2 weeks apart. Challenge 2 Saline 40,000 EU 80,000 EU | Biological | Challenge |
Primary outcome
Ascertain individuals homozygous, and heterozygous for mutant TLR4 genotype, along with wild types by recruitment of healthy screening subjects in the community.
Time frame: completed
1 secondary outcome
Assess the effect of TLR4 genotype on LPS endotoxin induced immune responses and assess the association of the LPS-induced immune response with LPS-induced airway responses.
Time frame: 24 hours
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 16 Jul 2013.
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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.
John S Sundy, M.D., PhD. principal investigator
Duke University
1 site in 1 country: see every site and its status.
Questions about this trial
What is this clinical trial studying?
A Phase 1 study testing Lipopolysaccharide endotoxin in people with Asthma, run by John Sundy 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 9 inclusion and 14 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 16 Jul 2013. 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.
What does this phase mean?
Phase 1 studies test a treatment in a small group of people for the first time or in a new way, mainly to check safety and find the right dose.
Not every study follows the same path, and some studies (observational studies, device studies) have no phase.
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?
Ascertain individuals homozygous, and heterozygous for mutant TLR4 genotype, along with wild types by recruitment of healthy screening subjects in the community. (time frame: completed). 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 16 Jul 2013.