Chronic Beryllium DiseaseBeEpiGenNCT02604693
Exposure in Epigenetic Regulation of Immune Response in Chronic Beryllium Disease (CBD)
An observational study of Chronic Beryllium Disease, run by National Jewish Health at 1 site in United States.
Trial summary
This study will provide important results for each aim, while also providing an integrative transcriptional and epigenomic profile of CBD. In Aim 1 the Investigator will define genome-wide epigenetic alterations of CBD, by determining genes that are DM in pivotal immune cells, in the target organ (CD4+ BAL cells) in… Read more about this study
- Who is it for?
- Ages 18 to 80 yearsHealthy volunteers can take part
- Conditions the study is for
- Chronic Beryllium Disease
- What is being tested?
- Nothing
- How many people
- 148 participants
- Where
- 1 siteUnited States
- Study dates
- 14 Dec 2014to 31 Dec 2020
- 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 80 years
- All sexes
- Healthy volunteers accepted
- Adult, Older adult
Study population: We will enroll subjects using standard case and control definitions. We will enroll up to 150 subjects. Controls will be frequency matched on age, gender, race and smoking status to limit methylation changes related to these factors.
Who may be able to join
- Chronic Beryllium Disease (CBD):
- History of Beryllium exposure
- Positive blood and/or bronchoalveolar lavage (BAL) Beryllium Lymphocyte Proliferation Tests (BeLPT)
- Biopsy-proven pathologic changes consistent with CBD, specifically non-caseating granulomas and/or mononuclear cell interstitial infiltrates.
- Beryllium Sensitization:
- History of Beryllium exposure
Show all 11Show fewer
- Two or more positive blood beryllium lymphocyte proliferation tests (BeLPT) or positive bronchoalveolar lavage (BAL) BeLPT
- Normal lung tissue (no histology suggestive of CBD).
- Normal Controls:
- No history of beryllium exposure
- Former smokers or never smokers -
Who cannot join
- Chronic Beryllium Disease:
- Immunosuppressive therapy within the last three months
- Current cigarette smoking or smoking within six months prior to the study
- Positive lung washing or biopsy cultures for fungi, mycobacteria or other respiratory pathogen consistent with an acute or chronic infection
- Weight less than 110 lbs. (for venipuncture)
- Pregnancy
Show all 25Show fewer
- Severe room air hypoxemia and or hypercapnia (precluding BAL), e.g., resting PaO2 < 45, PaCO2 > 45 mm Hg; (Denver altitude 5,280 feet)
- Presence of another disease that may be expected to significantly affect patient mortality and or the immune response (e.g., HIV, HCV, cancer, uncorrected bleeding diathesis, acute hypercapnia with a resting PaCO2 above 45 mm Hg; serious cardiac arrhythmia, recent myocardial infarction within 6 weeks)
- Patient inability to participate in the study, such as inability to undergo venipuncture and BAL procedures that form part of the inclusion/exclusion criteria or part of the outcome measure
- Beryllium Sensitization:
- Known underlying systemic or lung disease;
- Current cigarette smoking or smoking within six months prior to the study
- Positive lung pathology consistent with CBD
- Pregnancy
- Weight less than 110 lbs. (for venipuncture)
- Presence of another disease that may be expected to significantly affect patient mortality and or the immune response (e.g., HIV, HCV, cancer, uncorrected bleeding diathesis, serious cardiac arrhythmia; recent myocardial infarction within 6 weeks)
- Patient inability to participate in the study, such as inability to undergo venipuncture and BAL procedures that form part of the inclusion/exclusion criteria or part of the outcome measure
- Normal Controls:
- History of beryllium exposure
- Known underlying systemic or lung disease;
- Immunosuppressive therapy or other medication for as systemic disease process in the last 3 months;
- Current smokers or smoking within 6 months of study
- Pregnancy
- Weight less than 110 lbs. (for venipuncture)
- Inability to undergo BAL or venipuncture procedures -
Trial locations and contacts
1 site in 1 country.
About this study
Official title: Exposure in Epigenetic Regulation of Immune Response in Chronic Beryllium
This study will provide important results for each aim, while also providing an integrative transcriptional and epigenomic profile of CBD.
In Aim 1 the Investigator will define genome-wide epigenetic alterations of CBD, by determining genes that are DM in pivotal immune cells, in the target organ (CD4+ BAL cells) in CBD compared to BeS and healthy controls. In addition, the Investigator will determine the impact of Be exposure on the methylation profile of CBD and BeS cells compared to each other and normal controls. This information will be used to define DM regions, genes and their networks.
Using the cases and controls from Aim 1, we will evaluate the gene-expression from these same subjects in Aim 2 to define functional epigenetic loci based on DE in CD4+ BAL cells with and without Be exposure. The Investigator will also integrate ENCODE/RE methylation, histone modification, and chromatin accessibility data as well as our genome-wide association study (GWAS) data to prioritize epigenetic marks and networks for confirmation and validation in Aim 3. In Aim 3, the Investigator will test the generalizability of their findings, explore the potential of methylation marks as biomarkers of disease in PBMCs and determine if change in methylation of these targets with AZA or folic acid affects key immune and regulatory pathways in a second set of CBD and BeS subjects. Throughout the Aims, the Investigator will use both fresh CD4+ T cells to directly assess disease relevance and Be-stimulated cultured CD4+ T cells (compared to unstimulated cultured T cells) to assess the impact of environmental exposure .
- Conditions
- Chronic Beryllium Disease
- Being tested
- Nothing
What participants receive
What participants receive. In a randomised study each person is assigned to one group by chance.
NothingOther
No interventions will be administered.
| Study group | Role | What they receive |
|---|---|---|
| Chronic Beryllium Disease | Those that have been diagnosed with the disease. No interventions will be administered. Receives: Other: Nothing | |
| Beryllium Sensitization | Those that have been diagnosed with beryllium sensitization and do not have chronic beryllium disease. No interventions will be administered. Receives: Other: Nothing | |
| normal controls | Those that do not have chronic beryllium disease or beryllium sensitization. No interventions will be administered Receives: Other: Nothing |
What is being measured
The primary outcome is the main question the study is designed to answer.
Determine the critical immune and environmentally-induced epigenetic alterations in the CD4+ T cells at the site of disease involvement from CBD compared to BeS and control subjects.
The Investigators goal is to define an epigenomic profile for BeS and CBD and for Be exposure in the lung. Most studies using similar methods have demonstrated significant hypo- and hyper-methylation, in disease states, which we also expect to find. In addition, we expect to confirm an association between CBD and Th1 epigenetic regulation, finding DM in regions such as FOXP3, Th1 differentiation pathways and TNFalpha, likely with modulation of these and other regions with Be exposure. There is no information regarding methylation alterations induced by an immune mediated exposure such as Be. The investigator expects to define new and unique genes with DM, some involved in the immune response and others in pathways and networks not known to be associated with granulomatous inflammation, shedding light on the pathogenesis of this and similar diseases.
Measured: Year 1 through year 2
Define the functional impact of critical immune and environmentally-induced epigenetic alterations in gene expression from BAL CD4+ T cells from CBD compared to BeS and control subjects used in Aim 1
At the end of Aim 2, the Investigator will have 20 genes with validated methylation and expression changes. These methylation changes are likely to be regulatory in CD4+ T cells not only based on relationship with expression but also network analysis of methylation changes (Aim 1), relationship with immune cell phenotypes, cell specific chromatin/histone marks from ENCODE and RE datasets, and our CBD GWAS SNPs (Aim 2). The Investigator has a pipeline of data analysis currently in place as evidenced by our preliminary data; as new approaches such as these become available, we will use them to analyze our data.
Measured: year 1 through year 4
Secondary outcomes (1)
Test the generalizability of our findings and validity of identified methylation and gene expression changes as potential biomarkers and therapeutic targets.
This Aim will result in a set of key data, including potential new biomarkers of disease and exposure in CBD. The Investigator expects to be able to validate the 20 loci identified in Aim 2 in BAL as well as PBMCs. Even with a sample size of n=10 in their gene-expression studies, the Investigator was able to define significant DE in PBMCs in CBD that they are currently exploring as biomarkers in a larger population; the Investigator expects that with changes found evaluating the relationship between DM and DE that they will be able to use the PBMCs as a biomarker of disease and exposure.
Measured: Year 3 through year 5
Timeline
From the start of the study to its completion; the mark is today. Estimated dates are the sponsor’s plan.
- First posted13 Nov 2015 (estimated)
- Study start14 Dec 2014
- Primary completion31 Dec 2020
- Study completion31 Dec 2020
Resources
- Official record on ClinicalTrials.govThe registry entry this page is built from, with its full change history.
- Other trials for Chronic Beryllium DiseaseStudies 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
- Cohort
- Time perspective
- Prospective
- Enrolment
- 148 participants (actual)
Sponsor and investigators
- Lead sponsor
- National Jewish Health
- Sponsor type
- University, hospital or other
- Responsible party
- Principal investigator, Lisa Maier, National Jewish Health
- Investigators
- Lisa Maier, MD, Principal investigator, National Jewish Health
IDs, dates and publications
- ClinicalTrials.gov ID
- NCT02604693
- Sponsor's protocol ID
- HS-2866
- Acronym
- BeEpiGen
- Status last verified
- Apr 2021
- First submitted
- 10 Nov 2015
- Last updated
- 29 Apr 2021
- Results posted
- No
- Data monitoring committee
- No
Study at a glance
From the registry record, last updated by the sponsor on 29 Apr 2021. Recruitment status is as the sponsor reported it: confirm with the study team.
- Official title
- Exposure in Epigenetic Regulation of Immune Response in Chronic Beryllium
- ClinicalTrials.gov ID
- NCT02604693
- Acronym / sponsor ID
- BeEpiGen / HS-2866
- Conditions
- Chronic Beryllium Disease
- Study type
- Observational
- Recruitment status
- Completed
- Enrolment
- 148 participants (actual)
- Lead sponsor
- National Jewish HealthUniversity, hospital or other
- Study start
- 14 Dec 2014 (actual)
- Primary completion
- 31 Dec 2020 (actual)
- Study completion
- 31 Dec 2020 (actual)
- First posted
- 13 Nov 2015 (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.
This study will provide important results for each aim, while also providing an integrative transcriptional and epigenomic profile of CBD.
In Aim 1 the Investigator will define genome-wide epigenetic alterations of CBD, by determining genes that are DM in pivotal immune cells, in the target organ (CD4+ BAL cells) in CBD compared to BeS and healthy controls. In addition, the Investigator will determine the impact of Be exposure on the methylation profile of CBD and BeS cells compared to each other and normal controls. This information will be used to define DM regions, genes and their networks.
Using the cases and controls from Aim 1, we will evaluate the gene-expression from these same subjects in Aim 2 to define functional epigenetic loci based on DE in CD4+ BAL cells with and without Be exposure. The Investigator will also integrate ENCODE/RE methylation, histone modification, and chromatin accessibility data as well as our genome-wide association study (GWAS) data to prioritize epigenetic marks and networks for confirmation and validation in Aim 3. In Aim 3, the Investigator will test the generalizability of their findings, explore the potential of methylation marks as biomarkers of disease in PBMCs and determine if change in methylation of these targets with AZA or folic acid affects key immune and regulatory pathways in a second set of CBD and BeS subjects. Throughout the Aims, the Investigator will use both fresh CD4+ T cells to directly assess disease relevance and Be-stimulated cultured CD4+ T cells (compared to unstimulated cultured T cells) to assess the impact of environmental exposure .
Study design
- Observational model
- Cohort
- Time perspective
- Prospective
- Number of arms
- 3
| Arm | Type | Receives |
|---|---|---|
| Chronic Beryllium Disease | – | Other: NothingThose that have been diagnosed with the disease. No interventions will be administered. |
| Beryllium Sensitization | – | Other: NothingThose that have been diagnosed with beryllium sensitization and do not have chronic beryllium disease. No interventions will be administered. |
| normal controls | – | Other: NothingThose that do not have chronic beryllium disease or beryllium sensitization. No interventions will be administered |
Who may qualify
- Ages
- 18 to 80 years
- Sex
- All
- Healthy volunteers
- Accepted
- Age groups
- Adult, Older adult
- Study population
- We will enroll subjects using standard case and control definitions. We will enroll up to 150 subjects. Controls will be frequency matched on age, gender, race and smoking status to limit methylation changes related to these factors.
Key inclusion criteria (11 listed)
- History of Beryllium exposure
- Positive blood and/or bronchoalveolar lavage (BAL) Beryllium Lymphocyte Proliferation Tests (BeLPT)
- Biopsy-proven pathologic changes consistent with CBD, specifically non-caseating granulomas and/or mononuclear cell interstitial infiltrates.
- History of Beryllium exposure
- Two or more positive blood beryllium lymphocyte proliferation tests (BeLPT) or positive bronchoalveolar lavage (BAL) BeLPT
Key exclusion criteria (25 listed)
- Immunosuppressive therapy within the last three months
- Current cigarette smoking or smoking within six months prior to the study
- Positive lung washing or biopsy cultures for fungi, mycobacteria or other respiratory pathogen consistent with an acute or chronic infection
- Weight less than 110 lbs. (for venipuncture)
- Pregnancy
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 |
|---|---|---|
| NothingNo interventions will be administered. | Other | Beryllium Sensitization, Chronic Beryllium Disease, normal controls |
Primary outcome
Determine the critical immune and environmentally-induced epigenetic alterations in the CD4+ T cells at the site of disease involvement from CBD compared to BeS and control subjects.
Time frame: Year 1 through year 2
The Investigators goal is to define an epigenomic profile for BeS and CBD and for Be exposure in the lung. Most studies using similar methods have demonstrated significant hypo- and hyper-methylation, in disease states, which we also expect to find. In addition, we expect to confirm an association between CBD and Th1 epigenetic regulation, finding DM in regions such as FOXP3, Th1 differentiation pathways and TNFalpha, likely with modulation of these and other regions with Be exposure. There is no information regarding methylation alterations induced by an immune mediated exposure such as Be. The investigator expects to define new and unique genes with DM, some involved in the immune response and others in pathways and networks not known to be associated with granulomatous inflammation, shedding light on the pathogenesis of this and similar diseases.
Define the functional impact of critical immune and environmentally-induced epigenetic alterations in gene expression from BAL CD4+ T cells from CBD compared to BeS and control subjects used in Aim 1
Time frame: year 1 through year 4
At the end of Aim 2, the Investigator will have 20 genes with validated methylation and expression changes. These methylation changes are likely to be regulatory in CD4+ T cells not only based on relationship with expression but also network analysis of methylation changes (Aim 1), relationship with immune cell phenotypes, cell specific chromatin/histone marks from ENCODE and RE datasets, and our CBD GWAS SNPs (Aim 2). The Investigator has a pipeline of data analysis currently in place as evidenced by our preliminary data; as new approaches such as these become available, we will use them to analyze our data.
1 secondary outcome
Test the generalizability of our findings and validity of identified methylation and gene expression changes as potential biomarkers and therapeutic targets.
Time frame: Year 3 through year 5
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 Apr 2021.
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.
Lisa Maier, MD principal investigator
National Jewish Health
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 Chronic Beryllium Disease, run by National Jewish Health 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 11 inclusion and 25 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 Apr 2021. 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?
Determine the critical immune and environmentally-induced epigenetic alterations in the CD4+ T cells at the site of disease involvement from CBD compared to BeS and control subjects. (time frame: Year 1 through year 2). The study lists 2 primary outcomes in all. 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 Apr 2021.