Denver, Colorado 80206


Purpose:

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 .


Criteria:

Inclusion Criteria: Chronic Beryllium Disease (CBD): 1. History of Beryllium exposure 2. Positive blood and/or bronchoalveolar lavage (BAL) Beryllium Lymphocyte Proliferation Tests (BeLPT) 3. Biopsy-proven pathologic changes consistent with CBD, specifically non-caseating granulomas and/or mononuclear cell interstitial infiltrates. Beryllium Sensitization: 1. History of Beryllium exposure 2. Two or more positive blood beryllium lymphocyte proliferation tests (BeLPT) or positive bronchoalveolar lavage (BAL) BeLPT 3. Normal lung tissue (no histology suggestive of CBD). Normal Controls: 1. No history of beryllium exposure 2. Former smokers or never smokers - Exclusion Criteria: Chronic Beryllium Disease: 1. Immunosuppressive therapy within the last three months 2. Current cigarette smoking or smoking within six months prior to the study 3. Positive lung washing or biopsy cultures for fungi, mycobacteria or other respiratory pathogen consistent with an acute or chronic infection 4. Weight less than 110 lbs. (for venipuncture) 5. Pregnancy 6. Severe room air hypoxemia and or hypercapnia (precluding BAL), e.g., resting PaO2 < 45, PaCO2 > 45 mm Hg; (Denver altitude 5,280 feet) 7. 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) 8. 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: 1. Known underlying systemic or lung disease; 2. Current cigarette smoking or smoking within six months prior to the study 3. Positive lung pathology consistent with CBD 4. Pregnancy 5. Weight less than 110 lbs. (for venipuncture) 6. 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) 7. 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: 1. History of beryllium exposure 2. Known underlying systemic or lung disease; 3. Immunosuppressive therapy or other medication for as systemic disease process in the last 3 months; 4. Current smokers or smoking within 6 months of study 5. Pregnancy 6. Weight less than 110 lbs. (for venipuncture) 7. Inability to undergo BAL or venipuncture procedures -


Study is Available At:


Original ID:

HS-2866


NCT ID:

NCT02604693


Secondary ID:


Study Acronym:

BeEpiGen


Brief Title:

Exposure in Epigenetic Regulation of Immune Response in Chronic Beryllium Disease (CBD)


Official Title:

Exposure in Epigenetic Regulation of Immune Response in Chronic Beryllium


Overall Status:

Recruiting


Study Phase:

N/A


Genders:

N/A


Minimum Age:

18 Years


Maximum Age:

80 Years


Quick Facts

Healthy Volunteers
Oversight Has DMC
Study Is FDA Regulated
Study Is Section 801
Has Expanded Access

Study Source:

National Jewish Health


Oversight Authority:

United States: Institutional Review Board


Reasons Why Stopped:


Study Type:

Observational


Study Design:


Number of Arms:

0


Number of Groups:

3


Total Enrollment:

150


Enrollment Type:

Anticipated


Overall Contact Information

Official Name:Lisa Maier, MD
Principal Investigator
National Jewish Health
Primary Contact:Peggy Mroz, MSPH
303-398-1730
mrozp@njhealth.org
Backup Contact:Christina Riley, BA
303-270-2049
rileyc@njhealth.org

Study Dates

Start Date:December 2014
Completion Date:December 2019
Completion Type:Anticipated
Primary Completion Date:December 2019
Primary Completion Type:Anticipated
Verification Date:March 2019
Last Changed Date:March 11, 2019
First Received Date:November 10, 2015

Study Outcomes

Outcome Type:Primary Outcome
Measure: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
Safety Issues:False
Description: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 m
Outcome Type:Secondary Outcome
Measure: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
Safety Issues:False
Description: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
Outcome Type: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
Safety Issues:False
Description: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 ad

Study Interventions

Intervention Type:Other
Name:Nothing
Description:No interventions will be administered.
Arm Name:Chronic Beryllium Disease

Study Arms

Study Arm Type:Other
Arm Name:Chronic Beryllium Disease
Description:Those that have been diagnosed with the disease. No interventions will be administered.
Study Arm Type:Other
Arm Name:Beryllium Sensitization
Description:Those that have been diagnosed with beryllium sensitization and do not have chronic beryllium disease. No interventions will be administered.
Study Arm Type:Other
Arm Name:normal controls
Description:Those that do not have chronic beryllium disease or beryllium sensitization. No interventions will be administered

Study Agencies

Agency Class:Other
Agency Type:Lead Sponsor
Agency Name:National Jewish Health

Samples and Retentions

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.
Sample Method:Probability Sample

Study References

There are no available Study References

Data Source: ClinicalTrials.gov

Date Processed: January 21, 2020

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