Targeting Oxidative Stress in Chronic Beryllium Disease

Study Description

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Brief Summary:

The purpose of this study is to understand if a drug called mesalamine helps to control inflammation associated with chronic beryllium disease (CBD). We hypothesize that in CBD subjects treated with prednisone, mesalamine treatment will enhance the immunosuppressive effects of prednisone, and thus reduce the immune response to beryllium.

Condition or disease	Intervention/treatment	Phase
Chronic Beryllium Disease	Drug: Mesalamine; Drug: Placebo	Phase 1; Phase 2

Detailed Description:

The overall goal of this study is to understand the role of oxidative stress as a potential therapeutic target in the pathogenesis of chronic beryllium disease (CBD). CBD is an inflammatory hypersensitivity lung disease that occurs in an estimated 800,000 beryllium-exposed workers in the United Sates. CBD is characterized by the presence of pulmonary non-caseating granulomas with accumulation of macrophages and beryllium specific CD4+ T cells (Newman et al. 1998). Upon beryllium stimulation in vitro, beryllium specific CD4+ T cells proliferate and produce Th1 cytokines (i.e. TNF-α, IFN-γ, and IL-2) at unusually high levels (Tinkle et al. 1997). The molecular mechanism(s) by which beryllium regulates the chronic production of these cytokines is unknown. Exciting preliminary studies indicate that beryllium alters the redox status of T cells which may adversely modulate the immune response in CBD. Based on these points, a novel hypothesis is proposed: 1) oxidative stress enhances the T cells response to antigen and this enhancement may explain both the excessive cytokine response and the pathogenesis of pulmonary granulomas in CBD and; 2) an inherent difference in T cell antioxidant status is a critical factor in the pathogenesis of CBD. This proposal is a pilot clinical trial examining an approved drug for the treatment of ulcerative colitis (5-amino salicylic acid, 5-ASA), which has anti-inflammatory and antioxidant properties, as a potential new approach for CBD treatment. In this clinical trial, 40 CBD subjects already treated with prednisone, will be treated with either placebo or 5-ASA to determine it effects on the beryllium stimulated immune response in the lung by undergoing bronchoscopy with bronchoalveolar lavage and in blood by undergoing venipuncture before and after 6 weeks of treatment with 5-ASA. As a secondary outcome, we will also assess subjects clinical response to this short course of 5-ASA using spirometry. Bronchoscopies are optional. Patients have the option to participate by undergoing venipuncture and lung function tests only.

Study Design

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Study Type :	Interventional (Clinical Trial)
Actual Enrollment :	18 participants
Allocation:	Randomized
Intervention Model:	Parallel Assignment
Masking:	Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor)
Primary Purpose:	Treatment
Official Title:	Targeting Oxidative Stress in Chronic Beryllium Disease
Study Start Date :	March 2010
Actual Primary Completion Date :	March 2015
Actual Study Completion Date :	March 2015

Arms and Interventions

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Arm	Intervention/treatment
Experimental: Mesalamine; Mesalamine (5-ASA) 500 mg capsules four times per day for 6 weeks in Chronic Beryllium Disease subjects.	Drug: Mesalamine; Mesalamine (5-ASA) 500 mg capsules four times per day for 6 weeks in Chronic Beryllium Disease subjects.; Other Names: Pentasa; 5-ASA
Placebo Comparator: Placebo; Sugar pill 500 mg capsules four times per day for 6 weeks in Chronic Beryllium Disease subjects.	Drug: Placebo; Sugar pill 500 mg capsules four times per day for 6 weeks in Chronic Beryllium Disease subjects.

Outcome Measures

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Primary Outcome Measures :

1. Change in Beryllium Lymphocyte Proliferation Responses (BeLPT) From Baseline to Week 6 [ Time Frame: baseline and week 6 ]
   Primary endpoints are beryllium proliferation responses (BeLPT) in PBMCs (peripheral blood mononuclear cells) and BAL (bronchoalveolar lavage) cells. The BeLPT is a blood test that measures the immune response to beryllium exposure. If immune cells multiply in response to beryllium, this is considered an abnormal test results. If immune cells do not multiple, this is considered a normal test results. Results are reported as "stimulation index", which is a ratio of the number of cells grown with beryllium compared to the number of cells grown without beryllium. A value of 2.5 or less is considered normal, and a value greater than 2.5 is abnormal.

Secondary Outcome Measures :

1. Changes in Bronchoalveolar Lavage (BAL) Tumor Necrosis Factor Alpha (TNFa) [ Time Frame: baseline and week 6 ]
   Secondary outcomes include changes in bronchoalveolar lavage (BAL) tumor necrosis factor alpha (TNFa)
2. Changes in Steady-state Glutathione (GSH) Levels From Baseline to Week 6 [ Time Frame: baseline and week 6 ]
   Secondary outcomes include changes in steady-state GSH levels in beryllium specific CD4+ T cell in bronchoalveolar lavage fluid (BALF)
3. HDAC2 Levels [ Time Frame: baseline and week 6 ]
   Secondary outcomes include changes in HDAC2 levels
4. Glucocorticoid Receptors [ Time Frame: baseline and week 6 ]
   Secondary outcomes include changes in glucocorticoid receptors modification in PBMCs and BAL cells.
5. Lung Function [ Time Frame: baseline and week 6 ]
   Secondary outcomes include changes in lung function, which will be assessed with Forced expiratory volume in 1 second percent predicted (FEV1), Forced vital capacity percent predicted (FVC) and Diffusing capacity percent predicted (DLCO).

Eligibility Criteria

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Ages Eligible for Study:	18 Years to 80 Years (Adult, Senior)
Sexes Eligible for Study:	All
Accepts Healthy Volunteers:	No

Criteria

Inclusion Criteria:

• Diagnosis of chronic beryllium disease based on the criteria below:

  1. History of beryllium exposure, and;
  2. Positive blood and/or bronchoalveolar lavage Beryllium Lymphocyte Proliferation Tests (BeLPT), and;
  3. Biopsy-proven pathologic changes consistent with CBD-non-caseating granulomas and/or mononuclear cell interstitial infiltrates, and;
  4. Positive bronchoalveolar lavage (BAL) BeLPT and > 15% lymphocytes in BAL fluid.

Exclusion Criteria:

• History of Hepatic disease
• History of Renal disease
• Hypersensitivity to Pentasa (5-ASA) or salicylates.
• Pregnancy
• Presence of another disease that may be expected to significantly affect patient mortality (e.g., HIV), severe cor pulmonale);
• The use of blood thinners.
• Current use of tobacco (smoking or otherwise) in the past 6 months
• Patient inability to participate in the study, such as inability to undergo venipuncture and BAL procedures (if undergoing bronchoscopy) that form part of the inclusion/exclusion criteria or part of the outcome measure.

If undergoing bronchoscopy:

• Severe room air hypoxemia (precluding transbronchial lung biopsy and/or BAL), e.g., pO2 < 45 (Denver altitude 5,280 feet);

Contacts and Locations

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Study Description Study Design Arms and Interventions Outcome Measures Eligibility Criteria Contacts and Locations More Information

Locations

United States, Colorado
National Jewish Health
Denver, Colorado, United States, 80206

Sponsors and Collaborators

National Jewish Health

Investigators

Principal Investigator:	Lisa A. Maier, M.D., MSPH	National Jewish Health
Principal Investigator:	Brian Day, PhD	National Jewish Health

More Information

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Study Description Study Design Arms and Interventions Outcome Measures Eligibility Criteria Contacts and Locations More Information

Publications automatically indexed to this study by ClinicalTrials.gov Identifier (NCT Number):

Day BJ, Huang J, Barkes BQ, Gillespie M, Li L, Maier LA. A Pilot Study Assessing the Ability of 5-Aminosalicylic Acid to Modulate the Immune Response in Chronic Beryllium Disease. Ann Am Thorac Soc. 2018 Apr;15(Supplement_2):S133. doi: 10.1513/AnnalsATS.201709-720MG.

Responsible Party:	Lisa Maier, Associate Professor of Medicine, National Jewish Health
ClinicalTrials.gov Identifier:	NCT01088243 History of Changes
Other Study ID Numbers:	HS-2360B
First Posted:	March 17, 2010
Results First Posted:	December 12, 2017
Last Update Posted:	January 10, 2018
Last Verified:	December 2017

Keywords provided by Lisa Maier, National Jewish Health:

Berylliosis; Beryllium Disease

Additional relevant MeSH terms:

Berylliosis; Pneumoconiosis; Lung Diseases, Interstitial; Lung Diseases; Respiratory Tract Diseases; Lung Injury; Occupational Diseases; Mesalamine	Anti-Inflammatory Agents, Non-Steroidal; Analgesics, Non-Narcotic; Analgesics; Sensory System Agents; Peripheral Nervous System Agents; Physiological Effects of Drugs; Anti-Inflammatory Agents; Antirheumatic Agents