Targeting Oxidative Stress in Chronic Beryllium Disease

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.

Study Overview

• Status: Completed
• Conditions: Chronic Beryllium Disease
• Intervention / Treatment: Drug: Mesalamine; Drug: Placebo

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 Type: Interventional
• Enrollment (Actual): 18
• Phase: Phase 2; Phase 1

Contacts and Locations

Study Locations

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

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years to 80 years (ADULT, OLDER_ADULT)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

Description

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);

Study Plan

How is the study designed?

Design Details

• Primary Purpose: TREATMENT
• Allocation: RANDOMIZED
• Interventional Model: PARALLEL
• Masking: QUADRUPLE

Number of Arms

2

Arms and Interventions

Participant Group / 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: 5-ASA; Pentasa
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.; Other Names: Sugar Pill

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Change in Beryllium Lymphocyte Proliferation Responses (BeLPT) From Baseline to 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.	baseline and week 6

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Changes in Bronchoalveolar Lavage (BAL) Tumor Necrosis Factor Alpha (TNFa)	Secondary outcomes include changes in bronchoalveolar lavage (BAL) tumor necrosis factor alpha (TNFa)	baseline and week 6
Changes in Steady-state Glutathione (GSH) Levels From Baseline to Week 6	Secondary outcomes include changes in steady-state GSH levels in beryllium specific CD4+ T cell in bronchoalveolar lavage fluid (BALF)	baseline and week 6
HDAC2 Levels	Secondary outcomes include changes in HDAC2 levels	baseline and week 6
Glucocorticoid Receptors	Secondary outcomes include changes in glucocorticoid receptors modification in PBMCs and BAL cells.	baseline and week 6
Lung Function	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).	baseline and week 6

Collaborators and Investigators

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

Study record dates

Study Major Dates

• Study Start: March 1, 2010
• Primary Completion (ACTUAL): March 1, 2015
• Study Completion (ACTUAL): March 1, 2015

Study Registration Dates

• First Submitted: March 15, 2010
• First Submitted That Met QC Criteria: March 16, 2010
• First Posted (ESTIMATE): March 17, 2010

Study Record Updates

• Last Update Posted (ACTUAL): October 12, 2018
• Last Update Submitted That Met QC Criteria: September 12, 2018
• Last Verified: September 1, 2018

More Information

Terms related to this study

• Keywords: Berylliosis; Beryllium Disease
• Additional Relevant MeSH Terms: Respiratory Tract Diseases; Lung Diseases; Occupational Diseases; Pneumoconiosis; Lung Diseases, Interstitial; Lung Injury; Berylliosis; Physiological Effects of Drugs; Peripheral Nervous System Agents; Analgesics; Sensory System Agents; Anti-Inflammatory Agents, Non-Steroidal; Analgesics, Non-Narcotic; Anti-Inflammatory Agents; Antirheumatic Agents; Mesalamine
• Other Study ID Numbers: HS-2360B