Targeting Oxidative Stress in Chronic Beryllium Disease

NCT ID: NCT01088243

Last Updated: 2018-10-12

Basic Information

• Recruitment Status: COMPLETED
• Clinical Phase: PHASE1/PHASE2
• Total Enrollment: 18 participants
• Study Classification: INTERVENTIONAL
• Study Start Date: 2010-03-31
• Study Completion Date: 2015-03-31

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.

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.

Conditions

Chronic Beryllium Disease

Study Design

• Allocation Method: RANDOMIZED
• Intervention Model: PARALLEL
• Primary Study Purpose: TREATMENT
• Blinding Strategy: QUADRUPLE

Study Groups

Mesalamine

Mesalamine (5-ASA) 500 mg capsules four times per day for 6 weeks in Chronic Beryllium Disease subjects.

Group Type: EXPERIMENTAL

Mesalamine

Intervention Type: DRUG

Mesalamine (5-ASA) 500 mg capsules four times per day for 6 weeks in Chronic Beryllium Disease subjects.

Placebo

Sugar pill 500 mg capsules four times per day for 6 weeks in Chronic Beryllium Disease subjects.

Group Type: PLACEBO_COMPARATOR

Placebo

Intervention Type: DRUG

Sugar pill 500 mg capsules four times per day for 6 weeks in Chronic Beryllium Disease subjects.

Interventions

Mesalamine

Mesalamine (5-ASA) 500 mg capsules four times per day for 6 weeks in Chronic Beryllium Disease subjects.

Intervention Type: DRUG

Placebo

Sugar pill 500 mg capsules four times per day for 6 weeks in Chronic Beryllium Disease subjects.

Intervention Type: DRUG

Other Intervention Names

Pentasa; 5-ASA; Sugar Pill

Eligibility 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

If undergoing bronchoscopy:

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

• Minimum Eligible Age: 18 Years
• Maximum Eligible Age: 80 Years
• Eligible Sex: ALL
• Accepts Healthy Volunteers: No

Sponsors

National Jewish Health

OTHER

Sponsor Role: lead

Responsible Party

Lisa Maier

Associate Professor of Medicine

Responsibility Role: PRINCIPAL_INVESTIGATOR

Principal Investigators

Lisa A. Maier, M.D., MSPH

Role: PRINCIPAL_INVESTIGATOR

National Jewish Health

Brian Day, PhD

Role: PRINCIPAL_INVESTIGATOR

National Jewish Health

Locations

National Jewish Health

Denver, Colorado, United States

Countries

United States

Other Identifiers

HS-2360B

Identifier Type: -

Identifier Source: org_study_id