Targeting Oxidative Stress in Chronic Beryllium Disease - Full Text View

Purpose

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	Intervention	Phase
Chronic Beryllium Disease	Drug: Mesalamine Drug: Placebo	Phase 1 Phase 2


Study Type:	Interventional
Study Design:	Allocation: Randomized Endpoint Classification: Efficacy Study Intervention Model: Parallel Assignment Masking: Double Blind (Subject, Caregiver, Investigator, Outcomes Assessor) Primary Purpose: Treatment
Official Title:	Targeting Oxidative Stress in Chronic Beryllium Disease

Resource links provided by NLM:

Genetics Home Reference related topics: pulmonary alveolar microlithiasis

Drug Information available for: Mesalamine Mesalamine hydrochloride

Genetic and Rare Diseases Information Center resources: Beryllium Disease Coal Worker's Pneumoconiosis

U.S. FDA Resources

Further study details as provided by National Jewish Health:

Primary Outcome Measures:

Beryllium lymphocyte proliferation responses (BeLPT) [ Time Frame: baseline and week 6 ] [ Designated as safety issue: No ]
Primary endpoints are beryllium proliferation responses (BeLPT) in PBMCs and BAL cells.

Secondary Outcome Measures:

Th1 cytokines [ Time Frame: baseline and week 6 ] [ Designated as safety issue: No ]
Secondary outcomes include changes in Th1 cytokines (e.g. INFγ)
Steady-state GSH levels [ Time Frame: baseline and week 6 ] [ Designated as safety issue: No ]
Secondary outcomes include changes in steady-state GSH levels in beryllium specific CD4+ T cell, HDAC2 levels
HDAC2 levels [ Time Frame: baseline and week 6 ] [ Designated as safety issue: No ]
Secondary outcomes include changes in HDAC2 levels
Glucocorticoid receptors [ Time Frame: baseline and week 6 ] [ Designated as safety issue: No ]
Secondary outcomes include changes in glucocorticoid receptors modification in PBMCs and BAL cells.
Lung function [ Time Frame: baseline and week 6 ] [ Designated as safety issue: No ]
Secondary outcomes include changes in lung function, which will be assessed with spirometry and DLCO.


Enrollment:	18
Study Start Date:	March 2010
Study Completion Date:	March 2015
Primary Completion Date:	March 2015 (Final data collection date for primary outcome measure)

Arms	Assigned Interventions
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.

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.

Eligibility


Ages Eligible for Study:	18 Years to 80 Years (Adult, Senior)
Genders Eligible for Study:	Both
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

Choosing to participate in a study is an important personal decision. Talk with your doctor and family members or friends about deciding to join a study. To learn more about this study, you or your doctor may contact the study research staff using the Contacts provided below. For general information, see Learn About Clinical Studies.

Please refer to this study by its ClinicalTrials.gov identifier: NCT01088243

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


Responsible Party:	Lisa Maier, Associate Professor of Medicine, National Jewish Health
ClinicalTrials.gov Identifier:	NCT01088243 History of Changes
Other Study ID Numbers:	HS-2360B
Study First Received:	March 15, 2010
Last Updated:	March 19, 2015
Health Authority:	United States: Institutional Review Board

Keywords provided by 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

ClinicalTrials.gov processed this record on September 23, 2016