Targeting Oxidative Stress in Chronic Beryllium Disease

Status

Completed

Phases

Phase 1Phase 2

Study type

Interventional

Source

ClinicalTrials.gov

Registry ID

NCT01088243

Enrollment

Registered

2010-03-17

Start date

2010-03-31

Completion date

2015-03-31

Last updated

2018-10-12

For informational purposes only — not medical advice. Sourced from public registries and may not reflect the latest updates. Terms

Conditions

Chronic Beryllium Disease

Keywords

Berylliosis, Beryllium Disease

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.

Interventions

DRUGMesalamine

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

DRUGPlacebo

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

Study design

Allocation

RANDOMIZED

Intervention model

PARALLEL

Primary purpose

TREATMENT

Masking

QUADRUPLE (Subject, Caregiver, Investigator, Outcomes Assessor)

Eligibility

Sex/Gender

ALL

Age

18 Years to 80 Years

Healthy volunteers

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/

Design outcomes

Primary

Measure	Time frame	Description
Change in Beryllium Lymphocyte Proliferation Responses (BeLPT) From Baseline to Week 6	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

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

Countries

United States

Participant flow

Participants by arm

Arm	Count
Mesalamine Mesalamine (5-ASA) 500 mg capsules four times per day for 6 weeks in Chronic Beryllium Disease subjects. Mesalamine: Mesalamine (5-ASA) 500 mg capsules four times per day for 6 weeks in Chronic Beryllium Disease subjects.	13
Placebo Sugar pill 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.	5
Total	18

Withdrawals & dropouts

Period	Reason	FG000	FG001
Overall Study	Adverse Event	1	0

Baseline characteristics

Characteristic	Mesalamine	Placebo	Total
Age, Continuous	63.3 years	62.8 years	63.16 years
Region of Enrollment United States	13 Participants	5 Participants	18 Participants
Sex: Female, Male Female	2 Participants	1 Participants	3 Participants
Sex: Female, Male Male	11 Participants	4 Participants	15 Participants
Smoking Status Former	8 Count of Participants	3 Count of Participants	11 Count of Participants
Smoking Status Never	5 Count of Participants	2 Count of Participants	7 Count of Participants

Adverse events

Event type	EG000 affected / at risk	EG001 affected / at risk
deaths Total, all-cause mortality	— / —	— / —
other Total, other adverse events	2 / 13	2 / 5
serious Total, serious adverse events	0 / 13	0 / 5

Outcome results

Primary

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.