Targeting Oxidative Stress in Chronic Beryllium Disease

• Sponsor: National Jewish Health (Other)
• Overall Status: Completed
• CT.gov ID: NCT01088243
• Collaborator: (none)
• Enrollment: 18
• Location: 1
• Arms: 2
• Duration (Months): 60
• Patients Per Site Per Month: 0.3

Study Details

Study Description

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

• Study Type: Interventional
• 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: Mar 1, 2010
• Actual Primary Completion Date: Mar 1, 2015
• Actual Study Completion Date: Mar 1, 2015

Arms and Interventions

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.; Other Names: Sugar Pill

Outcome Measures

Primary Outcome Measures

1. 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 Outcome Measures

1. 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)

2. 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)

3. HDAC2 Levels [baseline and week 6]

   Secondary outcomes include changes in HDAC2 levels

4. Glucocorticoid Receptors [baseline and week 6]

   Secondary outcomes include changes in glucocorticoid receptors modification in PBMCs and BAL cells.

5. 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).

Eligibility Criteria

Criteria

• Ages Eligible for Study: 18 Years to 80 Years
• Sexes Eligible for Study: All
• Accepts Healthy Volunteers: No

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

Locations

	Site	City	State	Country	Postal Code
1	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

Study Documents (Full-Text)

None provided.

More Information

Publications

None provided.

• Responsible Party: Lisa Maier, Associate Professor of Medicine, National Jewish Health
• ClinicalTrials.gov Identifier: NCT01088243
• Other Study ID Numbers: HS-2360B
• First Posted: Mar 17, 2010
• Last Update Posted: Oct 12, 2018
• Last Verified: Sep 1, 2018

• Keywords provided by Lisa Maier, Associate Professor of Medicine, National Jewish Health: Berylliosis; Beryllium Disease
• Additional relevant MeSH terms: Berylliosis; Mesalamine

Study Results

Participant Flow

Arm/Group Title	Mesalamine	Placebo
Arm/Group Description	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.	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.
Period Title: Overall Study
STARTED	13	5
COMPLETED	12	5
NOT COMPLETED	1	0

Baseline Characteristics

Arm/Group Title	Mesalamine	Placebo	Total
Arm/Group Description	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.	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.	Total of all reporting groups
Overall Participants	13	5	18
Age (years) [Mean (Full Range) ]
Mean (Full Range) [years]	63.3	62.8	63.16
Sex: Female, Male (Count of Participants)
Female	2 15.4%	1 20%	3 16.7%
Male	11 84.6%	4 80%	15 83.3%
Region of Enrollment (Count of Participants)
United States	13 100%	5 100%	18 100%
Smoking Status (Count of Participants) [Number]
Never	5 38.5%	2 40%	7 38.9%
Former	8 61.5%	3 60%	11 61.1%

Outcome Measures

1. Primary Outcome

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

Outcome Measure Data

Analysis Population Description

Because bronchoscopy was not required for participation, only three placebo and six 5-ASA-treated subjects underwent bronchoscopy and is reported under BAL.

Arm/Group Title	Mesalamine	Placebo
Arm/Group Description	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.	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.
Measure Participants	13	5
BAL	48.61 (57.18)	9.33 (14.08)
PBMC	22.07 (20.30)	3.8 (6.09)

2. Secondary Outcome

Title	Changes in Bronchoalveolar Lavage (BAL) Tumor Necrosis Factor Alpha (TNFa)
Description	Secondary outcomes include changes in bronchoalveolar lavage (BAL) tumor necrosis factor alpha (TNFa)
Time Frame	baseline and week 6

Outcome Measure Data

Analysis Population Description

We did not have sufficient cells to run experiments on all participants. However, below is a summary of what data was received.

Arm/Group Title	Mesalamine	Placebo
Arm/Group Description	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.	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.
Measure Participants	6	3
Mean (Standard Deviation) [pg/ml]	62 (35.76)	-1750 (2734)

3. Secondary Outcome

Title	Changes in Steady-state Glutathione (GSH) Levels From Baseline to Week 6
Description	Secondary outcomes include changes in steady-state GSH levels in beryllium specific CD4+ T cell in bronchoalveolar lavage fluid (BALF)
Time Frame	baseline and week 6

Outcome Measure Data

Analysis Population Description

We did not receive enough cells from participants to be able to run experiments on all. However, below is a summary of what data was received.

Arm/Group Title	Mesalamine	Placebo
Arm/Group Description	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.	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.
Measure Participants	6	3
Mean (Standard Deviation) [mmol/mg]	4.93 (20.08)	10.38 (16.5)

4. Secondary Outcome

Title	HDAC2 Levels
Description	Secondary outcomes include changes in HDAC2 levels
Time Frame	baseline and week 6

Outcome Measure Data

Analysis Population Description

We were not able to perform due to insufficient samples and data collected from each participant to summarize changes in HDAC2 levels.

Arm/Group Title	Mesalamine	Placebo
Arm/Group Description	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.	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.
Measure Participants	0	0

5. Secondary Outcome

Title	Glucocorticoid Receptors
Description	Secondary outcomes include changes in glucocorticoid receptors modification in PBMCs and BAL cells.
Time Frame	baseline and week 6

Outcome Measure Data

Analysis Population Description

We were not able to perform due to insufficient samples and data collected from each participant to summarize changes.

Arm/Group Title	Mesalamine	Placebo
Arm/Group Description	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.	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.
Measure Participants	0	0

6. Secondary Outcome

Title	Lung Function
Description	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).
Time Frame	baseline and week 6

Outcome Measure Data

Analysis Population Description

One participant did not complete follow up in Mesalamine group. However, below is a summary of what data was received.

Arm/Group Title	Mesalamine	Placebo
Arm/Group Description	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.	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.
Measure Participants	12	5
FEV1 % pred	2.2 (4.49)	-0.91 (4.73)
FVC % pred	1.6 (3.5)	-0.08 (5.55)
DLCO % pred	2.4 (4.39)	-0.16 (6.01)

Adverse Events

Time Frame	The patients will be monitored after baseline evaluation, during drug therapy, and after 2 week follow-up evaluation by a study coordinator and Dr. Maier who will follow-up for adverse events at each visit. All adverse events (serious and moderate/mild) associated with bronchoscopy procedures and study drug will be assessed individually by study PIs for appropriate action if necessary.
Arm/Group Title	Mesalamine		Placebo
Arm/Group Description	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.		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.
All Cause Mortality
	Mesalamine		Placebo
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	/ (NaN)		/ (NaN)
Serious Adverse Events
	Mesalamine		Placebo
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	0/13 (0%)		0/5 (0%)
Other (Not Including Serious) Adverse Events
	Mesalamine		Placebo
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	2/13 (15.4%)		2/5 (40%)
Cardiac disorders
Mobitz Type II heart block	0/13 (0%)	0	1/5 (20%)	1
General disorders
One 5-ASA-treated subject developed dizziness, constipation, stomach pain and chest pain two weeks	1/13 (7.7%)	1	0/5 (0%)	0
One 5-ASA-treated subject experienced coughing and low energy after the follow-up bronchoscopy	1/13 (7.7%)	1	0/5 (0%)	0
Skin and subcutaneous tissue disorders
Swelling	0/13 (0%)	0	1/5 (20%)	1

Limitations/Caveats

[Not Specified]

More Information

Certain Agreements

Principal Investigators are NOT employed by the organization sponsoring the study.

There is NOT an agreement between Principal Investigators and the Sponsor (or its agents) that restricts the PI's rights to discuss or publish trial results after the trial is completed.