BISCIT: Beryllium Infliximab Study: Clinical Interventional Trial

• Sponsor: Maier, Lisa, M.D. (Other)
• Overall Status: Terminated
• CT.gov ID: NCT00111917
• Collaborator: Centocor, Inc. (Industry), National Center for Research Resources (NCRR) (NIH)
• Enrollment: 13
• Location: 1
• Arms: 2
• Duration (Months): 47
• Patients Per Site Per Month: 0.3

Study Details

Study Description

Brief Summary

The goal of this research study is to test the clinical effectiveness of a drug called infliximab (Remicade) in chronic beryllium disease (CBD). This drug may reduce tumor necrosis factor-alpha (TNF-a), which is associated with more severe disease and inflammation in the lung. Receiving infliximab may help with symptoms, and may improve clinical testing data normally ordered by your doctor, such as breathing tests. Baseline and follow-up testing will look for improvements in breathing tests (pulmonary function testing), exchange of oxygen in the lungs (exercise test), chest x ray, and lung inflammation.

Condition or Disease	Intervention/Treatment	Phase
Berylliosis; Beryllium Disease	Drug: Infliximab; Other: Placebo	Phase 1/Phase 2

Detailed Description

Hypothesis:

The central hypothesis of this study is that infliximab will prove to be efficacious in the treatment of chronic beryllium disease (CBD), and that it will do so by inhibiting beryllium specific T cell proliferation and cytokine production.

Specific Aims:

Specific Aim 1: To determine the clinical effectiveness of infliximab on chronic beryllium disease. The efficacy of infliximab will be measured by improvement in arterial gas exchange, or arterial alveolar oxygen gradient (A-ad02) at end exercise in subjects with CBD who remain symptomatic and with pulmonary impairment despite current treatment with prednisone and/or methotrexate. Secondary outcome measures will include change in airflow, lung volume, diffusing capacity (DLCO), profusion of small opacities on chest x-ray, dyspnea score, and quality of life questionnaires.

Specific Aim 2: To determine the effect of infliximab on intermediate markers of biological function in CBD. In vitro studies will examine the effect of infliximab on blood and lung cells in culture, as measured by a decrease in beryllium (Be)-stimulated lymphocyte proliferation; a decrease in Be-stimulated cytokine production, including TNF-a, IFN-g, and IL-2; altered Be-stimulated apoptosis of macrophages or lymphocytes.

Research Design and Methods: Since no information is available regarding the pharmacokinetics of infliximab in patients with CBD, the pharmacokinetic information available from the use of infliximab in other similar inflammatory conditions formed the basis for selecting the dose regimen for this protocol. Particularly, a 5mg/kg dose will be used for this study, based on the dose selection used in the sarcoidosis protocol C0168T48 presently underway in a multi-center trial (NJC IRB HS-1771).

This is an investigator initiated, 40 week, randomized, double-blind, placebo controlled study to evaluate the efficacy of infliximab dosed at 5mg/kg, compared to placebo, in individuals with symptomatic CBD with pulmonary involvement despite prednisone and/or methotrexate treatment. Infliximab or placebo will be infused at weeks 0, 2, 6, 12, 18, and 24 including spirometry, lung volumes and DLCO. Approximately 20 participants will be enrolled in the study at National Jewish Medical and Research Center at a 3:1 drug: placebo rate.

The primary endpoint of this study will be a change from baseline testing to week 28 testing in the A-adO2 at end exercise on a 6 minute walk. At baseline evaluation, subjects will undergo full pulmonary function testing, a blood draw for the beryllium lymphocyte proliferation test (BeLPT), 6 minute walk, chest x-ray, and quality of life and dyspnea questionnaires. Follow-up full pulmonary function testing, rest and end exercise A-ad02, pulse oximetry with total distance (workload) achieved on a 6 minute walk, and chest radiograph will be measured at week 12. Final outcome measurements (same as baseline testing), including bronchoscopy with BAL, will be repeated at week 28. A follow-up appointment will be scheduled at week 40 to assess patients' general health, as well as measure rest and end exercise A-ad02 and pulse oximetry with 6 minute walk, pulmonary function test, QOL/dyspnea scoring, and chest radiograph interstitial lung opacity profusion score.

The effects of infliximab on the Be-stimulated immune response will be assessed by comparing the following markers before and after infliximab therapy: 1. BeLPT from blood and lavage cells (BAL); 2. Be-stimulated cytokine production from BAL cells including TNF-a, IFN-γ, and IL-2; 3. Cell-specific apoptosis. The assay will include an unstimulated control, 100 mM BeSO4, 100 mM Al2(SO4)3 metal-salt control, PHA - lymphocyte proliferation control, infliximab control, infliximab + BeSO4, infliximab + Al2(SO4)3. At days 4, 5, and 6 after Be exposure, the wells are pulsed with the DNA-specific precursor, 3H-TdR, incubated for four hours, harvested on glass fiber filters, and liquid scintillation methods are used for counting. Results are reported as a stimulation index, which is a ratio of the counts per minute of the treatment group to the counts per minute of the unstimulated group. To determine the effect of infliximab on cytokine production, CBD BAL and CBD PBMC will be stimulated with Be for 24 hours. ELISA will be used to determine TNF-α, IFN-γ, and IL-2 supernatant levels. After 24 hours of beryllium exposure, we will harvest supernatants and perform ELISA testing for TNF-α, IFN-γ, and IL-2. In order to determine if infliximab causes an increase in lymphocyte or macrophage apoptosis, CBD BAL cells will be cultured for 24 hours with Be. Cells will be double stained for CD4+ (Th1) and CD71+ macrophages versus intracellular activated caspase-3, caspase-8 and caspase-9. These in vitro studies will be used to assess the potential biologic function of infliximab on immune mediated diseases using a disease model with known antigen, CBD.

Study Design

• Study Type: Interventional
• Actual Enrollment: 13 participants
• Allocation: Randomized
• Intervention Model: Parallel Assignment
• Masking: Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor)
• Primary Purpose: Treatment
• Official Title: Clinical Efficacy of Remicade in Chronic Beryllium Disease: A Randomized, Double-Blind, Placebo-Controlled, Investigator Initiated Trial
• Study Start Date: Feb 1, 2005
• Actual Primary Completion Date: Jan 1, 2009
• Actual Study Completion Date: Jan 1, 2009

Arms and Interventions

Arm	Intervention/Treatment
Experimental: Infliximab infusion: 3:1 infliximab:placebo ratio administered at 0, 2, 6, 12, 18 and 24 weeks.	Drug: Infliximab; anti-TNF; Other Names: Remicade
Placebo Comparator: Placebo infusion: 3:1 infliximab:placebo ratio administered at 0, 2, 6, 12, 18 and 24 weeks.	Other: Placebo; Placebo infusion

Outcome Measures

Primary Outcome Measures

1. A-a Gradient at End Exercise [after 28 week follow-up. The Alveolar-arterial gradient (A-a gradient), is a measure of the difference between the alveolar partial pressure (A) of oxygen and the arterial (a) partial pressure of oxygen]

   change in end-exercise A-a gradient

Eligibility Criteria

Criteria

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

Inclusion Criteria:

• Ages 18-80.

• Noncaseating granulomas and/or mononuclear cell infiltrates demonstrated on transbronchial lung biopsy.

• Abnormal blood and/or BAL BeLPT results.

• Current treatment with prednisone and/or methotrexate specifically for CBD and not any other condition, at any range of dosage, for at least 6 months prior to enrollment, and on a stable dosage for at least 1 month prior to first infusion.

• Moderate CBD severity, such that participants can safely undergo bronchoscopy with BAL including PaO2 >= 50 mmHg on room air (at Denver altitude of 5,280 ft).

• Availability to come back to National Jewish Medical and Research Center for infusions, evaluations, and follow-ups.

• Capable of providing informed consent.

• Willing and able to adhere to the study visit schedule and other protocol-specified procedures.

Exclusion Criteria:

• Positive tuberculosis (TB) skin test upon screening: An intradermal tuberculin skin test must be performed within 1 month prior to the first administration of study agent.

• Any evidence of TB.

• Considered ineligible according to the TB eligibility assessment, screening, and early detection of reactivation rules.

• Positive pregnancy test.

• Women who are pregnant, nursing, or planning pregnancy within one year after screening

• Contraindications to bronchoscopy and BAL such as bleeding diathesis, PaO2 <50 mmHg on room air, evidence of acute infection, hemodynamic instability with labile blood pressure, either <90/60 or >160/110, untreated coronary artery disease, or other medical reason for which a subject will not be able to safely undergo bronchoscopy.

• Positive cultures from prior BAL indicating mycobacterial or fungal infection.

• Positive special stains for acid fast bacilli (AFB) or fungi on prior lung biopsies.

• Known atypical mycobacterium infection.

• Clinical evidence of active infection at time of enrollment.

• Serious acute infections (e.g., viral hepatitis, pneumonia or pyelonephritis) in the previous 3 months.

• Have or have had an opportunistic infection (e.g., herpes zoster [shingles], cytomegalovirus, Pneumocystis carinii, aspergillosis, histoplasmosis, or mycobacteria other than TB) within 6 months prior to screening.

• Documented HIV infection.

• Positive serology for active hepatitis B or C. A positive result will indicate the need for referral to a consultant Hepatologist for further investigation and support.

• Use of any investigational drug within 1 month prior to screening or within 5 half lives of the investigational agent, whichever is longer.

• Treatment with any other therapeutic agent targeted at reducing TNF-a (e.g. pentoxifylline, thalidomide, etanercept, etc.) within 3 months of screening.

• Prior use of Enbrel® or Humera®.

• Previous administration of infliximab.

• Known allergy to murine (mouse) products.

• Have current signs or symptoms of severe, progressive, or uncontrolled renal, hepatic, hematological, gastrointestinal, endocrine, cardiac, neurologic, or cerebral disease (including demyelinating diseases such as multiple sclerosis).

• Any history of congestive heart failure, severe right sided heart failure, or cor pulmonale.

• Presence of a transplanted organ (with the exception of a corneal transplant > 3 months prior to screening).

• Major surgery in the previous 3 months.

• Malignancy within the past 5 years (except for squamous or basal cell carcinoma of the skin that has been treated with no evidence of recurrence).

• History of lymphoproliferative disease, including lymphoma, or signs and symptoms suggestive of possible lymphoproliferative disease, such as lymphadenopathy of unusual size or location (such as nodes in the posterior triangle of the neck, infraclavicular, epitrochlear, or perioaortic areas), or splenomegaly.

• Known recent substance abuse (drug or alcohol).

• Poor tolerability of venipuncture or lack of adequate venous access for required blood sampling during the study period.

Contacts and Locations

Locations

	Site	City	State	Country	Postal Code
1	National Jewish Health	Denver	Colorado	United States	80401

Sponsors and Collaborators

• Maier, Lisa, M.D.
• Centocor, Inc.
• National Center for Research Resources (NCRR)

Investigators

• Principal Investigator: Lisa A Maier, MD,MSPH, National Jewish Health

Study Documents (Full-Text)

None provided.

More Information

Publications

None provided.

• Responsible Party: Maier, Lisa, M.D.
• ClinicalTrials.gov Identifier: NCT00111917
• Other Study ID Numbers: NJ202; 1UL1RR025780
• First Posted: May 27, 2005
• Last Update Posted: Jun 2, 2016
• Last Verified: Mar 1, 2016

• Keywords provided by Maier, Lisa, M.D.: Chronic Beryllium Disease; Berylliosis; Beryllium Disease; CBD; Infliximab
• Additional relevant MeSH terms: Berylliosis; Infliximab

Study Results

Participant Flow

Recruitment Details	We aimed to enroll 20 CBD subjects on stable doses of corticosteroids and/or methotrexate, with no evidence of active or chronic infection, malignancy, other chronic disease, or past treatment with another biologic with a 3:1 infliximab:placebo ratio
Pre-assignment Detail	the sponsor stopped the study due to slow recruitment

Arm/Group Title	Group 1 - Infliximab	Group 2 - Placebo
Arm/Group Description	This group was given an infusion of inliximab	This group was given a placebo infusion
Period Title: Overall Study
STARTED	9	4
COMPLETED	8	3
NOT COMPLETED	1	1

Baseline Characteristics

Arm/Group Title	Infliximab	Control	Total
Arm/Group Description	patients who will be placed on infliximab and controls who will get placebo	CBD placed on placebo	Total of all reporting groups
Overall Participants	9	4	13
Age (years) [Mean (Full Range) ]
Mean (Full Range) [years]	54.63	69.75	56.5
Sex: Female, Male (Count of Participants)
Female	4 44.4%	1 25%	5 38.5%
Male	5 55.6%	3 75%	8 61.5%

Outcome Measures

1. Post-Hoc Outcome

Title	Absolute Numbers of Lymphocytes
Description	Absolute number of lymphocytes*10^6/cc in blood
Time Frame	after 28 week follow-up

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	Infliximab	Placebo
Arm/Group Description	Infliximab infusion	Placebo infusion
Measure Participants	8	2
Median (Standard Error) [absolute number*10^6/cc]	1.7 (0.18)	1.02 (0.56)

2. Primary Outcome

Title	A-a Gradient at End Exercise
Description	change in end-exercise A-a gradient
Time Frame	after 28 week follow-up. The Alveolar-arterial gradient (A-a gradient), is a measure of the difference between the alveolar partial pressure (A) of oxygen and the arterial (a) partial pressure of oxygen

Outcome Measure Data

Analysis Population Description

Accurate measures were not obtained on all patients at both timepoints.

Arm/Group Title	Infliximab	Placebo
Arm/Group Description	Infliximab infusion	Placebo infusion
Measure Participants	7	2
Median (Standard Error) [mmHg]	27.3 (10.56)	94.17 (18.73)

3. Post-Hoc Outcome

Title	BAL WBC/cc
Description	WBC * 10^6/cc in bronchalveolar lavage
Time Frame	after 28 weeks

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	Infliximab	Placebo
Arm/Group Description	Infliximab received	Placebo received
Measure Participants	5	2
Median (Standard Deviation) [absolute WBC*10^6/cc]	0.23 (0.04)	0.25 (0.03)

4. Post-Hoc Outcome

Title	BAL % Lymphocytes
Description	% of WBCs that are lymphocytes in bronchoalveolar lavage
Time Frame	after 28 week infusion

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	Group 1	Group 2
Arm/Group Description	Infliximab	Placebo received
Measure Participants	5	2
Median (Standard Deviation) [percentage of lymphocytes in BAL]	4.68 (7.84)	14.7 (0)

Adverse Events

Time Frame	through week 40
Adverse Event Reporting Description	adverse events reported through week 40
Arm/Group Title	Group 1 - Infliximab		Group 2 - Placebo
Arm/Group Description	Infliximab infusion received		Placebo infusion received
All Cause Mortality
	Group 1 - Infliximab		Group 2 - Placebo
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	/ (NaN)		/ (NaN)
Serious Adverse Events
	Group 1 - Infliximab		Group 2 - Placebo
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	3/8 (37.5%)		1/3 (33.3%)
Gastrointestinal disorders
Nausea, vomiting	1/8 (12.5%)	1	0/3 (0%)	0
Hepatobiliary disorders
Acute cholecystitis	1/8 (12.5%)	1	0/3 (0%)	0
liver function levels	1/8 (12.5%)	1	0/3 (0%)	0
Renal and urinary disorders
Kidney stone	0/8 (0%)	0	1/3 (33.3%)	1
Other (Not Including Serious) Adverse Events
	Group 1 - Infliximab		Group 2 - Placebo
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	0/8 (0%)		0/3 (0%)

Limitations/Caveats

Although our goal was 20 CBD subjects, only 11 subjects were enrolled, 8:3 in the infliximab:placebo treatment arms as the study was stopped by the sponsor due to slow recruitment.

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.