Berylliosis Clinical Trial
Official title:
Clinical Efficacy of Remicade in Chronic Beryllium Disease: A Randomized, Double-Blind, Placebo-Controlled, Investigator Initiated Trial
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.
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.
;
Allocation: Randomized, Endpoint Classification: Efficacy Study, Intervention Model: Parallel Assignment, Masking: Double Blind (Subject, Caregiver, Investigator, Outcomes Assessor), Primary Purpose: Treatment
| Status | Clinical Trial | Phase | |
|---|---|---|---|
| Completed |
NCT00560989 -
Identifying Shared Genetic Susceptibility Regions in Chronic Beryllium Disease and Sarcoidosis
|
N/A |