Beryllium Infliximab Study: Clinical Interventional Trial (BISCIT)
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.
|Study Design:||Allocation: Randomized
Endpoint Classification: Efficacy Study
Masking: Double Blind (Subject, Caregiver, 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|
- arterial alveolar oxygen gradient (A-adO2) at end exercise [ Time Frame: between baseline and week 28 ] [ Designated as safety issue: No ]
- airflow [ Time Frame: between baseline and week 28 ] [ Designated as safety issue: No ]
- lung volume [ Time Frame: between baseline and week 28 ] [ Designated as safety issue: No ]
- diffusing capacity (DLCO) [ Time Frame: between baseline and week 28 ] [ Designated as safety issue: No ]
- profusion of small opacities on chest x-ray [ Time Frame: between baseline and week 28 ] [ Designated as safety issue: No ]
- dyspnea score [ Time Frame: between baseline and week 28 ] [ Designated as safety issue: No ]
- quality of life (QOL) questionnaires [ Time Frame: between baseline and week 28 ] [ Designated as safety issue: No ]
|Study Start Date:||February 2005|
|Study Completion Date:||January 2009|
|Primary Completion Date:||January 2009 (Final data collection date for primary outcome measure)|
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 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.
|United States, Colorado|
|National Jewish Medical and Research Center|
|Denver, Colorado, United States, 80401|
|Principal Investigator:||Lisa A Maier, MD,MSPH||National Jewish Health|