Ignite Creation Date:
2024-05-05 @ 11:43 AM
Last Modification Date:
2024-10-26 @ 9:12 AM
Study NCT ID:
NCT00111917
Status:
TERMINATED
Last Update Posted:
2016-06-02
First Post:
2005-05-26
Brief Title:
Beryllium Infliximab Study Clinical Interventional Trial
Sponsor:
Maier Lisa MD
Organization:
Maier Lisa MD
Study Overview
Official Title:
Clinical Efficacy of Remicade in Chronic Beryllium Disease A Randomized Double-Blind Placebo-Controlled Investigator Initiated Trial
Status:
TERMINATED
Status Verified Date:
2016-03
Last Known Status:
None
Delayed Posting:
No
If Stopped, Why?:
Not enough patients meeting criteria to enroll in the time period
Has Expanded Access:
False
If Expanded Access, NCT#:
N/A
Has Expanded Access, NCT# Status:
N/A
Acronym:
BISCIT
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
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 andor 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 5mgkg 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 5mgkg compared to placebo in individuals with symptomatic CBD with pulmonary involvement despite prednisone andor 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 31 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 QOLdyspnea 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 Al2SO43 metal-salt control PHA - lymphocyte proliferation control infliximab control infliximab BeSO4 infliximab Al2SO43 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
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 andor 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 5mgkg 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 5mgkg compared to placebo in individuals with symptomatic CBD with pulmonary involvement despite prednisone andor 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 31 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 QOLdyspnea 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 Al2SO43 metal-salt control PHA - lymphocyte proliferation control infliximab control infliximab BeSO4 infliximab Al2SO43 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 Oversight
Has Oversight DMC:
None
Is a FDA Regulated Drug?:
None
Is a FDA Regulated Device?:
None
Is an Unapproved Device?:
None
Is a PPSD?:
None
Is a US Export?:
None
Is an FDA AA801 Violation?:
None
Secondary IDs
| Secondary ID | Type | Domain | Link |
|---|---|---|---|
| 1UL1RR025780 | NIH | None | httpsreporternihgovquickSearch1UL1RR025780 |