Clinical trial NCT00111917: Beryllium Infliximab Study: Clinical Interventional Trial
Official title: Clinical Efficacy of Remicade in Chronic Beryllium Disease: A Randomized, Double-Blind, Placebo-Controlled, Investigator Initiated Trial
Study type: INTERVENTIONAL
Overall status: TERMINATED
Phase: PHASE1
PHASE2
Conditions: Berylliosis
Beryllium Disease
Keywords: Chronic Beryllium Disease
Berylliosis
Beryllium Disease
CBD
Infliximab
Lead sponsor: Maier, Lisa, M.D.
Sponsor class: INDIV
Collaborators: name: Centocor, Inc.
name: National Center for Research Resources (NCRR)
First posted: 2005-05-27
Enrollment: 13
Sex: ALL
Minimum age (years): 18
Maximum age (years): 80
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: PARALLEL
Primary purpose: TREATMENT

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 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.

Eligibility criteria: 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.

Primary outcomes:
measure: A-a Gradient at End Exercise
timeFrame: 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
Secondary outcomes:
Other outcomes:
Locations:
city: Denver
country: United States
facility: National Jewish Health
state: Colorado
Study officials:
affiliation: National Jewish Health
name: Lisa A Maier, MD,MSPH
role: PRINCIPAL_INVESTIGATOR
References:
citation: Maier LA, Barkes BQ, Mroz M, Rossman MD, Barnard J, Gillespie M, Martin A, Mack DG, Silveira L, Sawyer RT, Newman LS, Fontenot AP. Infliximab therapy modulates an antigen-specific immune response in chronic beryllium disease. Respir Med. 2012 Dec;106(12):1810-3. doi: 10.1016/j.rmed.2012.08.014. Epub 2012 Sep 11. No abstract available.