Clinical Efficacy of Remicade in Chronic Beryllium Disease: A Randomized, Double-Blind, Placebo-Controlled, Investigator Initiated Trial
18 Years
80 Years
Both
Berylliosis, Beryllium Disease
Trial Information
Clinical Efficacy of Remicade in Chronic Beryllium Disease: A Randomized, Double-Blind, Placebo-Controlled, Investigator Initiated Trial
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.
Inclusion Criteria:
- Adults 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.
Type of Study:
Interventional
Study Design:
Allocation: Randomized, Endpoint Classification: Efficacy Study, Masking: Double Blind (Subject, Caregiver, Investigator, Outcomes Assessor), Primary Purpose: Treatment
Outcome Measure:
arterial alveolar oxygen gradient (A-adO2) at end exercise
Outcome Time Frame:
between baseline and week 28
Safety Issue:
No
Principal Investigator
Lisa A Maier, MD,MSPH
Investigator Role:
Principal Investigator
Investigator Affiliation:
National Jewish Health
Authority:
United States: Food and Drug Administration
Study ID:
NJ202
NCT ID:
NCT00111917
Start Date:
February 2005
Completion Date:
January 2009
Related Keywords:
- Berylliosis
- Beryllium Disease
- Chronic Beryllium Disease
- Berylliosis
- Beryllium Disease
- CBD
- Infliximab
- Berylliosis
Name | Location |
|---|---|
| National Jewish Medical and Research Center | Denver, Colorado 80401 |
