Clinical Efficacy of Remicade in Chronic Beryllium Disease: A Randomized, Double-Blind, Placebo-Controlled, Investigator Initiated Trial
试验速览
- 阶段
- 1 期
- 状态
- 终止
- 发起方
- 入组人数
- 13
- 试验地点
- 1
- 主要终点
- A-a Gradient at End Exercise
研究概览
简要总结
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.
详细描述
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.
研究设计
- 研究类型
- Interventional
- 分配方式
- Randomized
- 干预模型
- Parallel
- 主要目的
- Treatment
- 盲法
- Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor)
入排标准
- 年龄范围
- 18 Years 至 80 Years（Adult, Older Adult）
- 性别
- All
- 接受健康志愿者
- 否
入选标准
- •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.
排除标准
- •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.
研究组 & 干预措施
Infliximab
infusion: 3:1 infliximab:placebo ratio administered at 0, 2, 6, 12, 18 and 24 weeks.
干预措施: Infliximab (Drug)
Placebo
infusion: 3:1 infliximab:placebo ratio administered at 0, 2, 6, 12, 18 and 24 weeks.
干预措施: Placebo (Other)
结局指标
主要结局
A-a Gradient at End Exercise
时间窗: 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
change in end-exercise A-a gradient
次要结局
未报告次要终点