Airway Remodeling Changes Induced by Mepolizumab in Severe Eosinophil Asthma
试验速览
- 阶段
- 不适用
- 状态
- 已完成
- 入组人数
- 37
- 试验地点
- 1
- 主要终点
- Changes in reticular basement membrane (RBM) thickening
研究概览
简要总结
Chronic airway changes, such as smooth muscle hypertrophy/hyperplasia, reticular basement membrane (RBM) thickening, goblet cells hyperplasia characterize severe asthma. Chronic inflammation, and especially eosinophilia and T2 cytokines are involved in these structural changes. The aim of this prospective observational study is to assess airway changes, assessed by bronchial biopsies before treatment, then after 6 months and 12 months, induced by mepolizumab in 40 severe asthma patients who will receive the treatment as part of their standard care. Changes in RBM thickening, in airway smooth muscle (ASM) area, in the number of PGP9 sections will be assessed on bronchial biopsies after 6 months and 12 months of mepolizumab treatment. Bronchoalveolar lavage (BAL) levels of inflammatory and remodeling mediators and of extra-cellular matrix (ECM) components will be measured after 6 months and 12 months of mepolizumab treatment. Relationship between clinical response to mepolizumab and remodeling changes after 6 months and 12 months will be assessed.
详细描述
- Scientific Rationale & Hypothesis:
Chronic airway changes, such as smooth muscle hypertrophy/hyperplasia, reticular basement membrane thickening, goblet cells hyperplasia characterize severe asthma. Chronic inflammation, and especially eosinophilia and T2 cytokines are involved in these structural changes. Increased ASM layer has been associated with eosinophilia for example, but not RBM thickening, suggesting that differential patterns of remodeling can be observed according to inflammatory patterns. Omalizumab, an anti IgE therapy, can reduce some features of airway remodeling, especially RBM and some parameters related to ASM. No data are available on potential changes in airway remodeling induced by mepolizumab.
The aim of the study is to assess airway changes, assessed by bronchial biopsies, induced by mepolizumab in severe asthma patients who will receive the treatment as part of their standard care.
All asthma patients refered to the asthma clinic are proposed to participate to the COBRA cohort (French national asthma cohort). Serum and DNA are collected at inclusion and every 6 months. Fiberoptic bronchoscopy (FOB) is routinely performed as part of the standard care for difficult-to-severe asthma in our centre for many years, to assess differential diagnosis and inflammatory pattern since Fractional exhaled nitric oxide (FeNO) is not routinely performed in France. BAL and 4 to 6 bronchial biopsies are performed. 2. Study Population:
Severe asthma patients, refered to Severe Asthma Centre in Bichat and Bicetre Hospitals, receiving mepolizumab according to French recommendations (eos >300mm3 in the previous year, >2 exacerbations, despite optimal step 4-5 therapy, including daily use of steroids). 3. Study Design & Methods:
研究设计
- 研究类型
- Observational
- 观察模型
- Cohort
- 时间视角
- Prospective
入排标准
- 年龄范围
- 18 Years 至 —（Adult, Older Adult）
- 性别
- All
- 接受健康志愿者
- 否
入选标准
- 未提供
排除标准
- 未提供
结局指标
主要结局
Changes in reticular basement membrane (RBM) thickening
时间窗: 0, 6 and 12 months
The absolute variation in RBM thickening (µm, morphometry measurement on bronchial biopsies) over 12 months is defined as the difference between month twelve and baseline (V1). The absolute variation in RBM thickening over 6 months is defined as the difference between month six and baseline (V1).
Number of nerve endings
时间窗: 0, 6 and 12 months
Evaluated by PGP9 and expressed as number of positive cells per biopsy surface in mm2
Number of inflammatory cells in the BAL
时间窗: 0, 6 and 12 months
Number of inflammatory cells (neutrophils, lymphocytes and eosinophils) expressed as % of total cells in the BAL
Number of vascular sections
时间窗: 0, 6 and 12 months
Measured with an anti-CD31 antibody, expressed in number of sections per mm2.
Changes in airway smooth muscle (ASM) area
时间窗: 0, 6 and 12 months
Measured in morphometry in µm2 and expressed as a percentage of smooth muscle surface area relative to the biopsy surface. The absolute variation in ASM area over 12 months is defined as the difference between month twelve and baseline (V1). The absolute variation in ASM area over 6 months is defined as the difference between month six and baseline (V1).
Number of infiltrating inflammatory cells in the biopsies
时间窗: 0, 6 and 12 months
Number of infiltrating inflammatory cells (infiltrating neutrophils, lymphocytes and eosinophils) expressed as number of positive cells per biopsy surface in mm2
Proportion of eosinophils expressing MBP/IL3R
时间窗: 0, 6 and 12 months
Measured on bronchial biopsies, expressed as number of cells per biopsy surface in mm2
Number of proliferating muscle cells
时间窗: 0, 6 and 12 months
Evaluated by anti proliferating cell nuclear antigen (PCNA) antibodies, expressed as the number of positive cells per muscle surface.
次要结局
- Periostin concentration(0, 6 and 12 months)
- IL-17A concentration(0, 6 and 12 months)
- Tenascin concentration(0, 6 and 12 months)
- Forced expiratory volume (FEV1)(0, 6 and 12 months)
- IL-22 concentration(0, 6 and 12 months)
- IL-13 concentration(0, 6 and 12 months)
- Thymic Stromal Lymphopoietin (TSLP) concentration(0, 6 and 12 months)
- Fibulin-1 concentration(0, 6 and 12 months)
- EGF concentration(0, 6 and 12 months)
- PDGF-BB concentration(0, 6 and 12 months)
- Fibronectin concentration(0, 6 and 12 months)
- Interferon-gamma concentration(0, 6 and 12 months)
- IL-33 concentration(0, 6 and 12 months)
- bFGF concentration(0, 6 and 12 months)
- Proportion of patients with pre-bronchodilator FEV1 greater than 80%(6 and 12 months)
- Monocyte chemoattractant protein-1 (CCL/MCP-1) concentration(0, 6 and 12 months)
- Total score at Asthma Control Test(0, 6 and 12 months)
- Global evaluation of mepolizumab benefit(6 and 12 months)
- Proportion of patients with an increase from baseline in pre-bronchodilator FEV1 greater than 20%(6 and 12 months)
- Forced expiratory volume/Vital capacity (FEV1/VC)(0, 6 and 12 months)
- Total lung capacity (TLC)(0, 6 and 12 months)
- Residual volume (RV)(0, 6 and 12 months)