Mepolizumab Pharmacokinetics Among Patients With Severe Asthma: Protocol for a Case Control Study Comparing Clinical Responders Versus Non Responders
试验速览
- 阶段
- 不适用
- 状态
- 已完成
- 入组人数
- 50
- 试验地点
- 4
- 主要终点
- Change in Mepolizumab serum concentration
研究概览
简要总结
Asthma is a chronic disease characterized by inflammation and obstruction of the airways. Identification of the mechanisms of action of corticosteroids has made it possible to define the type 2 inflammation present in nearly 80% of patients with asthma.
Monoclonal antibodies (MAb) in severe asthma target type-2 inflammation. Mepolizumab is a humanized IgG1 (immunoglobulin gamma-1) kappa subclass monoclonal antibody directed specifically against interleukin 5 (IL-5). It acts specifically on eosinophil homeostasis, with IL-5 being a key interleukin in eosinophil maturation.
The investigators propose to measure the concentrations of mepolizumab in the serum of asthmatic patients treated with this mAb. The investigators hypothesize that the individual pharmacokinetics (PK) of mepolizumab may differ between clinical responders and non-responders.
详细描述
Asthma is a chronic disease characterized by inflammation and obstruction of the airways. Understanding the biological effects of the corticosteroids allowed to identify and to define the type 2 inflammation present in nearly 80% of patients with asthma.
Monoclonal antibodies (MAb) in severe asthma target type-2 inflammation. Mepolizumab is a humanized IgG1 kappa subclass monoclonal antibody directed specifically against interleukin 5 (IL-5). It acts specifically on eosinophil homeostasis, since IL-5 is a key interleukin in eosinophil maturation.
Poor MAb responses can hypothetically arise in situations of poor treatment compliance. And after excluding the latter, several biological mechanisms have been mentioned: i) insufficient bioavailability of the MAb to reach the eosinophils of the bronchial compartment; ii) he development of autoimmunity with the formation of circulating immune complexes; and iii) immunization against mepolizumab, with the formation of neutralizing anti-drug antibodies (ADA).
ADA were detected in up to 20% of a treated population and were rarely neutralizing.
Interestingly, these ADA could also be detected in naïve populations, suggesting a possible cross-immunization related to previous exposure to MAbs and/or to insufficient assay specificity. In any case, all three possibilities have a common outcome, i.e. decreased circulating concentrations of the MAb in the blood.
研究设计
- 研究类型
- Interventional
- 分配方式
- Na
- 干预模型
- Single Group
- 主要目的
- Other
- 盲法
- None
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
- •Minimum age: 18 years old
- •History of severe asthma diagnosed by a physician (according to Global Initiative for Asthma (GINA) criteria)
- •Subject on a combination of high-dose (ICS equivalent to 1000 μg beclomethasone) and medium dose inhaled corticosteroid and long acting beta-agonists at least 12 months before inclusion
- •Treatment with mepolizumab in line with the Marketing Authorization
- •Having received at least 6 doses of mepolizumab (monthly subcutaneous administration)
- •Documented initial clinical response to mepolizumab
排除标准
- •Other respiratory diseases
- •Potential interference from another study
- •Immunosuppressive treatment (i.e methotrexate, polyvalent immunoglobulins, other monoclonal antibody for other condition such as cancer; oral and/or inhaled corticosteroids are allowed)
- •Populations protected according to the French public health code
- •Patient is unavailable, unable or unwilling to attend future visits
- •Non-beneficiary of the French national health insurance system
- •Lack of informed consent
结局指标
主要结局
Change in Mepolizumab serum concentration
时间窗: 1 month
The primary outcome is the change in trough concentration of mepolizumab in serum at 1-month post-enrolment. Mepolizumab serum concentration will be determine by ELISA
次要结局
- Comparison of asthma control by ACQ-6 score(6 months)
- Comparison of exacerbation rate(6 months)
- Number of days alive and not exacerbating(6 months)
- Comparison of change in oral corticosteroid(6 months)
- Complete blood cell count at 1 month(1 month)
- Presence/absence of a >50% reduction in exacerbation rate(6 months)
- Complete blood cell count at 6 months(6 months)
- Mepolizumab serum concentration(6 months)
- Presence/absence of monoclonal antibody switching(6 months)
- Comparison of lung function by airway obstruction(6 months)
- Comparison of chronic rhinosinusitis by SNOT-22 score(6 months)