A Two-arm, Placebo-controlled Randomized Clinical Trial to Evaluate the Effect of Dupilumab on Airway Hyper-responsiveness and Ventilation Heterogeneity in Patients With Asthma With a "T2 Immune Signature"
试验速览
- 阶段
- 3 期
- 状态
- 已完成
- 入组人数
- 24
- 试验地点
- 2
- 主要终点
- Proportion of patients that achieve at least one doubling dose improvement in PC20 methacholine and/or a 50% reduction in FEV1 reversibility after bronchodilator.
研究概览
简要总结
In asthmatics with airway hyperresponsiveness and a "T2 immune signature" (type 2), Dupilumab will suppress airway hyperresponsiveness (assessed by methacholine PC20 ≤ 4 mg/mL (PC20: provocative concentration causing a 20% fall in FEV1) OR ≥15% decreased in forced expired volume in 1 second (FEV1) during saline inhalation for sputum induction OR ≥25% improvement in FEV1 after bronchodilator) and airway eosinophilia (assessed by sputum eosinophils) and this will be associated with greater asthma control and improved ventilation heterogeneity.
详细描述
Along with these features of eosinophil recruitment, degranulation and autoantibody generation, that are partly dependent on (interleukin-4) IL-4 and (interleukin-13) IL-13 signalling, two additional characteristic features of asthma ie airway hyperresponsiveness and mucus hypersecretion are also determined by IL-13 biology. Neither of these important features have been investigated in any clinical trials of anti-IL-13 molecules. Accurate endotyping to identify patients in whom IL-13 mediated biology is the dominant pathobiology of asthma (selecting patients with significant airway hyperresponsiveness and mucus secretion) may elicit greater clinical effect. Taken together, we propose to investigate the effects of Dupilumab on airway hyperresponsiveness, on airway eosinophilia and mucus biology and their relation to airway structure and function (ventilation heterogeneity), and airway autoimmune responses.
To satisfy the proposed objective we will evaluate well-established outcome measures of airway hyperresponsiveness (provocation concentration of methacholine causing a 20% fall in FEV1 (PC20), type 2 inflammation (sputum eosinophils, blood eosinophils and exhaled nitric oxide (eNO)) and mucus biology.
研究设计
- 研究类型
- Interventional
- 分配方式
- Randomized
- 干预模型
- Single Group
- 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 —（Adult, Older Adult）
- 性别
- All
- 接受健康志愿者
- 否
入选标准
- •Able and willing to provide written informed consent.
- •Able and willing to comply with the study protocol.
- •Males and females ≥ 18 years of age.
- •Asthma-related
- •Asthma diagnosed by a respiratory physician ≥ 12 months prior to study enrolment based on the Global Initiative for Asthma (GINA) 2014 guidelines.
- •ACQ > 1 during the screening period.
- •Airway hyperresponsiveness (methacholine PC20 ≤ 4 mg/mL OR ≥15% decreased in FEV1 during saline inhalation for sputum induction OR ≥25% improvement in FEV1 after bronchodilator) during the screening period.
- •Fraction of exhaled nitric oxide (FeNO) >25 ppb and either ≥3% sputum eosinophils (preferred) OR blood eos ≥300/µL during the screening period.
- •Inhaled corticosteroids (ICS) dose ≥500 mcg of fluticasone equivalent/day. Patients on prednisone would not be excluded as long as they meet the rest of the inclusion criteria.
排除标准
- •Patients who meet any of the following criteria will be excluded from study entry:
- •Prior Medical Conditions and Treatment History
- •Acute or chronic parasitic, bacterial, fungal or viral infections that required, or currently requires, hospitalization or antimicrobial treatment during the last four weeks.
- •Acute asthma exacerbation event treated with increased doses of oral, or any dose of intramuscular (IM) or intravenous (IV) corticosteroids within six weeks prior to screening.
- •Other relevant pulmonary diseases (e.g. chronic obstructive pulmonary disease, idiopathic pulmonary fibrosis, cystic fibrosis, pulmonary arterial hypertension, tuberculosis) requiring treatment within 12 months prior to screening.
- •Alcohol or substance abuse within 12 months prior to screening.
- •Current smoker defined as having smoked at least one cigarette (or pipe, cigar, or marijuana) per day for ≥ 30 days within the three months prior to screening.
- •Ex-smokers with ≥ 10 pack-year smoking history.
- •Treatment with anti-IgE (immunoglobulin E), anti-IL-4, anti-IL-5 (interleukin-5), or anti-IL-13 targeted therapy currently or within three months prior to screening.
- •MRI (Magnetic Resonance Imaging )Related
- •Patient has an implanted mechanically, electrically or magnetically activated device or any metal in their body which cannot be removed, including but not limited to pacemakers, neurostimulators, biostimulators, implanted insulin pumps, aneurysm clips, bioprosthesis, artificial limb, metallic fragment or foreign body, shunt, surgical staples (including clips or metallic sutures and/or ear implants) (at the discretion of the MRI Technologist).
- •In the investigator's opinion, subject suffers from any physical, psychological or other condition(s) that might prevent performance of the MRI, such as severe claustrophobia.
- •Participation in any clinical trial of an investigational agent or procedure within six months prior to screening or during the study.
结局指标
主要结局
Proportion of patients that achieve at least one doubling dose improvement in PC20 methacholine and/or a 50% reduction in FEV1 reversibility after bronchodilator.
时间窗: Between screening (week -4) and week 16.
For patients that can undergo a methacholine challenge, one doubling dose improvement in PC20 methacholine. For those that cannot undergo a methacholine challenge a 50% reduction in FEV1 reversibility.
次要结局
- Change in FEV1 (pre-bronchodilator)(Between randomization (week 0) and week 16.)
- Change in geometric mean PC20 methacholine.(Between screening (week -4) and week 16.)
- Change in FEV1 reversibility.(Between randomization (week 0) and week 16.)
- Change in sputum eosinophil percentage (%)(Between randomization (week 0) and week 16.)
- Change in blood eosinophil count(Between randomization (week 0) and week 16.)
- Change in Asthma Control Questionnaire-5 (ACQ-5)(Between randomization (week 0) and week 16.)
- Change in Asthma Control Questionnaire-5 (AQLQ)(Between randomization (week 0) and week 16.)
- Change in Asthma Control Test (ACT)(Between randomization (week 0) and week 16.)
- Change in fraction of exhaled nitric oxide (FeNO)(Between randomization (week 0) and week 16.)