A Two-arm, Placebo-controlled, Randomized Clinical Trial to Evaluate the Effect of Tezepelumab on Airway Structure and Function in Patients With Uncontrolled Moderate-to-severe Asthma
试验速览
- 阶段
- 3 期
- 状态
- 已完成
- 入组人数
- 27
- 试验地点
- 1
- 主要终点
- Change in pre-bronchodilator 129Xe MRI ventilation defect percent (VDP).
研究概览
简要总结
In adult patients with uncontrolled moderate-to-severe asthma, blocking TSLP with tezepelumab will improve ventilation heterogeneity (evaluated by hyperpolarized 129Xe MRI), and this will be associated with reduced airway inflammation (evaluated by sputum composition), luminal narrowing and plugging (evaluated by CT).
详细描述
The luminal obstruction in asthma that contributes to symptoms is due to inflammatory cells (usually eosinophils or neutrophils), mucus, smooth muscle constriction, airway wall thickness, or a combination of the above. This obstruction can be regionally visualized and quantified by computed tomography (CT), and its functional consequence can be assessed at high resolution using inhaled hyperpolarized 129Xe gas magnetic resonance imaging (MRI). Thymic stromal lymphopoietin (TSLP), an epithelial cell derived cytokine that is produced in response to environmental and proinflammatory stimuli, may contribute to all of these features of asthma through its downstream effects on a wide variety of immune (e.g. eosinophils, mast cells, group 2 innate lymphoid cells (ILC2s), Th2 cell, and Th17 cells) and structural cells (e.g. smooth muscle cells, and fibroblasts). Of note, TSLP is believed to upregulate multiple downstream inflammatory pathways, including IL-4, IL-5 and IL-13 signalling. It is also believed to mediate structural mechanisms that contribute to airway remodelling and smooth muscle dysfunction.
The consequence of blocking TSLP with tezepelumab on airway structure and function has not been investigated. This study will use CT to quantify airway wall and lumen structure according to previously described methods. CT images will also be evaluated for intraluminal plugging and a visual mucus score will be generated. Ventilation heterogeneity in asthmatics, the functional consequence of luminal obstruction, can be regionally measured with high temporal and spatial resolution using inhaled hyperpolarized gas MRI. In asthmatics, focal ventilation defects are observed and these have been shown to be spatially related to airway abnormalities and to respond to bronchoconstriction, bronchodilation, and anti-T2 biologics.
Due to the potential effect of tezepelumab on luminal inflammation, smooth muscle dysfunction and mucus hypersecretion, it is believed that MRI-detectable improvements in ventilation heterogeneity will be observed in asthmatics.
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 —（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) 2021 guidelines.
- •ACQ ≥1.5 at screening.
- •Methacholine PC20 ≤ 4 mg/mL OR ≥15% decrease in FEV1 during saline inhalation for sputum induction OR ≥15% improvement in FEV1 after bronchodilator during the screening period.
- •Criteria met for moderate or severe asthma defined by GINA 2021 guidelines, i.e. treatment with low, medium or high dose ICS (<250 mcg, 251 - 500 mcg, >500 mcg of fluticasone equivalent/day respectively) plus another controller. Patients on prednisone would not be excluded, as long as they meet the rest of the inclusion criteria.
- •FeNO >25 ppb OR ≥3% sputum eosinophils (preferred) OR blood eos ≥300/µL during the screening period.
- •History of ≥1 exacerbation in the previous year.
排除标准
- •-- Participation in any clinical trial of an investigational agent or procedure within six months prior to screening or during the study.
- •Medical conditions and treatment history
- •History of anaphylaxis to any previous biologic therapy received.
- •Receipt of live attenuated vaccine within 30 days, receipt of COVID vaccine within 28 days, known or suspected COVID infection at the time of enrollment.
- •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.
- •Pregnancy.
- •Treatment with anti-IgE, anti-IL-4, anti-IL-5, or anti-IL-13 targeted therapy currently or within three months prior to screening.
- •MRI-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.
研究组 & 干预措施
Tezepelumab
Tezepelumab 210 mg subcutaneous injections every 4 weeks as an investigational drug.
Sterile tezepelumab will be provided 110 mg/mL pre-filled vial, with a dose of 210 mg delivered by pre-filled syringe.
干预措施: Tezepelumab (Biological)
Matched placebo
Sterile placebo for tezepelumab will be provided in identically matched pre-filled syringes.
干预措施: Placebo (Biological)
结局指标
主要结局
Change in pre-bronchodilator 129Xe MRI ventilation defect percent (VDP).
时间窗: 16 weeks from randomization (week 0) to endpoint assessment (week 16)
Change from baseline to week 16 in the pre-bronchodilator 129Xe MRI ventilation defect percent (VDP).
次要结局
- Change in the CT mucus score (i.e. intraluminal plugging).(From baseline (week 0) to endpoint (week 16))
- Change in the CT airway lumen area.(From baseline (week 0) to endpoint (week 16))
- Change in the CT airway wall area percentage.(From baseline (week 0) to endpoint (week 16))
- Change in the CT total airway count.(From baseline (week 0) to endpoint (week 16))
- Change in the CT airway wall area.(From baseline (week 0) to endpoint (week 16))
- Change in the CT gas trapping.(From baseline (week 0) to endpoint (week 16))
- Change in the post-bronchodilator reversibility of 129Xe MRI VDP.(From baseline (week 0) to endpoint (week 16))
- Change in the post-bronchodilator 129Xe MRI ventilation defect percent (VDP).(From baseline (week 0) to endpoint (week 16))