REVErsing Airway Remodelling With Tezepelumab : a Protocol for a Double-blind Randomized Controlled Trial for Patients With Asthma
试验速览
- 阶段
- 3 期
- 状态
- 已完成
- 入组人数
- 90
- 试验地点
- 22
- 主要终点
- Comparaison on CT-scan in the change in mean percentage bronchial wall area (%WA) at the B1 and B8 bronchi, generations 3, 4 and 5
研究概览
简要总结
The aim of this protocol is to perform a first randomized controlled trial evaluating how Tezepelumab affects the bronchial morphology (and computed tomographic variables in general) of asthmatic patients. In parallel, the investigators also hope to reproduce clinical benefits and perform a transcriptomic study that will juxtapose changes in genetic expression with changes in bronchial morphology and inflammatory signatures. The general hypothesis is that tezepelumab treatment is capable of at least partially reversing bronchial remodelling as detected on computed-tomographic (CT) scans. The investigators also expect such reversal to occur within a unique physiological repair environment that will be reflected by transcriptomic profiles
详细描述
Tezepelumab is a human IgG2l monoclonal antibody (mAb) directed against TSLP. Double-blind, randomized controlled trials comparing Tezepelumab treatment against placebo demonstrate net positive benefits in asthma patients. Animal research currently indicates that blocking TSLP can prevent bronchial remodelling in murine models (Chen et al. 2013), but no such observations have been attempted in humans. Within this context, the aim of this protocol is to perform a first randomized controlled trial evaluating how Tezepelumab affects the bronchial morphology (and computed tomographic variables in general) of asthmatic patients. In parallel, the investigators also hope to reproduce clinical benefits and perform a transcriptomic study that will juxtapose changes in genetic expression with changes in bronchial morphology and inflammatory signatures.
The general hypothesis is that tezepelumab treatment is capable of at least partially reversing bronchial remodelling as detected on computed-tomographic (CT) scans. The investigators also expect such reversal to occur within a unique physiological repair environment that will be reflected by transcriptomic profiles.
The primary objective of this protocol is therefore to compare the change-from-baseline in the average percentage bronchial wall area (%WA = (wall area (mm2)/ (wall area (mm2) + lumen area (mm2)))×100) for patients with asthma and undergoing 6 months of tezepelumab treatment with a similar population treated via placebo. Secondarily, continued treatment effects associated with longer treatment (12 months) or remanence after treatment stopping at 6 months will also be quantified. Study arms will additionally be compared in terms of:
- Changes in radiomics (CT-scan data);
- Changes in exacerbation rates and lung function;
- Changes in serum club cell secretory protein (CCSP);
- Changes in nasal single-cell transcriptomic signatures.
This study also has an exploratory component designed to characterize the physiological repair environment. In depth radiomic and transcriptomic (including single-cell analyses) profiling will be performed. Finally, the capacity of baseline data to predict the response to tezepelumab will also be explored.
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
- Triple (Participant, Investigator, Outcomes Assessor)
入排标准
- 年龄范围
- 18 Years 至 85 Years（Adult, Older Adult）
- 性别
- All
- 接受健康志愿者
- 否
入选标准
- •Admitted to screening visit:
- •Minimum age: 18
- •Maximum age: 85
- •Able to perform an inspiratory and expiratory thoracic computed tomography (CT) scan, plus a nasal CT
- •In stable condition for CT scan
- •Physician-diagnosed asthma according to GINA criteria
- •Disease with clinical impact: at least 1 severe or 2 moderate exacerbations in the previous 12 months despite treatment according to the best standards of care
- •Maximal inhaled therapy comprising high dose ICS and at least a second controller according to GINA
- •Based on results of screening visit and run-in:
- •Post-bronchodilator forced expiratory volume in 1 second (FEV1) predicted values must be at 25-90%
- •Asthma Control Questionnaire 6 (ACQ6) > 1.5
- •Oral corticosteroid maintenance therapy (if used) ≤7.5 mg/day
- •On CT scan, the average percentage wall area index at the B1 and B8 bronchi (generation 3, 4, 5) is >65%
排除标准
- •CT abnormalities evocative of any respiratory condition other than asthma
- •Treatment regimen discordant with best practices
- •Pulmonary disease other than asthma requiring treatment during the previous 12 months
- •A smoking history of >20 pack years
- •Receipt of any marketed or investigational biologic agent§ within 3 months or 5 halflives (whichever is longer) prior to randomization or receipt of any investigational non biologic agent within 30 days or 5 half-lives (whichever is longest) prior to randomization or receipt of live attenuated vaccines 30 days prior to the date of randomization. Participants enrolled in current or previous tezepelumab studies will not be included. Participants on previous biologics treatment are allowed to enter the study provided the appropriate washout period is fulfilled.
- •Absence of signed consent
- •Non-beneficiary of the French social security, single-payer health insurance system
- •Presence of any condition (physical, psychological or other) that might, in the investigator's opinion, hinder study performance
- •The patient is unavailable or unwilling to participate in future visits
- •Potential interference from other studies
- •Protected populations according to the French public health code
- •Male or female patients seeking to conceive a child
- •Women of childbearing potential and fertile men not using birth control method
- •Pregnant, breastfeeding or lactating women
- •History of a clinically significant infection, including upper (URTI) or lower respiratory tract infection (LRTI), requiring treatment with antibiotics or antiviral medications finalised < 2 weeks before randomization. Patients with preexisting serious infections should be treated before initiating therapy with tezepelumab.
- •A helminth parasitic infection diagnosed within 6 months prior to Visit 1 that has not been treated with, or has failed to respond to, standard of care therapy.
- •Patients using vaping products, including electronic cigarettes (because may induce abnormality at CT scan).
- •Bronchial thermoplasty in the last 12 months prior to Visit
- •History of documented immune complex disease (Type III hypersensitivity reactions) following any biologic therapy.
- •History of known immunodeficiency disorder including a positive human immunodeficiency virus test or the participant taking antiretroviral medications as determined by medical history and/or participant's verbal report.
- •Receipt of the T2 cytokine inhibitor Suplatast tosilate within 15 days prior to randomization.
- •Treatment with systemic immunosuppressive/immunomodulating drugs (eg, methotrexate, cyclosporine, etc.), except for OCS used in the treatment of asthma/asthma exacerbations, within the last 12 weeks or 5 half-lives (whichever is longer) prior to randomization.
- •Receipt of immunoglobulin or blood products within 30 days prior to randomization.
- •Receipt of allergen immunotherapy not stable within 30 days prior to randomization or with anticipated change during the treatment period.
研究组 & 干预措施
Placebo / Tezepelumab
After 6-months of treatment, patients initially receiving placebo will switch to Tezepelumab for an additional 6 months.
For 6 months of treatment, six subcutaneous (injections in accessorized pre-filled syringes (APFS)) are performed every 4 weeks. Each subcutaneous injection corresponds to 210 mg of Tezepelumab or analogous placebo.
干预措施: placebo (Other)
Tezepelumab / Placebo
After 6-months of treatment, patients receiving Tezepelumab will be switched to a placebo for an additional 6 months.
For 6 months of treatment, six subcutaneous (injections in accessorized pre-filled syringes (APFS)) are performed every 4 weeks. Each subcutaneous injection corresponds to 210 mg of Tezepelumab or analogous placebo.
干预措施: placebo (Other)
Tezepelumab / Placebo
After 6-months of treatment, patients receiving Tezepelumab will be switched to a placebo for an additional 6 months.
For 6 months of treatment, six subcutaneous (injections in accessorized pre-filled syringes (APFS)) are performed every 4 weeks. Each subcutaneous injection corresponds to 210 mg of Tezepelumab or analogous placebo.
干预措施: Tezepelumab (Drug)
Placebo / Tezepelumab
After 6-months of treatment, patients initially receiving placebo will switch to Tezepelumab for an additional 6 months.
For 6 months of treatment, six subcutaneous (injections in accessorized pre-filled syringes (APFS)) are performed every 4 weeks. Each subcutaneous injection corresponds to 210 mg of Tezepelumab or analogous placebo.
干预措施: Tezepelumab (Drug)
Tezepelumab / Tezepelumab
After 6-months of treatment, patients receiving Tezepelumab will continue Tezepelumab for an additional 6 months. For 6 months of treatment, six subcutaneous (injections in accessorized pre-filled syringes (APFS)) are performed every 4 weeks.Each subcutaneous injection corresponds to 210 mg of Tezepelumab.
干预措施: Tezepelumab (Drug)
结局指标
主要结局
Comparaison on CT-scan in the change in mean percentage bronchial wall area (%WA) at the B1 and B8 bronchi, generations 3, 4 and 5
时间窗: Between baseline and 6 months
%WA = (wall area (mm²)/ (wall area (mm²) + lumen area (mm²)))×100) at bronchial levels likely to be affected.
次要结局
- Change in Total small Airway Count (TAC)(Between Baseline and 12 months)
- Change in forced vital capacity(Between Baseline and 12 months)
- compare on CT-scan the change in lumen circularity at the B1 and B8 bronchi, generations 3, 4 and 5(Between baseline and 6 months)
- Change in ECRHS III Main Questionnaire(Between Baseline and 12 months)
- Changes in serum Club cell secretory protein (CCSP)(Between baseline and 12 months)
- compare on CT-scan the change in mean %WA between arms(Between baseline and 12 months)
- Comparaison on CT-scan in the average percentage bronchia wall thickness index (%WT) at the B1 and B8 bronchi, generations 3, 4 and 5(Between baseline and 12 months)
- compare on CT-scan the change in wall area at the B1 and B8 bronchi, generations 3, 4 and 5(Between baseline and 6 months)
- compare on CT-scan the change in lumen area at the B1 and B8 bronchi, generations 3, 4 and 5(Between baseline and 6 months)
- compare on CT-scan the change in ratio wall area (WA) / lumen area(LM) at the B1 and B8 bronchi, generations 3, 4 and 5(Between baseline and 6 months)
- compare on CT-scan the change in lumen diameter at the B1 and B8 bronchi, generations 3, 4 and 5(Between baseline and 6 months)
- Comparaison on CT-scan in the average percentage bronchial wall area(%WA) corrected by body surface area(BSA) at the B1 and B8 bronchi, generations 3, 4 and 5(Between baseline and 6 months)
- Change in Annualized exacerbation rates(Between Baseline and 12 months)
- Change in forced expiratory volume in 1 second(Between Baseline and 12 months)
- Change in residual volume(Between Baseline and 12 months)
- Change in Breathlessness, Cough and Sputum Scale (BCSS)(Between Baseline and 12 months)
- Change in Days alive and not exacerbating(Between Baseline and 12 months)
- Change in forced expiratory volume in 1 second / forced vital capacity Ratio(Between Baseline and 12 months)
- Change in total lung capacity(Between Baseline and 12 months)
- Comparaison on CT-scan in the average percentage bronchial wall thickness (%WT) corrected by body surface area(BSA) at the B1 and B8 bronchi, generations 3, 4 and 5(Between baseline and 6 months)
- Change in the expiratory to inspiration ratio of mean lung density (MLDe/i),(At Baseline, 6 months and 12 months)
- Quantitative computed tomography measurements to evaluate airflow obstruction(At Baseline, 6 months and 12 months)
- Change in Lund Mackay score(Between Baseline and 12 months)
- Change in Presence/absence of nasal polyposis(Between Baseline and 12 months)
- Change in Days alive and not hospitalized(Between Baseline and 12 months)
- Change in total lung capacity (TLC)/ residual volume(RV) ratio(Between Baseline and 12 months)
- Change in mean ACQ (Asthma Control Questionnaire)-6 score(Between Baseline and 12 months)
- Number of adverse event between arms(Between baseline and 6 months)
- Change in Sino Nasal Outcome Test 22(Between Baseline and 12 months)
- Change in St George Respiratory Questionnaire (SGRQ)(Between Baseline and 12 months)
- Comparaison on CT-scan in the average percentage bronchia wall thickness index (%WT) at the B1 and B8 bronchi, generations 3, 4 and 5(Between baseline and 6 months)
- Change in Total small Airway Count (TAC)(Between Baseline and 6 months)
- Change in Lund Mackay score(Between Baseline and 6 months)
- Change in Presence/absence of nasal polyposis(Between Baseline and 6 months)
- Change in forced expiratory volume in 1 second(Between Baseline and 6 months)
- Change in forced vital capacity(Between Baseline and 6 months)
- Change in forced expiratory volume in 1 second / forced vital capacity Ratio(Between Baseline and 6 months)
- Change in total lung capacity(Between Baseline and 6 months)
- Change in residual volume(Between Baseline and 6 months)
- Change in total lung capacity (TLC)/ residual volume(RV) ratio(Between Baseline and 6 months)
- Change in mean ACQ (Asthma Control Questionnaire)-6 score(Between Baseline and 6 months)
- Change in Breathlessness, Cough and Sputum Scale (BCSS)(Between Baseline and 6 months)
- Change in Sino Nasal Outcome Test 22(Between Baseline and 6 months)
- Change in St George Respiratory Questionnaire (SGRQ)(Between Baseline and 6 months)
- Change in ECRHS III Main Questionnaire(Between Baseline and 6 months)
- Changes in serum Club cell secretory protein (CCSP)(Between baseline and 6 months)