3TR Asthma Biologics Cohort (ABC) Study

Overview

The 3TR-ABC study is a multicentre observational prospective cohort study platform that follows patients with severe asthma from the start of biological therapy and three years onwards. In the 3TR-ABC platform, individual studies are conducted on specific biologics, using aligned study designs. The aim of the study is to assess response to treatment and examine clinical characteristics, biomarkers, and immunological mechanisms related to response, including remission and non-response, that might be new targets or explanations for insufficient treatment. Patients will be extensively characterized at baseline and then followed throughout the years with formal clinical and biological assessment at 4, 16, 52 weeks, and 2, 3 years. Based on the response to treatment, patients will be stratified into remission, clinical responders, and non-responders, and pre-treatment biomarker profiles obtained at the baseline visit will be compared, as well as the immunological response to treatment. Healthy individuals and patients with mild/moderate controlled asthma are included as reference groups and will undergo the same baseline visit as patients with severe asthma. Several bio-samples, to perform multi-omic analysis, will be taken to examine biological pathways associated with response and non-response to biologics.

The 3TR Consortium is the overall generator behind the 3TR-ABC study. The 3TR Consortium consists of 15 European countries and a total of 69 partners who collaborate on seven different autoimmune, inflammatory, and allergic diseases: chronic obstructive pulmonary disease, asthma, Crohn's disease, ulcerative colitis, multiple sclerosis, systemic lupus erythematosus, rheumatoid arthritis. The ambition of the consortium is to accelerate precision medicine by fundamentally increasing the knowledge of molecular pathways and mechanisms related to response and non-response to therapy. To date, the 3TR Consortium is the largest immunology project funded by the Innovative Medicine Initiative (IMI). The 3TR-ABC platform study is anchored in the so-called work package 8 (WP8) within the 3TR Consortium and will contribute with knowledge about the effect of biological therapies in severe asthma: With the advent of highly targeted biological therapies for severe asthma, several important questions arise; what determines a good clinical response versus non-response? Can we induce remission of severe asthma, and improve long-term outcomes? The 3TR-ABC study platform is a clinical trial platform and network, in which intervention-specific studies on different biologics are conducted. Via the 3TR-ABC study platform, conducting advanced translational studies in a real-life cohort of asthma patients is made possible, in collaboration with key opinion leaders and scientific experts in the field from across Europe. The 3TR-ABC study design includes a core study visit structure, which can be expanded or amended per study to suit individual focus points. Overall, the study design includes enrollment of bio-naïve patients with severe asthma, who have been assessed with systematic assessment, and who meet the criteria for commencing a biologic, according to national criteria in each country. Patients are then followed from the time of starting a biological treatment for three years, during which time they are followed at set time points as well as at the time of exacerbations, with sampling consisting of a core package and expanded packages, depending on the site. By using a range of state-of-the-art and novel methods for assessing immune activation, and applying advanced bioinformatics analysis methods, The investigators expect to be able to identify immune activation patterns and response profiles that will further our understanding of disease drivers in the treatment of refractory severe asthma. Furthermore, healthy participants and patients with mild/moderate controlled asthma will be acting as controls for baseline markers thus constituting a healthy as well as mild/moderate controlled asthma reference population. Benralizumab Cohort Study: The AIR-BIO-OCT study Allocation to biologicals occurs by means of asthma phenotyping including clinical parameters including OCS use and blood or sputum / bronchoalveolar lavage (BAL) eosinophils (reflecting Th2 high - Th2 low inflammation). It is unclear if and how biologics impact on airway remodeling and how they act within the airway wall and which airway cells are targeted in vivo, directly or indirectly by a reduction in eosinophils. Important pathophysiological features of asthma that relate to disease severity and prognosis are airway inflammation and remodeling, including an increase in airway smooth muscle (ASM) and extracellular matrix (ECM) alterations. Therefore, with the AIR-BIO-OCT substudy as part of the 3TR-ABC Study, next to performing a complete unbiased multi-omics approach the investigators also have some already identified multi-omics phenotypes within severe asthma that the investigators would like to investigate in a cohort of benralizumab users. As such extensive phenotyping before and after treatment, by combining exhaled breath VOCs (GC-MS and eNose) technology with minimal invasive omics (molecular) and innovative imaging technology by OCT, including polarization-sensitive OCT PS-OCT (impact of benralizumab on remodeling). Primary Objective Determine baseline biomarkers of remission after 1 year of biological therapy, defined as ACQ-5 \<1.5, post-bronchodilator FEV1 percent predicted ≥80% OR \>10% improvement as well as no exacerbations, or use of maintenance steroids for the past 12 months ("remission on treatment"). Secondary Objectives Determine baseline biomarkers of remission after 3 years of biological therapy. Additionally, i) Change in biomarker profiles in remission versus non-remission groups, ii) baseline and change in biomarker profile for a) each response outcome individually, b) Global evaluation treatment efficacy (GETE), patient and physician rated response, and c) 3TR agreed on a composite assessment of response, iii) determine the change in all response variables against baseline biomarker data and change in biomarkers as continuous variables. Exploratory Objectives: Novel analytical science approaches including but not limited to network and cluster analyses and partial least-squared discriminate analysis (PLSDA), topographical discriminant analysis of omic data derived from the biosamples collected at planned visits as well as daily FENO to determine possible novel biomarker signatures (including FENO) and relate to asthma remission, clinical response, interactomes of the multi-omic and clinical data, host-microbiome interactions. AIR-BIO-OCT substudy objectives Primary Objective: * To identify and measure an eNose/ volatile organic compound (VOC)- multi-omics extensive severe asthma phenotyping strategy before treatment with biologicals to reveal add-on response characteristics to better predict treatment response. * To identify and measure minimal invasive predicting "signature" of biological treatment response in severe eosinophilic asthma by extensive asthma pheno-endotyping using innovative minimal invasive exhaled breath technologies including eNose/VOCs and omics. Secondary Objective(s) * To measure airway remodeling (extracellular matrix and airway smooth muscle) after treatment with Benralizumab * Establish the reduction of extracellular matrix (ECM) and airway smooth muscle (ASM) by the standard - polarization-sensitive (PS) - OCT and endobronchial biopsy analyses after 6 months - 1 year of Benralizumab treatment. Study Design The 3TR-ABC study is a multicentre observational prospective cohort study that follows patients with severe asthma from the time of commencement of biological therapy and three years onwards. Healthy individuals and patients with mild/moderate controlled asthma are included as reference groups and will undergo the same baseline visit as patients with severe asthma. Informed Consent must be obtained from all participants who accept enrollment in the study in order to allow the collection of data and biological materials for the database and biobank, respectively. The study follows each patient with severe asthma at six visits over a period of three years. The first visit is the so-called baseline visit and is performed before the beginning of a biological treatment. This visit consists of a standard examination package, a site-specific extended package (i.e., tests in this package will only be done at specific sites), and an optional extended package (i.e., the participant decides). The remaining five visits are so-called follow-up visits and are made respectively 4 weeks, 16 weeks, 52 weeks, 2 years, and 3 years after the baseline visit. These visits consist of a follow-up sampling package and a site-specific extended package. An optional extended package is furthermore possible for the 4 weeks, 52 weeks, 2 years, and 3 years visits. Between scheduled visits, patients with severe asthma are asked to come for an extra visit if they experience a sudden exacerbation. Participants in the control groups will only be invited for the baseline visit. The AIR-BIO-OCT study is a sub-study within the 3TR-ABC Study performed in the Netherlands that will select severe eosinophilic asthma patients that start treatment with Benralizumab and will phenotype those patients (combining exhaled breath analysis and OCT technology) before and after 16 weeks and additional 52 weeks from the start of the biological. In the Netherlands, the AIR-Bio-OCT substudy consists of two parts: the first, aligned with the 3TR - ABC study, where samples of the abovementioned packages will be collected (n=34) and merged with the Benralizumab subjects recruited within the 3TR consortium (total 60-90 patients). The second part, additional bronchoscopy with standard and PS-OCT before and after 6 months-1 year will be performed (n=15).