Puente Genil, Spain

Evaluating Treatable Traits Across the Spectrum of Chronic Obstructive Airways Disease

Clinical Relevance of Small Airways Disease in Severe Asthma Patients Treated With Anti-InterLeukin-5 Therapy

Small Airways Disease (SAD) in Severe Asthma as a Novel Endpoint and Distinct Target for Biological Therapy.

Study hypothesis We hypothesize that biological therapy has a significant beneficial effect on small airways disease in severe asthmatics and that the evaluation of small airways before and during treatment may represent a distinctive marker of response and a novel target for a preferential use of one over other biological therapies currently available for severe asthmatic patients. Study objectives - To evaluate small airway endpoints in severe asthmatics before starting biologic treatment. - To evaluate longitudinal changes of these endpoints at different time points during biologic treatment. - To relate small airway endpoints recorded at baseline and their changes over time to other functional, laboratory, clinical and patient-reported outcomes. - To make comparisons for subgroups identified on the basis of the type of the biological drug used. Study center The study will be conducted at the Asthma Center of Fondazione Policlinico Universitario Agostino Gemelli. Asthma Clinic evaluates approximately 1000 asthmatic patients per year; furthermore, it is part of the Italian Severe Asthma Network (SANI) and one of the coordinating centers for the newborn Italian Mild-Moderate Asthma Network (MANI), therefore representing a center of excellence and reference at a national level, with easy and wide access to the study population. Study design This is a 24-month, single-site observational retrospective and prospective longitudinal cohort study involving asthmatic patients referred to the Asthma Center and eligible for starting one of the biological therapy currently available. The patient will be considered eligible only after having optimized adherence, inhalation technique, comorbidity management and following a multidisciplinary assessment. Subjects will be monitored for 12 months and SA endpoints as well as other functional, clinical, laboratory and patient-reported outcomes will be recorded at the beginning of the biological therapy (T0) and after 3,6,12 months (T3, T6, T12). Values and changes in SA endpoints will be also related to other functional, clinical and patient-reported outcomes. Study procedures The following study procedures will be performed in the framework of the standard care for severe asthmatic patients: - Clinical history; - Demographics data (such as age, sex, race et.) - Questionnaires (i.e. Asthma Control Test [ACT], Asthma Control Questionnaire [ACQ], Asthma Quality of Life Questionnaire [AQLQ]) - Pulmonary function tests (i.e. spirometry [Forced Expiratory volume in 1 second (FEV1),Forced Vital Capacity (FVC), FEV1/FVC, body plethysmography [Residual Volume (RV), Total Lung Capacity (TLC), RV/TLC, impulse oscillometry as resistance at 5 and 20 Hz (R5, R20). - Airway inflammatory markers (i.e. fraction exhaled nitric oxide - FeNO) - Allergy tests (i.e. skin-prick tests and immunoassays for total and specific serum IgE) - Biological sampling (i.e. blood and sputum eosinophils). - Imaging (i.e. chest XR and HRCT) Study endpoints The primary endpoint will be represented by the R5-R20 parameter registered through impulsoscillometry. Baseline values and changes over the one-year follow-up period at preplanned timepoints (i.e. 3, 6, and 12 months) will be recorded. According to literature evidence, baseline values ≥0.07 support the evidence of small airways dysfunction. Secondary endpoints will be represented by indirect parameters of SA involvement (i.e. TLC, RV, TLC/RV, FEF25-75). Baseline values and changes over the one-year follow-up period at preplanned timepoints (i.e. 3, 6, and 12 months) will be recorded. Variations in primary and secondary endpoints will be also related to changes in functional parameters (i.e FEV1), clinical parameters (exacerbation rate), inflammatory markers (FeNO) and patients' questionnaire scores (ACT, AQLQ, ACQ). Established minimal clinically important difference (MCID) thresholds will be taken into consideration for correlation analyses. Statistical analysis Statistical analysis will be performed using a statistical software. Data will be tested for normality and will be expressed as mean (SD) or median (IQR). Comparative analysis will be performed using parametric and non-parametric methods as appropriate. Single and multiple linear regression analyses will be run to determine correlation between small airway endpoints and clinical, functional, laboratory, and patients' reported outcomes. A p-value≥0.05 will be considered statistically significant. Most appropriate statistical analyses and models will be anyway chosen and run, following the advice of statisticians at the institutional Department of Public Health. Considering the "R5-R20 Delta", measured through impulse oscillometry, as the primary endpoint for the study, and aiming for a minimal difference of 0.02 (according to literature data), in order to have an a error of 0.5 and a study power of 80%, at least 54 subjects will have to be enrolled in the study. Documentation will be stored for a minimum of 10 years after the completion of the study, including the follow-up period. Study significance and innovation Systems biology approaches are establishing the links between disease pathways/mechanisms, and clinical/physiologic features. Validation of these pathways may contribute to better defining severe asthma endotypes and treatable mechanisms. Precision medicine approaches are necessary to link treatable mechanisms with treatable traits and biomarkers derived from clinical, physiologic, inflammatory, molecular and genetic variables. A deep and proper assessment of airway samples along with non-invasive biomarkers may have a highly relevant translational significance and enable better knowledge and management of severe asthma. Risk analysis No major difficulties are expected in view of the study's observational design. No additional costs will be held.

Small Airways Disease (SAD) in Severe Asthma as a Novel Endpoint and Distinct Target for Mepolizumab (SASAM Study)

Study hypothesis We hypothesize that mepolizumab has a significant beneficial effect on small airways disease in severe asthmatics and that the evaluation of small airways before and during treatment may represent a distinctive marker of response and a novel target for a preferential use of this drug vs other biologics available for severe eosinophilic asthmatic patients. Study objectives - To evaluate a wide panel of validated small airways endpoints in eosinophilic severe asthmatics before mepolizumab treatment - To evaluate longitudinal changes of these endpoints at different time points during mepolizumab treatment - To relate small airways endpoints recorded at baseline and their changes over time to other functional, laboratory, clinical and patient reported outcomes Study center The study will be conducted at the Asthma Center of the Fondazione Policlinico Universitario A. Gemelli, IRCCS, Respiratory, Allergy and ENT Physicians closely and sinergically collaborate in the framework of the Asthma Center with shared clinical and research activities aimed to an optimal management of asthma and its comorbidities, as well as with regular meetings for multidisciplinary clinical case discussion and collective decisions on treatment strategies. The Asthma Center is part of the Italian Severe Asthma Network (SANI) and will be soon one of the coordinating centers for the newborn Italian Mild-Moderate Asthma Network (MANI), therefore representing a center of excellence and reference at a national level, with easy and wide access to the study population. Study design Asthmatic patients referred to the Asthma Center and eligible for starting Mepolizumab, after having optimized adherence, inhalation technique and comorbidity management following multidisciplinary assessment, will enter a single-site oservational prospective longitudinal cohort study. Subjects will be monitored for 12 months and SA endpoints will be recorded at the beginning of the biological therapy (T0) and after 3,6,12 months (T3, T6, T12). SA endpoints will be also related to other functional, clinical and patient reported outcomes. Study population Male and female subjects addressed to the Asthma Center, aged ≥12 yrs with severe asthma as defined by ATS/ERS guidelines (≥12months high-dose ICS + additional controller treatments), ≥2 exacerbations (corticosteroid and/or ED visit and/or hospitalization in the previous 12 months), blood eosinophil ≥150 cells/µl at study entrance or ≥300cells/µl historically and a smoking history <2 pack/year. Study drug Mepolizumab 100mg via subcoutaneous administration Study procedures The following methodologies will be included in the study: Clinical history, Demographics and questionnaires (i.e. ACT, ACQ, ACQLQ) Pulmonary function tests (i.e. spirometry, body plethysmography, single- and multi-breath nitrogen washout, impulse oscillometry) Airway inflammatory markers (i.e. fraction exhaled nitric oxide - FeNO) Allergy tests (i.e. skin-prick tests and immunoassays for total and specific serum IgE) Biological sampling (i.e. blood and sputum eosinophils) Study endpoints The following endpoints relating to small airways involvement will be considered: R5, R20, X5, AX, RF, FEF25-75, TLC, RV, Raw, Gaw, DLCO, KCO, LCI

Moving Towards Precision Medicine in United Airways Disease: Unraveling Inflammatory Patterns in Asthmatic Patients With or Without Nasal Polyps

1. Background Both, asthma and chronic rhinosinusitis (CRS) are inflammatory conditions of the airways. The prevalence of asthma - with its cardinal symptoms wheezing, breathlessness, chest tightness, and coughing - has risen over the past decades not only in industrial but also in developing countries. For instance, about 8% of the United States' population and 8.2% of Europeans are diagnosed with asthma. Chronic rhinosinusitis with (CRSwNP) and without nasal polyps (CRSsNP) is a condition affecting up to 16% and 11% of the US and European population, respectively3. Both diseases, asthma and CRS, can severely impair quality of life as well as productivity and therefore embody an immense socioeconomic burden. Despite the distinction of the respiratory tract in the upper and lower airways, both parts are anatomically and immunologically related. This led to the concept of "United airway diseases" assuming that upper and lower airways form a single organ. Consequently, inflammation in the upper affects the lower respiratory tract and vice versa. This concept initially described in the context of allergic respiratory disease can also be extended to the link between sinonasal and lower airway diseases. Accordingly, the association between asthma and CRS prevalence has been unambiguously shown in epidemiological studies: around 20% of CRSsNP patients and around 48% of CRSwNP patients suffer from asthma. Conversely, nasal polyposis is detected in 19 to 25% of asthmatics. In cases of severe asthma, even up to 54% of patients were reported to have a history of nasal polyposis. However, the pathophysiological mechanism underlying the association of asthma and CRS has been poorly investigated so far. Based on the predominant inflammatory profile, asthma can be separated into T2-high and T2-low endotypes. Thereby, around 60% of severe asthma patients show a T2-high profile. The picture is becoming even more complex regarding classifications of CRS. Phenotypically we distinguish between CRSsNP and CRSwNP. However, up to 10 different endotypes of CRS can be defined based on various different inflammatory markers in nasal polyps or nasal secretions. Approaches to characterize endotypes describing conditions involving both asthma and CRS have barely been made so far. On a cellular and protein level, it seems that higher concentrations of Staphylococcus enterotoxin-specific IgE, total IgE and eosinophil cationic protein in nasal polyp tissue are indicators for a higher risk of asthma. Furthermore, it was observed that patients with CRS and eosinophilic asthma (as determined by FeNO levels only) show high numbers of eosinophils in their nasal polyps. This nasal polyp eosinophilia was associated with a more severe asthma phenotype as well as larger polyps and a significantly higher nasal polyp recurrence rate compared to non-eosinophilic patients. However, up to this point, no study investigated whether inflammatory profiles in polyps and asthmatic lungs correspond and how inflammatory profiles of patients suffering from asthma with or without polyps may differ. Novel antibody-based therapies targeting mediators of type 2 immune response are constantly emerging as new treatment options for patients with severe chronic airway diseases. Therapeutic antibodies targeting IgE or IL-4/IL-13, IL-5, or IL-5 receptor-mediated pathways are currently licensed for the treatment of asthma but have also successfully been used to treat CRSwNP to some extent. In this respect, anti-IgE (omalizumab) and anti-IL4α receptor (dupilumab) specific monoclonal antibodies have recently been licensed for the treatment of nasal polyps and CRSwNP respectively. Antibodies targeting molecules further upstream in the inflammatory cascade such as TSLP or IL-33 are currently under development. Anti-TSLP antibodies showed first promising results in clinical trials including patients suffering from uncontrolled asthma. Despite targeting molecular pathways involved in the pathogenesis of both diseases, some monoclonal antibodies such as reslizumab are effective in treating asthma but fail to significantly ameliorate nasal polyposis. Interestingly, a post-hoc responder analysis showed that the group of patients with high baseline IL-5 levels in nasal secretions improved upon reslizumab treatment, while the other patient groups did not. These findings illustrate the urgent need to better understand the pathomechanism and potential links underlying both diseases in order to choose the right therapy for the right patient. 2. Study rationale In this study, we aim to unravel the pathophysiological mechanisms underlying T2-high asthma with or without nasal polyposis. Therefore, we plan to thoroughly examine T2-high asthmatic patients with and without nasal polyposis at the cellular and molecular level and compare them to patients suffering from eosinophilic polyps in the absence of asthma. Deep analysis of nose, oropharynx, and lung samples will yield information on inflammatory patterns at protein and mRNA level, cellular tissue architecture in the different disease subtypes as well as microbiome composition. This pilot study will help to unravel underlying pathomechanisms in these united airway diseases and, therefore, provide a rationale for new therapy approaches including biologicals. 3. Study objectives In this study we plan to: - evaluate the inflammatory profile in different sections of the airways; - evaluate the endotype and immunological profile of CRSwNP (when applicable); - determine the microbiome composition in nose, oropharynx, and bronchi in T2-high asthmatic patients with and without CRSwNP, N-ERD compared to patients with CRSwNP in absence of asthma