Clinical trial NCT06288516: BenRalizumab Effect on Airway Remodeling in Severe asTHma
Official title: BenRalizumab Effect on Airway Remodeling in Severe Eosinophilic asTHmatics
Study type: INTERVENTIONAL
Overall status: RECRUITING
Phase: PHASE4
Conditions: Asthma; Eosinophilic
Airway Remodeling
Keywords: severe asthma
airway remodeling
eosinophilic
biomarkers
bronchoscopy
Lead sponsor: Aristotle University Of Thessaloniki
Sponsor class: OTHER
Collaborators: name: Pulmonary Clinic, University of Ioannina
name: Pulmonary Clinic, Democritus University of Thrace
name: 2nd Pulmonary Clinic, Kapodistrian University of Athens
name: University Hospital of Crete
name: Pulmonary and Respiratory Failure Department, National and Kapodistrian University of Athens
name: University Hospital of Patras
First posted: 2024-03-01
Enrollment: 45
Sex: ALL
Minimum age (years): 18
Maximum age (years): 85
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: NON_RANDOMIZED
Intervention model: PARALLEL
Intervention model description: Benralizumab (30mg) administered subcutaneously every 4 weeks for the first 3 dose and then every 8 weeks
Primary purpose: TREATMENT

Brief summary: Response to biologic therapies in severe asthma is variable, with patients being either non-responders, responders or super-responders. There is currently no explanation for this broad variation in response. It is important to examine whether these patients have distinct characteristics that could help the treating physician in making the correct diagnosis in clinical practice.

Aim of this clinical study is to evaluate the efficacy of benralizumab, a humanized an anti-interleukin 5 receptor α monoclonal antibody in patients with severe eosinophilic asthma and to evaluate airway remodeling before and after benralizumab treatment.

Hypothesis Identification of pathological and clinical characteristics in patients with severe eosinophilic asthma after benralizumab treatment regarding the airway remodeling, inflammatory cells, and other biomarkers on a long-term basis.

Research questions Is there any improvement in airway remodeling? Are there any biomarkers to predict response to benralizumab treatment in severe eosinophilic asthmatic patients?

Detailed description: Interleukin (IL)-5 is the main cytokine responsible for the activation of eosinophils, hence therapeutic strategies have been investigated and developed for clinical use. Biologics targeting IL-5 and its receptor have been recently approved and used as add-on therapy for severe eosinophilic asthma resulting in a reduction in the circulating eosinophil count, improvement in lung function and exacerbation reduction in patients with severe asthma.

Response to biologic therapies in severe asthma is variable, with patients being either non-responders, responders or super-responders. There is currently no explanation for this broad variation in response. It is important to examine whether these patients have distinct characteristics that could help the treating physician in making the correct diagnosis in clinical practice.

Aim of this clinical study is to evaluate the efficacy of benralizumab, a humanized an anti-interleukin 5 receptor α monoclonal antibody in patients with severe eosinophilic asthma and to evaluate airway remodeling before and after benralizumab treatment. Every patient will be a control to himself by comparing baseline's biomarker measurements of each patient to the following timepoint's measurements. However, we have added 10 severe asthmatics with no intervention, receiving standard of care as control groups to make more comparisons.

Several methods are used to investigate airway inflammation: direct measurements (like bronchial biopsies or bronchoalveolar lavages) and indirect methods (like symptom assessment, blood sample analysis and lung function tests). The direct techniques have the advantage of reliably assessing the airway inflammation, but they are invasive and not feasible at large scale because of patient discomfort and the risk incurred. As for the indirect methods, they poorly correlate with the direct assessment of airway inflammation.

In this study, among patients' clinical characteristics spirometry, biomarkers of inflammation such as blood eosinophils, Fractional Exhaled Nitric Oxide (FeNO), immunoglobulin E (IgE) levels), and airway remodeling via bronchoscopy will be evaluated. The precise effects of increased airway smooth muscle area on airway narrowing are not known and may vary with disease severity. In addition, biomarkers of inflammation will also be evaluated before and after 52-week of benralizumab treatment in biological fluids (serum and bronchial samples). Biomarkers of inflammation are very important to identify treatment response.

Besides, asthmatic disease is characterized by a chronic mucosal inflammatory process, which results in irreversible changes of the bronchial wall, known today as "bronchial remodeling". Glandular and smooth muscle fibers hyperplasia and/or hypertrophy, goblet cells hyperplasia, and variable thickening of basement membrane (BM) present under the respiratory epithelium are part of these morphological changes. the changes generated at the epithelium-connective interface account for an "adaptive response" to inflammatory stress and sporadic bronchoconstriction. However, current data on BM reactivity in asthmatic patient are still incomplete for an accurate assessment of its involvement in pathogenesis and specifically in bronchial wall remodeling, mainly as collagen deposits in lamina reticularis are not correlated to the degree of disease severity.

Moreover, it is increasingly evident that severe asthma is not a single disease, as evidenced by the variety of clinical presentations, physiologic characteristics, and outcomes seen in patients with asthma. To better understand this heterogeneity, the concept of asthma phenotyping and endotyping has emerged. Phenotyping integrates both biological and clinical features, from molecular, cellular, morphologic, and functional to patient-oriented characteristics with the goal to improve therapy. Ultimately, these phenotypes evolve into asthma "endotypes," which combine clinical characteristics with identifiable mechanistic pathways. Biomarkers, defined as characteristics that can be objectively measured and serve as an indicator of underlying biological processes or pathogenesis, are crucial in defining phenotypes and endotypes. In asthma, genetic polymorphisms, measures of airway physiology, and levels of inflammatory mediators in urine, blood, sputum, tissue, exhaled gas, and breath condensate have all been studied as potential markers to improve and objectify asthma diagnosis and management. Developing such tools will allow us to phenotype and endotype the various clinical patterns described in asthma, with the ultimate goal of tailoring therapy based on a specific biomarker profile. Biomarkers can then be used to help better understand the pharmacologic response to an intervention and adjust therapy accordingly.

Biomarkers have been critical for studies of disease pathogenesis and the development of new therapies in severe asthma. In particular, biomarkers of type 2 inflammation have proven valuable for endotyping and targeting new biological agents. Because of these successes in understanding and marking type 2 inflammation, lack of knowledge regarding non-type 2 inflammatory mechanisms in asthma will soon be the major obstacle to the development of new treatments and management strategies in severe asthma. Other potential biomarkers include innate lymphoid cells, IL-33 or thymic stromal lymphopoietin.

Eligibility criteria: Inclusion Criteria:

* Written informed consent must be obtained at screening visit, before any assessment will be performed. Subjects should be able to provide informed written consent (study participation informed consent form): Able to give written informed consent prior to participation in the study, which will include the ability to comply with the requirements and restrictions listed in the consent form. Subjects must be able to read, comprehend, and write at a level sufficient to complete study related materials.
* Confirmed severe asthma diagnosis and treatment requirements according to American Thoracic Society(ATS)/European Respiratory Society (ERS) guidelines and Global Initiative for Asthma (GINA) 2023.
* Blood eosinophils ≥150cells/ul at screening visit or ≥300cells/ul the last 12 months.
* Patients with history ≥ 1 exacerbation the previous year under the treatment of high dose of inhaled corticosteroid(ICS)+LABA±LAMA or receiving oral/systemic corticosteroids at least 3 days. For subjects on maintenance oral corticosteroids, an exacerbation requiring oral corticosteroids was defined as the use of oral/systemic corticosteroids at least double the existing dose for at least 3 days.
* Meet requirements for biologic therapy with Benralizumab.

Exclusion Criteria:

* Asthma exacerbation, within 6 weeks prior to screening that required hospitalization or emergency room visit.
* Prior use of other biologics that has potential to interfere/ affect disease progression.
* Pregnant or nursing women, or women of child-bearing potential.
* History of malignancy of any organ system or any other serious co-morbidities defined by the treating physician.
* Patients with a history of conditions other than asthma that could result in elevated eosinophils (e.g. hypereosinophilic syndromes, Churg-Strauss Syndrome, eosinophilic esophagitis).

Primary outcomes:
measure: Change in sub-basement membrane thickness
timeFrame: through study completion, 52 weeks
measure: Change in airway smooth muscle area
timeFrame: through study completion, 52 weeks
measure: Change in airway smooth muscle layer thickness
timeFrame: through study completion, 52 weeks
measure: Change in submucosal eosinophil number
timeFrame: through study completion, 52 weeks
measure: Change in epithelial integrity
timeFrame: through study completion, 52 weeks
measure: Change in collagen thickness
timeFrame: through study completion, 52 weeks
Secondary outcomes:
measure: Change of cytokine and protein levels
timeFrame: through study completion, 52 weeks
measure: Change in exacerbation rate
timeFrame: through study completion, 52 weeks
measure: Change in blood eosinophil levels
timeFrame: through study completion, 52 weeks
measure: dentification of clinical characteristics of response, change in Forced Expiratory Volume (FEV1)
timeFrame: through study completion, 52 weeks
Other outcomes:
Locations:
city: Thessaloniki
country: Greece
facility: Pulmonary Clinic, Aristotle University of Thessaloniki, George Papanikolaou Hospital
Study officials:
affiliation: Aristotle University Of Thessaloniki
name: Kalliopi Domvri, Dr
role: PRINCIPAL_INVESTIGATOR
References:
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