Ignite Creation Date:
2024-05-06 @ 7:35 PM
Last Modification Date:
2024-10-26 @ 3:10 PM
Study NCT ID:
NCT06069310
Status:
RECRUITING
Last Update Posted:
2023-10-05
First Post:
2023-09-06
Brief Title:
Mepolizumab Effectiveness in Patients With Chronic Rhinosinusitis Nasal Polyps and Comorbid Severe Eosinophilic Asthma
Sponsor:
National and Kapodistrian University of Athens
Organization:
National and Kapodistrian University of Athens
Study Overview
Official Title:
Evaluation of Mepolizumab Effectiveness in Patients With Chronic Rhinosinusitis With Nasal Polyps and Comorbid Severe Eosinophilic Asthma an Integrative Multi-omics Approach to Assess Biomarker Signatures of Responsive Disease Endotypes
Status:
RECRUITING
Status Verified Date:
2023-09
Last Known Status:
None
Delayed Posting:
No
If Stopped, Why?:
Not Stopped
Has Expanded Access:
False
If Expanded Access, NCT#:
N/A
Has Expanded Access, NCT# Status:
N/A
Acronym:
MepoRiNaPAs
Brief Summary:
The goal of this observational study is to learn about clinical and functional outcomes in patients with Chronic rhinosinusitis with nasal polyps and comorbid Severe Eosinophilic Asthma and patients with Chronic rhinosinusitis with nasal polyps only treated with mepolizumab compared to healthy controls
Participants will be asked to give nasal blood and sputum samples before mepolizumab administration T0 and at 3 T3 6 T6 and 12 T12 months after mepolizumab initiation The main aims are to identify airways microbiota modifications and differential gene expression after mepolizumab initiation
Researchers will compare
Patients with Chronic rhinosinusitis with nasal polyps and comorbid Severe Eosinophilic Asthma
Patients with Chronic rhinosinusitis with nasal polyps only
Healthy subjects
The research will address the following questions
1 What are the prospective clinical and functional outcomes of mepolizumab treatment
2 What is the impact of mepolizumab therapy on the airways microbiota and how this may relate to a potentially reduced need for steroids
3 What are the host differential gene expression patterns and the immuneinflammatory cytokineschemokines profile alterations in airways microenvironment and in systemic circulation in response to therapy
4 What are the associations between host and microbiome variables for building up diagnostic and predictive biomarker classifiers of responsive disease endotypes
Participants will be asked to give nasal blood and sputum samples before mepolizumab administration T0 and at 3 T3 6 T6 and 12 T12 months after mepolizumab initiation The main aims are to identify airways microbiota modifications and differential gene expression after mepolizumab initiation
Researchers will compare
Patients with Chronic rhinosinusitis with nasal polyps and comorbid Severe Eosinophilic Asthma
Patients with Chronic rhinosinusitis with nasal polyps only
Healthy subjects
The research will address the following questions
1 What are the prospective clinical and functional outcomes of mepolizumab treatment
2 What is the impact of mepolizumab therapy on the airways microbiota and how this may relate to a potentially reduced need for steroids
3 What are the host differential gene expression patterns and the immuneinflammatory cytokineschemokines profile alterations in airways microenvironment and in systemic circulation in response to therapy
4 What are the associations between host and microbiome variables for building up diagnostic and predictive biomarker classifiers of responsive disease endotypes
Detailed Description:
Chronic rhinosinusitis CRS has been divided into two subtypes CRS with CRSwNP and without nasal polyps CRSsNP which not only differ in terms of presence of polyps but also appear to have distinct pathogenesis and clinical presentations It is known that CRSwNP patients have a greater disease burden compared with those suffering from CRSsNP with respect to disease severity and poor treatment More specifically approximately 85 of CRSwNP patients are characterized by severe symptoms recurrent disease and a dominant Th2 endotype associated with a marked infiltration of eosinophils and mast cells goblet hyperplasia and increased levels of Th2 inflammatory cytokines including Interleukin IL-4 IL-5 and IL-13 An additional hallmark of CRSwNP is the loss of healthy barrier function in sinonasal epithelial cells increased permeability decreased epithelial resistance and a high degree of tissue remodeling compared with cells from CRSsNP patients and control individuals This loss of barrier function is reflective of a general inflammatory process though it is unclear if the epithelial cells are inherently abnormal or if the state is induced Treatment for CRS is most frequently glucocorticoid-based but response is quite variable in patients with nasal polyps and side-effects from oral steroids limit their long-term efficacy An inverse relationship between glucocorticoid receptor β expression in nasal polyp tissue and steroid efficacy has been observed Furthermore neutrophil accumulation in nasal polyp tissue has been related to corticosteroid insensitivity Some individuals exhibit a very high level of resistance to steroid therapy thus underscoring the need for therapeutics targeting non-steroid-responsive pathophysiologic mechanisms involved in sinus polyp formation
Asthma is frequently a comorbid condition sharing similar pathophysiology in CRSwNP patients which affects 20-60 of diseased individuals Yet specific subsets of patients such as those with IL-5-enriched nasal polyps are characterized by a greater percentage of asthma and revision surgery Clinically CRSwNP with comorbid asthma CRSwNP AS is associated with even more severe sinonasal symptoms and worse quality of life and it is more difficult to treat both medically and surgically Correspondingly asthma in the presence of nasal polyposis is harder to control being more exacerbation prone with increased airway obstruction and more extensive eosinophilic inflammation
Although a clear correlation apparently exists between sinonasal and lower airway inflammation in patients with CRSwNPAS the definitive underlying mechanisms remains poorly elucidated The airways microbiota ie the niche-specific communities of microbes including bacteria fungi archaea and viruses that inhabit the respiratory tract has been proved to play a critical role in airway health and immune cells homeostasis -including eosinophils regulation- through its constant interaction with the mucosal immune system Alterations in the composition and diversity of microbiome across the respiratory tract may contribute to the observed inflammatory crosstalk in CRSwNP AS and perhaps influence patients response to treatment Nasal and lower airway microbiota dysbiosis have been proved to be implicated in the persistence of characteristic inflammatory endotypes in both CRSwNP and asthma It has been shown that bacterial dysbiosis is correlated with CRS status and that specific microbiota taxonomic classifications are correlated with patient phenotypes including the presence of nasal polyps A high proportion of patients with CRSwNP are colonized with Staphylococcus S aureus and IgE antibodies to S aureus enterotoxins are frequently found in diseased tissue specimens Both S aureus and Pseudomonas aeruginosa bacteria can disrupt the epithelial barrier contributing to presumed physiologic mechanisms for CRSwNP development It has been previously demonstrated that S aureus is able to drive Th2 type inflammation in CRSwNPand that the expression of IL-5 and of IgE against S aureus superantigens SE-IgE within polyp tissue is associated with comorbid asthma and CRSwNP recurrence Furthermore antimicrobial compounds including lysozyme S100 proteins and β-defensins all are decreased in CRSwNP patients compared to matched controls This reduction in natural defenses could play a key role in shifting the balance towards dysbiosis Furthermore in addition to bacterial microbiome which has been the focus of most recent studies the contribution of fungal microbiota to allergic airway diseases has been recently emerged An alternative proposed pathogenic mechanism for Th2-biased CRS is that T-cells are allergically sensitized to fungi in the ambient environment leading to allergic inflammation characterized by a Th2-high state Overall a distinct microbiome role in CRSwNP and asthma pathogenesis is actually recognized However the significance of interactions between the lowerupper airways flora and the host local and systemic inflammatory response has not yet been well defined neither such a knowledge is exploited for a more accurate patients classification and selection of best possible therapeutic manipulation to change disease progression
Evidently an optimal diagnostic approach for CRSwNP AS would include use of very specific biomarkers ensuring a detailed endotyping whereas there is a growing consensus that both diseases should be treated to improve therapeutic outcome However the management of CRSwNP AS patients who remain uncontrolled despite medical and often surgical intervention poses a great challenge to clinicians Fortunately there has been significant innovation and expansion in the treatment armamentarium since the advent of biological therapies Targeted biologics monoclonal antibodies against IL-4 IL-5 IL-13 and IgE for treating asthma are now being used for CRSwNP with encouraging results
Recently mepolizumab Nucala GlaxoSmithKline an anti-IL5 humanized mab known to efficiently down-regulate the eosinophilic inflammatory pathway and to exhibit clinical benefit in patients with severe eosinophilic asthma has completed a phase 3 trial SYNAPSE NCT03085797 including 413 subjects with CRSwNP Early results showed treatment with mepolizumab had a significant difference in median nasal polyp score compared to baseline -073 95 CI -111 to -034 and nasal obstruction visual analog score compared to baseline -314 95 CI -409 to -218 unpublished data However there are only limited longitudinal studies evaluating this biologics efficacy in CRSwNPAS patients while the assessment of action mode and biomarkers predicting responsiveness remain to be elucidated
Despite the persuasive rationale for systemic targeting of shared pathways in CRSwNPAS with novel biologics in clinical practice the nose and lungs are often treated as separate entities and these therapeutics are considered rather challenging for the clinicians due to their high cost and necessity for careful selection of patients and right treatment Furthermore therapeutic decision-making is still based on a rather trial-and-error approach resulting in treatment failures or relapses There is clearly a need for a personalized medicine approach that would allow for a more accurate prediction of the appropriate choice of the drug at the initial assessment and ideally would communicate chances of long-term success to an individual patient
The principal goal of this three arms RWE study CRSwNPAS CRSwNP-AS healthy controls study is to develop signatures of host-microbiome biomarkers of both diagnostic and predicting value in order to provide a rational guideline for mepolizumab selection in precision treatment of patients with CRSwNPAS
In this frame mepolizumab therapeutic potential will be assessed in relation to the rather heterogeneous presentations of Th2 inflammation and airways microbiome structure The protocol will take on the question of microbiome dysbiosis involvement in immune activation and dysfunction contributing to CRSwNP AS diversity and delving into the complex patterns of host-microbiota molecular interactions in the upper and lower airways that may shape patients clinical predisposition to mepolizumab therapy
To address the study objectives a longitudinal design is proposed combining clinical assessments with high-throughput multi-omics analyses of patients samples and advanced bioinformatics for data integration The starting point of the project will be the consent recruitment of healthy controls CRSwNP AS and CRSwNP - AS participants Collection of biological samples from patients and clinical assessmentmeasurements of cell counts will take place at baseline ie the day of treatment initiation before mepolizumab administration T0 and at 3 T3 6 T6 and 12 T12 months after mepolizumab initiation Samples from healthy participants will be collected only at baseline T0 and analyzed in parallel with the corresponding samples from CRSwNP patients DNA and RNA will be isolated from induced sputum and nasal samples collected at T0 and T3 for subsequent 16S rRNA gene amplicon sequencing DNA shot-gun sequencing applied only in selected number of patients and healthy controls and bulk RNA sequencing RNAseq to identify airways microbiota modifications and differential gene expression respectively Peripheral blood mononuclear cells PBMC from a representative number of patients and healthy controls will be also analyzed at the same time points by single-cell RNA sequencing scRNAseq In parallel the dynamic pattern of cytokineschemokines in serumairways samples will be determined by xMAP immunoassays at T0 and T3 Subsequently multiple comparisons at the level of microbiome and host parameters will be undertaken mainly through two paths First between patients and healthy controls at T0 to assess differences of disease versus normal condition Second pairwise in each patient at T0 and at time intervals mostly at T3 after treatment intervention to capture potential alterations in response to mepolizumab Next a thorough integrative analysis engaging clinical data and multi-omics data from microbiome bulk RNAseq scRNAseq as well as cytokinomechemokinome analyses will be undertaken to investigate possible microbiome-host interactions Finally this integrative analysis will be exploited to gain a global view of hub genes inflammatory mediators and microbial taxa involved in key interactions and to build biomarker signatures that might serve as indicators of specific disease subtypes andor predictors of mepolizumab treatment outcome
Asthma is frequently a comorbid condition sharing similar pathophysiology in CRSwNP patients which affects 20-60 of diseased individuals Yet specific subsets of patients such as those with IL-5-enriched nasal polyps are characterized by a greater percentage of asthma and revision surgery Clinically CRSwNP with comorbid asthma CRSwNP AS is associated with even more severe sinonasal symptoms and worse quality of life and it is more difficult to treat both medically and surgically Correspondingly asthma in the presence of nasal polyposis is harder to control being more exacerbation prone with increased airway obstruction and more extensive eosinophilic inflammation
Although a clear correlation apparently exists between sinonasal and lower airway inflammation in patients with CRSwNPAS the definitive underlying mechanisms remains poorly elucidated The airways microbiota ie the niche-specific communities of microbes including bacteria fungi archaea and viruses that inhabit the respiratory tract has been proved to play a critical role in airway health and immune cells homeostasis -including eosinophils regulation- through its constant interaction with the mucosal immune system Alterations in the composition and diversity of microbiome across the respiratory tract may contribute to the observed inflammatory crosstalk in CRSwNP AS and perhaps influence patients response to treatment Nasal and lower airway microbiota dysbiosis have been proved to be implicated in the persistence of characteristic inflammatory endotypes in both CRSwNP and asthma It has been shown that bacterial dysbiosis is correlated with CRS status and that specific microbiota taxonomic classifications are correlated with patient phenotypes including the presence of nasal polyps A high proportion of patients with CRSwNP are colonized with Staphylococcus S aureus and IgE antibodies to S aureus enterotoxins are frequently found in diseased tissue specimens Both S aureus and Pseudomonas aeruginosa bacteria can disrupt the epithelial barrier contributing to presumed physiologic mechanisms for CRSwNP development It has been previously demonstrated that S aureus is able to drive Th2 type inflammation in CRSwNPand that the expression of IL-5 and of IgE against S aureus superantigens SE-IgE within polyp tissue is associated with comorbid asthma and CRSwNP recurrence Furthermore antimicrobial compounds including lysozyme S100 proteins and β-defensins all are decreased in CRSwNP patients compared to matched controls This reduction in natural defenses could play a key role in shifting the balance towards dysbiosis Furthermore in addition to bacterial microbiome which has been the focus of most recent studies the contribution of fungal microbiota to allergic airway diseases has been recently emerged An alternative proposed pathogenic mechanism for Th2-biased CRS is that T-cells are allergically sensitized to fungi in the ambient environment leading to allergic inflammation characterized by a Th2-high state Overall a distinct microbiome role in CRSwNP and asthma pathogenesis is actually recognized However the significance of interactions between the lowerupper airways flora and the host local and systemic inflammatory response has not yet been well defined neither such a knowledge is exploited for a more accurate patients classification and selection of best possible therapeutic manipulation to change disease progression
Evidently an optimal diagnostic approach for CRSwNP AS would include use of very specific biomarkers ensuring a detailed endotyping whereas there is a growing consensus that both diseases should be treated to improve therapeutic outcome However the management of CRSwNP AS patients who remain uncontrolled despite medical and often surgical intervention poses a great challenge to clinicians Fortunately there has been significant innovation and expansion in the treatment armamentarium since the advent of biological therapies Targeted biologics monoclonal antibodies against IL-4 IL-5 IL-13 and IgE for treating asthma are now being used for CRSwNP with encouraging results
Recently mepolizumab Nucala GlaxoSmithKline an anti-IL5 humanized mab known to efficiently down-regulate the eosinophilic inflammatory pathway and to exhibit clinical benefit in patients with severe eosinophilic asthma has completed a phase 3 trial SYNAPSE NCT03085797 including 413 subjects with CRSwNP Early results showed treatment with mepolizumab had a significant difference in median nasal polyp score compared to baseline -073 95 CI -111 to -034 and nasal obstruction visual analog score compared to baseline -314 95 CI -409 to -218 unpublished data However there are only limited longitudinal studies evaluating this biologics efficacy in CRSwNPAS patients while the assessment of action mode and biomarkers predicting responsiveness remain to be elucidated
Despite the persuasive rationale for systemic targeting of shared pathways in CRSwNPAS with novel biologics in clinical practice the nose and lungs are often treated as separate entities and these therapeutics are considered rather challenging for the clinicians due to their high cost and necessity for careful selection of patients and right treatment Furthermore therapeutic decision-making is still based on a rather trial-and-error approach resulting in treatment failures or relapses There is clearly a need for a personalized medicine approach that would allow for a more accurate prediction of the appropriate choice of the drug at the initial assessment and ideally would communicate chances of long-term success to an individual patient
The principal goal of this three arms RWE study CRSwNPAS CRSwNP-AS healthy controls study is to develop signatures of host-microbiome biomarkers of both diagnostic and predicting value in order to provide a rational guideline for mepolizumab selection in precision treatment of patients with CRSwNPAS
In this frame mepolizumab therapeutic potential will be assessed in relation to the rather heterogeneous presentations of Th2 inflammation and airways microbiome structure The protocol will take on the question of microbiome dysbiosis involvement in immune activation and dysfunction contributing to CRSwNP AS diversity and delving into the complex patterns of host-microbiota molecular interactions in the upper and lower airways that may shape patients clinical predisposition to mepolizumab therapy
To address the study objectives a longitudinal design is proposed combining clinical assessments with high-throughput multi-omics analyses of patients samples and advanced bioinformatics for data integration The starting point of the project will be the consent recruitment of healthy controls CRSwNP AS and CRSwNP - AS participants Collection of biological samples from patients and clinical assessmentmeasurements of cell counts will take place at baseline ie the day of treatment initiation before mepolizumab administration T0 and at 3 T3 6 T6 and 12 T12 months after mepolizumab initiation Samples from healthy participants will be collected only at baseline T0 and analyzed in parallel with the corresponding samples from CRSwNP patients DNA and RNA will be isolated from induced sputum and nasal samples collected at T0 and T3 for subsequent 16S rRNA gene amplicon sequencing DNA shot-gun sequencing applied only in selected number of patients and healthy controls and bulk RNA sequencing RNAseq to identify airways microbiota modifications and differential gene expression respectively Peripheral blood mononuclear cells PBMC from a representative number of patients and healthy controls will be also analyzed at the same time points by single-cell RNA sequencing scRNAseq In parallel the dynamic pattern of cytokineschemokines in serumairways samples will be determined by xMAP immunoassays at T0 and T3 Subsequently multiple comparisons at the level of microbiome and host parameters will be undertaken mainly through two paths First between patients and healthy controls at T0 to assess differences of disease versus normal condition Second pairwise in each patient at T0 and at time intervals mostly at T3 after treatment intervention to capture potential alterations in response to mepolizumab Next a thorough integrative analysis engaging clinical data and multi-omics data from microbiome bulk RNAseq scRNAseq as well as cytokinomechemokinome analyses will be undertaken to investigate possible microbiome-host interactions Finally this integrative analysis will be exploited to gain a global view of hub genes inflammatory mediators and microbial taxa involved in key interactions and to build biomarker signatures that might serve as indicators of specific disease subtypes andor predictors of mepolizumab treatment outcome
Study Oversight
Has Oversight DMC:
None
Is a FDA Regulated Drug?:
False
Is a FDA Regulated Device?:
False
Is an Unapproved Device?:
None
Is a PPSD?:
None
Is a US Export?:
None
Is an FDA AA801 Violation?:
None