Functional Lung MRI for Early Treatment Response Assessment for Patients With Eosinophilic Asthma

Study Overview
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Brief Summary
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Patients with severe eosinophilic asthma will be placed on biologics if they continue to be uncontrolled despite maximized inhalation therapy or if they are only controlled under oral corticosteroids. Among biologics, 80% of patients respond to treatment and improve clinically, but approximately 20% are non-responders and up to date no established predictive factors for treatment response exist. Among the responders, about 30% respond very well (so-called super responders), the rest shows moderate improvements. As the lung function, one main criterion to evaluate treatment response improves in most patients with delay, the response (or non-response) to treatment can only be reliably estimated after 4 to 12 months. This can lead to prolonged use of medication in non-responders (overtreatment) on one hand and to unjustified and premature termination of therapy (undertreatment) on the other hand (GINA report 2019). Functional lung MRI has the potential to show early changes in lung microstructure, regional ventilation and perfusion and thus has the potential for early detection of therapy response. Very promising results of dynamic regional ventilation and perfusion mapping using phase resolved functional lung (PREFUL) MRI have been shown recently. However, if functional lung MRI can reliably detect treatment effects under Mepolizumab therapy and can help to predict a long-term patient outcome is still unknown. As these findings could directly influence clinical decision making this question is of high clinical relevance.

Detailed Description
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Asthma is a chronic disease and affects approximately 300 million people worldwide. Of these patients 3-10% have severe asthma which is defined as asthma remaining uncontrolled despite treatment with high-dose inhaled glucocorticoids combined with other controllers (long-acting β2-agonist, long-acting antimuscarinic agent, leukotriene receptor antagonist or theophylline) and/or treatment with systemic glucocorticoids for at least 6 months. Severe asthma causes a high amount of medical expenses in asthma. For patients suffering from severe uncontrolled asthma, an IL-5 antibody (mepolizumab) has been approved for therapy when a type 2 inflammation was present. Treatment is well tolerated and a significant reduction of exacerbations, oral glucocorticoid use was reported. Another IL-5 antibody (reslizumab) and an IL-5 receptor antibody (benralizumab) are available now. Patients with severe eosinophilic asthma will be placed on biologics if they continue to be uncontrolled under maximal therapy or if they are only controlled under oral corticosteroids. Among biologics, 80% of patients improve, 20% are non-responders, but there is no way to identify them early. Among the responders, about 30% respond very well (so-called super responders), the rest shows moderate improvements. The main problems at the moment are that lung function improvements are only delayed, the response (or non-response) can only be reliably estimated after 4 to 12 months. This leads on the one hand to prolonged use of medication in non-responders (overtreatment), on the other hand to unjustified and premature termination of therapy (undertreatment) (GINA report 2019). Study Rationale Functional lung MRI has the potential to show early changes in lung microstructure, regional ventilation and perfusion and thus has the potential for early detection of therapy response. Very promising results of dynamic regional ventilation and perfusion mapping using phase resolved functional lung (PREFUL) MRI have been shown recently. This technique holds the promise to mature into a patient friendly sensitive MRI spirometry test, with novel clinically relevant information to guide clinical decision making and improve patient monitoring. PREFUL MRI typically uses standard 1.5T or 3T MRI equipment and is based on a routine gradient echo fast low angle shot (FLASH) sequence. PREFUL is well suited also for children, because it is a free breathing exam without the need for i.v. contrast and has a relatively short examination time. The ventilation, perfusion and dynamic flow-volume loop maps are reconstructed entirely after the image acquisition using complex registration and post processing algorithms developed and validated at Hannover Medical School. Preliminary unpublished data show that PREFUL MRI may detect changes in regional ventilation 3 months after anti IL 5 antibody therapy treatment. However, if functional lung MRI can reliably detect changes at 3 months of Mepolizumab treatment and can predict long term patient outcome is still unknown, which is of high clinical relevance for future clinical decision making. The aim of this study is to examine if early treatment changes of Mepolizumab treatment can be detected at 3 months measured by functional lung MRI and predict clinical outcome at 12 months of treatment.

Official Title
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FUNLUM: Functional Lung MRI for Early Treatment Response Assessment and Outcome Prediction for Patients With Severe Eosinophilic Asthma on Anti IL 5 Antibody Therapy

Conditions
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Asthma; Eosinophilic

Intervention / Treatment
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* Drug: Mepolizumab


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Able and willing to give written informed consent. Male and female subjects, aged ≥ 18 years. Patients which are eligible for treatment using anti-IL-5 -antibody treatment following guidelines: severe eosinophilic asthma and blood eosinophils of ≥150 cells/μL at screening or ≥ 300 cells/μL within 12 months prior to treatment Physician-diagnosed severe asthma according to ERS/ATS guidelines Treatment with a total daily dose of medium or high-dose ICS (e.g. ≥ 500μg fluticasone propionate, ≥ 800μg budesonide or equivalent total daily dose). ICS can be contained within an ICS/LABA combination product. At least one additional maintenance asthma controller e.g. LABA, LTRA, theophylline, LAMA, etc. with or without OCS Exclusion Criteria: Any clinically relevant abnormal findings in physical examination, clinical chemistry, hematology, urinalysis, vital signs, lung function at screening visit, which, in the opinion of the investigator, may either put the subject at risk because of participation in the study or may influence the results of the study, or the subject's ability to participate in the study. Past or present disease, which as judged by the investigator, may affect the outcome of this study. These diseases include, but are not limited to, cardiovascular disease, malignancy, hepatic disease, renal disease, hematological disease, neurological disease, endocrine disease or pulmonary disease other than Asthma (including but not confined to tuberculosis, bronchiectasis, cystic fibrosis, pulmonary hypertension, sarcoidosis, interstitial lung disease or lung fibrosis). History of drug or alcohol abuse. Risk of non-compliance with study procedures. Suspected inability to understand the protocol requirements, instructions and study-related restrictions, the nature, scope, and possible consequences of the study. History of an acute respiratory infection four weeks prior to enrolment. These patients will not be eligible, but will be permitted to be rescreened 4 weeks after the resolution of the respiratory tract infection. Subjects with severe renal impairment (GFR ≤ 30 mL/min) including those with end-stage renal disease requiring dialysis or urinary retention. Subjects with active/ clinical history of COPD. Subjects unable to undergo MRI scans, including claustrophobia or presence of any metal objects within the patient, preventing from MRI scan (e.g. pacemaker, aneurysm clips). History of asthma exacerbation that required treatment with antibiotics, systemic steroids (oral or intravenous) or hospitalization within 3 months prior to enrolment. Subjects with a body mass index (BMI) of more than 35 kg/m2.

Ages Eligible for Study
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Minimum Age: 18 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| eosinophilic asthma<br> | Drug: Mepolizumab<br>* Mepolizumab therapy<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Baseline ventilation-defect percentage by pulmonary MRI | Baseline airway function by measuring ventilation-defect percentage by pulmonary MRI. | baseline | 
| Ventilation-defect percentage by pulmonary MRI after 3 months treatment with Mepolizumab | To study the effect of Mepolizumab treatment after 3 months treatment compared to baseline on airway function by measuring ventilation-defect percentage by pulmonary MRI. | 3 months | 
| Baseline perfusion-defect percentage by pulmonary MRI | Baseline vascular function by measuring pulmonary perfusion-defect percentage by pulmonary MRI | baseline | 
| Perfusion-defect percentage by pulmonary MRI after 3 months treatment with Mepolizumab | To study the effect of Mepolizumab treatment after 3 months treatment compared to baseline on vascular function by measuring pulmonary perfusion-defect percentage by pulmonary MRI | 3 months | 
| Baseline ventilation/Perfusion mismatch by pulmonary MRI | Baseline Ventilation/Perfusion match and mismatch measured by pulmonary MRI. | baseline | 
| Ventilation/Perfusion mismatch by pulmonary MRI after 3 months treatment with Mepolizumab | To study the effect of Mepolizumab treatment after 3 months treatment compared to baseline as Ventilation/Perfusion match and mismatch measured by pulmonary MRI. | 3 months | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Ventilation-defect percentage by pulmonary MRI after 6 weeks treatment with Mepolizumab | To study the effect of Mepolizumab treatment after 6 weeks treatment compared to baseline on airway function by measuring ventilation-defect percentage by pulmonary MRI. | 6 weeks | 
| Perfusion-defect percentage by pulmonary MRI after 6 weeks treatment with Mepolizumab | To study the effect of Mepolizumab treatment after 6 weeks treatment compared to baseline on airway function by measuring perfusion-defect percentage by pulmonary MRI. | 6 weeks | 
| Ventilation/Perfusion mismatch by pulmonary MRI after 6 weeks treatment with Mepolizumab | To study the effect of Mepolizumab treatment after 6 weeks treatment compared to baseline on airway function by measuring ventilation/perfusion mismatch by pulmonary MRI. | 6 weeks | 
| Baseline asthma control test | Baseline airway function measured by asthma control test (ACT) | baseline | 
| Asthma control test after 12 months of treatment with Mepolizumab | To study the effect of Mepolizumab treatment after 12 months compared to baseline on airway function measured by asthma control test (ACT). | 12 months | 
| Baseline Clinical lung function | Baseline airway function measured by Clinical lung function via bodyplesmography | baseline | 
| Clinical lung function after 12 months of treatment with Mepolizumab | To study the effect of Mepolizumab treatment after 12 months compared to baseline on airway function measured by Clinical lung function via bodyplesmography | 12 months | 
| Baseline fractional exhaled nitric oxide | Baseline airway function measured by fractional exhaled nitrix oxide (FeNO) | baseline | 
| Fractional exhaled nitric oxide after 12 months of treatment with Mepolizumab | To study the effect of Mepolizumab treatment after 12 months compared to baseline on airway function measured by fractional exhaled nitrix oxide (FeNO) | 12 months | 
| Baseline capillary blood gas analysis | Baseline airway function measured by capillary blood gas analysis | baseline | 
| Capillary blood gas analysis after 12 months of treatment with Mepolizumab | To study the effect of Mepolizumab treatment after 12 months compared to baseline on airway function measured by capillary blood gas analysis | 12 months | 
| Baseline blood eosinophil cell count | Baseline airway function measured by blood eosinophil cell count | baseline | 
| Blood eosinophil cell count after 12 months of treatment with Mepolizumab | To study the effect of Mepolizumab treatment after 12 months compared to baseline on airway function measured by blood eosinophil cell count | 12 months | 
| Baseline exacerbation rate | Baseline airway function measured by exacerbation rate | baseline | 
| Exacerbation rate after 12 months of treatment with Mepolizumab | To study the effect of Mepolizumab treatment after 12 months compared to baseline on airway function measured by exacerbation rate | 12 months |