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

Asthma; Eosinophilic Clinical Trial

— FUNLUM  

Official title:

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

Clinical Trial Details — Status: Recruiting

Administrative data

• NCT number: NCT04512521
• Other study ID #: 8832_BO_S_2020
• Secondary ID: 213598
• Status: Recruiting
• Start date: May 4, 2020
• Est. completion date: August 2025

Study information

• Verified date: March 2023
• Source: Hannover Medical School
• Contact: Hendrik Suhling, MD
• Phone: 00495115323230
• Email: Suhling.Hendrik[@]mh-hannover.de
• Is FDA regulated: No
• Study type: Observational

Clinical Trial Summary

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.

Description:

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.

Recruitment information / eligibility

• Status: Recruiting
• Enrollment: 40
• Est. completion date: August 2025
• Est. primary completion date: February 2025
• Accepts healthy volunteers: No
• Gender: All
• Age group: 18 Years and older

Eligibility

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.

Related Conditions & MeSH terms

• Asthma
• Asthma; Eosinophilic
• Pulmonary Eosinophilia

Intervention

Drug:
• Mepolizumab
Mepolizumab therapy

Locations

Country	Name	City	State
Germany	Hannover Medical School	Hanover	Niedersachsen

Sponsors (2)

Lead Sponsor	Collaborator
Hannover Medical School	GlaxoSmithKline

Country where clinical trial is conducted

Germany, 

References & Publications (25)

Bauman G, Puderbach M, Deimling M, Jellus V, Chefd'hotel C, Dinkel J, Hintze C, Kauczor HU, Schad LR. Non-contrast-enhanced perfusion and ventilation assessment of the human lung by means of fourier decomposition in proton MRI. Magn Reson Med. 2009 Sep;62(3):656-64. doi: 10.1002/mrm.22031. — View Citation

Bel EH, Wenzel SE, Thompson PJ, Prazma CM, Keene ON, Yancey SW, Ortega HG, Pavord ID; SIRIUS Investigators. Oral glucocorticoid-sparing effect of mepolizumab in eosinophilic asthma. N Engl J Med. 2014 Sep 25;371(13):1189-97. doi: 10.1056/NEJMoa1403291. Epub 2014 Sep 8. — View Citation

Braman SS. The global burden of asthma. Chest. 2006 Jul;130(1 Suppl):4S-12S. doi: 10.1378/chest.130.1_suppl.4S. — View Citation

Capaldi DPI, Sheikh K, Eddy RL, Guo F, Svenningsen S, Nair P, McCormack DG, Parraga G; Canadian Respiratory Research Network. Free-breathing Functional Pulmonary MRI: Response to Bronchodilator and Bronchoprovocation in Severe Asthma. Acad Radiol. 2017 Oct;24(10):1268-1276. doi: 10.1016/j.acra.2017.04.012. Epub 2017 May 24. — View Citation

Castro M, Zangrilli J, Wechsler ME, Bateman ED, Brusselle GG, Bardin P, Murphy K, Maspero JF, O'Brien C, Korn S. Reslizumab for inadequately controlled asthma with elevated blood eosinophil counts: results from two multicentre, parallel, double-blind, randomised, placebo-controlled, phase 3 trials. Lancet Respir Med. 2015 May;3(5):355-66. doi: 10.1016/S2213-2600(15)00042-9. Epub 2015 Feb 23. Erratum In: Lancet Respir Med. 2015 Apr;3(4):e15. Lancet Respir Med. 2016 Oct;4(10 ):e50. — View Citation

Chung KF, Wenzel SE, Brozek JL, Bush A, Castro M, Sterk PJ, Adcock IM, Bateman ED, Bel EH, Bleecker ER, Boulet LP, Brightling C, Chanez P, Dahlen SE, Djukanovic R, Frey U, Gaga M, Gibson P, Hamid Q, Jajour NN, Mauad T, Sorkness RL, Teague WG. International ERS/ATS guidelines on definition, evaluation and treatment of severe asthma. Eur Respir J. 2014 Feb;43(2):343-73. doi: 10.1183/09031936.00202013. Epub 2013 Dec 12. Erratum In: Eur Respir J. 2014 Apr;43(4):1216. Dosage error in article text. Eur Respir J. 2018 Jul 27;52(1): Eur Respir J. 2022 Jun 9;59(6): — View Citation

Couch MJ, Ball IK, Li T, Fox MS, Biman B, Albert MS. 19 F MRI of the Lungs Using Inert Fluorinated Gases: Challenges and New Developments. J Magn Reson Imaging. 2019 Feb;49(2):343-354. doi: 10.1002/jmri.26292. Epub 2018 Sep 24. — View Citation

Drick N, Seeliger B, Welte T, Fuge J, Suhling H. Anti-IL-5 therapy in patients with severe eosinophilic asthma - clinical efficacy and possible criteria for treatment response. BMC Pulm Med. 2018 Jul 18;18(1):119. doi: 10.1186/s12890-018-0689-2. — View Citation

Eddy RL, Svenningsen S, McCormack DG, Parraga G. What is the minimal clinically important difference for helium-3 magnetic resonance imaging ventilation defects? Eur Respir J. 2018 Jun 28;51(6):1800324. doi: 10.1183/13993003.00324-2018. Print 2018 Jun. No abstract available. — View Citation

Gutberlet M, Kaireit TF, Voskrebenzev A, Lasch F, Freise J, Welte T, Wacker F, Hohlfeld JM, Vogel-Claussen J. Free-breathing Dynamic 19F Gas MR Imaging for Mapping of Regional Lung Ventilation in Patients with COPD. Radiology. 2018 Mar;286(3):1040-1051. doi: 10.1148/radiol.2017170591. Epub 2017 Oct 3. — View Citation

Hekking PW, Wener RR, Amelink M, Zwinderman AH, Bouvy ML, Bel EH. The prevalence of severe refractory asthma. J Allergy Clin Immunol. 2015 Apr;135(4):896-902. doi: 10.1016/j.jaci.2014.08.042. Epub 2014 Oct 16. — View Citation

Horn FC, Marshall H, Collier GJ, Kay R, Siddiqui S, Brightling CE, Parra-Robles J, Wild JM. Regional Ventilation Changes in the Lung: Treatment Response Mapping by Using Hyperpolarized Gas MR Imaging as a Quantitative Biomarker. Radiology. 2017 Sep;284(3):854-861. doi: 10.1148/radiol.2017160532. Epub 2017 May 4. — View Citation

Hueper K, Parikh MA, Prince MR, Schoenfeld C, Liu C, Bluemke DA, Dashnaw SM, Goldstein TA, Hoffman EA, Lima JA, Skrok J, Zheng J, Barr RG, Vogel-Claussen J. Quantitative and semiquantitative measures of regional pulmonary microvascular perfusion by magnetic resonance imaging and their relationships to global lung perfusion and lung diffusing capacity: the multiethnic study of atherosclerosis chronic obstructive pulmonary disease study. Invest Radiol. 2013 Apr;48(4):223-30. doi: 10.1097/RLI.0b013e318281057d. — View Citation

Kaireit TF, Gutberlet M, Voskrebenzev A, Freise J, Welte T, Hohlfeld JM, Wacker F, Vogel-Claussen J. Comparison of quantitative regional ventilation-weighted fourier decomposition MRI with dynamic fluorinated gas washout MRI and lung function testing in COPD patients. J Magn Reson Imaging. 2018 Jun;47(6):1534-1541. doi: 10.1002/jmri.25902. Epub 2017 Nov 21. — View Citation

Kaireit TF, Voskrebenzev A, Gutberlet M, Freise J, Jobst B, Kauczor HU, Welte T, Wacker F, Vogel-Claussen J. Comparison of quantitative regional perfusion-weighted phase resolved functional lung (PREFUL) MRI with dynamic gadolinium-enhanced regional pulmonary perfusion MRI in COPD patients. J Magn Reson Imaging. 2019 Apr;49(4):1122-1132. doi: 10.1002/jmri.26342. Epub 2018 Oct 22. — View Citation

Klimes F, Voskrebenzev A, Gutberlet M, Kern A, Behrendt L, Kaireit TF, Czerner C, Renne J, Wacker F, Vogel-Claussen J. Free-breathing quantification of regional ventilation derived by phase-resolved functional lung (PREFUL) MRI. NMR Biomed. 2019 Jun;32(6):e4088. doi: 10.1002/nbm.4088. Epub 2019 Mar 25. — View Citation

Mepolizumab treatment in patients with severe eosinophilic asthma. N Engl J Med. 2015 Apr 30;372(18):1777. doi: 10.1056/NEJMx150017. Epub 2015 Apr 10. No abstract available. — View Citation

Moher Alsady T, Voskrebenzev A, Greer M, Becker L, Kaireit TF, Welte T, Wacker F, Gottlieb J, Vogel-Claussen J. MRI-derived regional flow-volume loop parameters detect early-stage chronic lung allograft dysfunction. J Magn Reson Imaging. 2019 Dec;50(6):1873-1882. doi: 10.1002/jmri.26799. Epub 2019 May 27. — View Citation

Nair P, Wenzel S, Rabe KF, Bourdin A, Lugogo NL, Kuna P, Barker P, Sproule S, Ponnarambil S, Goldman M; ZONDA Trial Investigators. Oral Glucocorticoid-Sparing Effect of Benralizumab in Severe Asthma. N Engl J Med. 2017 Jun 22;376(25):2448-2458. doi: 10.1056/NEJMoa1703501. Epub 2017 May 22. — View Citation

Pavord ID, Korn S, Howarth P, Bleecker ER, Buhl R, Keene ON, Ortega H, Chanez P. Mepolizumab for severe eosinophilic asthma (DREAM): a multicentre, double-blind, placebo-controlled trial. Lancet. 2012 Aug 18;380(9842):651-9. doi: 10.1016/S0140-6736(12)60988-X. — View Citation

Svenningsen S, Eddy RL, Lim HF, Cox PG, Nair P, Parraga G. Sputum Eosinophilia and Magnetic Resonance Imaging Ventilation Heterogeneity in Severe Asthma. Am J Respir Crit Care Med. 2018 Apr 1;197(7):876-884. doi: 10.1164/rccm.201709-1948OC. — View Citation

Svenningsen S, Kirby M, Starr D, Leary D, Wheatley A, Maksym GN, McCormack DG, Parraga G. Hyperpolarized (3) He and (129) Xe MRI: differences in asthma before bronchodilation. J Magn Reson Imaging. 2013 Dec;38(6):1521-30. doi: 10.1002/jmri.24111. Epub 2013 Apr 15. — View Citation

To T, Stanojevic S, Moores G, Gershon AS, Bateman ED, Cruz AA, Boulet LP. Global asthma prevalence in adults: findings from the cross-sectional world health survey. BMC Public Health. 2012 Mar 19;12:204. doi: 10.1186/1471-2458-12-204. Erratum In: BMC Public Health. 2021 Oct 8;21(1):1809. — View Citation

Vogel-Claussen J, Schonfeld CO, Kaireit TF, Voskrebenzev A, Czerner CP, Renne J, Tillmann HC, Berschneider K, Hiltl S, Bauersachs J, Welte T, Hohlfeld JM. Effect of Indacaterol/Glycopyrronium on Pulmonary Perfusion and Ventilation in Hyperinflated Patients with Chronic Obstructive Pulmonary Disease (CLAIM). A Double-Blind, Randomized, Crossover Trial. Am J Respir Crit Care Med. 2019 May 1;199(9):1086-1096. doi: 10.1164/rccm.201805-0995OC. — View Citation

Voskrebenzev A, Gutberlet M, Klimes F, Kaireit TF, Schonfeld C, Rotarmel A, Wacker F, Vogel-Claussen J. Feasibility of quantitative regional ventilation and perfusion mapping with phase-resolved functional lung (PREFUL) MRI in healthy volunteers and COPD, CTEPH, and CF patients. Magn Reson Med. 2018 Apr;79(4):2306-2314. doi: 10.1002/mrm.26893. Epub 2017 Aug 30. — View Citation

* Note: There are 25 references in all — Click here to view all references

Outcome

Type	Measure	Description	Time frame	Safety issue
Primary	Baseline ventilation-defect percentage by pulmonary MRI	Baseline airway function by measuring ventilation-defect percentage by pulmonary MRI.	baseline
Primary	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
Primary	Baseline perfusion-defect percentage by pulmonary MRI	Baseline vascular function by measuring pulmonary perfusion-defect percentage by pulmonary MRI	baseline
Primary	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
Primary	Baseline ventilation/Perfusion mismatch by pulmonary MRI	Baseline Ventilation/Perfusion match and mismatch measured by pulmonary MRI.	baseline
Primary	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	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
Secondary	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
Secondary	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
Secondary	Baseline asthma control test	Baseline airway function measured by asthma control test (ACT)	baseline
Secondary	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
Secondary	Baseline Clinical lung function	Baseline airway function measured by Clinical lung function via bodyplesmography	baseline
Secondary	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
Secondary	Baseline fractional exhaled nitric oxide	Baseline airway function measured by fractional exhaled nitrix oxide (FeNO)	baseline
Secondary	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
Secondary	Baseline capillary blood gas analysis	Baseline airway function measured by capillary blood gas analysis	baseline
Secondary	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
Secondary	Baseline blood eosinophil cell count	Baseline airway function measured by blood eosinophil cell count	baseline
Secondary	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
Secondary	Baseline exacerbation rate	Baseline airway function measured by exacerbation rate	baseline
Secondary	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