Severe Asthma Clinical Trial
— P-CLESAOfficial title:
P-CLESA: Phenotyping Circulating and Lung Resident Eosinophils in Severe Asthma
Title: Phenotyping circulating and lung resident eosinophils in severe asthma (3 years).
Background: Asthma is a long-term condition that affects the airways. When a person with
asthma comes into contact with something that irritates their sensitive airways, the lungs
respond with contracting the muscles around the airway tubes, an inflammation process and
mucus production. The airway will become narrower and inflamed making it hard to breathe and
results in symptoms such as wheezing and coughing. The treatment of asthma consists of using
inhalers that work to widen the airway to relief these symptoms. Often severe asthmatics have
difficulty in controlling their disease, despite good medical care and taking asthma
medicines. At the moment there is no cure for asthma. A new medicine called Mepolizumab
(anti-Interleukin(IL)-5 therapy) has now shown to improve the symptoms of asthma particularly
patients with severe asthma in whom the normal medicines prescribed for asthma are not highly
effective in controlling their disease. You have been chosen receive this new medicine as we
believe it will improve the control of your disease. The aim for this study is to understand
the effect of Mepolizumab on a particular type of cell, called an eosinophil, which in
present lungs and blood of all people but is increased in asthma patients.
Rationale: The relationship between subsets of circulating and lung resident eosinophils in
severe asthma and Mepolizumab (anti-IL-5 therapy) efficacy has not been explored.
Objectives: To determine the gene expression and release of inflammatory proteins (mediator
profiles) of eosinophils from the circulation and the lung, specifically blood and tissue
resident, in patients with severe asthma at baseline and on Mepolizumab therapy.
Study 1: Phenotype subsets of circulating eosinophils in patients with severe asthma at one
time-point Recruit: 15 biologic naïve SA and 15 SA currently on Mepo therapy. Blood
eosinophils will be isolated by negative selection. Single-cell RNA-seq 10xGenomics and
bulk-RNA-seq to be used to simultaneously measure gene and cell surface protein expression in
the same cell to understand cellular heterogeneity in asthmatic eosinophils and identify
novel targets and biomarkers for non-responsiveness Study 2: Phenotype subsets of circulating
and lung eosinophils in patients with severe asthma on Mepolizumab therapy over one year.
Treat 30 appropriately characterised severe asthmatics (Eos>300/ul) with Mepolizumab Blood
eosinophils will be isolated by negative selection. Single-cell RNA-seq 10xGenomics and bulk
-RNA -seq to be used to understand cellular heterogeneity in asthmatic eosinophils post Mepo
Therapy. Sampling at baseline, 3 and 12 months post Mepo Therapy.
Bronchoscopy performed on 30 patients, sampling endobronchial lung biopsy at baseline and 1
yr post Mepo Therapy. Single-cell RNA-seq 10xGenomics on lung resident eosinophils at
baseline and 1yr post Mepolizumab therapy. Immunohistochemistry will also be performed to
characterise cellular content and structure.
Status | Not yet recruiting |
Enrollment | 66 |
Est. completion date | August 31, 2023 |
Est. primary completion date | February 28, 2023 |
Accepts healthy volunteers | |
Gender | All |
Age group | 18 Years to 70 Years |
Eligibility |
Inclusion Criteria: - Male or female subject aged between 18 years and 70 years. - Give written informed consent prior to participation in the study including all of its procedures. - Comply with study protocol requirements - Able to read, comprehend, and write at a sufficient level to complete study related materials. - Able to complete the study and all measurements. - All participants have been through a severe asthma protocol that have ascertained the diagnosis of severe asthma, maximised treatments and ensured adherence to therapy. - Stable asthma therapy for at least a month before screening - On <10 mg maintenance OCS therapy Exclusion criteria: Subjects will not be eligible if any of the following apply: - - As a result of medical interview, physical examination or screening investigation the investigators consider the subject unfit either because of risk to the subject due to the study or the influence this may have on the study results. - A history of recreational drug use or allergy which in the opinion of the investigators contra-indicates their participation. - Participation within 3 months in any a trial testing a new molecular entity or drug. - Those, in the opinion of the investigator, who may prove non-compliant with study procedures. - Within 4 weeks of screening visit been hospitalized or required high dose oral corticosteroid (>30 mg prednisolone per day) therapy, asthma not been stable. - Participants who have had prior treatment with bronchial thermoplasty, defined as completion of all thermoplasty treatment sessions within 6 months of screening - History of significant pulmonary disease other than severe asthma. - History of pulmonary eosinophilic syndrome or hyper eosinophilic syndrome. - History of bronchopulmonary aspergillosis Exclusion Criteria: - |
Country | Name | City | State |
---|---|---|---|
United Kingdom | Royal Brompton & Harefield NHS Trust, | London |
Lead Sponsor | Collaborator |
---|---|
Imperial College London |
United Kingdom,
Barthel SR, Johansson MW, McNamee DM, Mosher DF. Roles of integrin activation in eosinophil function and the eosinophilic inflammation of asthma. J Leukoc Biol. 2008 Jan;83(1):1-12. Epub 2007 Oct 10. Review. — 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
Bousquet J, Chanez P, Lacoste JY, Barnéon G, Ghavanian N, Enander I, Venge P, Ahlstedt S, Simony-Lafontaine J, Godard P, et al. Eosinophilic inflammation in asthma. N Engl J Med. 1990 Oct 11;323(15):1033-9. — View Citation
Chu VT, Beller A, Rausch S, Strandmark J, Zänker M, Arbach O, Kruglov A, Berek C. Eosinophils promote generation and maintenance of immunoglobulin-A-expressing plasma cells and contribute to gut immune homeostasis. Immunity. 2014 Apr 17;40(4):582-93. doi: 10.1016/j.immuni.2014.02.014. — 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. Erratum in: Eur Respir J. 2018 Jul 27;52(1):. — View Citation
Chung KF. Targeting the interleukin pathway in the treatment of asthma. Lancet. 2015 Sep 12;386(9998):1086-96. doi: 10.1016/S0140-6736(15)00157-9. Review. — View Citation
Håkansson L, Heinrich C, Rak S, Venge P. Priming of eosinophil adhesion in patients with birch pollen allergy during pollen season: effect of immunotherapy. J Allergy Clin Immunol. 1997 Apr;99(4):551-62. — View Citation
Hart TK, Cook RM, Zia-Amirhosseini P, Minthorn E, Sellers TS, Maleeff BE, Eustis S, Schwartz LW, Tsui P, Appelbaum ER, Martin EC, Bugelski PJ, Herzyk DJ. Preclinical efficacy and safety of mepolizumab (SB-240563), a humanized monoclonal antibody to IL-5, in cynomolgus monkeys. J Allergy Clin Immunol. 2001 Aug;108(2):250-7. — View Citation
Hogan SP, Rosenberg HF, Moqbel R, Phipps S, Foster PS, Lacy P, Kay AB, Rothenberg ME. Eosinophils: biological properties and role in health and disease. Clin Exp Allergy. 2008 May;38(5):709-50. doi: 10.1111/j.1365-2222.2008.02958.x. Epub 2008 Apr 1. Review. — View Citation
Johansson MW, Mosher DF. Integrin activation States and eosinophil recruitment in asthma. Front Pharmacol. 2013 Apr 1;4:33. doi: 10.3389/fphar.2013.00033. eCollection 2013. — View Citation
Kankaanranta H, Ilmarinen P, Zhang X, Adcock IM, Lahti A, Barnes PJ, Giembycz MA, Lindsay MA, Moilanen E. Tumour necrosis factor-a regulates human eosinophil apoptosis via ligation of TNF-receptor 1 and balance between NF-?B and AP-1. PLoS One. 2014 Feb 28;9(2):e90298. doi: 10.1371/journal.pone.0090298. eCollection 2014. — View Citation
Kuo CS, Pavlidis S, Zhu J, Loza M, Baribaud F, Rowe A, Pandis I, Gibeon D, Hoda U, Sousa A, Wilson SJ, Howarth P, Shaw D, Fowler S, Dahlen B, Chanez P, Krug N, Sandstrom T, Fleming L, Corfield J, Auffray C, Djukanovic R, Sterk PJ, Guo Y, Adcock IM, Chung KF; U-BIOPRED Project Team. Contribution of airway eosinophils in airway wall remodeling in asthma: Role of MMP-10 and MET. Allergy. 2019 Jun;74(6):1102-1112. doi: 10.1111/all.13727. Epub 2019 Feb 11. — View Citation
Létuvé S, Druilhe A, Grandsaigne M, Aubier M, Pretolani M. Involvement of caspases and of mitochondria in Fas ligation-induced eosinophil apoptosis: modulation by interleukin-5 and interferon-gamma. J Leukoc Biol. 2001 Nov;70(5):767-75. — View Citation
Lopez AF, Sanderson CJ, Gamble JR, Campbell HD, Young IG, Vadas MA. Recombinant human interleukin 5 is a selective activator of human eosinophil function. J Exp Med. 1988 Jan 1;167(1):219-24. — View Citation
Mesnil C, Raulier S, Paulissen G, Xiao X, Birrell MA, Pirottin D, Janss T, Starkl P, Ramery E, Henket M, Schleich FN, Radermecker M, Thielemans K, Gillet L, Thiry M, Belvisi MG, Louis R, Desmet C, Marichal T, Bureau F. Lung-resident eosinophils represent a distinct regulatory eosinophil subset. J Clin Invest. 2016 Sep 1;126(9):3279-95. doi: 10.1172/JCI85664. Epub 2016 Aug 22. — View Citation
Ortega HG, Liu MC, Pavord ID, Brusselle GG, FitzGerald JM, Chetta A, Humbert M, Katz LE, Keene ON, Yancey SW, Chanez P; MENSA Investigators. Mepolizumab treatment in patients with severe eosinophilic asthma. N Engl J Med. 2014 Sep 25;371(13):1198-207. doi: 10.1056/NEJMoa1403290. Epub 2014 Sep 8. Erratum in: N Engl J Med. 2015 Apr 30;372(18):1777. — View Citation
Ortega HG, Yancey SW, Mayer B, Gunsoy NB, Keene ON, Bleecker ER, Brightling CE, Pavord ID. Severe eosinophilic asthma treated with mepolizumab stratified by baseline eosinophil thresholds: a secondary analysis of the DREAM and MENSA studies. Lancet Respir Med. 2016 Jul;4(7):549-556. doi: 10.1016/S2213-2600(16)30031-5. Epub 2016 May 10. — 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
Rosenberg HF, Dyer KD, Foster PS. Eosinophils: changing perspectives in health and disease. Nat Rev Immunol. 2013 Jan;13(1):9-22. doi: 10.1038/nri3341. Epub 2012 Nov 16. Review. — View Citation
Rothenberg ME, Hogan SP. The eosinophil. Annu Rev Immunol. 2006;24:147-74. Review. — View Citation
Travers J, Rothenberg ME. Eosinophils in mucosal immune responses. Mucosal Immunol. 2015 May;8(3):464-75. doi: 10.1038/mi.2015.2. Epub 2015 Mar 25. Review. — View Citation
Wenzel S, Ford L, Pearlman D, Spector S, Sher L, Skobieranda F, Wang L, Kirkesseli S, Rocklin R, Bock B, Hamilton J, Ming JE, Radin A, Stahl N, Yancopoulos GD, Graham N, Pirozzi G. Dupilumab in persistent asthma with elevated eosinophil levels. N Engl J Med. 2013 Jun 27;368(26):2455-66. doi: 10.1056/NEJMoa1304048. Epub 2013 May 21. — View Citation
Wenzel S, Wilbraham D, Fuller R, Getz EB, Longphre M. Effect of an interleukin-4 variant on late phase asthmatic response to allergen challenge in asthmatic patients: results of two phase 2a studies. Lancet. 2007 Oct 20;370(9596):1422-31. — View Citation
Yancey SW, Keene ON, Albers FC, Ortega H, Bates S, Bleecker ER, Pavord I. Biomarkers for severe eosinophilic asthma. J Allergy Clin Immunol. 2017 Dec;140(6):1509-1518. doi: 10.1016/j.jaci.2017.10.005. Review. — View Citation
* Note: There are 24 references in all — Click here to view all references
Type | Measure | Description | Time frame | Safety issue |
---|---|---|---|---|
Primary | Phenotype subsets of circulating eosinophils from participants with severe asthma at one time-point | Determine the transcriptomic and mediator profiles of eosinophils from the circulation, specifically blood, in participants with severe asthma on Mepolizumab therapy. | 18 months | |
Primary | Phenotype subsets of circulating and lung eosinophils from participants with severe asthma on Mepolizumab therapy over one year. | Determine the transcriptomic and mediator profiles of eosinophils from the circulation and the airway, specifically blood and tissue resident, in participants with severe asthma at baseline and on Mepolizumab therapy at one year. | 3 years |
Status | Clinical Trial | Phase | |
---|---|---|---|
Recruiting |
NCT05018299 -
Evaluate the Efficacy and Safety of FB704A in Adult With Severe Asthma
|
Phase 2 | |
Recruiting |
NCT05472324 -
Evaluate the Efficacy and Safety of TQC2731 Injection in Patients With Severe Asthma.
|
Phase 2 | |
Recruiting |
NCT04914078 -
Severe Asthma Exacerbations and Mepolizumab Treatment
|
||
Completed |
NCT05576454 -
Evaluate the Pharmacokinetics of BAT2606 Injection in Healthy Chinese Male Subjects
|
Phase 1 | |
Recruiting |
NCT04520165 -
Effect of Biologicals on Alternative Functions of Eosinophils in Severe Asthma
|
||
Recruiting |
NCT04438408 -
National Survey on Care Pathway and Quality of Life in Patients With Severe Asthma According to Their Phenotype.
|
||
Enrolling by invitation |
NCT06421402 -
K-HEALTH in AIR - Barcelona Pilot - Cohort
|
||
Recruiting |
NCT03377920 -
Predictive Value of Spirometric PIF to Produce PIF Rate Needed for the Use of Current DPI's.
|
N/A | |
Recruiting |
NCT04565483 -
Predictive Signature of Benralizumab Response
|
Phase 4 | |
Recruiting |
NCT04045587 -
International Severe Asthma Registry: Canadian Cohort
|
||
Completed |
NCT05616338 -
Modeling Bronchial Epithelium in Severe Asthma With Human Induced Pluripotent Stem Cells (iPSC)
|
N/A | |
Active, not recruiting |
NCT02038374 -
Clinico-biological Correlation of Severe Asthma in Children
|
N/A | |
Active, not recruiting |
NCT02114034 -
Cohort Analysis of Clinical and Biological Severe Childhood Asthma
|
||
Recruiting |
NCT06035289 -
Register Schweres Asthma - German Asthma Net e.V.
|
||
Not yet recruiting |
NCT03532685 -
Clinical, Inflammatory and Functional Evaluation of a Population of Severe and Obese Asthmatics: Follow up
|
N/A | |
Completed |
NCT03931954 -
Prevalence of the Eosinophilic Phenotype Among Severe Asthma Patients
|
||
Recruiting |
NCT03984253 -
Swiss Severe Asthma Register
|
||
Recruiting |
NCT03435237 -
Phenotyping Asthma for Bronchial Thermoplasty
|
||
Recruiting |
NCT03476109 -
Study of Magnitude and Prediction of Response to Omalizumab and Mepolizumab in Adult Severe Asthma.
|
Phase 4 | |
Active, not recruiting |
NCT06389058 -
Using NLP and Neural Networks to Autonomously Identify Severe Asthma and Determine Study Eligibility in a Large Healthcare System
|