Severe Eosinophilic Asthma w/wo CRSwNPNCT05365841
Role of Epithelial Barrier Integrity in Biologic Treatment Response of Severe Asthmatics With/Out Chronic Rhinosinusitis With Nasal Polyps (CRSwNP).
An observational study of Severe Eosinophilic Asthma w/wo CRSwNP, run by University of Crete at 2 sites in Greece.
Trial summary
Advances in understanding the pathophysiology of asthma development and severity have pointed towards a prominent role of the bronchial epithelium, especially in more chronic and severe disease. Read more about this study
- Who is it for?
- Ages 18 years and older
- Conditions the study is for
- Severe Eosinophilic Asthma w/wo CRSwNP
- What is being tested?
- Mepolizumab 100 MG
- How many people
- 85 participants
- Where
- 2 sitesGreece
- Study dates
- 15 May 2022to 16 Nov 2025
- Phase
- Observational
- Are there results?
- None posted in the registry
Key requirements
Who can take part, as listed by the sponsor. Only the study team can confirm whether you are eligible, so take this list to your doctor.
- Ages 18 years and older
- All sexes
- No healthy volunteers
- Adult, Older adult
Study population: Adults with severe eosinophilic asthma, naive to anti-IL5/anti-IL5R treatment with or without CRSwNP who meet requirements for biologic therapy with anti-IL5 (Mepolizumab)
Who may be able to join
- 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.
- Anti-IL5/IL5R naïve
- Confirmed asthma diagnosis and severity and treatment requirements (for severe asthma group see boxes 1-3). For the 2nd control group, patients with CRSwNP must have a diagnosis of mild asthma (GINA steps 1-2) or no asthma by pulmonologist.
- Polyposis must be bilateral, to be considered as CRSwNP
- Triggers and relevant co-morbidity have been assessed and are well controlled Triggers such as active or passive smoking, beta-blockers, aspirin/NSAIDs, allergen exposure;Comorbidities such as rhinitis, obesity, GERD, OSA, VCD, depression/anxiety.
- Age: Adults ≥18 years of age
Show all 16Show fewer
- Any smoking status
- Any ethnicity
- Be affiliated to or a beneficiary of a social security category and/health insurance.
- Gender: Male and Eligible Female. To be eligible for entry into the study, females of childbearing potential must commit to consistent and correct use of an acceptable method of birth control for the duration of the follow up (and for 4 months after the last injection administration). A serum pregnancy test is required of all females. This test will be performed at the initial screening visit. In addition, a urine pregnancy test can be offered (optional) for all females during each scheduled treatment visit prior to the infusion of biologic product until the 1-year follow-up visit.
- Laboratory abnormality: No evidence of clinically significant abnormality (other than those seen in SEA) in the haematological, biochemical or urinalysis screen at Visit 1, as judged by the investigator.
- Asthma Exacerbation: Subjects with an ongoing asthma exacerbation should have their screening and treatment initiation visit delayed until the investigator considers the subject has returned to their baseline asthma status. If the 4-week screening period (visits 1 and 1a) has elapsed, then the subject should be considered a screening failure. An exacerbation is defined as worsening of asthma requiring the use of systemic CS and/or emergency department visit, or hospitalisation. For subjects on maintenance oral corticosteroids, an exacerbation requiring oral CS is defined as the use of oral/systemic corticosteroids at least double the existing dose for at least 3 days.
- Maintenance Asthma Therapy: No changes in the dose or regimen of baseline ICS and/or additional controller medication during the screening period (except for treatment of an exacerbation).
- Maintenance CRSwNP: No changes in the dose or regimen of baseline intranasal CS and/or additional controller medication during the screening period (except for treatment of an exacerbation).
- Subjects with a previous surgery for the removal of nasal polyps are allowed to participate and will be considered as subjects with CRSwNP (with severe asthma or not). However, any subject who had at least one surgery for removal of nasal polyps, even if at study screening he/she is free of nasal polyps, cannot be considered as a subject without CRSwNP.
- Severe asthma patients must meet requirements for biologic therapy with anti-IL5 treatment (Mepolizumab)
Who cannot join
- Pregnancy
- Current exacerbation at visit 1 (repeat screening when stable). If exacerbation is lasting up until Visit 1a then exclude subject.
- Cognitive impairment preventing completion of data collection forms
- People highly dependent on medical care
- People with significant life limiting co-morbidity
- Other eosinophilic conditions (eosinophilic granulomatosis polyangiitis (Churg-Strauss syndrome), eosinophilic oesophagitis etc)
Show all 12Show fewer
- Unilateral polyposis
- Primary diagnosis of lung disease other than asthma (chronic obstructive lung disease (COPD), asthma-COPD overlap (ACO), interstitial lung disease, sarcoidosis, bronchiectasis, cystic fibrosis, primary ciliary dyskinesia, active tuberculosis, allergic bronchopulmonary aspergillosis (ABPA))
- Current lung cancer or other blood, lymphatic or solid organ malignancy
- Autoimmune diseases of the skin, muscle-skeletal or gastrointestinal system needing systemic corticosteroids, immunosuppressants or biologic treatment as well as individuals with granulomatosis with polyangiitis (Wegener's granulomatosis)
- Inability to attend study and treatment visits
- Inability to understand and speak Greek or English language
Trial locations and contacts
2 sites in 1 country.
Greece2 sites, 1 recruiting
- Active, not recruiting
"PAGNI" University Hospital, Crete
Heraklion, Crete, 71500
- Recruiting
Aikaterini Antoniou
Heraklion, Crete, 71500
Aikaterini Antoniou, Professor, +306972300105, kantoniou@uoc.gr
Aikaterini Antoniou, Professor
About this study
Official title: Role of Epithelial Barrier Integrity in Biologic Treatment Response of Severe Asthmatics With/Out Chronic Rhinosinusitis With Nasal Polyps (CRSwNP). Can Shedding of Epithelial Barrier Proteins be Used as Biomarker in Severe Asthma With/Out CRSwNP Management?
Advances in understanding the pathophysiology of asthma development and severity have pointed towards a prominent role of the bronchial epithelium, especially in more chronic and severe disease. Studies suggest that airway eosinophilic inflammation in asthma is linked to epithelial injury and structural changes of the airways, co called airway wall remodeling. Together the chronic airway inflammation and remodeling are associated with bronchial hyperresponsiveness, fixed airflow obstruction or progressive loss of lung function and clinical severity of asthma. Chronic rhinosinusitis with nasal polyps (CRSwNP), is another respiratory inflammatory disease often co-existing with severe asthma, sharing similar pathophysiology. The investigators hypothesize that epithelial barrier integrity may play a role in the pathophysiology of severe eosinophilic asthma and nasal polyposis and in response to anti-IL5 therapy of severe asthmatics, and that shedding of epithelial barrier proteins may be used as biomarker in the management of severe asthma. In order to study that, the investigators will conduct a prospective cohort study of adult severe asthmatics with/out CRSwNP, who live on the island of Crete, Greece and who meet the criteria for entering anti-IL5 treatment, as assessed by pulmonologist. The participants will be recruited with a convenience sampling in a period of 2 years, under real life conditions, and will be followed up for 1 year after treatment initiation. A control group of subjects diagnosed with nasal polyposis without severe asthma will be used. Eligible subjects will undergo clinical assessment with radiological (CT) and endoscopic investigations. Samples of serum, sputum, nasal secretions, as well as nasal and bronchial biopsies will be obtain for assessing clinicopathological differences among the 3 groups but also response to anti-IL5 therapy in SEA w/o CRSwNP.
- Conditions
- Severe Eosinophilic Asthma w/wo CRSwNP
- Being tested
- Mepolizumab 100 MG
What participants receive
What participants receive. In a randomised study each person is assigned to one group by chance.
Mepolizumab 100 MGDrug
Patients with SEA eligible to receive anti-IL5 treatment, which is a biologic treatment for SEA
| Study group | Role | What they receive |
|---|---|---|
| Severe asthma without CRSwNP | control group; n~20 of anti-IL5 naïve severe asthmatics Receives: Drug: Mepolizumab 100 MG | |
| Severe asthma with CRSwNP | n~40 of anti-IL5 naïve severe asthmatics Receives: Drug: Mepolizumab 100 MG | |
| subjects CRSwNP with mild or no asthma | ~25;2nd control group |
What is being measured
The primary outcome is the main question the study is designed to answer.
Differences in sputum columnar epithelial cells (CEPs) among 3 groups (SEA w/o CRSwNP and CRSwNP with mild or no asthma) at baseline, and change in sputum CEPs in 1-year post anti-IL5 treatment initiation in SEA w/o CRSwNP
We will employ flow cytometry on freshly isolated sputum cell suspensions from participants to measure CEPs proportion and count. Previously proposed cut-off value for normal range sputum CEP proportion (CEP % high = ≥11%) or number (CEP count high = ≥18.1 × 10^4/mL) may be considered.
Measured: Baseline and 1 year
Differences in E-cadherin protein level in sputum and nasal secretions among 3 groups (SEA w/o CRSwNP and CRSwNP with mild or no asthma) at baseline, and change in E-cadherin protein level in 1-year post anti-IL5 treatment initiation in SEA w/o CRSwNP
Soluble E-cadherin in sputum and nasal secretions measured with ELISA. Data will be expressed as nanograms per milliliter in original sputum/secretion. Cell surface expression of E-cadherin on columnar epithelial cells may be analyzed by flow cytometry.
Measured: Baseline and 1 year
Differences in nasal and bronchial epithelial thickness among 3 groups (SEA w/o CRSwNP and CRSwNP with mild or no asthma) at baseline, and change in epithelial thickness in 1-year post anti-IL5 treatment initiation in SEA w/o CRSwNP
Epithelial thickness will be determined in biopsies by dividing the epithelial surface area by the basement membrane (BM) length
Measured: Baseline and 1 year
Differences in nasal and bronchial epithelial integrity among 3 groups (SEA w/o CRSwNP and CRSwNP with mild or no asthma) at baseline, and change in epithelial integrity in 1-year post anti-IL5 treatment initiation in SEA w/o CRSwNP
Epithelial integrity will be assessed in biopsy sections and expressed as percentage (%) of BM covered with normal epithelium (a layer of basal and ciliated columnar epithelial cells without detachment from the BM)
Measured: Baseline and 1 year
Differences in nasal and bronchial epithelial E-cadherin expression among 3 groups (SEA w/o CRSwNP and CRSwNP with mild or no asthma) at baseline, and change in protein expression in 1-year post anti-IL5 treatment initiation in SEA w/o CRSwNP
Epithelial E-cadherin expression in biopsies will be measure with immonohistochemistry and expressed as the percentage of BM covered with E-cadherin-positive intact epithelium and/or as strong, moderate and weak epithelial E-cadherin staining
Measured: Baseline and 1 year
Differences in nasal and bronchial basement membrane thickness (BM) among 3 groups (SEA w/o CRSwNP and CRSwNP with mild or no asthma) at baseline, and change in Basement membrane thickness in 1-year post anti-IL5 treatment initiation in SEA w/o CRSwNP
BM thickness in biopsies will be expressed as BM surface area divided by BM length
Measured: Baseline and 1 year
Differences in CT-assessed airway wall thickness (WT) among 3 groups (SEA w/o CRSwNP and CRSwNP with mild or no asthma) at baseline, and change in WT in 1-year post anti-IL5 treatment initiation in SEA w/o CRSwNP
We will use high resolution computer tomography of the chest to measureairway wall thickness (WT). Airway dimensions will be measured at on contiguous slices of the right apical segmental bronchus and right posterior basal segmental bronchus, from which tangential views of the bronchi can be obtained. The averaged values of the 2 bronchi will be used for analysis
Measured: Baseline and 1 year
Differences in CRSwNP stage among 3 groups (SEA w/o CRSwNP and CRSwNP with mild or no asthma) at baseline, and change in CRSwNP stage in 1-year post anti-IL5 treatment initiation in SEA w/o CRSwNP
The Lund-Mackay score is widely used in radiological staging of chronic rhinosinusitis. Although there are many scoring systems in place for sinonasal computed tomography (CT) analysis, the Lund-Mackay system has the best inter- and intraob-server agreement. In LMK scoring, the sinuses (maxillary, anterior/posterior ethmoid, sphenoid, and frontal) are each scored on a scale of 0-2 opacification (0, normal; 1, partial opacification; 2, total opacification). The ostiomeatal complex is scored on a two-point scale of 0 and 2 (0, not occluded; 2, occluded). The scores on each side ranged from 0 (complete translucency of all sinuses) to 12 (complete opacity of all sinuses), leading to a total LMK score of 24 for both sides.Of note, an aplastic (absent) frontal sinus receives a score of 0.
Measured: Baseline and 1 year
Differences in exacerbation rate among 3 groups (SEA w/o CRSwNP and CRSwNP with mild or no asthma) at baseline, and change in exacerbation rate in 1-year post anti-IL5 treatment initiation in SEA w/o CRSwNP
Number of exacerbation in the past 12 months. An exacerbation is defined as worsening of asthma requiring the use of systemic CS and/or emergency department visit, or hospitalisation. For subjects on maintenance oral corticosteroids, an exacerbation requiring oral CS is defined as the use of oral/systemic corticosteroids at least double the existing dose for at least 3 days
Measured: Baseline and 1 year
Differences in lung function among 3 groups (SEA w/o CRSwNP and CRSwNP with mild or no asthma) at baseline, and change in lung function in 1-year post anti-IL5 treatment initiation in SEA w/o CRSwNP
FEV1 (liters and %predicted), FVC (liters and %predicted, FEV1/FVC (%) including pre and post bronchodilator test
Measured: Baseline and 1 year
Differences in need for sinus surgery among 3 groups (SEA w/o CRSwNP and CRSwNP with mild or no asthma) at baseline, and change in need for sinus surgery in 1-year post anti-IL5 treatment initiation in SEA w/o CRSwNP
Number (%) of participants with a reduced need for sinus surgery at 1 year. Surgery will be deemed required with an ENP score of >=3, or an ENP score of 2 and a TNSS score of >7.
Polyp (ENP) score: 0=No polyps,1=Small polyps in the middle meatus not reaching below the inferior border of the middle turbinate, 2=Polyps reaching below the lower border of the middle turbinate, 3=Large polyps reaching the lower border of the inferior turbinate or polyps medial to the middle turbinate, 4=Large polyps causing complete obstruction of the inferior nasal cavity. The higher of the two nostril scores will be derived and used for the analysis.
With a VAS (0 to 10 cm) the severity of 4 nasal polyposis symptoms (one VAS for each symptom): rhinorrhea; mucus in the throat; nasal blockage; loss of smell, and for total nasal symptom score (TNSS). The left-hand side of the scale (0) represents "not troublesome," and the right-hand side of the scale (10) represents "worst possible troublesome.
Measured: Baseline and 1 year
Secondary outcomes (6)
Differences in total IgE among 3 groups (SEA w/o CRSwNP and CRSwNP with mild or no asthma) at baseline, and change in total IgE in 1-year post anti-IL5 treatment initiation in SEA w/o CRSwNP
Total serum IgE (UI/ml)
Measured: Baseline and 1 year
Differences in blood eosinophil count among 3 groups (SEA w/o CRSwNP and CRSwNP with mild or no asthma) at baseline, and change in blood eosninophil count in 1-year post anti-IL5 treatment initiation in SEA w/o CRSwNP
Blood eosinophil differential counts (number and percentage)
Measured: Baseline and 1 year
Differences in sputum eosinophil count among 3 groups (SEA w/o CRSwNP and CRSwNP with mild or no asthma) at baseline, and change in sputum eosinophil count in 1-year post anti-IL5 treatment initiation in SEA w/o CRSwNP
Eosinophils count (number x10^4/mL and %) in a differential cell count obtained from induced sputum
Measured: Baseline and 1 year
Differences in FeNO among 3 groups (SEA w/o CRSwNP and CRSwNP with mild or no asthma) at baseline, and change in FeNO in 1-year post anti-IL5 treatment initiation in SEA w/o CRSwNP
Fractional Exhaled Nitric Oxide (FeNO in parts per billion)
Measured: Baseline and 1 year
Differences in Asthma Control Test (ACT) among 3 groups (SEA w/o CRSwNP and CRSwNP with mild or no asthma) at baseline, and change in asthma control in1-year post anti-IL5 treatment initiation in SEA w/o CRSwNP
ACT includes 5 items, with 4-week recall (on symptoms and daily functioning). More specifically, ACT assesses the frequency of shortness of breath and general asthma symptoms, use of rescue medications, the effect of asthma on daily functioning, and overall self-assessment of asthma control. There is 5-point scale (for symptoms and activities: 1=all the time to 5= not at all; for asthma control rating: 1=not controlled at all to 5=completely controlled).The scores range from 5 (poor control of asthma) to 25 (complete control of asthma), with higher scores reflecting greater asthma control. An ACT score >19 indicates well-controlled asthma.
Measured: Baseline and 1 year
Differences in quality of life among 3 groups (SEA w/o CRSwNP and CRSwNP with mild or no asthma) at baseline, and change in quality of life in 1-year post anti-IL5 treatment initiation in SEA w/o CRSwNP
With the Asthma Quality of Life Questionnaire (AQLQ) we will assess quality of life and psychological morbidity. The Asthma Quality of Life Questionnaire (AQLQ) is a 32-item questionnaire used to assess the physical, occupational, emotional, and social qualities of adults aged 17 to 70 years with asthma (Juniper et al, 2005).
The AQLQ has 4 domains: symptoms (12 items), activity limitation (6 generic and 5 patient-specific items), emotional function (5 items), and environmental stimuli (4 items). The AQLQ was developed for patients exhibiting mild to moderate asthma (Aburuz et al, 2007). The AQLQ items are each scored on a 7-point Likert scale, with 1 representing maximal impairment and 7 representing no impairment. The original AQLQ includes 5 patient-specific questions in the activity limitation domain. As part of the initial interview, the patient indicates 5 activity limitations due to asthma. These 5 activity limitations are used for the remaining follow-up visits.
Measured: Baseline and 1 year
Timeline
From the start of the study to its completion; the mark is today. Estimated dates are the sponsor’s plan.
- First posted9 May 2022
- Study start15 May 2022
- Primary completion15 May 2025 (estimated)
- Study completion16 Nov 2025 (estimated)
Resources
- Official record on ClinicalTrials.govThe registry entry this page is built from, with its full change history.
- Publications (64)Papers the sponsor has linked to this study.
- Other trials for Severe Eosinophilic Asthma w/wo CRSwNPStudies of the same condition, open and under way.
- What the trial phases meanHow a treatment moves from first tests in people to approval.
More details
For doctors and researchers: how the study is designed, who runs it, and its registry IDs.
Study design
- Study type
- Observational
- Observational model
- Cohort
- Time perspective
- Prospective
- Enrolment
- 85 participants (estimated)
Sponsor and investigators
- Lead sponsor
- University of Crete
- Sponsor type
- University, hospital or other
- Responsible party
- Principal investigator, Nikolaos Tzanakis, University of Crete
IDs, dates and publications
- ClinicalTrials.gov ID
- NCT05365841
- Sponsor's protocol ID
- 10961[213755]
- Status last verified
- Jan 2024
- First submitted
- 18 Jan 2022
- Last updated
- 18 Jan 2024
- Results posted
- No
- FDA-regulated drug
- Yes
- FDA-regulated device
- No
- Individual data sharing
- No
Publications
Knight DA, Stick SM, Hackett TL. Defective function at the epithelial junction: a novel therapeutic frontier in asthma? J Allergy Clin Immunol. 2011 Sep;128(3):557-8. doi: 10.1016/j.jaci.2011.07.031. No abstract available.
PubMed 21878242NAYLOR B. The shedding of the mucosa of the bronchial tree in asthma. Thorax. 1962 Mar;17(1):69-72. doi: 10.1136/thx.17.1.69. No abstract available.
PubMed 14478653Hoshino M, Ohtawa J. Effects of adding omalizumab, an anti-immunoglobulin E antibody, on airway wall thickening in asthma. Respiration. 2012;83(6):520-8. doi: 10.1159/000334701. Epub 2012 Jan 11.
PubMed 22236804Watelet JB, Gevaert P, Holtappels G, Van Cauwenberge P, Bachert C. Collection of nasal secretions for immunological analysis. Eur Arch Otorhinolaryngol. 2004 May;261(5):242-6. doi: 10.1007/s00405-003-0691-y. Epub 2003 Oct 9.
PubMed 14551791Lund VJ, Kennedy DW. Quantification for staging sinusitis. The Staging and Therapy Group. Ann Otol Rhinol Laryngol Suppl. 1995 Oct;167:17-21.
PubMed 7574265Hopkins C, Browne JP, Slack R, Lund V, Brown P. The Lund-Mackay staging system for chronic rhinosinusitis: how is it used and what does it predict? Otolaryngol Head Neck Surg. 2007 Oct;137(4):555-61. doi: 10.1016/j.otohns.2007.02.004.
PubMed 17903570Fokkens WJ, Lund VJ, Mullol J, Bachert C, Alobid I, Baroody F, Cohen N, Cervin A, Douglas R, Gevaert P, Georgalas C, Goossens H, Harvey R, Hellings P, Hopkins C, Jones N, Joos G, Kalogjera L, Kern B, Kowalski M, Price D, Riechelmann H, Schlosser R, Senior B, Thomas M, Toskala E, Voegels R, Wang de Y, Wormald PJ. European Position Paper on Rhinosinusitis and Nasal Polyps 2012. Rhinol Suppl. 2012 Mar;23:3 p preceding table of contents, 1-298.
PubMed 22764607Bousquet J, Heinzerling L, Bachert C, Papadopoulos NG, Bousquet PJ, Burney PG, Canonica GW, Carlsen KH, Cox L, Haahtela T, Lodrup Carlsen KC, Price D, Samolinski B, Simons FE, Wickman M, Annesi-Maesano I, Baena-Cagnani CE, Bergmann KC, Bindslev-Jensen C, Casale TB, Chiriac A, Cruz AA, Dubakiene R, Durham SR, Fokkens WJ, Gerth-van-Wijk R, Kalayci O, Kowalski ML, Mari A, Mullol J, Nazamova-Baranova L, O'Hehir RE, Ohta K, Panzner P, Passalacqua G, Ring J, Rogala B, Romano A, Ryan D, Schmid-Grendelmeier P, Todo-Bom A, Valenta R, Woehrl S, Yusuf OM, Zuberbier T, Demoly P; Global Allergy and Asthma European Network; Allergic Rhinitis and its Impact on Asthma. Practical guide to skin prick tests in allergy to aeroallergens. Allergy. 2012 Jan;67(1):18-24. doi: 10.1111/j.1398-9995.2011.02728.x. Epub 2011 Nov 4.
PubMed 22050279Heinzerling LM, Burbach GJ, Edenharter G, Bachert C, Bindslev-Jensen C, Bonini S, Bousquet J, Bousquet-Rouanet L, Bousquet PJ, Bresciani M, Bruno A, Burney P, Canonica GW, Darsow U, Demoly P, Durham S, Fokkens WJ, Giavi S, Gjomarkaj M, Gramiccioni C, Haahtela T, Kowalski ML, Magyar P, Murakozi G, Orosz M, Papadopoulos NG, Rohnelt C, Stingl G, Todo-Bom A, Von Mutius E, Wiesner A, Wohrl S, Zuberbier T. GA(2)LEN skin test study I: GA(2)LEN harmonization of skin prick testing: novel sensitization patterns for inhalant allergens in Europe. Allergy. 2009 Oct;64(10):1498-1506. doi: 10.1111/j.1398-9995.2009.02093.x.
PubMed 19772515Horvath I, Barnes PJ, Loukides S, Sterk PJ, Hogman M, Olin AC, Amann A, Antus B, Baraldi E, Bikov A, Boots AW, Bos LD, Brinkman P, Bucca C, Carpagnano GE, Corradi M, Cristescu S, de Jongste JC, Dinh-Xuan AT, Dompeling E, Fens N, Fowler S, Hohlfeld JM, Holz O, Jobsis Q, Van De Kant K, Knobel HH, Kostikas K, Lehtimaki L, Lundberg J, Montuschi P, Van Muylem A, Pennazza G, Reinhold P, Ricciardolo FLM, Rosias P, Santonico M, van der Schee MP, van Schooten FJ, Spanevello A, Tonia T, Vink TJ. A European Respiratory Society technical standard: exhaled biomarkers in lung disease. Eur Respir J. 2017 Apr 26;49(4):1600965. doi: 10.1183/13993003.00965-2016. Print 2017 Apr.
PubMed 28446552American Thoracic Society; European Respiratory Society. ATS/ERS recommendations for standardized procedures for the online and offline measurement of exhaled lower respiratory nitric oxide and nasal nitric oxide, 2005. Am J Respir Crit Care Med. 2005 Apr 15;171(8):912-30. doi: 10.1164/rccm.200406-710ST. No abstract available.
PubMed 15817806Coates AL, Wanger J, Cockcroft DW, Culver BH; Bronchoprovocation Testing Task Force: Kai-Hakon Carlsen; Diamant Z, Gauvreau G, Hall GL, Hallstrand TS, Horvath I, de Jongh FHC, Joos G, Kaminsky DA, Laube BL, Leuppi JD, Sterk PJ. ERS technical standard on bronchial challenge testing: general considerations and performance of methacholine challenge tests. Eur Respir J. 2017 May 1;49(5):1601526. doi: 10.1183/13993003.01526-2016. Print 2017 May.
PubMed 28461290Miller MR, Crapo R, Hankinson J, Brusasco V, Burgos F, Casaburi R, Coates A, Enright P, van der Grinten CP, Gustafsson P, Jensen R, Johnson DC, MacIntyre N, McKay R, Navajas D, Pedersen OF, Pellegrino R, Viegi G, Wanger J; ATS/ERS Task Force. General considerations for lung function testing. Eur Respir J. 2005 Jul;26(1):153-61. doi: 10.1183/09031936.05.00034505. No abstract available.
PubMed 15994402Bulathsinhala L, Eleangovan N, Heaney LG, Menzies-Gow A, Gibson PG, Peters M, Hew M, van Boven JFM, Lehtimaki L, van Ganse E, Belhassen M, Harvey ES, Perez de Llano L, Maitland-van der Zee AH, Papadopoulos NG, FitzGerald JM, Porsbjerg C, Canonica GW, Backer V, Rhee CK, Verhamme KMC, Buhl R, Cosio BG, Carter V, Price C, Le T, Stagno d'Alcontres M, Gopalan G, Tran TN, Price D. Development of the International Severe Asthma Registry (ISAR): A Modified Delphi Study. J Allergy Clin Immunol Pract. 2019 Feb;7(2):578-588.e2. doi: 10.1016/j.jaip.2018.08.016. Epub 2018 Sep 1.
PubMed 30179741Chung 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.
PubMed 24337046
Study at a glance
From the registry record, last updated by the sponsor on 18 Jan 2024. Recruitment status is as the sponsor reported it: confirm with the study team.
- Official title
- Role of Epithelial Barrier Integrity in Biologic Treatment Response of Severe Asthmatics With/Out Chronic Rhinosinusitis With Nasal Polyps (CRSwNP). Can Shedding of Epithelial Barrier Proteins be Used as Biomarker in Severe Asthma With/Out CRSwNP Management?
- ClinicalTrials.gov ID
- NCT05365841
- Acronym / sponsor ID
- 10961[213755]
- Conditions
- Severe Eosinophilic Asthma w/wo CRSwNP
- Study type
- Observational
- Recruitment status
- Unknown status
- Enrolment
- 85 participants (estimated)
- Lead sponsor
- University of CreteUniversity, hospital or other
- Study start
- 15 May 2022 (actual)
- Primary completion
- 15 May 2025 (estimated)
- Study completion
- 16 Nov 2025 (estimated)
- First posted
- 9 May 2022 (actual)
- Results
- Not posted in the source record
Clinical summary
The research question as the sponsor registered it. This describes what the study plans to test, not what it found.
Advances in understanding the pathophysiology of asthma development and severity have pointed towards a prominent role of the bronchial epithelium, especially in more chronic and severe disease. Studies suggest that airway eosinophilic inflammation in asthma is linked to epithelial injury and structural changes of the airways, co called airway wall remodeling. Together the chronic airway inflammation and remodeling are associated with bronchial hyperresponsiveness, fixed airflow obstruction or progressive loss of lung function and clinical severity of asthma. Chronic rhinosinusitis with nasal polyps (CRSwNP), is another respiratory inflammatory disease often co-existing with severe asthma, sharing similar pathophysiology. The investigators hypothesize that epithelial barrier integrity may play a role in the pathophysiology of severe eosinophilic asthma and nasal polyposis and in response to anti-IL5 therapy of severe asthmatics, and that shedding of epithelial barrier proteins may be used as biomarker in the management of severe asthma. In order to study that, the investigators will conduct a prospective cohort study of adult severe asthmatics with/out CRSwNP, who live on the island of Crete, Greece and who meet the criteria for entering anti-IL5 treatment, as assessed by pulmonologist. The participants will be recruited with a convenience sampling in a period of 2 years, under real life conditions, and will be followed up for 1 year after treatment initiation. A control group of subjects diagnosed with nasal polyposis without severe asthma will be used. Eligible subjects will undergo clinical assessment with radiological (CT) and endoscopic investigations. Samples of serum, sputum, nasal secretions, as well as nasal and bronchial biopsies will be obtain for assessing clinicopathological differences among the 3 groups but also response to anti-IL5 therapy in SEA w/o CRSwNP.
Study design
- Observational model
- Cohort
- Time perspective
- Prospective
- Number of arms
- 3
| Arm | Type | Receives |
|---|---|---|
| Severe asthma without CRSwNP | – | Drug: Mepolizumab 100 MGcontrol group; n~20 of anti-IL5 naïve severe asthmatics |
| Severe asthma with CRSwNP | – | Drug: Mepolizumab 100 MGn~40 of anti-IL5 naïve severe asthmatics |
| subjects CRSwNP with mild or no asthma | – | –~25;2nd control group |
Who may qualify
- Ages
- 18 years and older
- Sex
- All
- Healthy volunteers
- Not accepted
- Age groups
- Adult, Older adult
- Study population
- Adults with severe eosinophilic asthma, naive to anti-IL5/anti-IL5R treatment with or without CRSwNP who meet requirements for biologic therapy with anti-IL5 (Mepolizumab)
Key inclusion criteria (16 listed)
- 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.
- Anti-IL5/IL5R naïve
- Confirmed asthma diagnosis and severity and treatment requirements (for severe asthma group see boxes 1-3). For the 2nd control group, patients with CRSwNP must have a diagnosis of mild asthma (GINA steps 1-2) or no asthma by pulmonologist.
- Polyposis must be bilateral, to be considered as CRSwNP
- Triggers and relevant co-morbidity have been assessed and are well controlled Triggers such as active or passive smoking, beta-blockers, aspirin/NSAIDs, allergen exposure;Comorbidities such as rhinitis, obesity, GERD, OSA, VCD, depression/anxiety.
Key exclusion criteria (12 listed)
- Pregnancy
- Current exacerbation at visit 1 (repeat screening when stable). If exacerbation is lasting up until Visit 1a then exclude subject.
- Cognitive impairment preventing completion of data collection forms
- People highly dependent on medical care
- People with significant life limiting co-morbidity
Eligibility is decided by the study team after screening; this overview does not establish that a patient qualifies. Full inclusion and exclusion criteria.
Interventions
| Intervention | Type | Arms |
|---|---|---|
| Mepolizumab 100 MGPatients with SEA eligible to receive anti-IL5 treatment, which is a biologic treatment for SEA | Drug | Severe asthma with CRSwNP, Severe asthma without CRSwNP |
Primary outcome
Differences in sputum columnar epithelial cells (CEPs) among 3 groups (SEA w/o CRSwNP and CRSwNP with mild or no asthma) at baseline, and change in sputum CEPs in 1-year post anti-IL5 treatment initiation in SEA w/o CRSwNP
Time frame: Baseline and 1 year
We will employ flow cytometry on freshly isolated sputum cell suspensions from participants to measure CEPs proportion and count. Previously proposed cut-off value for normal range sputum CEP proportion (CEP % high = ≥11%) or number (CEP count high = ≥18.1 × 10^4/mL) may be considered.
Differences in E-cadherin protein level in sputum and nasal secretions among 3 groups (SEA w/o CRSwNP and CRSwNP with mild or no asthma) at baseline, and change in E-cadherin protein level in 1-year post anti-IL5 treatment initiation in SEA w/o CRSwNP
Time frame: Baseline and 1 year
Soluble E-cadherin in sputum and nasal secretions measured with ELISA. Data will be expressed as nanograms per milliliter in original sputum/secretion. Cell surface expression of E-cadherin on columnar epithelial cells may be analyzed by flow cytometry.
Differences in nasal and bronchial epithelial thickness among 3 groups (SEA w/o CRSwNP and CRSwNP with mild or no asthma) at baseline, and change in epithelial thickness in 1-year post anti-IL5 treatment initiation in SEA w/o CRSwNP
Time frame: Baseline and 1 year
Epithelial thickness will be determined in biopsies by dividing the epithelial surface area by the basement membrane (BM) length
Differences in nasal and bronchial epithelial integrity among 3 groups (SEA w/o CRSwNP and CRSwNP with mild or no asthma) at baseline, and change in epithelial integrity in 1-year post anti-IL5 treatment initiation in SEA w/o CRSwNP
Time frame: Baseline and 1 year
Epithelial integrity will be assessed in biopsy sections and expressed as percentage (%) of BM covered with normal epithelium (a layer of basal and ciliated columnar epithelial cells without detachment from the BM)
Differences in nasal and bronchial epithelial E-cadherin expression among 3 groups (SEA w/o CRSwNP and CRSwNP with mild or no asthma) at baseline, and change in protein expression in 1-year post anti-IL5 treatment initiation in SEA w/o CRSwNP
Time frame: Baseline and 1 year
Epithelial E-cadherin expression in biopsies will be measure with immonohistochemistry and expressed as the percentage of BM covered with E-cadherin-positive intact epithelium and/or as strong, moderate and weak epithelial E-cadherin staining
Differences in nasal and bronchial basement membrane thickness (BM) among 3 groups (SEA w/o CRSwNP and CRSwNP with mild or no asthma) at baseline, and change in Basement membrane thickness in 1-year post anti-IL5 treatment initiation in SEA w/o CRSwNP
Time frame: Baseline and 1 year
BM thickness in biopsies will be expressed as BM surface area divided by BM length
Differences in CT-assessed airway wall thickness (WT) among 3 groups (SEA w/o CRSwNP and CRSwNP with mild or no asthma) at baseline, and change in WT in 1-year post anti-IL5 treatment initiation in SEA w/o CRSwNP
Time frame: Baseline and 1 year
We will use high resolution computer tomography of the chest to measureairway wall thickness (WT). Airway dimensions will be measured at on contiguous slices of the right apical segmental bronchus and right posterior basal segmental bronchus, from which tangential views of the bronchi can be obtained. The averaged values of the 2 bronchi will be used for analysis
Differences in CRSwNP stage among 3 groups (SEA w/o CRSwNP and CRSwNP with mild or no asthma) at baseline, and change in CRSwNP stage in 1-year post anti-IL5 treatment initiation in SEA w/o CRSwNP
Time frame: Baseline and 1 year
The Lund-Mackay score is widely used in radiological staging of chronic rhinosinusitis. Although there are many scoring systems in place for sinonasal computed tomography (CT) analysis, the Lund-Mackay system has the best inter- and intraob-server agreement. In LMK scoring, the sinuses (maxillary, anterior/posterior ethmoid, sphenoid, and frontal) are each scored on a scale of 0-2 opacification (0, normal; 1, partial opacification; 2, total opacification). The ostiomeatal complex is scored on a two-point scale of 0 and 2 (0, not occluded; 2, occluded). The scores on each side ranged from 0 (complete translucency of all sinuses) to 12 (complete opacity of all sinuses), leading to a total LMK score of 24 for both sides.Of note, an aplastic (absent) frontal sinus receives a score of 0.
Differences in exacerbation rate among 3 groups (SEA w/o CRSwNP and CRSwNP with mild or no asthma) at baseline, and change in exacerbation rate in 1-year post anti-IL5 treatment initiation in SEA w/o CRSwNP
Time frame: Baseline and 1 year
Number of exacerbation in the past 12 months. An exacerbation is defined as worsening of asthma requiring the use of systemic CS and/or emergency department visit, or hospitalisation. For subjects on maintenance oral corticosteroids, an exacerbation requiring oral CS is defined as the use of oral/systemic corticosteroids at least double the existing dose for at least 3 days
Differences in lung function among 3 groups (SEA w/o CRSwNP and CRSwNP with mild or no asthma) at baseline, and change in lung function in 1-year post anti-IL5 treatment initiation in SEA w/o CRSwNP
Time frame: Baseline and 1 year
FEV1 (liters and %predicted), FVC (liters and %predicted, FEV1/FVC (%) including pre and post bronchodilator test
Differences in need for sinus surgery among 3 groups (SEA w/o CRSwNP and CRSwNP with mild or no asthma) at baseline, and change in need for sinus surgery in 1-year post anti-IL5 treatment initiation in SEA w/o CRSwNP
Time frame: Baseline and 1 year
Number (%) of participants with a reduced need for sinus surgery at 1 year. Surgery will be deemed required with an ENP score of >=3, or an ENP score of 2 and a TNSS score of >7. Polyp (ENP) score: 0=No polyps,1=Small polyps in the middle meatus not reaching below the inferior border of the middle turbinate, 2=Polyps reaching below the lower border of the middle turbinate, 3=Large polyps reaching the lower border of the inferior turbinate or polyps medial to the middle turbinate, 4=Large polyps causing complete obstruction of the inferior nasal cavity. The higher of the two nostril scores will be derived and used for the analysis. With a VAS (0 to 10 cm) the severity of 4 nasal polyposis symptoms (one VAS for each symptom): rhinorrhea; mucus in the throat; nasal blockage; loss of smell, and for total nasal symptom score (TNSS). The left-hand side of the scale (0) represents "not troublesome," and the right-hand side of the scale (10) represents "worst possible troublesome.
6 secondary outcomes
Differences in total IgE among 3 groups (SEA w/o CRSwNP and CRSwNP with mild or no asthma) at baseline, and change in total IgE in 1-year post anti-IL5 treatment initiation in SEA w/o CRSwNP
Time frame: Baseline and 1 year
Differences in blood eosinophil count among 3 groups (SEA w/o CRSwNP and CRSwNP with mild or no asthma) at baseline, and change in blood eosninophil count in 1-year post anti-IL5 treatment initiation in SEA w/o CRSwNP
Time frame: Baseline and 1 year
Differences in sputum eosinophil count among 3 groups (SEA w/o CRSwNP and CRSwNP with mild or no asthma) at baseline, and change in sputum eosinophil count in 1-year post anti-IL5 treatment initiation in SEA w/o CRSwNP
Time frame: Baseline and 1 year
Differences in FeNO among 3 groups (SEA w/o CRSwNP and CRSwNP with mild or no asthma) at baseline, and change in FeNO in 1-year post anti-IL5 treatment initiation in SEA w/o CRSwNP
Time frame: Baseline and 1 year
Differences in Asthma Control Test (ACT) among 3 groups (SEA w/o CRSwNP and CRSwNP with mild or no asthma) at baseline, and change in asthma control in1-year post anti-IL5 treatment initiation in SEA w/o CRSwNP
Time frame: Baseline and 1 year
Differences in quality of life among 3 groups (SEA w/o CRSwNP and CRSwNP with mild or no asthma) at baseline, and change in quality of life in 1-year post anti-IL5 treatment initiation in SEA w/o CRSwNP
Time frame: Baseline and 1 year
Results and safety
Results are not available in the source record.
Research links
- Official record on ClinicalTrials.govLast updated by the sponsor 18 Jan 2024.
- Background: PubMed 21878242Knight DA, Stick SM, Hackett TL. Defective function at the epithelial junction: a novel therapeutic frontier in asthma? J Allergy Clin Immunol. 2011 Sep;128(3):557-8. doi: 10.1016/j.jaci.2011.07.031. No abstract available.
- Background: PubMed 14478653NAYLOR B. The shedding of the mucosa of the bronchial tree in asthma. Thorax. 1962 Mar;17(1):69-72. doi: 10.1136/thx.17.1.69. No abstract available.
- Background: PubMed 22236804Hoshino M, Ohtawa J. Effects of adding omalizumab, an anti-immunoglobulin E antibody, on airway wall thickening in asthma. Respiration. 2012;83(6):520-8. doi: 10.1159/000334701. Epub 2012 Jan 11.
- Background: PubMed 14551791Watelet JB, Gevaert P, Holtappels G, Van Cauwenberge P, Bachert C. Collection of nasal secretions for immunological analysis. Eur Arch Otorhinolaryngol. 2004 May;261(5):242-6. doi: 10.1007/s00405-003-0691-y. Epub 2003 Oct 9.
- Background: PubMed 7574265Lund VJ, Kennedy DW. Quantification for staging sinusitis. The Staging and Therapy Group. Ann Otol Rhinol Laryngol Suppl. 1995 Oct;167:17-21.
- Background: PubMed 17903570Hopkins C, Browne JP, Slack R, Lund V, Brown P. The Lund-Mackay staging system for chronic rhinosinusitis: how is it used and what does it predict? Otolaryngol Head Neck Surg. 2007 Oct;137(4):555-61. doi: 10.1016/j.otohns.2007.02.004.
- Background: PubMed 22764607Fokkens WJ, Lund VJ, Mullol J, Bachert C, Alobid I, Baroody F, Cohen N, Cervin A, Douglas R, Gevaert P, Georgalas C, Goossens H, Harvey R, Hellings P, Hopkins C, Jones N, Joos G, Kalogjera L, Kern B, Kowalski M, Price D, Riechelmann H, Schlosser R, Senior B, Thomas M, Toskala E, Voegels R, Wang de Y, Wormald PJ. European Position Paper on Rhinosinusitis and Nasal Polyps 2012. Rhinol Suppl. 2012 Mar;23:3 p preceding table of contents, 1-298.
- Background: PubMed 22050279Bousquet J, Heinzerling L, Bachert C, Papadopoulos NG, Bousquet PJ, Burney PG, Canonica GW, Carlsen KH, Cox L, Haahtela T, Lodrup Carlsen KC, Price D, Samolinski B, Simons FE, Wickman M, Annesi-Maesano I, Baena-Cagnani CE, Bergmann KC, Bindslev-Jensen C, Casale TB, Chiriac A, Cruz AA, Dubakiene R, Durham SR, Fokkens WJ, Gerth-van-Wijk R, Kalayci O, Kowalski ML, Mari A, Mullol J, Nazamova-Baranova L, O'Hehir RE, Ohta K, Panzner P, Passalacqua G, Ring J, Rogala B, Romano A, Ryan D, Schmid-Grendelmeier P, Todo-Bom A, Valenta R, Woehrl S, Yusuf OM, Zuberbier T, Demoly P; Global Allergy and Asthma European Network; Allergic Rhinitis and its Impact on Asthma. Practical guide to skin prick tests in allergy to aeroallergens. Allergy. 2012 Jan;67(1):18-24. doi: 10.1111/j.1398-9995.2011.02728.x. Epub 2011 Nov 4.
- Background: PubMed 19772515Heinzerling LM, Burbach GJ, Edenharter G, Bachert C, Bindslev-Jensen C, Bonini S, Bousquet J, Bousquet-Rouanet L, Bousquet PJ, Bresciani M, Bruno A, Burney P, Canonica GW, Darsow U, Demoly P, Durham S, Fokkens WJ, Giavi S, Gjomarkaj M, Gramiccioni C, Haahtela T, Kowalski ML, Magyar P, Murakozi G, Orosz M, Papadopoulos NG, Rohnelt C, Stingl G, Todo-Bom A, Von Mutius E, Wiesner A, Wohrl S, Zuberbier T. GA(2)LEN skin test study I: GA(2)LEN harmonization of skin prick testing: novel sensitization patterns for inhalant allergens in Europe. Allergy. 2009 Oct;64(10):1498-1506. doi: 10.1111/j.1398-9995.2009.02093.x.
- Background: PubMed 28446552Horvath I, Barnes PJ, Loukides S, Sterk PJ, Hogman M, Olin AC, Amann A, Antus B, Baraldi E, Bikov A, Boots AW, Bos LD, Brinkman P, Bucca C, Carpagnano GE, Corradi M, Cristescu S, de Jongste JC, Dinh-Xuan AT, Dompeling E, Fens N, Fowler S, Hohlfeld JM, Holz O, Jobsis Q, Van De Kant K, Knobel HH, Kostikas K, Lehtimaki L, Lundberg J, Montuschi P, Van Muylem A, Pennazza G, Reinhold P, Ricciardolo FLM, Rosias P, Santonico M, van der Schee MP, van Schooten FJ, Spanevello A, Tonia T, Vink TJ. A European Respiratory Society technical standard: exhaled biomarkers in lung disease. Eur Respir J. 2017 Apr 26;49(4):1600965. doi: 10.1183/13993003.00965-2016. Print 2017 Apr.
- Background: PubMed 15817806American Thoracic Society; European Respiratory Society. ATS/ERS recommendations for standardized procedures for the online and offline measurement of exhaled lower respiratory nitric oxide and nasal nitric oxide, 2005. Am J Respir Crit Care Med. 2005 Apr 15;171(8):912-30. doi: 10.1164/rccm.200406-710ST. No abstract available.
- Background: PubMed 28461290Coates AL, Wanger J, Cockcroft DW, Culver BH; Bronchoprovocation Testing Task Force: Kai-Hakon Carlsen; Diamant Z, Gauvreau G, Hall GL, Hallstrand TS, Horvath I, de Jongh FHC, Joos G, Kaminsky DA, Laube BL, Leuppi JD, Sterk PJ. ERS technical standard on bronchial challenge testing: general considerations and performance of methacholine challenge tests. Eur Respir J. 2017 May 1;49(5):1601526. doi: 10.1183/13993003.01526-2016. Print 2017 May.
- Individual participant dataSharing planned: No
Referral and contact
AzTrials does not enrol participants or take referrals. Contact the study team or a site listed below; they decide who can take part. This study is not recruiting at the moment.
2 sites in 1 country: see every site and its status.
Questions about this trial
What is this clinical trial studying?
An observational study of Severe Eosinophilic Asthma w/wo CRSwNP, run by University of Crete at 2 sites in Greece.
The full registered description is in the About this study section and the official record.
Who may be eligible to take part?
The sponsor lists 16 inclusion and 12 exclusion criteria. Eligibility is decided by the study team after screening, so read the full criteria and contact a listed site.
Is this clinical trial currently recruiting?
The record says: status not confirmed, as of the sponsor's last update on 18 Jan 2024. Status can change between updates, so confirm with the study contact before making plans.
Where is the study taking place?
The record lists 2 sites in Greece. Whether a site is taking part right now should be confirmed with that site. See every site.
What are the possible benefits and risks?
They depend on the study and the treatment, and no study can promise a benefit. The study team explains the known risks during informed consent, before anyone joins; the record itself does not list them.
Are results available for this study?
Results are not available in the source record.
How can a doctor refer a patient or contact the research team?
Contact Nikolaos Tzanakis, Professor (6984643636, tzanakis@med.uoc.gr), or a site near the patient. AzTrials does not enrol participants or take referrals.
What does the primary outcome measure?
Differences in sputum columnar epithelial cells (CEPs) among 3 groups (SEA w/o CRSwNP and CRSwNP with mild or no asthma) at baseline, and change in sputum CEPs in 1-year post anti-IL5 treatment initiation in SEA w/o CRSwNP (time frame: Baseline and 1 year). The study lists 11 primary outcomes in all. It is what the study was designed to measure, not a finding.
Where can I read the original study information?
On the ClinicalTrials.gov record for NCT05365841, which also lists 64 linked publications.
Does a listing mean the treatment is approved or proven to work?
No. A listing means the study is registered. It does not show that the treatment is safe, works, or is approved by a regulator.
How often is this information updated?
AzTrials copies changed records from ClinicalTrials.gov every night and reloads the whole registry every week. The sponsor last updated this record on 18 Jan 2024.