Airway Remodeling During Mepolizumab Treatment

NCT ID: NCT03797404

Last Updated: 2023-01-20

Basic Information

• Recruitment Status: COMPLETED
• Total Enrollment: 37 participants
• Study Classification: OBSERVATIONAL
• Study Start Date: 2019-04-24
• Study Completion Date: 2022-06-21

Brief Summary

Chronic airway changes, such as smooth muscle hypertrophy/hyperplasia, reticular basement membrane (RBM) thickening, goblet cells hyperplasia characterize severe asthma. Chronic inflammation, and especially eosinophilia and T2 cytokines are involved in these structural changes. The aim of this prospective observational study is to assess airway changes, assessed by bronchial biopsies before treatment, then after 6 months and 12 months, induced by mepolizumab in 40 severe asthma patients who will receive the treatment as part of their standard care. Changes in RBM thickening, in airway smooth muscle (ASM) area, in the number of PGP9 sections will be assessed on bronchial biopsies after 6 months and 12 months of mepolizumab treatment. Bronchoalveolar lavage (BAL) levels of inflammatory and remodeling mediators and of extra-cellular matrix (ECM) components will be measured after 6 months and 12 months of mepolizumab treatment. Relationship between clinical response to mepolizumab and remodeling changes after 6 months and 12 months will be assessed.

Detailed Description

1. Scientific Rationale & Hypothesis:

Chronic airway changes, such as smooth muscle hypertrophy/hyperplasia, reticular basement membrane thickening, goblet cells hyperplasia characterize severe asthma. Chronic inflammation, and especially eosinophilia and T2 cytokines are involved in these structural changes. Increased ASM layer has been associated with eosinophilia for example, but not RBM thickening, suggesting that differential patterns of remodeling can be observed according to inflammatory patterns. Omalizumab, an anti IgE therapy, can reduce some features of airway remodeling, especially RBM and some parameters related to ASM. No data are available on potential changes in airway remodeling induced by mepolizumab.

The aim of the study is to assess airway changes, assessed by bronchial biopsies, induced by mepolizumab in severe asthma patients who will receive the treatment as part of their standard care.

All asthma patients refered to the asthma clinic are proposed to participate to the COBRA cohort (French national asthma cohort). Serum and DNA are collected at inclusion and every 6 months. Fiberoptic bronchoscopy (FOB) is routinely performed as part of the standard care for difficult-to-severe asthma in our centre for many years, to assess differential diagnosis and inflammatory pattern since Fractional exhaled nitric oxide (FeNO) is not routinely performed in France. BAL and 4 to 6 bronchial biopsies are performed.

2. Study Population:

Severe asthma patients, refered to Severe Asthma Centre in Bichat and Bicetre Hospitals, receiving mepolizumab according to French recommendations (eos >300mm3 in the previous year, >2 exacerbations, despite optimal step 4-5 therapy, including daily use of steroids).

3. Study Design & Methods:

• General study design Prospective, observational study in one Severe Asthma Centre : Bichat Hospital (Prof C.Taillé).

40 patients will be prospectively included during a 32 months period.

This study aims to assess :

• Changes in RBM thickening, in ASM area after 6 months and 12 months of mepolizumab treatment
• Changes in BAL levels of inflammatory and remodeling mediators and of ECM components after 6 months and 12 months of mepolizumab treatment
• Changes in the number of PGP9 sections in the bronchial wall after 6 months and 12 months of mepolizumab treatment
• Relationship between clinical response to mepolizumab and remodeling changes after 6 months and 12 months of mepolizumab treatment
• Demographic and clinical characteristics of asthma (atopy, level of asthma control, FEV1…) will be available at inclusion and follow up, to assess clinical effect of mepolizumab treatment.

The following will perform at inclusion, 6 months and 12 months after initiating mepolizumab:

• clinical evaluation (age, BMI, atopic status, chronic rhinosinusitis, daily doses of steroids, exacerbations…)
• benefit of mepolizumab will be evaluated according to the physician's Global Evaluation of Treatment Effectiveness (GETE)
• asthma control test
• lung function test (FEV1, FEV1/VC, TLC, RV, pre/post salbutamol)
• FOB with BAL and 6 biopsies at inclusion, 6 months and 12 months
• Blood test for eosinophil count and serum conservation.

• Study groups/arms Group 1 (prospective) : patients initiating a mepolizumab treatment. Group 2 (retrospective): to assess airway changes that can "spontaneously" occur during a 12 month-period, a retrospective "historical group" of patients included in the previous ASMATHERM study who had 2 sets of biopsies and BAL within a 6 to 12 month-interval, without exposure to mepolizumab and without change in their treatment during this interval, will be studied as a control group . Clinical data are available at inclusion and after 12 months.
• Main tests or procedures All biopsies, BAL and serum analysis will be performed in the UMR1152 lab unit (Head: Dr Marina Pretolani).

Biopsies are fixed in formaldehyde and processed to paraffin wax for immunohistochemical (IHC) and morphometric studies. One biopsy will be stored at -80°C for further RNAseq analyses.

RBM thickening (morphometry), ASM area and the rate of ASM-proliferating cells (PCNA immuno-staining) will be measured. PGP9 staining can assess the number of nerves in the bronchial wall.

The number of inflammatory cells (eosinophils, neutrophils, mast cells, T-lymphocytes evaluated respectively by MBP, elastase, tryptase, CD4 expression) and vascular sections will also be enumerated after IHC. Eosinophils localization in the airway will be described.

Cytospin preparations from BAL cell pellets will be used to assess the proportion of eosinophils and neutrophils.

In parallel, the levels of different pro-inflammatory and remodeling mediators will be measured in BAL aliquots concentrated x 10, by specific Elisa and Luminex assays.

• Trial plan

V0: screening visit

V1: inclusion visit

• clinical evaluation
• Asthma control test
• Lung function test
• Fiber optic fibroscopy with BAL and bronchial biopsies (note that if a fiber optic fibroscopy with BAL and bronchial biopsies has already been performed in the month prior to inclusion, it will not be repeated at inclusion and the tissue and BAL samples will be retrieved for analysis)
• Blood sampling
• first treatment by Mepolizumab is administrated in the hospital.
• Patient injection training if this prescription is chosen
• Prescription for Mepolizumab, given at home for the next 6 months

V2: 6-month visit

• Clinical response assessment by GETE and ACT, clinical evaluation
• Lung function test
• Fiber optic fibroscopy with BAL and bronchial biopsies
• Blood sampling
• If responders, continuation of Mepolizumab treatment
• Compliance evaluation (file signed by the nurse or patient after each injection)

V3: 12-month visit

• clinical response assessment by GETE and ACT, clinical evaluation
• Lung function test
• Fiber optic fibroscopy with BAL and bronchial biopsies
• Blood sampling
• Compliance evaluation (file signed by the nurse or patient after each injection)

Conditions

Asthma

Study Design

• Observational Model Type: COHORT
• Study Time Perspective: PROSPECTIVE

Study Groups

Mepolizumab

Patients receiving mepolizumab

No interventions assigned to this group

Patients w/o mepolizumab (retrospective)

Retrospective control group of patients not exposed to mepolizumab, included in the COBRA cohort and the ASMATHERM protocol, who had 2 sets of biopsies and BAL within a 6 to 12 month-interval, without change in their treatment. Clinical data for this patients are available at inclusion and after 12 months.

No interventions assigned to this group

Eligibility Criteria

Inclusion Criteria

• adult >18 years,
• severe uncontrolled asthma, defined as eosinophil blood count >300/mm3 in the previous 12 months and at least 2 exacerbations in the previous 12 months or requiring oral steroids for more than half of the previous year,
• indication for mepolizumab decided by an asthma specialist,
• efficient contraception, for women of reproductive age

Exclusion Criteria

• pregnancy,
• smokers or ex smokers >10 pack/yr,
• contra indication for fiberoptic bronchoscopy (allergy to xylocain, antiaggregant or anticoagulant treatment...),
• contra indication for mepolizumab,
• patient who previously received mepolizumab or already received mepolizumab at inclusion,
• participation in another interventional trial

• Minimum Eligible Age: 18 Years
• Eligible Sex: ALL
• Accepts Healthy Volunteers: No

Sponsors

GlaxoSmithKline

INDUSTRY

Sponsor Role: collaborator

Institut National de la Santé Et de la Recherche Médicale, France

OTHER_GOV

Sponsor Role: collaborator

Assistance Publique - Hôpitaux de Paris

OTHER

Sponsor Role: lead

Responsible Party

Responsibility Role: SPONSOR

Principal Investigators

Camille TAILLE, MD, PhD

Role: PRINCIPAL_INVESTIGATOR

Assistance Publique - Hôpitaux de Paris

Locations

Bichat hospital

Paris, , France

Countries

France

Other Identifiers

2018-002591-40

Identifier Type: EUDRACT_NUMBER

Identifier Source: secondary_id

P180501J

Identifier Type: -

Identifier Source: org_study_id