Clinical trial NCT03797404: Airway Remodeling During Mepolizumab Treatment
Official title: Airway Remodeling Changes Induced by Mepolizumab in Severe Eosinophil Asthma
Study type: OBSERVATIONAL
Overall status: COMPLETED
Conditions: Asthma
Keywords: Eosinophil
Bronchial biopsies
Mepolizumab
Severe
Lead sponsor: Assistance Publique - Hôpitaux de Paris
Sponsor class: OTHER
Collaborators: name: GlaxoSmithKline
name: Institut National de la Santé Et de la Recherche Médicale, France
First posted: 2019-01-09
Enrollment: 37
Sex: ALL
Minimum age (years): 18
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Observational model: COHORT
Time perspective: PROSPECTIVE
Sampling method: NON_PROBABILITY_SAMPLE
Study population: Patients with severe uncontrolled eosinophil asthma with an indication for mepolizumab according to French recommandations (eos \>300mm3 in the previous year, \>2 exacerbations, despite optimal step 4-5 therapy, including daily use of steroids).

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)

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

Primary outcomes:
measure: Changes in reticular basement membrane (RBM) thickening
timeFrame: 0, 6 and 12 months
measure: Changes in airway smooth muscle (ASM) area
timeFrame: 0, 6 and 12 months
measure: Number of proliferating muscle cells
timeFrame: 0, 6 and 12 months
measure: Number of nerve endings
timeFrame: 0, 6 and 12 months
measure: Number of vascular sections
timeFrame: 0, 6 and 12 months
measure: Number of infiltrating inflammatory cells in the biopsies
timeFrame: 0, 6 and 12 months
measure: Number of inflammatory cells in the BAL
timeFrame: 0, 6 and 12 months
measure: Proportion of eosinophils expressing MBP/IL3R
timeFrame: 0, 6 and 12 months
Secondary outcomes:
measure: Interferon-gamma concentration
timeFrame: 0, 6 and 12 months
measure: IL-13 concentration
timeFrame: 0, 6 and 12 months
measure: Periostin concentration
timeFrame: 0, 6 and 12 months
measure: IL-17A concentration
timeFrame: 0, 6 and 12 months
measure: IL-22 concentration
timeFrame: 0, 6 and 12 months
measure: IL-33 concentration
timeFrame: 0, 6 and 12 months
measure: Thymic Stromal Lymphopoietin (TSLP) concentration
timeFrame: 0, 6 and 12 months
measure: Fibronectin concentration
timeFrame: 0, 6 and 12 months
measure: Tenascin concentration
timeFrame: 0, 6 and 12 months
measure: Fibulin-1 concentration
timeFrame: 0, 6 and 12 months
measure: Monocyte chemoattractant protein-1 (CCL/MCP-1) concentration
timeFrame: 0, 6 and 12 months
measure: EGF concentration
timeFrame: 0, 6 and 12 months
measure: bFGF concentration
timeFrame: 0, 6 and 12 months
measure: PDGF-BB concentration
timeFrame: 0, 6 and 12 months
measure: Total score at Asthma Control Test
timeFrame: 0, 6 and 12 months
measure: Global evaluation of mepolizumab benefit
timeFrame: 6 and 12 months
measure: Forced expiratory volume (FEV1)
timeFrame: 0, 6 and 12 months
measure: Forced expiratory volume (FEV1)
timeFrame: 0, 6 and 12 months
measure: Forced expiratory volume/Vital capacity (FEV1/VC)
timeFrame: 0, 6 and 12 months
measure: Total lung capacity (TLC)
timeFrame: 0, 6 and 12 months
measure: Total lung capacity (TLC)
timeFrame: 0, 6 and 12 months
measure: Residual volume (RV)
timeFrame: 0, 6 and 12 months
measure: Residual volume (RV)
timeFrame: 0, 6 and 12 months
measure: Proportion of patients with pre-bronchodilator FEV1 greater than 80%
timeFrame: 6 and 12 months
measure: Proportion of patients with an increase from baseline in pre-bronchodilator FEV1 greater than 20%
timeFrame: 6 and 12 months
Other outcomes:
Locations:
city: Paris
country: France
facility: Bichat hospital
Study officials:
affiliation: Assistance Publique - Hôpitaux de Paris
name: Camille TAILLE, MD, PhD
role: PRINCIPAL_INVESTIGATOR
References: