Airway Remodeling During Mepolizumab Treatment

Asthma Clinical Trial

— REMOMEPO  

Official title:

Airway Remodeling Changes Induced by Mepolizumab in Severe Eosinophil Asthma

Clinical Trial Details — Status: Completed

Administrative data

• NCT number: NCT03797404
• Other study ID #: P180501J
• Secondary ID: 2018-002591-40
• Status: Completed
• Start date: April 24, 2019
• Est. completion date: June 21, 2022

Study information

• Verified date: January 2023
• Source: Assistance Publique - Hôpitaux de Paris
• Contact: n/a
• Is FDA regulated: No
• Study type: Observational [Patient Registry]

Clinical Trial 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.

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)

Recruitment information / eligibility

• Status: Completed
• Enrollment: 37
• Est. completion date: June 21, 2022
• Est. primary completion date: June 21, 2022
• Accepts healthy volunteers: No
• Gender: All
• Age group: 18 Years and older

Eligibility

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

Related Conditions & MeSH terms

• Airway Remodeling
• Asthma

Locations

Country	Name	City	State
France	Bichat hospital	Paris

Sponsors (3)

Lead Sponsor	Collaborator
Assistance Publique - Hôpitaux de Paris	GlaxoSmithKline, Institut National de la Santé Et de la Recherche Médicale, France

Country where clinical trial is conducted

France, 

Outcome

Type	Measure	Description	Time frame	Safety issue
Primary	Changes in reticular basement membrane (RBM) thickening	The absolute variation in RBM thickening (µm, morphometry measurement on bronchial biopsies) over 12 months is defined as the difference between month twelve and baseline (V1).; The absolute variation in RBM thickening over 6 months is defined as the difference between month six and baseline (V1).	0, 6 and 12 months
Primary	Changes in airway smooth muscle (ASM) area	Measured in morphometry in µm2 and expressed as a percentage of smooth muscle surface area relative to the biopsy surface.; The absolute variation in ASM area over 12 months is defined as the difference between month twelve and baseline (V1).; The absolute variation in ASM area over 6 months is defined as the difference between month six and baseline (V1).	0, 6 and 12 months
Primary	Number of proliferating muscle cells	Evaluated by anti proliferating cell nuclear antigen (PCNA) antibodies, expressed as the number of positive cells per muscle surface.	0, 6 and 12 months
Primary	Number of nerve endings	Evaluated by PGP9 and expressed as number of positive cells per biopsy surface in mm2	0, 6 and 12 months
Primary	Number of vascular sections	Measured with an anti-CD31 antibody, expressed in number of sections per mm2.	0, 6 and 12 months
Primary	Number of infiltrating inflammatory cells in the biopsies	Number of infiltrating inflammatory cells (infiltrating neutrophils, lymphocytes and eosinophils) expressed as number of positive cells per biopsy surface in mm2	0, 6 and 12 months
Primary	Number of inflammatory cells in the BAL	Number of inflammatory cells (neutrophils, lymphocytes and eosinophils) expressed as % of total cells in the BAL	0, 6 and 12 months
Primary	Proportion of eosinophils expressing MBP/IL3R	Measured on bronchial biopsies, expressed as number of cells per biopsy surface in mm2	0, 6 and 12 months
Secondary	Interferon-gamma concentration	Interferon-gamma (Th1 cytokine) will be measured in BAL and serum	0, 6 and 12 months
Secondary	IL-13 concentration	IL-13 (Th2 cytokine) will be measured in BAL and serum	0, 6 and 12 months
Secondary	Periostin concentration	Periostin (Th2 cytokine) will be measured in BAL and serum	0, 6 and 12 months
Secondary	IL-17A concentration	IL-17A (Th17 cytokine) will be measured in BAL and serum	0, 6 and 12 months
Secondary	IL-22 concentration	IL-22 (Th17 cytokine) will be measured in BAL and serum	0, 6 and 12 months
Secondary	IL-33 concentration	IL-33 (innate immune cytokines) will be measured in BAL and serum	0, 6 and 12 months
Secondary	Thymic Stromal Lymphopoietin (TSLP) concentration	TSLP (innate immune cytokines) will be measured in BAL and serum	0, 6 and 12 months
Secondary	Fibronectin concentration	Fibronectin (soluble hallmarks of ECM remodeling) will be measured in BAL and serum	0, 6 and 12 months
Secondary	Tenascin concentration	Tenascin (soluble hallmarks of ECM remodeling) will be measured in BAL and serum	0, 6 and 12 months
Secondary	Fibulin-1 concentration	Fibulin-1 (soluble hallmarks of ECM remodeling) will be measured in BAL and serum	0, 6 and 12 months
Secondary	Monocyte chemoattractant protein-1 (CCL/MCP-1) concentration	Will be measured in BAL and serum	0, 6 and 12 months
Secondary	EGF concentration	Will be measured in BAL and serum	0, 6 and 12 months
Secondary	bFGF concentration	Will be measured in BAL and serum	0, 6 and 12 months
Secondary	PDGF-BB concentration	Will be measured in BAL and serum	0, 6 and 12 months
Secondary	Total score at Asthma Control Test	Measured using the Asthma Control Test (ACT) scale (range: 5 to 25). 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.; 5 items, with 4-week recall (on symptoms and daily functioning); each item is evaluated by a 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 total score ranges 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.	0, 6 and 12 months
Secondary	Global evaluation of mepolizumab benefit	Benefit of mepolizumab will be evaluated by patient and by physician according to the physician's Global Evaluation of Treatment Effectiveness (GETE).; Patients will be considered as "responders" if classified as "excellent response" or "good response" by their physician.	6 and 12 months
Secondary	Forced expiratory volume (FEV1)	Measured during lung function test, pre/post salbutamol, expressed in ml.	0, 6 and 12 months
Secondary	Forced expiratory volume (FEV1)	Measured during lung function test, pre/post salbutamol, expressed in % of predicted value.	0, 6 and 12 months
Secondary	Forced expiratory volume/Vital capacity (FEV1/VC)	Measured during lung function test, pre/post salbutamol, expressed in %	0, 6 and 12 months
Secondary	Total lung capacity (TLC)	Measured during lung function test, pre/post salbutamol, expressed in ml.	0, 6 and 12 months
Secondary	Total lung capacity (TLC)	Measured during lung function test, pre/post salbutamol, expressed in % of predicted value.	0, 6 and 12 months
Secondary	Residual volume (RV)	Measured during lung function test, pre/post salbutamol, expressed in ml.	0, 6 and 12 months
Secondary	Residual volume (RV)	Measured during lung function test, pre/post salbutamol, expressed in % of predicted value.	0, 6 and 12 months
Secondary	Proportion of patients with pre-bronchodilator FEV1 greater than 80%	In order to assess functional response to treatment	6 and 12 months
Secondary	Proportion of patients with an increase from baseline in pre-bronchodilator FEV1 greater than 20%	In order to assess functional response to treatment	6 and 12 months