Airway Remodeling During Mepolizumab Treatment (REMOMEPO)

• ClinicalTrials.gov Identifier: NCT03797404
• Recruitment Status: Recruiting
• First Posted: January 9, 2019
• Last Update Posted: January 25, 2022
• Sponsor: Assistance Publique - Hôpitaux de Paris
• Collaborators: GlaxoSmithKline; Institut National de la Santé Et de la Recherche Médicale, France
• Information provided by (Responsible Party): Assistance Publique - Hôpitaux de Paris

Study Description

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.

Condition or disease
Asthma

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)

Study Design

• Study Type: Observational [Patient Registry]
• Estimated Enrollment: 40 participants
• Observational Model: Cohort
• Time Perspective: Prospective
• Target Follow-Up Duration: 12 Months
• Official Title: Airway Remodeling Changes Induced by Mepolizumab in Severe Eosinophil Asthma
• Actual Study Start Date: April 24, 2019
• Estimated Primary Completion Date: December 1, 2022
• Estimated Study Completion Date: June 1, 2023

Groups and Cohorts

Group/Cohort
Mepolizumab; Patients receiving mepolizumab
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.

Outcome Measures

Primary Outcome Measures :

1. Changes in reticular basement membrane (RBM) thickening [ Time Frame: 0, 6 and 12 months ]

   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).

2. Changes in airway smooth muscle (ASM) area [ Time Frame: 0, 6 and 12 months ]

   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).

3. Number of proliferating muscle cells [ Time Frame: 0, 6 and 12 months ]
   Evaluated by anti proliferating cell nuclear antigen (PCNA) antibodies, expressed as the number of positive cells per muscle surface.
4. Number of nerve endings [ Time Frame: 0, 6 and 12 months ]
   Evaluated by PGP9 and expressed as number of positive cells per biopsy surface in mm2
5. Number of vascular sections [ Time Frame: 0, 6 and 12 months ]
   Measured with an anti-CD31 antibody, expressed in number of sections per mm2.
6. Number of infiltrating inflammatory cells in the biopsies [ Time Frame: 0, 6 and 12 months ]
   Number of infiltrating inflammatory cells (infiltrating neutrophils, lymphocytes and eosinophils) expressed as number of positive cells per biopsy surface in mm2
7. Number of inflammatory cells in the BAL [ Time Frame: 0, 6 and 12 months ]
   Number of inflammatory cells (neutrophils, lymphocytes and eosinophils) expressed as % of total cells in the BAL
8. Proportion of eosinophils expressing MBP/IL3R [ Time Frame: 0, 6 and 12 months ]
   Measured on bronchial biopsies, expressed as number of cells per biopsy surface in mm2

Secondary Outcome Measures :

1. Interferon-gamma concentration [ Time Frame: 0, 6 and 12 months ]
   Interferon-gamma (Th1 cytokine) will be measured in BAL and serum
2. IL-13 concentration [ Time Frame: 0, 6 and 12 months ]
   IL-13 (Th2 cytokine) will be measured in BAL and serum
3. Periostin concentration [ Time Frame: 0, 6 and 12 months ]
   Periostin (Th2 cytokine) will be measured in BAL and serum
4. IL-17A concentration [ Time Frame: 0, 6 and 12 months ]
   IL-17A (Th17 cytokine) will be measured in BAL and serum
5. IL-22 concentration [ Time Frame: 0, 6 and 12 months ]
   IL-22 (Th17 cytokine) will be measured in BAL and serum
6. IL-33 concentration [ Time Frame: 0, 6 and 12 months ]
   IL-33 (innate immune cytokines) will be measured in BAL and serum
7. Thymic Stromal Lymphopoietin (TSLP) concentration [ Time Frame: 0, 6 and 12 months ]
   TSLP (innate immune cytokines) will be measured in BAL and serum
8. Fibronectin concentration [ Time Frame: 0, 6 and 12 months ]
   Fibronectin (soluble hallmarks of ECM remodeling) will be measured in BAL and serum
9. Tenascin concentration [ Time Frame: 0, 6 and 12 months ]
   Tenascin (soluble hallmarks of ECM remodeling) will be measured in BAL and serum
10. Fibulin-1 concentration [ Time Frame: 0, 6 and 12 months ]
    Fibulin-1 (soluble hallmarks of ECM remodeling) will be measured in BAL and serum
11. Monocyte chemoattractant protein-1 (CCL/MCP-1) concentration [ Time Frame: 0, 6 and 12 months ]
    Will be measured in BAL and serum
12. EGF concentration [ Time Frame: 0, 6 and 12 months ]
    Will be measured in BAL and serum
13. bFGF concentration [ Time Frame: 0, 6 and 12 months ]
    Will be measured in BAL and serum
14. PDGF-BB concentration [ Time Frame: 0, 6 and 12 months ]
    Will be measured in BAL and serum
15. Total score at Asthma Control Test [ Time Frame: 0, 6 and 12 months ]

    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.

16. Global evaluation of mepolizumab benefit [ Time Frame: 6 and 12 months ]

    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.

17. Forced expiratory volume (FEV1) [ Time Frame: 0, 6 and 12 months ]
    Measured during lung function test, pre/post salbutamol, expressed in ml.
18. Forced expiratory volume (FEV1) [ Time Frame: 0, 6 and 12 months ]
    Measured during lung function test, pre/post salbutamol, expressed in % of predicted value.
19. Forced expiratory volume/Vital capacity (FEV1/VC) [ Time Frame: 0, 6 and 12 months ]
    Measured during lung function test, pre/post salbutamol, expressed in %
20. Total lung capacity (TLC) [ Time Frame: 0, 6 and 12 months ]
    Measured during lung function test, pre/post salbutamol, expressed in ml.
21. Total lung capacity (TLC) [ Time Frame: 0, 6 and 12 months ]
    Measured during lung function test, pre/post salbutamol, expressed in % of predicted value.
22. Residual volume (RV) [ Time Frame: 0, 6 and 12 months ]
    Measured during lung function test, pre/post salbutamol, expressed in ml.
23. Residual volume (RV) [ Time Frame: 0, 6 and 12 months ]
    Measured during lung function test, pre/post salbutamol, expressed in % of predicted value.
24. Proportion of patients with pre-bronchodilator FEV1 greater than 80% [ Time Frame: 6 and 12 months ]
    In order to assess functional response to treatment
25. Proportion of patients with an increase from baseline in pre-bronchodilator FEV1 greater than 20% [ Time Frame: 6 and 12 months ]
    In order to assess functional response to treatment

Eligibility Criteria

• Ages Eligible for Study: 18 Years and older (Adult, Older Adult)
• Sexes Eligible for Study: All
• Accepts Healthy Volunteers: No
• 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).

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

Contacts and Locations

Contacts

Contact: Camille TAILLE, MD, PhD; +33140456863; camille.taille@aphp.fr

Locations

France

Bichat hospital; Recruiting

Paris, France, 75018

Sponsors and Collaborators

Assistance Publique - Hôpitaux de Paris

GlaxoSmithKline

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

Investigators

• Principal Investigator: Camille TAILLE, MD, PhD; Assistance Publique - Hôpitaux de Paris

More Information

Additional Information:

• Responsible Party: Assistance Publique - Hôpitaux de Paris
• ClinicalTrials.gov Identifier: NCT03797404
• Other Study ID Numbers: P180501J; 2018-002591-40 ( EudraCT Number )
• First Posted: January 9, 2019
• Last Update Posted: January 25, 2022
• Last Verified: January 2022

Individual Participant Data (IPD) Sharing Statement:

• Plan to Share IPD: Undecided

• Studies a U.S. FDA-regulated Drug Product: No
• Studies a U.S. FDA-regulated Device Product: No

Keywords provided by Assistance Publique - Hôpitaux de Paris:

Eosinophil; Bronchial biopsies; Mepolizumab; Severe

Additional relevant MeSH terms:

Asthma; Airway Remodeling; Bronchial Diseases; Respiratory Tract Diseases; Lung Diseases, Obstructive; Lung Diseases; Respiratory Hypersensitivity; Hypersensitivity, Immediate; Hypersensitivity; Immune System Diseases; Pathological Conditions, Anatomical