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Assessing the Expression and the Activity of Rac1 Protein in the Airway Smooth Muscle of Asthmatic Patient (NaRacAS)

Primary Purpose

Asthma

Status
Recruiting
Phase
Not Applicable
Locations
France
Study Type
Interventional
Intervention
Bronchial endoscopy
Bronchial biopsies
Bronchial alveolar enema
Sponsored by
Nantes University Hospital
About
Eligibility
Locations
Arms
Outcomes
Full info

About this trial

This is an interventional basic science trial for Asthma focused on measuring Severe Asthma, airway smooth muscle cells, Rac1 protein

Eligibility Criteria

18 Years - 70 Years (Adult, Older Adult)All SexesDoes not accept healthy volunteers

Inclusion Criteria:

  • Asthmatic Patient :

    • Male or Female from 18 to 70 years old,
    • Diagnosis of asthma confirmed by

      • Existence of one or more following symptoms over 3 months at least (wheezing dyspnea, wheezing, chronic cough and tightness in the chest…)
      • AND past pulmonary function test showing a reversible obstructive ventilatory syndrome after inhaled short-acting bronchodilators (improvement of FEV1 above 12% and at least 200 mL FEV1 gain compare to pre-bronchodilatator FEV1)
      • AND a removal of the clinically suspected differential diagnoses of asthma (vocal cord dysfunction, Churg-Strauss syndrome etc…). The comorbidities should have been explored and treated or on treatment at enrollment.
    • Subject agreed to participate to the study and the biological samples collection,
    • Subject is affiliate to a social security system.
  • Inclusion criteria for severe asthmatic patient :

Patient with one of the following criterion will be considered as severe asthmatic patient :

  • Patient with a controlled asthma but using high dose of inhaled corticosteroids with another therapeutic classes,
  • OR Patient with uncontrolled asthma despite treatment,
  • OR Patient with worsening asthma despite treatment.

    -->Inclusion criteria for non-severe asthmatic patients :

  • Moderate Asthmatic patient without standard of care treatment since at least one week before the exploratory visit.

    -->Controlled sample:

  • Non asthmatic cadaveric adults

Exclusion Criteria:

  • Asthmatic Patient :

    • Underage,
    • Pregnant or breast-feeding women,
    • Adult on guardianship
    • Active smoker (smoked or Inhaled),
    • former smokers (smoked or Inhaled) with a smoking history of ≥10 pack years since less than 5 years.
    • Patient with asthma exacerbation the 4 past weeks before the exploratory visit..
    • Patient treated by long term oral corticosteroids or ongoing biological therapy or stopped within the 3 months before exploratory visit.
    • Patient with severe acute or chronic organ disorder (cardiovascular, respiratory, hepatic, renal, malabsorption)
    • Patient with history of unstable angina,
    • Patient with platelet count abnormality, or primary or acquired thrombopathy, or an aPTT (activated Partial Thromboplastin Time) greater than or equal to 1,5 times normal or patient with a Quick Time > 26 seconds
    • Patient under a systemic immunomodulatory or immunosuppressive treatment
    • Patient with anticoagulants or anti-platelet aggregating drugs other than D-lysin acetylsalicylate and that could not be suspended before the bronchial fibroscopy.
    • Patient with hypersensitivity to the treatment used during the bronchial fibroscopy: Hydroxyzine, Midazolam, Xylocaine.
    • Patient with AME (Government Medical Assistance),
    • Patient having physical and psychological disabilities to follow the protocol,
    • Patient included in another interventional research protocol,
    • Patient having risk factors of Creutzfeld-Jakob disease
  • Controlled sample:

    • Asthmatic patient

Sites / Locations

  • University HospitalRecruiting

Arms of the Study

Arm 1

Arm 2

Arm 3

Arm Type

Other

Other

Other

Arm Label

Severe Asthma

Mild to moderate Asthma

Controlled Sample

Arm Description

patients affected with severe asthma s defined by ERS-ATS (European Respiratory Society - American Thoracic Society) without long term oral corticosteroids treatment

patients affected with untreated mild to moderate asthma

smooth muscle cells from Tracheobronchial rings of non-asthmatic cadaveric donor

Outcomes

Primary Outcome Measures

Activity level and expression of Rac1 protein in airway smooth muscle cells of asthmatics vs non asthmatics samples
Mean of fluorescence intensity of Rac1-GTP and Rac1 in paraffinised biopsies of airway smooth muscle cells

Secondary Outcome Measures

Assessing any difference between activity level and expression of Rac1 in airway smooth muscle cells of severe versus non severe asthmatic patients.
Mean of fluorescence intensity of Rac1-GTP and Rac1 in paraffinised biopsies of airway smooth muscle cells.
Assessing any correlation between Rac1-GTP/Rac1 ratio signal, pulmonary function tests and clinical data
Mean of fluorescence intensity of Rac1-GTP and Rac1 in paraffinised biopsies of airway smooth muscle cells.

Full Information

First Posted
October 20, 2017
Last Updated
February 27, 2023
Sponsor
Nantes University Hospital
Collaborators
L'institut du thorax - INSERM UMR 1087 / CNRS UMR6291 - IRS-Université de Nantes, IRSR-PL : Institut de Recherche en Santé Respiratoire des Pays de La Loire
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1. Study Identification

Unique Protocol Identification Number
NCT03325088
Brief Title
Assessing the Expression and the Activity of Rac1 Protein in the Airway Smooth Muscle of Asthmatic Patient
Acronym
NaRacAS
Official Title
Assessing the Expression and the Activity of Rac1 Protein in the Airway Smooth Muscle of
Study Type
Interventional

2. Study Status

Record Verification Date
February 2023
Overall Recruitment Status
Recruiting
Study Start Date
March 5, 2019 (Actual)
Primary Completion Date
March 2024 (Anticipated)
Study Completion Date
April 2024 (Anticipated)

3. Sponsor/Collaborators

Responsible Party, by Official Title
Sponsor
Name of the Sponsor
Nantes University Hospital
Collaborators
L'institut du thorax - INSERM UMR 1087 / CNRS UMR6291 - IRS-Université de Nantes, IRSR-PL : Institut de Recherche en Santé Respiratoire des Pays de La Loire

4. Oversight

Studies a U.S. FDA-regulated Drug Product
No
Studies a U.S. FDA-regulated Device Product
No
Data Monitoring Committee
No

5. Study Description

Brief Summary
Asthma is a chronic inflammatory respiratory disease affecting 6 to 7% of the French adult population and responsible of 1000 deaths in France every year. Many anti-inflammatory treatments are available but few had been developed to target hyperresponsiveness.Investigators and searchers of the Institut du thorax have recently demonstrated the main involvement of Rac1 monomeric G protein in the contraction of airway smooth muscle cells. They show that Rac1 is expressed in the airway smooth muscle cells in mice and its activity is increased in the bronchi of asthma induced mice sensitized to House-Dust Mite. They further demonstrate that Rac1 inhibition in mice by nebulisation reduces airway hyperresponsiveness and pulmonary inflammation. Investigators and searchers of the Institut du thorax would like to seek whether targeting Rac1 would be interesting in asthmatic patients. Primary objective of this study is to determine if Rac1 expression and activity in airway smooth muscle cells are increased in asthmatic patients compare to controlled samples (deceased donor samples). Secondary objective is to determine whether there is a correlation between Rac1 activity and asthma severity. If Rac1 activity in airway smooth muscles is indeed increased in asthmatic patients depending on asthma severity, Rac1 could be a potential target to treat airway hyperresponsiveness.
Detailed Description
Patients will be openly labeled in one of the following group 15 patients with severe asthma, without oral corticosteroids treatment., 6 patients with mild to moderate asthma without treatment, 21 controlled samples from smooth muscle cells of non-asthmatic deceased donor Bronchial endoscopy with bronchial biopsies will be assessed in all asthmatic patients, Control samples will be obtained from tracheobronchial rings of cadaveric donor. Expression and activity of Rac1 in airway smooth muscle will be determined by immuno-staining on paraffinised biopsies. Patients will undergo two study visits (D0: inclusion visit, D15: exploratory visit) and one phone call at D21. Inclusion Visit (D0): Signature of the Informed consent, Medical History, Clinical examination, Pulmonary Function Test, Blood samples for fibroscopy safety, ACT (Asthma Control Test), ACQ (Asthma Control Questionnaire), AQLQ (Asthma Quality of Life Questionnaire), Morisky questionnaire Exploratory visit (D15) Clinical examination, Bronchial endoscopy with biopsies Adverse event Phone Call (D21) - Adverse event Recruitment will last 4 years.

6. Conditions and Keywords

Primary Disease or Condition Being Studied in the Trial, or the Focus of the Study
Asthma
Keywords
Severe Asthma, airway smooth muscle cells, Rac1 protein

7. Study Design

Primary Purpose
Basic Science
Study Phase
Not Applicable
Interventional Study Model
Parallel Assignment
Masking
None (Open Label)
Allocation
Non-Randomized
Enrollment
42 (Anticipated)

8. Arms, Groups, and Interventions

Arm Title
Severe Asthma
Arm Type
Other
Arm Description
patients affected with severe asthma s defined by ERS-ATS (European Respiratory Society - American Thoracic Society) without long term oral corticosteroids treatment
Arm Title
Mild to moderate Asthma
Arm Type
Other
Arm Description
patients affected with untreated mild to moderate asthma
Arm Title
Controlled Sample
Arm Type
Other
Arm Description
smooth muscle cells from Tracheobronchial rings of non-asthmatic cadaveric donor
Intervention Type
Procedure
Intervention Name(s)
Bronchial endoscopy
Intervention Description
Bronchial endoscopy will be performed after clinical examination and pulmonary function tests
Intervention Type
Procedure
Intervention Name(s)
Bronchial biopsies
Intervention Description
5 biopsies will be done and analysed at the end of recruiting to assess monomeric GTP Rac1 protein expression and activity on bronchial biopsies
Intervention Type
Procedure
Intervention Name(s)
Bronchial alveolar enema
Intervention Description
For participants who had signed ancillary research consent
Primary Outcome Measure Information:
Title
Activity level and expression of Rac1 protein in airway smooth muscle cells of asthmatics vs non asthmatics samples
Description
Mean of fluorescence intensity of Rac1-GTP and Rac1 in paraffinised biopsies of airway smooth muscle cells
Time Frame
at day 15
Secondary Outcome Measure Information:
Title
Assessing any difference between activity level and expression of Rac1 in airway smooth muscle cells of severe versus non severe asthmatic patients.
Description
Mean of fluorescence intensity of Rac1-GTP and Rac1 in paraffinised biopsies of airway smooth muscle cells.
Time Frame
at day 15
Title
Assessing any correlation between Rac1-GTP/Rac1 ratio signal, pulmonary function tests and clinical data
Description
Mean of fluorescence intensity of Rac1-GTP and Rac1 in paraffinised biopsies of airway smooth muscle cells.
Time Frame
at day 15

10. Eligibility

Sex
All
Minimum Age & Unit of Time
18 Years
Maximum Age & Unit of Time
70 Years
Accepts Healthy Volunteers
No
Eligibility Criteria
Inclusion Criteria: Asthmatic Patient : Male or Female from 18 to 70 years old, Diagnosis of asthma confirmed by Existence of one or more following symptoms over 3 months at least (wheezing dyspnea, wheezing, chronic cough and tightness in the chest…) AND past pulmonary function test showing a reversible obstructive ventilatory syndrome after inhaled short-acting bronchodilators (improvement of FEV1 above 12% and at least 200 mL FEV1 gain compare to pre-bronchodilatator FEV1) AND a removal of the clinically suspected differential diagnoses of asthma (vocal cord dysfunction, Churg-Strauss syndrome etc…). The comorbidities should have been explored and treated or on treatment at enrollment. Subject agreed to participate to the study and the biological samples collection, Subject is affiliate to a social security system. Inclusion criteria for severe asthmatic patient : Patient with one of the following criterion will be considered as severe asthmatic patient : Patient with a controlled asthma but using high dose of inhaled corticosteroids with another therapeutic classes, OR Patient with uncontrolled asthma despite treatment, OR Patient with worsening asthma despite treatment. -->Inclusion criteria for non-severe asthmatic patients : Moderate Asthmatic patient without standard of care treatment since at least one week before the exploratory visit. -->Controlled sample: Non asthmatic cadaveric adults Exclusion Criteria: Asthmatic Patient : Underage, Pregnant or breast-feeding women, Adult on guardianship Active smoker (smoked or Inhaled), former smokers (smoked or Inhaled) with a smoking history of ≥10 pack years since less than 5 years. Patient with asthma exacerbation the 4 past weeks before the exploratory visit.. Patient treated by long term oral corticosteroids or ongoing biological therapy or stopped within the 3 months before exploratory visit. Patient with severe acute or chronic organ disorder (cardiovascular, respiratory, hepatic, renal, malabsorption) Patient with history of unstable angina, Patient with platelet count abnormality, or primary or acquired thrombopathy, or an aPTT (activated Partial Thromboplastin Time) greater than or equal to 1,5 times normal or patient with a Quick Time > 26 seconds Patient under a systemic immunomodulatory or immunosuppressive treatment Patient with anticoagulants or anti-platelet aggregating drugs other than D-lysin acetylsalicylate and that could not be suspended before the bronchial fibroscopy. Patient with hypersensitivity to the treatment used during the bronchial fibroscopy: Hydroxyzine, Midazolam, Xylocaine. Patient with AME (Government Medical Assistance), Patient having physical and psychological disabilities to follow the protocol, Patient included in another interventional research protocol, Patient having risk factors of Creutzfeld-Jakob disease Controlled sample: Asthmatic patient
Central Contact Person:
First Name & Middle Initial & Last Name or Official Title & Degree
François-Xavier BLANC, Pr
Phone
+33(0)240165533
Email
xavier.blanc@chu-nantes.fr
First Name & Middle Initial & Last Name or Official Title & Degree
François-Xavier BLANC
Phone
+33(0)240165533
Email
xavier.blanc@chu-nantes.fr
Facility Information:
Facility Name
University Hospital
City
Nantes
Country
France
Individual Site Status
Recruiting
Facility Contact:
First Name & Middle Initial & Last Name & Degree
François-Xavier BLANC
Phone
02.40.16.55.33
Email
xavier.blanc@chu-nantes.fr

12. IPD Sharing Statement

Plan to Share IPD
No

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Assessing the Expression and the Activity of Rac1 Protein in the Airway Smooth Muscle of Asthmatic Patient

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