<clinical_study>
  <!-- This xml conforms to an XML Schema at:
    https://clinicaltrials.gov/ct2/html/images/info/public.xsd -->
  <required_header>
    <download_date>ClinicalTrials.gov processed this data on September 20, 2023</download_date>
    <link_text>Link to the current ClinicalTrials.gov record.</link_text>
    <url>https://clinicaltrials.gov/ct2/show/NCT03008746</url>
  </required_header>
  <id_info>
    <org_study_id>PA16090*</org_study_id>
    <nct_id>NCT03008746</nct_id>
  </id_info>
  <brief_title>Pulmonary Microbiota in Patients With Chronic Obstructive Pulmonary Disease Colonized With P. Aeruginosa Resistant to Imipenem</brief_title>
  <acronym>MiPAD</acronym>
  <official_title>Pulmonary Microbiota in COPD Patients Colonized With P. Aeruginosa OprD Mutant Resistant to Imipenem</official_title>
  <sponsors>
    <lead_sponsor>
      <agency>CHU de Reims</agency>
      <agency_class>Other</agency_class>
    </lead_sponsor>
  </sponsors>
  <source>CHU de Reims</source>
  <brief_summary>
    <textblock>
      Pseudomonas aeruginosa (PA ) is associated with chronic lung infections in patients with&#xD;
      chronic obstructive pulmonary disease (COPD). Commensal flora (microbiota) in lung was&#xD;
      recently described using high-throughput sequencing techniques (NGS). PA strains isolated&#xD;
      during lung infection episodes of severe COPD patients often show resistance to antibiotics&#xD;
      including imipenem that is mainly due to mutation in oprD. In collaboration with Harvard&#xD;
      Medical School, the investigators have recently demonstrated that PA OprD mutant shows&#xD;
      increased survival (fitness) and its virulence. This bacterium could be more likely to&#xD;
      colonize. Colonization by PA OprD mutant could influence the pulmonary microbiota and may&#xD;
      worsen disease evolution, particularly in terms of frequency of exacerbations. Our objective&#xD;
      is to describe modification of pulmonary microbiota associated with PA colonization,&#xD;
      including OprD PA mutant, in severe COPD patients. The investigators will correlate the&#xD;
      microbiota modification to medical history. Stable severe COPD patients will be included.&#xD;
      Three groups of patients will be sampled: 1) not PA colonized, 2) PA colonized and 3) PA OprD&#xD;
      mutant colonized. Medical history will be recorded by the physician as usual and three&#xD;
      samples will be performed: 1) sputum, 2) oral wash and 3) water used for oral wash. Regular&#xD;
      bacterial culture will be performed and NGS will be performed also to characterize the&#xD;
      microbiota.&#xD;
    </textblock>
  </brief_summary>
  <detailed_description>
    <textblock>
      Patients: Severe COPD Patients (FEV/Forced vital capacity (FVC)&lt;70% and in FEV&lt;50% after&#xD;
      bronchodilation) hospitalized in the pulmonology Department of the Reims Teaching Hospital.&#xD;
      At the inclusion, patients should be stable. Inclusion of 20 patients needing 100 patients in&#xD;
      total will require 24 months.The study of associated factors with colonization to PA and PA&#xD;
      mutant OprD will be performed only for patients known to be not PA carrier. Microbiota&#xD;
      characterization will be performed on all patients colonized with PA and on non PA colonized&#xD;
      patients randomly selected. The analysis of of PA colonization influence on COPD evolution&#xD;
      will be done 12 months after sampling for all patients included.&#xD;
&#xD;
      Evaluation criteria:&#xD;
&#xD;
        -  Presence of P. aeruginosa resistance to imipenem (OprD mutation)&#xD;
&#xD;
        -  Pulmonary microbiota: Determination of the bacterial load (total number of bacterium)&#xD;
           and bacterial community diversity. Then, Opertional Taxonomic Unit (OTU) relative&#xD;
           abundance will be analyzed at phylum, class, order and family level.&#xD;
&#xD;
        -  Factors associated with colonization with PA and PA mutant OprD: antibiotics,&#xD;
           corticosteroids, hospitalization during the year preceding the inclusion, severity of&#xD;
           COPD, respiratory symptoms of cough and expectoration, exertional dyspnea assessed by&#xD;
           questionnaire the modified Respiratory Medical Council (MMRC), co-morbidities.&#xD;
&#xD;
        -  PA porting Influence and PA mutant OprD on changes to 12 months: the number of&#xD;
           exacerbation, severity of exacerbations, number of hospitalization, quality of life&#xD;
           assessed by the St George's respiratory questionnaire, death, evolution of ventilatory&#xD;
           disorders obstructive.&#xD;
&#xD;
      Investigation:&#xD;
&#xD;
        -  Proposal for participation to all eligible patients at a pulmonology consultation&#xD;
&#xD;
        -  If participation of acceptance (signed informed consent form): 3 bacteriological&#xD;
           samples: Sputum (usually done), oral wash with water before washing (made specifically&#xD;
           for this study). No change in the patient's medical care (treatment, monitoring, etc&#xD;
           ...). Clinical Data Collection: criteria for COPD, pulmonary function, dyspnea and&#xD;
           sputum symptoms, assessed by the MMRC scale, quality of life assessed by St George's&#xD;
           respiratory questionnaire, antibiotic therapy and hospitalization in the previous 12&#xD;
           months . Revaluation 12 months after sampling as part of the regular monitoring of&#xD;
           patients (idem as previously). All the samples will be sent to the clinical laboratory&#xD;
           of bacteriology (CHU Reims) as usually done for samples: separation of sample into 2&#xD;
           parts: 1 part stored at -80 ° C and 1 part commonly analyzed. Then, patients will be&#xD;
           classified as PA or PA non colonized based on sputum analysis. Mutation in oprD will be&#xD;
           characterized in a second step to classify patients as PA or PA OprD mutant carriers.&#xD;
           Samples of all patients colonized with PA and on non PA colonized patients randomly&#xD;
           selected which have been stored at -80°C will be sent to the &quot;PEGASE&quot; plateform of&#xD;
           Institut Pasteur de Lille. Characterization of pulmonary microbiota will be performed by&#xD;
           high-throughput sequencing on Illumina &quot;MiSeq&quot; allowing to reach 24 million reads in&#xD;
           2x300 bp paired-end.&#xD;
    </textblock>
  </detailed_description>
  <overall_status>Completed</overall_status>
  <start_date type="Actual">January 12, 2017</start_date>
  <completion_date type="Actual">May 17, 2022</completion_date>
  <primary_completion_date type="Actual">March 9, 2020</primary_completion_date>
  <phase>N/A</phase>
  <study_type>Interventional</study_type>
  <has_expanded_access>No</has_expanded_access>
  <study_design_info>
    <allocation>Non-Randomized</allocation>
    <intervention_model>Parallel Assignment</intervention_model>
    <primary_purpose>Basic Science</primary_purpose>
    <masking>None (Open Label)</masking>
  </study_design_info>
  <primary_outcome>
    <measure>Presence of P. aeruginosa resistance to imipenem (OprD mutation)</measure>
    <time_frame>12 months</time_frame>
  </primary_outcome>
  <primary_outcome>
    <measure>Pulmonary microbiota</measure>
    <time_frame>12 months</time_frame>
  </primary_outcome>
  <primary_outcome>
    <measure>questionnaire: the modified Respiratory Medical Council (MMRC)</measure>
    <time_frame>12 months</time_frame>
  </primary_outcome>
  <primary_outcome>
    <measure>St George's respiratory questionnaire</measure>
    <time_frame>12 months</time_frame>
  </primary_outcome>
  <number_of_arms>3</number_of_arms>
  <enrollment type="Actual">58</enrollment>
  <condition>Chronic Obstructive Pulmonary Disease</condition>
  <arm_group>
    <arm_group_label>not Pseudomonas aeruginosa colonized</arm_group_label>
    <arm_group_type>Experimental</arm_group_type>
  </arm_group>
  <arm_group>
    <arm_group_label>Pseudomonas aeruginosa colonized</arm_group_label>
    <arm_group_type>Experimental</arm_group_type>
  </arm_group>
  <arm_group>
    <arm_group_label>Pseudomonas aeruginosa OprD mutant colonized</arm_group_label>
    <arm_group_type>Experimental</arm_group_type>
  </arm_group>
  <intervention>
    <intervention_type>Other</intervention_type>
    <intervention_name>water used for oral wash</intervention_name>
    <arm_group_label>Pseudomonas aeruginosa OprD mutant colonized</arm_group_label>
    <arm_group_label>Pseudomonas aeruginosa colonized</arm_group_label>
    <arm_group_label>not Pseudomonas aeruginosa colonized</arm_group_label>
  </intervention>
  <intervention>
    <intervention_type>Other</intervention_type>
    <intervention_name>sputum</intervention_name>
    <arm_group_label>Pseudomonas aeruginosa OprD mutant colonized</arm_group_label>
    <arm_group_label>Pseudomonas aeruginosa colonized</arm_group_label>
    <arm_group_label>not Pseudomonas aeruginosa colonized</arm_group_label>
  </intervention>
  <intervention>
    <intervention_type>Other</intervention_type>
    <intervention_name>oral wash</intervention_name>
    <arm_group_label>Pseudomonas aeruginosa OprD mutant colonized</arm_group_label>
    <arm_group_label>Pseudomonas aeruginosa colonized</arm_group_label>
    <arm_group_label>not Pseudomonas aeruginosa colonized</arm_group_label>
  </intervention>
  <eligibility>
    <criteria>
      <textblock>
        Inclusion Criteria:&#xD;
&#xD;
          -  Severe COPD Patients (FEV/FVC&lt;70% and in FEV&lt;50% after bronchodilation) hospitalized&#xD;
             in the pulmonology Department of the Reims Teaching Hospital.&#xD;
&#xD;
          -  patients who agreed to participate in the study.&#xD;
&#xD;
          -  patients affiliated to a social security scheme.&#xD;
&#xD;
        Exclusion Criteria:&#xD;
&#xD;
          -  patients &lt;18yo&#xD;
&#xD;
          -  patients protected by the law.&#xD;
      </textblock>
    </criteria>
    <gender>All</gender>
    <minimum_age>18 Years</minimum_age>
    <maximum_age>N/A</maximum_age>
    <healthy_volunteers>No</healthy_volunteers>
  </eligibility>
  <location>
    <facility>
      <name>Chu Reims</name>
      <address>
        <city>Reims</city>
        <zip>51092</zip>
        <country>France</country>
      </address>
    </facility>
  </location>
  <location_countries>
    <country>France</country>
  </location_countries>
  <reference>
    <citation>Audebert C, Even G, Cian A; Blastocystis Investigation Group; Loywick A, Merlin S, Viscogliosi E, Chabe M. Colonization with the enteric protozoa Blastocystis is associated with increased diversity of human gut bacterial microbiota. Sci Rep. 2016 May 5;6:25255. doi: 10.1038/srep25255.</citation>
    <PMID>27147260</PMID>
  </reference>
  <reference>
    <citation>Wang Z, Bafadhel M, Haldar K, Spivak A, Mayhew D, Miller BE, Tal-Singer R, Johnston SL, Ramsheh MY, Barer MR, Brightling CE, Brown JR. Lung microbiome dynamics in COPD exacerbations. Eur Respir J. 2016 Apr;47(4):1082-92. doi: 10.1183/13993003.01406-2015. Epub 2016 Feb 25.</citation>
    <PMID>26917613</PMID>
  </reference>
  <verification_date>May 2022</verification_date>
  <study_first_submitted>December 27, 2016</study_first_submitted>
  <study_first_submitted_qc>December 30, 2016</study_first_submitted_qc>
  <study_first_posted type="Estimate">January 2, 2017</study_first_posted>
  <last_update_submitted>May 17, 2022</last_update_submitted>
  <last_update_submitted_qc>May 17, 2022</last_update_submitted_qc>
  <last_update_posted type="Actual">May 23, 2022</last_update_posted>
  <responsible_party>
    <responsible_party_type>Sponsor</responsible_party_type>
  </responsible_party>
  <condition_browse>
    <!-- CAUTION:  The following MeSH terms are assigned with an imperfect algorithm            -->
    <mesh_term>Lung Diseases</mesh_term>
    <mesh_term>Lung Diseases, Obstructive</mesh_term>
    <mesh_term>Pulmonary Disease, Chronic Obstructive</mesh_term>
  </condition_browse>
  <!-- Results have not yet been posted for this study                                          -->
</clinical_study>


download date: ClinicalTrials.gov processed this data on September 20, 2023
link text: Link to the current ClinicalTrials.gov record.
url: https://clinicaltrials.gov/ct2/show/NCT03008746
org study id: PA16090*
nct id: NCT03008746
lead sponsor: 
Pseudomonas aeruginosa (PA ) is associated with chronic lung infections in patients with
      chronic obstructive pulmonary disease (COPD). Commensal flora (microbiota) in lung was
      recently described using high-throughput sequencing techniques (NGS). PA strains isolated
      during lung infection episodes of severe COPD patients often show resistance to antibiotics
      including imipenem that is mainly due to mutation in oprD. In collaboration with Harvard
      Medical School, the investigators have recently demonstrated that PA OprD mutant shows
      increased survival (fitness) and its virulence. This bacterium could be more likely to
      colonize. Colonization by PA OprD mutant could influence the pulmonary microbiota and may
      worsen disease evolution, particularly in terms of frequency of exacerbations. Our objective
      is to describe modification of pulmonary microbiota associated with PA colonization,
      including OprD PA mutant, in severe COPD patients. The investigators will correlate the
      microbiota modification to medical history. Stable severe COPD patients will be included.
      Three groups of patients will be sampled: 1) not PA colonized, 2) PA colonized and 3) PA OprD
      mutant colonized. Medical history will be recorded by the physician as usual and three
      samples will be performed: 1) sputum, 2) oral wash and 3) water used for oral wash. Regular
      bacterial culture will be performed and NGS will be performed also to characterize the
      microbiota.
Patients: Severe COPD Patients (FEV/Forced vital capacity (FVC)<70% and in FEV<50% after
      bronchodilation) hospitalized in the pulmonology Department of the Reims Teaching Hospital.
      At the inclusion, patients should be stable. Inclusion of 20 patients needing 100 patients in
      total will require 24 months.The study of associated factors with colonization to PA and PA
      mutant OprD will be performed only for patients known to be not PA carrier. Microbiota
      characterization will be performed on all patients colonized with PA and on non PA colonized
      patients randomly selected. The analysis of of PA colonization influence on COPD evolution
      will be done 12 months after sampling for all patients included.

      Evaluation criteria:

        -  Presence of P. aeruginosa resistance to imipenem (OprD mutation)

        -  Pulmonary microbiota: Determination of the bacterial load (total number of bacterium)
           and bacterial community diversity. Then, Opertional Taxonomic Unit (OTU) relative
           abundance will be analyzed at phylum, class, order and family level.

        -  Factors associated with colonization with PA and PA mutant OprD: antibiotics,
           corticosteroids, hospitalization during the year preceding the inclusion, severity of
           COPD, respiratory symptoms of cough and expectoration, exertional dyspnea assessed by
           questionnaire the modified Respiratory Medical Council (MMRC), co-morbidities.

        -  PA porting Influence and PA mutant OprD on changes to 12 months: the number of
           exacerbation, severity of exacerbations, number of hospitalization, quality of life
           assessed by the St George's respiratory questionnaire, death, evolution of ventilatory
           disorders obstructive.

      Investigation:

        -  Proposal for participation to all eligible patients at a pulmonology consultation

        -  If participation of acceptance (signed informed consent form): 3 bacteriological
           samples: Sputum (usually done), oral wash with water before washing (made specifically
           for this study). No change in the patient's medical care (treatment, monitoring, etc
           ...). Clinical Data Collection: criteria for COPD, pulmonary function, dyspnea and
           sputum symptoms, assessed by the MMRC scale, quality of life assessed by St George's
           respiratory questionnaire, antibiotic therapy and hospitalization in the previous 12
           months . Revaluation 12 months after sampling as part of the regular monitoring of
           patients (idem as previously). All the samples will be sent to the clinical laboratory
           of bacteriology (CHU Reims) as usually done for samples: separation of sample into 2
           parts: 1 part stored at -80 ° C and 1 part commonly analyzed. Then, patients will be
           classified as PA or PA non colonized based on sputum analysis. Mutation in oprD will be
           characterized in a second step to classify patients as PA or PA OprD mutant carriers.
           Samples of all patients colonized with PA and on non PA colonized patients randomly
           selected which have been stored at -80°C will be sent to the "PEGASE" plateform of
           Institut Pasteur de Lille. Characterization of pulmonary microbiota will be performed by
           high-throughput sequencing on Illumina "MiSeq" allowing to reach 24 million reads in
           2x300 bp paired-end.
allocation: Non-Randomized
intervention model: Parallel Assignment
primary purpose: Basic Science
masking: None (Open Label)
measure: Presence of P. aeruginosa resistance to imipenem (OprD mutation)
time frame: 12 months
measure: Pulmonary microbiota
time frame: 12 months
measure: questionnaire: the modified Respiratory Medical Council (MMRC)
time frame: 12 months
measure: St George's respiratory questionnaire
time frame: 12 months
arm group label: not Pseudomonas aeruginosa colonized
arm group type: Experimental
arm group label: Pseudomonas aeruginosa colonized
arm group type: Experimental
arm group label: Pseudomonas aeruginosa OprD mutant colonized
arm group type: Experimental
intervention type: Other
intervention name: water used for oral wash
arm group label: Pseudomonas aeruginosa OprD mutant colonized
arm group label: Pseudomonas aeruginosa colonized
arm group label: not Pseudomonas aeruginosa colonized
intervention type: Other
intervention name: sputum
arm group label: Pseudomonas aeruginosa OprD mutant colonized
arm group label: Pseudomonas aeruginosa colonized
arm group label: not Pseudomonas aeruginosa colonized
intervention type: Other
intervention name: oral wash
arm group label: Pseudomonas aeruginosa OprD mutant colonized
arm group label: Pseudomonas aeruginosa colonized
arm group label: not Pseudomonas aeruginosa colonized
criteria: 
gender: All
minimum age: 18 Years
maximum age: N/A
healthy volunteers: No
facility: 
country: France
citation: Audebert C, Even G, Cian A; Blastocystis Investigation Group; Loywick A, Merlin S, Viscogliosi E, Chabe M. Colonization with the enteric protozoa Blastocystis is associated with increased diversity of human gut bacterial microbiota. Sci Rep. 2016 May 5;6:25255. doi: 10.1038/srep25255.
PMID: 27147260
citation: Wang Z, Bafadhel M, Haldar K, Spivak A, Mayhew D, Miller BE, Tal-Singer R, Johnston SL, Ramsheh MY, Barer MR, Brightling CE, Brown JR. Lung microbiome dynamics in COPD exacerbations. Eur Respir J. 2016 Apr;47(4):1082-92. doi: 10.1183/13993003.01406-2015. Epub 2016 Feb 25.
PMID: 26917613
responsible party type: Sponsor
mesh term: Lung Diseases
mesh term: Lung Diseases, Obstructive
mesh term: Pulmonary Disease, Chronic Obstructive