<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/NCT03016689</url>
  </required_header>
  <id_info>
    <org_study_id>MICRO-2016-25363</org_study_id>
    <nct_id>NCT03016689</nct_id>
  </id_info>
  <brief_title>The Sinonasal Cavity as a Reservoir for Upper Airway Bacterial Development</brief_title>
  <official_title>The Sinonasal Cavity as a Reservoir for Upper Airway Bacterial Development</official_title>
  <sponsors>
    <lead_sponsor>
      <agency>University of Minnesota</agency>
      <agency_class>Other</agency_class>
    </lead_sponsor>
  </sponsors>
  <source>University of Minnesota</source>
  <oversight_info>
    <has_dmc>No</has_dmc>
  </oversight_info>
  <brief_summary>
    <textblock>
      While the maternal-newborn exchange of airway microbiota is well-documented, no studies have&#xD;
      examined within-subject relationships among the mouth, sinuses, nasopharynx and lungs and the&#xD;
      relative abundance of bacterial taxa at those sites. Recent evidence suggests the oral cavity&#xD;
      may serve as a reservoir for pathogens that translocate to non-oral locations;&#xD;
      oral-associated microbes infect most other body sites as evidence by 16S sequencing.&#xD;
&#xD;
      By using a combination of oral and throat swabs, together with nasal suction of mucus&#xD;
      samples, the investigators will use metagenomic sequencing to characterize the composition of&#xD;
      bacterial communities at each anatomical site. Beginning at birth, a time-series of swabs&#xD;
      will be collected from each subject, and monitor changes in the development of microbiota&#xD;
      over time. By doing so, our studies will illuminate airway trafficking of both beneficial and&#xD;
      pathogenic microbes and may represent an essential pathophysiological step towards shifting&#xD;
      the balance between airway health and disease.&#xD;
    </textblock>
  </brief_summary>
  <detailed_description>
    <textblock>
      The study of microbial community dynamics is critically important to human health, including&#xD;
      how to maintain or restore a healthy microbiome. Metagenomic studies have revolutionized&#xD;
      microbiology by addressing these issues in a culture-independent manner, and have defined&#xD;
      essential roles of the microbiota in host development. The initial development of gut&#xD;
      microbiota begins in utero and is strongly influenced by exposures at birth (e.g. vaginal vs&#xD;
      caesarean birth). The initial seeding by the mother's microflora and its ensuing bacterial&#xD;
      succession is thought to have critical long-term impacts on human health. Recent longitudinal&#xD;
      studies have documented a gradual increased in bacterial diversity, non-random community&#xD;
      assembly, the effects of breast milk and introduction of table foods, and large taxonomic&#xD;
      shifts as a result of antibiotics and environmental stresses that occur during infancy. Since&#xD;
      perturbations of these early events have been linked to diabetes, cancer, mental health and a&#xD;
      range of other maladies, efforts are underway to learn how manipulation of the infant&#xD;
      microbiome to a &quot;healthy&quot; state translates into long-term clinical outcomes.&#xD;
&#xD;
      By contrast, little attention has been paid to factors that govern the early-life development&#xD;
      of respiratory tract microbiota, including the oral cavity. At birth, the oral and&#xD;
      nasopharyngeal flora resemble those of the maternal vaginal tract or skin (depending on mode&#xD;
      of delivery). Preliminary datasets suggest that during the first year of life, the airway&#xD;
      microbiome evolves into a rich, adult-like microbial ecosystem. The keystone colonizers of&#xD;
      the airways are thought to condition the subsequent colonization by over 600 species, some of&#xD;
      which serve to establish robust bacterial communities characteristic of human health. Other&#xD;
      secondary colonizers are frequently implicated in oral and respiratory infections, including&#xD;
      chronic sinusitis, pneumonia, and periodontal diseases. As an example, infant colonization by&#xD;
      Streptococcus pneumoniae is an important risk factor for childhood middle ear disease. Early&#xD;
      microbial communities, therefore, represent major factors that govern the colonization of the&#xD;
      airways by both pathogenic and protective microbes during infant microbiome development.&#xD;
      Understanding the acquisition of infant airway microbial communities and the factors that&#xD;
      alter their composition is critical to the promotion of human health and the prevention of&#xD;
      airway diseases that represent an annual multi-billion dollar burden on the US healthcare&#xD;
      system.&#xD;
&#xD;
      While the maternal-newborn exchange of airway microbiota is well-documented, no studies have&#xD;
      examined within-subject relationships among the mouth, sinuses, nasopharynx and lungs and the&#xD;
      relative abundance of bacterial taxa at those sites. Recent evidence suggests the oral cavity&#xD;
      may serve as a reservoir for pathogens that trans-locate to non-oral locations;&#xD;
      oral-associated microbes infect most other body sites as evidence by 16S sequencing. However,&#xD;
      two caveats make this bacterial metastasis controversial. First, that oral bacteria are not&#xD;
      located solely in the mouth but are also found elsewhere in the airways makes their origin&#xD;
      difficult to establish. Thus, the directionality of microbial exchange between airway niche&#xD;
      spaces is not known. Secondly, most 16S ribosomal RNA (rRNA) surveys only reveal bacterial&#xD;
      composition at the genus or phylum level, providing little information about strain lineages,&#xD;
      and whether individual strains can migrate between sites. These data are critical to promote&#xD;
      development of protective microbiota while restricting growth of recalcitrant pathogens.&#xD;
&#xD;
      A more complete understanding of this trafficking begins with in-depth, strain-level surveys&#xD;
      of the bacterial communities present in each airway niche shortly after birth, and their&#xD;
      development over time. As a step in this direction, this Academic Health Center-sponsored&#xD;
      study will use metagenomic sequencing to assess the exchange of specific bacterial strains&#xD;
      throughout the upper airways. Our mouse studies (explained elsewhere) will be complemented by&#xD;
      a study of cystic fibrosis (CF) infants, who represent a unique population that facilitates&#xD;
      the capture of oral, sinonasal, and lung microbiota over the first two years of life. By&#xD;
      using a combination of oral and throat swabs, together with nasal suction of mucus samples, a&#xD;
      metagenomic sequencing approach will be used to characterize the composition of bacterial&#xD;
      communities at each anatomical site. Beginning at birth, the investigators will collect a&#xD;
      time-series of swabs from each subject, and monitor changes in the development of microbiota&#xD;
      over time. By doing so, our studies will illuminate airway trafficking of both beneficial and&#xD;
      pathogenic microbes and may represent an essential pathophysiological step towards shifting&#xD;
      the balance between airway health and disease.&#xD;
&#xD;
      EXPERIMENTAL PLAN The development of airway bacterial communities will be monitored in a&#xD;
      small CF patient cohort. Since CF infants are monitored from birth and are routinely sampled&#xD;
      for airway microbiota during routine outpatient visits as part of their standard-of-care,&#xD;
      they represent a unique population to monitor bacterial trafficking between the oral, nasal&#xD;
      and lung cavities. All newborns at the University of Minnesota (UMN) are genetically&#xD;
      screened. Those testing positive for CF will be confirmed using a pilocarpine sweat test.&#xD;
      Positive subjects (with 2 Cystic Fibrosis Transmembrane Conductance Regulator [CFTR]&#xD;
      mutations) will then be sampled during the participants' visits to the CF treatment center;&#xD;
      on average, infants will be seen every month for the first 6 months, every other month until&#xD;
      1 year of age, followed by quarterly visits to the UMN CF Center (in accordance with Cystic&#xD;
      Fibrosis Foundation guidelines). As part of standard of care, nasal samples are collected by&#xD;
      suction at each visit. Nylon swabs will also be used to sample each infant's buccal mucosa.&#xD;
      Oropharyngeal swabs will also be obtained, which are considered to be an accurate proxy of&#xD;
      lower airway (lung) microbiomes. Based on the number of CF newborns expected over the study&#xD;
      period, the investigators plan to recruit up to 10 subjects. From each infant, up to 10&#xD;
      temporal swabs will be collected from each airway site (10 infants x 10 swabs x 3 sites = 300&#xD;
      samples). Swabs will be stored in saline, frozen at -80C and processed in parallel.&#xD;
&#xD;
      DNA will be extracted from each swab sample, and sequencing performed at the University of&#xD;
      Minnesota Genomics Center.&#xD;
    </textblock>
  </detailed_description>
  <overall_status>Recruiting</overall_status>
  <start_date type="Actual">May 31, 2017</start_date>
  <completion_date type="Anticipated">January 1, 2024</completion_date>
  <primary_completion_date type="Anticipated">January 1, 2024</primary_completion_date>
  <study_type>Observational</study_type>
  <has_expanded_access>No</has_expanded_access>
  <study_design_info>
    <observational_model>Case-Only</observational_model>
    <time_perspective>Prospective</time_perspective>
  </study_design_info>
  <primary_outcome>
    <measure>The sinonasal cavity as a reservoir for upper airway bacterial development</measure>
    <time_frame>3 years</time_frame>
    <description>The primary outcome measure will be the development and composition of bacterial communities throughout the respiratory tract during the first year of life. Community composition will be assessed using 16S rRNA sequencing, and differences between body sites will be calculated using standard ecological metrics.</description>
  </primary_outcome>
  <enrollment type="Anticipated">20</enrollment>
  <condition>Cystic Fibrosis</condition>
  <biospec_retention>Samples Without DNA</biospec_retention>
  <biospec_descr>
    <textblock>
      Oral and oropharyngeal swabs will be collected&#xD;
    </textblock>
  </biospec_descr>
  <eligibility>
    <study_pop>
      <textblock>
        Infants with Cystic Fibrosis who receive their care at the University of Minnesota&#xD;
        Discovery Care Clinic.&#xD;
      </textblock>
    </study_pop>
    <sampling_method>Non-Probability Sample</sampling_method>
    <criteria>
      <textblock>
        Inclusion Criteria:&#xD;
&#xD;
          -  Diagnosis of CF by sweat chloride test &gt;60 mEq/L or by presence of two known CF&#xD;
             genetic mutations&#xD;
&#xD;
          -  Age 0-3 years&#xD;
&#xD;
          -  Willingness to comply with study procedures&#xD;
&#xD;
          -  Willingness of parent/guardian to provide written consent.&#xD;
&#xD;
        Exclusion Criteria:&#xD;
&#xD;
        • Presence of vasculitis or rheumatologic disorder&#xD;
      </textblock>
    </criteria>
    <gender>All</gender>
    <minimum_age>7 Days</minimum_age>
    <maximum_age>3 Years</maximum_age>
    <healthy_volunteers>No</healthy_volunteers>
  </eligibility>
  <overall_official>
    <last_name>Ryan Hunter, PhD</last_name>
    <role>Principal Investigator</role>
    <affiliation>University of Minnesota</affiliation>
  </overall_official>
  <overall_contact>
    <last_name>Cynthia B Williams, CCRC</last_name>
    <phone>612/6257464</phone>
    <email>will1925@umn.edu</email>
  </overall_contact>
  <overall_contact_backup>
    <last_name>Ryan Hunter, PhD</last_name>
    <phone>612-625-1402</phone>
    <email>rchunter@umn.edu</email>
  </overall_contact_backup>
  <location>
    <facility>
      <name>University of Minnesota</name>
      <address>
        <city>Minneapolis</city>
        <state>Minnesota</state>
        <zip>55455</zip>
        <country>United States</country>
      </address>
    </facility>
    <status>Recruiting</status>
    <contact>
      <last_name>Ryan C Hunter, PhD</last_name>
      <phone>612-625-1402</phone>
      <email>rchunter@umn.edu</email>
    </contact>
    <contact_backup>
      <last_name>Terri A Laguna, MD</last_name>
      <phone>612/624-6967</phone>
      <email>laguun005@umn.edu</email>
    </contact_backup>
  </location>
  <location_countries>
    <country>United States</country>
  </location_countries>
  <verification_date>March 2023</verification_date>
  <study_first_submitted>January 9, 2017</study_first_submitted>
  <study_first_submitted_qc>January 9, 2017</study_first_submitted_qc>
  <study_first_posted type="Estimate">January 10, 2017</study_first_posted>
  <last_update_submitted>March 31, 2023</last_update_submitted>
  <last_update_submitted_qc>March 31, 2023</last_update_submitted_qc>
  <last_update_posted type="Actual">April 4, 2023</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>Cystic Fibrosis</mesh_term>
  </condition_browse>
  <patient_data>
    <sharing_ipd>No</sharing_ipd>
  </patient_data>
  <!-- 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/NCT03016689
org study id: MICRO-2016-25363
nct id: NCT03016689
lead sponsor: 
has dmc: No
While the maternal-newborn exchange of airway microbiota is well-documented, no studies have
      examined within-subject relationships among the mouth, sinuses, nasopharynx and lungs and the
      relative abundance of bacterial taxa at those sites. Recent evidence suggests the oral cavity
      may serve as a reservoir for pathogens that translocate to non-oral locations;
      oral-associated microbes infect most other body sites as evidence by 16S sequencing.

      By using a combination of oral and throat swabs, together with nasal suction of mucus
      samples, the investigators will use metagenomic sequencing to characterize the composition of
      bacterial communities at each anatomical site. Beginning at birth, a time-series of swabs
      will be collected from each subject, and monitor changes in the development of microbiota
      over time. By doing so, our studies will illuminate airway trafficking of both beneficial and
      pathogenic microbes and may represent an essential pathophysiological step towards shifting
      the balance between airway health and disease.
The study of microbial community dynamics is critically important to human health, including
      how to maintain or restore a healthy microbiome. Metagenomic studies have revolutionized
      microbiology by addressing these issues in a culture-independent manner, and have defined
      essential roles of the microbiota in host development. The initial development of gut
      microbiota begins in utero and is strongly influenced by exposures at birth (e.g. vaginal vs
      caesarean birth). The initial seeding by the mother's microflora and its ensuing bacterial
      succession is thought to have critical long-term impacts on human health. Recent longitudinal
      studies have documented a gradual increased in bacterial diversity, non-random community
      assembly, the effects of breast milk and introduction of table foods, and large taxonomic
      shifts as a result of antibiotics and environmental stresses that occur during infancy. Since
      perturbations of these early events have been linked to diabetes, cancer, mental health and a
      range of other maladies, efforts are underway to learn how manipulation of the infant
      microbiome to a "healthy" state translates into long-term clinical outcomes.

      By contrast, little attention has been paid to factors that govern the early-life development
      of respiratory tract microbiota, including the oral cavity. At birth, the oral and
      nasopharyngeal flora resemble those of the maternal vaginal tract or skin (depending on mode
      of delivery). Preliminary datasets suggest that during the first year of life, the airway
      microbiome evolves into a rich, adult-like microbial ecosystem. The keystone colonizers of
      the airways are thought to condition the subsequent colonization by over 600 species, some of
      which serve to establish robust bacterial communities characteristic of human health. Other
      secondary colonizers are frequently implicated in oral and respiratory infections, including
      chronic sinusitis, pneumonia, and periodontal diseases. As an example, infant colonization by
      Streptococcus pneumoniae is an important risk factor for childhood middle ear disease. Early
      microbial communities, therefore, represent major factors that govern the colonization of the
      airways by both pathogenic and protective microbes during infant microbiome development.
      Understanding the acquisition of infant airway microbial communities and the factors that
      alter their composition is critical to the promotion of human health and the prevention of
      airway diseases that represent an annual multi-billion dollar burden on the US healthcare
      system.

      While the maternal-newborn exchange of airway microbiota is well-documented, no studies have
      examined within-subject relationships among the mouth, sinuses, nasopharynx and lungs and the
      relative abundance of bacterial taxa at those sites. Recent evidence suggests the oral cavity
      may serve as a reservoir for pathogens that trans-locate to non-oral locations;
      oral-associated microbes infect most other body sites as evidence by 16S sequencing. However,
      two caveats make this bacterial metastasis controversial. First, that oral bacteria are not
      located solely in the mouth but are also found elsewhere in the airways makes their origin
      difficult to establish. Thus, the directionality of microbial exchange between airway niche
      spaces is not known. Secondly, most 16S ribosomal RNA (rRNA) surveys only reveal bacterial
      composition at the genus or phylum level, providing little information about strain lineages,
      and whether individual strains can migrate between sites. These data are critical to promote
      development of protective microbiota while restricting growth of recalcitrant pathogens.

      A more complete understanding of this trafficking begins with in-depth, strain-level surveys
      of the bacterial communities present in each airway niche shortly after birth, and their
      development over time. As a step in this direction, this Academic Health Center-sponsored
      study will use metagenomic sequencing to assess the exchange of specific bacterial strains
      throughout the upper airways. Our mouse studies (explained elsewhere) will be complemented by
      a study of cystic fibrosis (CF) infants, who represent a unique population that facilitates
      the capture of oral, sinonasal, and lung microbiota over the first two years of life. By
      using a combination of oral and throat swabs, together with nasal suction of mucus samples, a
      metagenomic sequencing approach will be used to characterize the composition of bacterial
      communities at each anatomical site. Beginning at birth, the investigators will collect a
      time-series of swabs from each subject, and monitor changes in the development of microbiota
      over time. By doing so, our studies will illuminate airway trafficking of both beneficial and
      pathogenic microbes and may represent an essential pathophysiological step towards shifting
      the balance between airway health and disease.

      EXPERIMENTAL PLAN The development of airway bacterial communities will be monitored in a
      small CF patient cohort. Since CF infants are monitored from birth and are routinely sampled
      for airway microbiota during routine outpatient visits as part of their standard-of-care,
      they represent a unique population to monitor bacterial trafficking between the oral, nasal
      and lung cavities. All newborns at the University of Minnesota (UMN) are genetically
      screened. Those testing positive for CF will be confirmed using a pilocarpine sweat test.
      Positive subjects (with 2 Cystic Fibrosis Transmembrane Conductance Regulator [CFTR]
      mutations) will then be sampled during the participants' visits to the CF treatment center;
      on average, infants will be seen every month for the first 6 months, every other month until
      1 year of age, followed by quarterly visits to the UMN CF Center (in accordance with Cystic
      Fibrosis Foundation guidelines). As part of standard of care, nasal samples are collected by
      suction at each visit. Nylon swabs will also be used to sample each infant's buccal mucosa.
      Oropharyngeal swabs will also be obtained, which are considered to be an accurate proxy of
      lower airway (lung) microbiomes. Based on the number of CF newborns expected over the study
      period, the investigators plan to recruit up to 10 subjects. From each infant, up to 10
      temporal swabs will be collected from each airway site (10 infants x 10 swabs x 3 sites = 300
      samples). Swabs will be stored in saline, frozen at -80C and processed in parallel.

      DNA will be extracted from each swab sample, and sequencing performed at the University of
      Minnesota Genomics Center.
observational model: Case-Only
time perspective: Prospective
measure: The sinonasal cavity as a reservoir for upper airway bacterial development
time frame: 3 years
description: The primary outcome measure will be the development and composition of bacterial communities throughout the respiratory tract during the first year of life. Community composition will be assessed using 16S rRNA sequencing, and differences between body sites will be calculated using standard ecological metrics.
Oral and oropharyngeal swabs will be collected
study pop: 
sampling method: Non-Probability Sample
criteria: 
gender: All
minimum age: 7 Days
maximum age: 3 Years
healthy volunteers: No
last name: Ryan Hunter, PhD
role: Principal Investigator
affiliation: University of Minnesota
last name: Cynthia B Williams, CCRC
phone: 612/6257464
email: will1925@umn.edu
last name: Ryan Hunter, PhD
phone: 612-625-1402
email: rchunter@umn.edu
facility: 
status: Recruiting
contact: 
contact backup: 
country: United States
responsible party type: Sponsor
mesh term: Cystic Fibrosis
sharing ipd: No