<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/NCT01661491</url>
  </required_header>
  <id_info>
    <org_study_id>1206010476</org_study_id>
    <nct_id>NCT01661491</nct_id>
  </id_info>
  <brief_title>Microbiome Acquisition and Progression of Inflammation and Airway Disease in Infants and Children With Cystic Fibrosis</brief_title>
  <official_title>Microbiome Acquisition and Progression of Inflammation and Airway Disease in Infants and Children With Cystic Fibrosis</official_title>
  <sponsors>
    <lead_sponsor>
      <agency>Yale University</agency>
      <agency_class>Other</agency_class>
    </lead_sponsor>
  </sponsors>
  <source>Yale University</source>
  <oversight_info>
    <has_dmc>No</has_dmc>
  </oversight_info>
  <brief_summary>
    <textblock>
      Cystic Fibrosis (CF) is a fatal, recessive genetic disorder characterized by progressive&#xD;
      inflammation and lung damage. It is unclear whether current treatment strategies, which focus&#xD;
      on detection and eradication of pathogenic microorganisms in the lung, are the best way to&#xD;
      prevent the initiation of early inflammation and lung damage. This study asks how early&#xD;
      acquisition of microbial flora occurs in infants with CF and healthy baby controls, and&#xD;
      whether this process initiates or influences early inflammation and clinical disease&#xD;
      progression in CF.&#xD;
    </textblock>
  </brief_summary>
  <detailed_description>
    <textblock>
      Cystic Fibrosis is the most common lethal genetic disorder in Caucasian populations.&#xD;
      Mutations of the Cystic Fibrosis Transmembrane Conductance Regulator (CFTR) affect its&#xD;
      ability to act as a chloride channel. The recent development of a transgenic pig model of CF&#xD;
      has demonstrated that newborn CF lungs, free of bacteria and inflammation at birth, become&#xD;
      colonized with a mixed microbial flora that likely initiates early inflammatory changes which&#xD;
      precede clinically apparent deterioration in lung function.&#xD;
&#xD;
      Because chronic infection and inflammation play central roles in CF disease progression and&#xD;
      exacerbations, many clinicians and researchers have focused on identifying pathogens&#xD;
      associated with CF infection and inflammation. Recent studies outside the area of CF,&#xD;
      however, have clearly demonstrated that &quot;non-pathogens&quot;, such as the commensal flora carried&#xD;
      by all humans at multiple mucosal sites, engage the host's innate and adaptive immune systems&#xD;
      constantly. This interaction between &quot;microbiome&quot; and host genome is responsible for&#xD;
      appropriate development and function of protective inflammatory and immune responses.&#xD;
&#xD;
      We hypothesize that acquisition of a commensal flora by newborns with CF may play a critical&#xD;
      role in initiating pathogenic inflammatory responses that subsequently lead to lung damage.&#xD;
      The acquired commensal flora may initially be identical to that of a non-CF infant, but may&#xD;
      be altered by the direct or indirect effects of CFTR mutation on the mucosal environment.&#xD;
      Such an altered flora is likely to encode different metabolic and regulatory functions, and&#xD;
      may directly influence host inflammatory responses. If so, a novel therapeutic opportunity&#xD;
      may exist to modulate this commensal flora, or to manipulate its immunomodulatory functions&#xD;
      in a way that interrupts the insidious cycle of inflammation and damage that characterizes&#xD;
      CF.&#xD;
&#xD;
      We propose to test our hypothesis in three specific aims: (1) Describe the acquisition and&#xD;
      evolution of gut and respiratory tract microbiomes in CF infants and non-CF controls; (2)&#xD;
      Determine the relationship between the microbiota and markers of inflammation in these two&#xD;
      cohorts; and (3) Determine whether early declines in lung function are associated with&#xD;
      inflammatory biomarkers or microbiome composition/function. This study is novel in its focus&#xD;
      on a rarely studied population, at a time when interventions might significantly impact&#xD;
      progression of this lethal disease and preserve pulmonary function. Its innovation lies in&#xD;
      applying state of the art technologies and methods to samples that can be collected simply&#xD;
      and non-invasively, thus increasing the likelihood that the findings of this study can be&#xD;
      translated into clinical practice.&#xD;
    </textblock>
  </detailed_description>
  <overall_status>Active, not recruiting</overall_status>
  <start_date>August 2012</start_date>
  <completion_date type="Anticipated">October 2023</completion_date>
  <primary_completion_date type="Actual">December 2020</primary_completion_date>
  <study_type>Observational</study_type>
  <has_expanded_access>No</has_expanded_access>
  <study_design_info>
    <observational_model>Case-Control</observational_model>
    <time_perspective>Prospective</time_perspective>
  </study_design_info>
  <primary_outcome>
    <measure>Change from Baseline in the Average Unifrac Value in Fecal Microbiome &amp; Metagenome Composition at 4 years</measure>
    <time_frame>4 years</time_frame>
    <description>High throughput sequencing will be used to identify microbial taxa and microbial genes present in feces, and to determine how these change over a period of 4 years</description>
  </primary_outcome>
  <secondary_outcome>
    <measure>Change from Baseline in the Amounts of Calprotectin at 4 years</measure>
    <time_frame>4 years</time_frame>
    <description>Fecal calprotectin will be measured by elisa</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Change from Baseline in the Amounts of Short Chain Fatty Acids at 4 years</measure>
    <time_frame>4 years</time_frame>
    <description>Fecal short chain fatty acids will be measured by gas chromatography</description>
  </secondary_outcome>
  <number_of_groups>2</number_of_groups>
  <enrollment type="Actual">40</enrollment>
  <condition>Cystic Fibrosis</condition>
  <arm_group>
    <arm_group_label>Cystic Fibrosis</arm_group_label>
    <description>Infants and toddlers with Cystic Fibrosis</description>
  </arm_group>
  <arm_group>
    <arm_group_label>Non-cystic fibrosis controls</arm_group_label>
    <description>Infants and toddlers without Cystic Fibrosis</description>
  </arm_group>
  <biospec_retention>Samples Without DNA</biospec_retention>
  <biospec_descr>
    <textblock>
      Fecal samples&#xD;
    </textblock>
  </biospec_descr>
  <eligibility>
    <study_pop>
      <textblock>
        Infants and children up to the age of 4 with Cystic Fibrosis, and age-matched controls&#xD;
        without cystic fibrosis will be eligible for this study. Participants will be recruited&#xD;
        from the Cystic Fibrosis clinic and Primary Care Clinic of the Yale New Haven Hospital.&#xD;
      </textblock>
    </study_pop>
    <sampling_method>Non-Probability Sample</sampling_method>
    <criteria>
      <textblock>
        Cystic Fibrosis participants:&#xD;
&#xD;
        Inclusion Criteria:&#xD;
&#xD;
          -  laboratory diagnosis of Cystic Fibrosis&#xD;
&#xD;
        Exclusion Criteria:&#xD;
&#xD;
          -  Major organ system disease other than Cystic Fibrosis&#xD;
&#xD;
          -  History of prematurity&#xD;
&#xD;
        Non Cystic Fibrosis control participants:&#xD;
&#xD;
        Inclusion Criteria:&#xD;
&#xD;
          -  Proof of a negative newborn CF screening test&#xD;
&#xD;
        Exclusion Criteria:&#xD;
&#xD;
          -  Major organ system disease&#xD;
&#xD;
          -  History of prematurity&#xD;
      </textblock>
    </criteria>
    <gender>All</gender>
    <minimum_age>3 Months</minimum_age>
    <maximum_age>4 Years</maximum_age>
    <healthy_volunteers>Accepts Healthy Volunteers</healthy_volunteers>
  </eligibility>
  <overall_official>
    <last_name>Barbara I Kazmierczak, MD PhD</last_name>
    <role>Principal Investigator</role>
    <affiliation>Yale University</affiliation>
  </overall_official>
  <overall_official>
    <last_name>Marie Egan, MD</last_name>
    <role>Principal Investigator</role>
    <affiliation>Yale University</affiliation>
  </overall_official>
  <location>
    <facility>
      <name>Cystic Fibrosis Clinic, Yale New Haven Hospital</name>
      <address>
        <city>New Haven</city>
        <state>Connecticut</state>
        <zip>06520</zip>
        <country>United States</country>
      </address>
    </facility>
  </location>
  <location_countries>
    <country>United States</country>
  </location_countries>
  <verification_date>March 2023</verification_date>
  <study_first_submitted>August 6, 2012</study_first_submitted>
  <study_first_submitted_qc>August 6, 2012</study_first_submitted_qc>
  <study_first_posted type="Estimate">August 9, 2012</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>
    <mesh_term>Fibrosis</mesh_term>
    <mesh_term>Inflammation</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/NCT01661491
org study id: 1206010476
nct id: NCT01661491
lead sponsor: 
has dmc: No
Cystic Fibrosis (CF) is a fatal, recessive genetic disorder characterized by progressive
      inflammation and lung damage. It is unclear whether current treatment strategies, which focus
      on detection and eradication of pathogenic microorganisms in the lung, are the best way to
      prevent the initiation of early inflammation and lung damage. This study asks how early
      acquisition of microbial flora occurs in infants with CF and healthy baby controls, and
      whether this process initiates or influences early inflammation and clinical disease
      progression in CF.
Cystic Fibrosis is the most common lethal genetic disorder in Caucasian populations.
      Mutations of the Cystic Fibrosis Transmembrane Conductance Regulator (CFTR) affect its
      ability to act as a chloride channel. The recent development of a transgenic pig model of CF
      has demonstrated that newborn CF lungs, free of bacteria and inflammation at birth, become
      colonized with a mixed microbial flora that likely initiates early inflammatory changes which
      precede clinically apparent deterioration in lung function.

      Because chronic infection and inflammation play central roles in CF disease progression and
      exacerbations, many clinicians and researchers have focused on identifying pathogens
      associated with CF infection and inflammation. Recent studies outside the area of CF,
      however, have clearly demonstrated that "non-pathogens", such as the commensal flora carried
      by all humans at multiple mucosal sites, engage the host's innate and adaptive immune systems
      constantly. This interaction between "microbiome" and host genome is responsible for
      appropriate development and function of protective inflammatory and immune responses.

      We hypothesize that acquisition of a commensal flora by newborns with CF may play a critical
      role in initiating pathogenic inflammatory responses that subsequently lead to lung damage.
      The acquired commensal flora may initially be identical to that of a non-CF infant, but may
      be altered by the direct or indirect effects of CFTR mutation on the mucosal environment.
      Such an altered flora is likely to encode different metabolic and regulatory functions, and
      may directly influence host inflammatory responses. If so, a novel therapeutic opportunity
      may exist to modulate this commensal flora, or to manipulate its immunomodulatory functions
      in a way that interrupts the insidious cycle of inflammation and damage that characterizes
      CF.

      We propose to test our hypothesis in three specific aims: (1) Describe the acquisition and
      evolution of gut and respiratory tract microbiomes in CF infants and non-CF controls; (2)
      Determine the relationship between the microbiota and markers of inflammation in these two
      cohorts; and (3) Determine whether early declines in lung function are associated with
      inflammatory biomarkers or microbiome composition/function. This study is novel in its focus
      on a rarely studied population, at a time when interventions might significantly impact
      progression of this lethal disease and preserve pulmonary function. Its innovation lies in
      applying state of the art technologies and methods to samples that can be collected simply
      and non-invasively, thus increasing the likelihood that the findings of this study can be
      translated into clinical practice.
observational model: Case-Control
time perspective: Prospective
measure: Change from Baseline in the Average Unifrac Value in Fecal Microbiome & Metagenome Composition at 4 years
time frame: 4 years
description: High throughput sequencing will be used to identify microbial taxa and microbial genes present in feces, and to determine how these change over a period of 4 years
measure: Change from Baseline in the Amounts of Calprotectin at 4 years
time frame: 4 years
description: Fecal calprotectin will be measured by elisa
measure: Change from Baseline in the Amounts of Short Chain Fatty Acids at 4 years
time frame: 4 years
description: Fecal short chain fatty acids will be measured by gas chromatography
arm group label: Cystic Fibrosis
description: Infants and toddlers with Cystic Fibrosis
arm group label: Non-cystic fibrosis controls
description: Infants and toddlers without Cystic Fibrosis
Fecal samples
study pop: 
sampling method: Non-Probability Sample
criteria: 
gender: All
minimum age: 3 Months
maximum age: 4 Years
healthy volunteers: Accepts Healthy Volunteers
last name: Barbara I Kazmierczak, MD PhD
role: Principal Investigator
affiliation: Yale University
last name: Marie Egan, MD
role: Principal Investigator
affiliation: Yale University
facility: 
country: United States
responsible party type: Sponsor
mesh term: Cystic Fibrosis
mesh term: Fibrosis
mesh term: Inflammation
sharing ipd: No