<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/NCT02197468</url>
  </required_header>
  <id_info>
    <org_study_id>2014/930 (REK)</org_study_id>
    <nct_id>NCT02197468</nct_id>
  </id_info>
  <brief_title>Preterm Infant Gut (PINGU) - a Norwegian Multi Centre Study</brief_title>
  <acronym>PINGU</acronym>
  <official_title>Gut Microbiome Study in Preterm Infants - a Norwegian Multi Centre Study</official_title>
  <sponsors>
    <lead_sponsor>
      <agency>University Hospital of North Norway</agency>
      <agency_class>Other</agency_class>
    </lead_sponsor>
    <collaborator>
      <agency>University of Tromso</agency>
      <agency_class>Other</agency_class>
    </collaborator>
    <collaborator>
      <agency>Oslo University Hospital</agency>
      <agency_class>Other</agency_class>
    </collaborator>
    <collaborator>
      <agency>Ullevaal University Hospital</agency>
      <agency_class>Other</agency_class>
    </collaborator>
    <collaborator>
      <agency>St. Olavs Hospital</agency>
      <agency_class>Other</agency_class>
    </collaborator>
    <collaborator>
      <agency>Haukeland University Hospital</agency>
      <agency_class>Other</agency_class>
    </collaborator>
    <collaborator>
      <agency>Helse Stavanger HF</agency>
      <agency_class>Other</agency_class>
    </collaborator>
  </sponsors>
  <source>University Hospital of North Norway</source>
  <oversight_info>
    <has_dmc>No</has_dmc>
  </oversight_info>
  <brief_summary>
    <textblock>
      Necrotizing enterocolitis (NEC) is a leading cause of morbidity and mortality among infants&#xD;
      in the neonatal intensive care unit (NICU). It has been postulated that abnormal colonization&#xD;
      of the preterm gut, or an unfavorable balance between gut bacteria may contribute to the&#xD;
      development of NEC.&#xD;
&#xD;
      Recent clinical randomized studies and meta-analysis have shown that proactive colonization&#xD;
      of probiotic bacteria reduce the frequency of NEC. Based on this evidence, in April 2014 all&#xD;
      Norwegian NICUs started routinely administration of probiotics to all extremely premature&#xD;
      neonates susceptible to NEC (gestational age &lt;28 weeks/birth weight &lt;1000g).&#xD;
&#xD;
      The current project is investigating the gut microbiome in patients receiving probiotics and&#xD;
      compare the the gut microbiome with moderate premature infants not receiving probiotics. In&#xD;
      addition, we are including a control of healthy full-term infants.&#xD;
&#xD;
      Samples containing feces from participants will be analyzed by state of the art whole-genome&#xD;
      sequencing techniques. Bacterial diversity will be analysed with bioinformatic tools.&#xD;
&#xD;
      Study hypotheses:&#xD;
&#xD;
        -  Probiotics given to extremely preterm infants will change the biodiversity of the gut&#xD;
           microflora.&#xD;
&#xD;
        -  Antibiotics given to these patients may influence the gut microflora also in infants&#xD;
           receiving probiotics. In particular use of vancomycin may change the gut flora.&#xD;
&#xD;
        -  After cessation of probiotic prophylaxis the gut flora of infants receiving probiotics&#xD;
           will gradually resemble the gut flora of infants not receiving probiotics.&#xD;
&#xD;
        -  A cross-contamination of probiotic bacteria between patients treated with probiotics and&#xD;
           patients not treated with antibiotics may occur.&#xD;
    </textblock>
  </brief_summary>
  <detailed_description>
    <textblock>
      Necrotizing enterocolitis (NEC) is a leading cause of morbidity and mortality among infants&#xD;
      in the neonatal intensive care unit (NICU). Prematurity is the most important risk factor for&#xD;
      NEC. The pathogenesis of NEC remains unclear, and prevention and treatment strategies are&#xD;
      limited. It has been postulated that abnormal colonization of the preterm gut, or an&#xD;
      unfavorable balance between gut bacteria, is significant in the pathogenesis of NEC.&#xD;
&#xD;
      Recent clinical randomized studies and meta-analysis have shown that proactive colonization&#xD;
      of probiotic bacteria reduce the frequency of NEC. Based on this evidence, in April 2014 all&#xD;
      Norwegian NICUs started routinely administration of probiotics to all extremely premature&#xD;
      neonates susceptible to NEC (gestational age (GA) &lt;28 weeks/birth birth weight (BW) &lt;1000 g).&#xD;
&#xD;
      The current project is investigating the gut microbiome in patients receiving probiotics and&#xD;
      compare the the gut microbiome with moderate premature infants not receiving probiotics. In&#xD;
      addition, we are including a control of healthy full-term infants.&#xD;
&#xD;
      Samples containing feces from participants will be analyzed by state of the art whole-genome&#xD;
      sequencing techniques. Bacterial diversity and taxonomy will be analysed using bioinformatic&#xD;
      tools&#xD;
&#xD;
      Inclusion criteria:&#xD;
&#xD;
        -  Preterm infants 24-27 weeks gestation/ birth weight &lt; 1000 g receiving probiotics&#xD;
&#xD;
        -  Preterm infants 28-31 weeks gestation/BW 1000-1500 g not receiving probiotics&#xD;
&#xD;
        -  Healthy term infants&#xD;
&#xD;
      Exclusion criteria&#xD;
&#xD;
        -  Preterm infants &lt; 24 weeks gestation&#xD;
&#xD;
        -  Preterm infants &lt; 32 weeks with severe lethal complication/poor prognosis around 1 week&#xD;
           of age&#xD;
&#xD;
        -  Infants with severe congenital malformations&#xD;
&#xD;
      Fecal samples will be obtained:&#xD;
&#xD;
        -  1 week of age&#xD;
&#xD;
        -  4 weeks of age&#xD;
&#xD;
        -  4 months corrected age&#xD;
&#xD;
        -  12 months corrected age&#xD;
&#xD;
      Study hypotheses:&#xD;
&#xD;
        -  Probiotics given to extremely preterm infants will change the biodiversity of the gut&#xD;
           microflora.&#xD;
&#xD;
        -  Antibiotics given to these patients may influence the gut microflora also in infants&#xD;
           receiving probiotics. In particular use of vancomycin may change the gut flora.&#xD;
&#xD;
        -  After cessation of probiotic prophylaxis the gut flora of infants receiving probiotics&#xD;
           will gradually resemble the gut flora of infants not receiving probiotics.&#xD;
&#xD;
        -  A cross-contamination of probiotic bacteria between patients treated with probiotics and&#xD;
           patients not treated with antibiotics may occur.&#xD;
&#xD;
      This is an explorative study. No formal sample size assessment is possible. Sequencing costs&#xD;
      will be substantial. We will limit the number of participants to 26 x 2 preterm infants and&#xD;
      10 control healthy infants.&#xD;
&#xD;
      Six Norwegian Neonatal Intensive care units wil participate in the study.&#xD;
    </textblock>
  </detailed_description>
  <overall_status>Completed</overall_status>
  <start_date>March 2015</start_date>
  <completion_date type="Actual">November 2015</completion_date>
  <primary_completion_date type="Actual">November 2015</primary_completion_date>
  <study_type>Observational [Patient Registry]</study_type>
  <has_expanded_access>No</has_expanded_access>
  <study_design_info>
    <observational_model>Cohort</observational_model>
    <time_perspective>Prospective</time_perspective>
  </study_design_info>
  <target_duration>1 Year</target_duration>
  <primary_outcome>
    <measure>To assess gut microbiome composition (meta genome sequencing) of preterm infants receiving probiotics versus preterm infants not receiving probiotics</measure>
    <time_frame>4 time points: 7 days of age, 4 weeks of age, 4 months corrected age and 12 months corrected age</time_frame>
    <description>Stools samples from preterm infants and term infants (control)</description>
  </primary_outcome>
  <secondary_outcome>
    <measure>Impact of antibiotic exposure on gut microbiome</measure>
    <time_frame>4 time points: 7 days of age, 4 weeks of age, 4 months corrected age and 12 months corrected age</time_frame>
    <description>Stool samples from preterm and term infants</description>
  </secondary_outcome>
  <other_outcome>
    <measure>Cross contamination of probiotic bacteria in a NICU</measure>
    <time_frame>7 days of age and 4 weeks of age</time_frame>
    <description>Detection of probiotic bacterial microbiome profiles in children not receiving probiotics</description>
  </other_outcome>
  <number_of_groups>1</number_of_groups>
  <enrollment type="Actual">60</enrollment>
  <condition>Mixed Flora; Infection</condition>
  <arm_group>
    <arm_group_label>Probiotics</arm_group_label>
    <description>Preterm infants given probiotics: GA 24-27 weeks/Birth weight &lt; 1000 g&#xD;
Preterm infants not given probiotics: GA 28-31 weeks/Birth weight 1000-1500 g&#xD;
Full-term infants not given probiotics (control)</description>
  </arm_group>
  <biospec_retention>Samples With DNA</biospec_retention>
  <biospec_descr>
    <textblock>
      Fecal samples for bacterial DNA analyses&#xD;
    </textblock>
  </biospec_descr>
  <eligibility>
    <study_pop>
      <textblock>
        Preterm infants hospitalized in 6 Norwegian NICUs; divided in one group extremely preterm&#xD;
        infants receiving probiotics and one group moderate preterm infants not receiving&#xD;
        antibiotics. A group of helathy infants from the post-natal ward will also be included&#xD;
      </textblock>
    </study_pop>
    <sampling_method>Non-Probability Sample</sampling_method>
    <criteria>
      <textblock>
        Inclusion Criteria:&#xD;
&#xD;
          -  Preterm infants with gestational age 24-27 weeks/birth weight &lt; 1000 g, treated with&#xD;
             probiotics (target number 26)&#xD;
&#xD;
          -  Preterm infants with gestational age 29-31 weeks/birth weight 1000-1500 g, not treated&#xD;
             with probiotics (target number 26)&#xD;
&#xD;
          -  Term infants (target number 10)&#xD;
&#xD;
        Exclusion Criteria:&#xD;
&#xD;
          -  Extremely preterm infants with gestational age below 24 weeks&#xD;
&#xD;
          -  Preterm infants (24-31 weeks) with life threatening complications during 1 week of age&#xD;
&#xD;
          -  Infants with congenital malformations&#xD;
      </textblock>
    </criteria>
    <gender>All</gender>
    <minimum_age>1 Hour</minimum_age>
    <maximum_age>12 Months</maximum_age>
    <healthy_volunteers>No</healthy_volunteers>
  </eligibility>
  <overall_official>
    <last_name>Claus Klingenberg, MD.phD.Prof.</last_name>
    <role>Study Chair</role>
    <affiliation>University Hospital of North Norway</affiliation>
  </overall_official>
  <overall_official>
    <last_name>Eirin Esaiassen, MD</last_name>
    <role>Principal Investigator</role>
    <affiliation>University Hospital of North-Noway</affiliation>
  </overall_official>
  <location>
    <facility>
      <name>Haukeland Universtiy Hospital</name>
      <address>
        <city>Bergen</city>
        <zip>5021</zip>
        <country>Norway</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Oslo University Hospital, Rikshospitalet</name>
      <address>
        <city>Oslo</city>
        <zip>0424</zip>
        <country>Norway</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Oslo University Hospital, Ullevaal</name>
      <address>
        <city>Oslo</city>
        <zip>0424</zip>
        <country>Norway</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Ahus University Hospital</name>
      <address>
        <city>Oslo</city>
        <country>Norway</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Stavanger University Hospital</name>
      <address>
        <city>Stavanger</city>
        <zip>4011</zip>
        <country>Norway</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>University Hospital of North Norway</name>
      <address>
        <city>Tromsø</city>
        <zip>9038</zip>
        <country>Norway</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>St Olavs Hospital, Trondheim University Hospital</name>
      <address>
        <city>Trondheim</city>
        <zip>7030</zip>
        <country>Norway</country>
      </address>
    </facility>
  </location>
  <location_countries>
    <country>Norway</country>
  </location_countries>
  <reference>
    <citation>Berrington JE, Stewart CJ, Cummings SP, Embleton ND. The neonatal bowel microbiome in health and infection. Curr Opin Infect Dis. 2014 Jun;27(3):236-43. doi: 10.1097/QCO.0000000000000061.</citation>
    <PMID>24751892</PMID>
  </reference>
  <reference>
    <citation>Stewart CJ, Marrs EC, Magorrian S, Nelson A, Lanyon C, Perry JD, Embleton ND, Cummings SP, Berrington JE. The preterm gut microbiota: changes associated with necrotizing enterocolitis and infection. Acta Paediatr. 2012 Nov;101(11):1121-7. doi: 10.1111/j.1651-2227.2012.02801.x. Epub 2012 Aug 31.</citation>
    <PMID>22845166</PMID>
  </reference>
  <verification_date>June 2016</verification_date>
  <study_first_submitted>July 21, 2014</study_first_submitted>
  <study_first_submitted_qc>July 21, 2014</study_first_submitted_qc>
  <study_first_posted type="Estimate">July 22, 2014</study_first_posted>
  <last_update_submitted>March 7, 2019</last_update_submitted>
  <last_update_submitted_qc>March 7, 2019</last_update_submitted_qc>
  <last_update_posted type="Actual">March 11, 2019</last_update_posted>
  <responsible_party>
    <responsible_party_type>Sponsor</responsible_party_type>
  </responsible_party>
  <keyword>Gut microbiome</keyword>
  <keyword>Necrotizing enterocolitis</keyword>
  <keyword>Antibiotics</keyword>
  <study_docs>
    <study_doc>
      <doc_type>Clinical Study Report</doc_type>
      <doc_url>https://www.frontiersin.org/articles/10.3389/fped.2018.00347/full</doc_url>
      <doc_comment>Publication from this study</doc_comment>
    </study_doc>
  </study_docs>
  <!-- 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/NCT02197468
org study id: 2014/930 (REK)
nct id: NCT02197468
lead sponsor: 
collaborator: 
collaborator: 
collaborator: 
collaborator: 
collaborator: 
collaborator: 
has dmc: No
Necrotizing enterocolitis (NEC) is a leading cause of morbidity and mortality among infants
      in the neonatal intensive care unit (NICU). It has been postulated that abnormal colonization
      of the preterm gut, or an unfavorable balance between gut bacteria may contribute to the
      development of NEC.

      Recent clinical randomized studies and meta-analysis have shown that proactive colonization
      of probiotic bacteria reduce the frequency of NEC. Based on this evidence, in April 2014 all
      Norwegian NICUs started routinely administration of probiotics to all extremely premature
      neonates susceptible to NEC (gestational age <28 weeks/birth weight <1000g).

      The current project is investigating the gut microbiome in patients receiving probiotics and
      compare the the gut microbiome with moderate premature infants not receiving probiotics. In
      addition, we are including a control of healthy full-term infants.

      Samples containing feces from participants will be analyzed by state of the art whole-genome
      sequencing techniques. Bacterial diversity will be analysed with bioinformatic tools.

      Study hypotheses:

        -  Probiotics given to extremely preterm infants will change the biodiversity of the gut
           microflora.

        -  Antibiotics given to these patients may influence the gut microflora also in infants
           receiving probiotics. In particular use of vancomycin may change the gut flora.

        -  After cessation of probiotic prophylaxis the gut flora of infants receiving probiotics
           will gradually resemble the gut flora of infants not receiving probiotics.

        -  A cross-contamination of probiotic bacteria between patients treated with probiotics and
           patients not treated with antibiotics may occur.
Necrotizing enterocolitis (NEC) is a leading cause of morbidity and mortality among infants
      in the neonatal intensive care unit (NICU). Prematurity is the most important risk factor for
      NEC. The pathogenesis of NEC remains unclear, and prevention and treatment strategies are
      limited. It has been postulated that abnormal colonization of the preterm gut, or an
      unfavorable balance between gut bacteria, is significant in the pathogenesis of NEC.

      Recent clinical randomized studies and meta-analysis have shown that proactive colonization
      of probiotic bacteria reduce the frequency of NEC. Based on this evidence, in April 2014 all
      Norwegian NICUs started routinely administration of probiotics to all extremely premature
      neonates susceptible to NEC (gestational age (GA) <28 weeks/birth birth weight (BW) <1000 g).

      The current project is investigating the gut microbiome in patients receiving probiotics and
      compare the the gut microbiome with moderate premature infants not receiving probiotics. In
      addition, we are including a control of healthy full-term infants.

      Samples containing feces from participants will be analyzed by state of the art whole-genome
      sequencing techniques. Bacterial diversity and taxonomy will be analysed using bioinformatic
      tools

      Inclusion criteria:

        -  Preterm infants 24-27 weeks gestation/ birth weight < 1000 g receiving probiotics

        -  Preterm infants 28-31 weeks gestation/BW 1000-1500 g not receiving probiotics

        -  Healthy term infants

      Exclusion criteria

        -  Preterm infants < 24 weeks gestation

        -  Preterm infants < 32 weeks with severe lethal complication/poor prognosis around 1 week
           of age

        -  Infants with severe congenital malformations

      Fecal samples will be obtained:

        -  1 week of age

        -  4 weeks of age

        -  4 months corrected age

        -  12 months corrected age

      Study hypotheses:

        -  Probiotics given to extremely preterm infants will change the biodiversity of the gut
           microflora.

        -  Antibiotics given to these patients may influence the gut microflora also in infants
           receiving probiotics. In particular use of vancomycin may change the gut flora.

        -  After cessation of probiotic prophylaxis the gut flora of infants receiving probiotics
           will gradually resemble the gut flora of infants not receiving probiotics.

        -  A cross-contamination of probiotic bacteria between patients treated with probiotics and
           patients not treated with antibiotics may occur.

      This is an explorative study. No formal sample size assessment is possible. Sequencing costs
      will be substantial. We will limit the number of participants to 26 x 2 preterm infants and
      10 control healthy infants.

      Six Norwegian Neonatal Intensive care units wil participate in the study.
observational model: Cohort
time perspective: Prospective
measure: To assess gut microbiome composition (meta genome sequencing) of preterm infants receiving probiotics versus preterm infants not receiving probiotics
time frame: 4 time points: 7 days of age, 4 weeks of age, 4 months corrected age and 12 months corrected age
description: Stools samples from preterm infants and term infants (control)
measure: Impact of antibiotic exposure on gut microbiome
time frame: 4 time points: 7 days of age, 4 weeks of age, 4 months corrected age and 12 months corrected age
description: Stool samples from preterm and term infants
measure: Cross contamination of probiotic bacteria in a NICU
time frame: 7 days of age and 4 weeks of age
description: Detection of probiotic bacterial microbiome profiles in children not receiving probiotics
arm group label: Probiotics
description: Preterm infants given probiotics: GA 24-27 weeks/Birth weight < 1000 g
Preterm infants not given probiotics: GA 28-31 weeks/Birth weight 1000-1500 g
Full-term infants not given probiotics (control)
Fecal samples for bacterial DNA analyses
study pop: 
sampling method: Non-Probability Sample
criteria: 
gender: All
minimum age: 1 Hour
maximum age: 12 Months
healthy volunteers: No
last name: Claus Klingenberg, MD.phD.Prof.
role: Study Chair
affiliation: University Hospital of North Norway
last name: Eirin Esaiassen, MD
role: Principal Investigator
affiliation: University Hospital of North-Noway
facility: 
facility: 
facility: 
facility: 
facility: 
facility: 
facility: 
country: Norway
citation: Berrington JE, Stewart CJ, Cummings SP, Embleton ND. The neonatal bowel microbiome in health and infection. Curr Opin Infect Dis. 2014 Jun;27(3):236-43. doi: 10.1097/QCO.0000000000000061.
PMID: 24751892
citation: Stewart CJ, Marrs EC, Magorrian S, Nelson A, Lanyon C, Perry JD, Embleton ND, Cummings SP, Berrington JE. The preterm gut microbiota: changes associated with necrotizing enterocolitis and infection. Acta Paediatr. 2012 Nov;101(11):1121-7. doi: 10.1111/j.1651-2227.2012.02801.x. Epub 2012 Aug 31.
PMID: 22845166
responsible party type: Sponsor
study doc: 