<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/NCT01735123</url>
  </required_header>
  <id_info>
    <org_study_id>1DP3DK094338-01</org_study_id>
    <nct_id>NCT01735123</nct_id>
  </id_info>
  <brief_title>Early Dietary Intervention and Later Signs of Beta-Cell Autoimmunity</brief_title>
  <acronym>EDIA</acronym>
  <official_title>Early Dietary Intervention and Later Signs of Beta-Cell Autoimmunity: Potential Mechanisms</official_title>
  <sponsors>
    <lead_sponsor>
      <agency>University of Helsinki</agency>
      <agency_class>Other</agency_class>
    </lead_sponsor>
    <collaborator>
      <agency>University of Turku</agency>
      <agency_class>Other</agency_class>
    </collaborator>
    <collaborator>
      <agency>Finnish Institute for Health and Welfare</agency>
      <agency_class>Other</agency_class>
    </collaborator>
    <collaborator>
      <agency>Tampere University Hospital</agency>
      <agency_class>Other</agency_class>
    </collaborator>
  </sponsors>
  <source>University of Helsinki</source>
  <oversight_info>
    <has_dmc>Yes</has_dmc>
  </oversight_info>
  <brief_summary>
    <textblock>
      The proposed mechanistic formula feeding study sets out to identify the mechanism(s) by which&#xD;
      an extensively hydrolyzed casein formula is able to protect children at risk for type 1&#xD;
      diabetes (T1D) from beta-cell autoimmunity.&#xD;
    </textblock>
  </brief_summary>
  <detailed_description>
    <textblock>
      Based on clinical and experimental observations the study will focus on defining the effects&#xD;
      of two different formulas on intestinal permeability, IL (interleukin)-17 immunity, serum&#xD;
      metabolome, and gut microflora. The study will be based on a randomized pilot intervention&#xD;
      trial using an intention to treat statistical analysis to compare e.g. gut permeability&#xD;
      between the two treatment groups. The investigators hypothesize that the extensively&#xD;
      hydrolyzed casein formula decreases intestinal permeability, down-regulates IL-17 immunity&#xD;
      and proinflammatory lysophosphatidylcholines, and stabilize Lactobacilli levels in the gut&#xD;
      microflora when compared to the conventional cow's milk formula. The study population&#xD;
      comprises 120 newborn infants with HLA(Human Leukocyte Antigen)-conferred susceptibility to&#xD;
      T1D. The mothers will be encouraged to exclusively breast-feed their infants as long as&#xD;
      possible. The timing of weaning and introduction of study formula will be left to the mother.&#xD;
      The infants are randomized to be weaned to one of two study formulas: ( i) standard cow's&#xD;
      milk formula and (ii) an extensively hydrolyzed casein formula. The target will be that the&#xD;
      infant should be exposed to his/her study formula for at least 90 days before the age of 270&#xD;
      days. The diet of the infant will be studied with 3-day food records at the age of 3, 6, 9,&#xD;
      and 12 months of age. To estimate the amount of breast milk received the weight of the infant&#xD;
      will be measured just before and after each lactation. The HLA genotype will be analyzed from&#xD;
      cord blood, and the result will be available within 10 days after birth. The family will&#xD;
      visit the Study Center when the infant is 3, 6, 9, and 12-month-old. Blood samples will be&#xD;
      obtained on each visit. In addition the families are asked to collect stool samples at home&#xD;
      once a month during the study. Intestinal permeability will be assessed with the&#xD;
      lactulose/mannitol test at the age of 3, 6, 9, and 12 months. Gut microflora will be analyzed&#xD;
      with high-throughput, culture-independent methods and serum metabolome with established&#xD;
      metabolomics platforms. Il-17 immunity will be studied using peripheral blood mononuclear&#xD;
      cells. This work will generate novel knowledge of the disease process leading to overt T1D by&#xD;
      studying potential mechanism(s) mediating the protective effect conferred by an extensively&#xD;
      hydrolyzed casein formula against beta-cell autoimmunity. The identification of such&#xD;
      mechanism(s) will most likely facilitate the refinement of effective preventive measures&#xD;
      based on modifications of early infant nutrition.&#xD;
    </textblock>
  </detailed_description>
  <overall_status>Completed</overall_status>
  <start_date>January 2013</start_date>
  <completion_date type="Actual">August 2016</completion_date>
  <primary_completion_date type="Actual">July 2016</primary_completion_date>
  <phase>N/A</phase>
  <study_type>Interventional</study_type>
  <has_expanded_access>No</has_expanded_access>
  <study_design_info>
    <allocation>Randomized</allocation>
    <intervention_model>Parallel Assignment</intervention_model>
    <primary_purpose>Prevention</primary_purpose>
    <masking>Double (Participant, Outcomes Assessor)</masking>
  </study_design_info>
  <primary_outcome>
    <measure>Intestinal permeability will be determined at the age of 3, 6, 9 and 12 months with the lactulose/mannitol test Intestinal permeability at the age of 9 months assessed with the lactulose/mannitol test</measure>
    <time_frame>3, 6, 9 and 12 months</time_frame>
    <description>Intestinal permeability will be determined at the age of 3, 6, 9 and 12 months with the lactulose/mannitol test</description>
  </primary_outcome>
  <secondary_outcome>
    <measure>Serum metabolic profile</measure>
    <time_frame>3, 6, 9 and 12 months</time_frame>
    <description>The serum metabolic profile wil be analyzed with metabolomics at the age of 3, 6, 9, and 12 months</description>
  </secondary_outcome>
  <other_outcome>
    <measure>Intestinal microbiome</measure>
    <time_frame>3, 6, 9 and 12 months</time_frame>
    <description>The intestinal microbiome will be analyzed at the age of 3, 6, 9 , and 12 months</description>
  </other_outcome>
  <number_of_arms>2</number_of_arms>
  <enrollment type="Actual">87</enrollment>
  <condition>Diabetes Mellitus, Type 1</condition>
  <arm_group>
    <arm_group_label>extensively hydrolyzed casein formula</arm_group_label>
    <arm_group_type>Experimental</arm_group_type>
    <description>The investigators plan to randomize 60 out of 120 infants to be weaned to an extensively hydrolyzed casein formula. Recruited mothers are encouraged to breast-feed. The dietary intervention will be applied until 9 months of age. The minimum exposure time to the study formula should be 90 days. Signs of beta-cell autoimmunity, i.e. diabetes-associated autoantibodies, will be monitored in the study participants, although the study will not have sufficient power to detect statistically significant differences in the seroconversion rate between the groups due to the limited number of infants randomized.</description>
  </arm_group>
  <arm_group>
    <arm_group_label>cow's milk based infant formula</arm_group_label>
    <arm_group_type>Experimental</arm_group_type>
    <description>The investigators plan to randomize 60 out of 120 infants to be weaned to a cow's milk based infant formula. Recruited mothers are encouraged to breast-feed. The dietary intervention will be applied until 9 months of age. The minimum exposure time to the study formula should be 90 days. Signs of beta-cell autoimmunity, i.e. diabetes-associated autoantibodies, will be monitored in the study participants, although the study will not have sufficient power to detect statistically significant differences in the seroconversion rate between the groups due to the limited number of infants randomized.</description>
  </arm_group>
  <intervention>
    <intervention_type>Dietary Supplement</intervention_type>
    <intervention_name>dietary intervention</intervention_name>
    <description>hydrolyzed vs. nonhydrolyzed infant formula</description>
    <arm_group_label>cow's milk based infant formula</arm_group_label>
    <arm_group_label>extensively hydrolyzed casein formula</arm_group_label>
    <other_name>An extensively hydrolyzed casein formula</other_name>
    <other_name>A regular cow's milk based formula</other_name>
  </intervention>
  <eligibility>
    <criteria>
      <textblock>
        Inclusion Criteria:&#xD;
&#xD;
        - The infant's parents give signed consent to participate and their HLA genotype is&#xD;
        eligible.&#xD;
&#xD;
        Exclusion Criteria:&#xD;
&#xD;
          -  An older sibling of the newborn infant has been included in this study;&#xD;
&#xD;
          -  Multiple gestation;&#xD;
&#xD;
          -  The parents are unwilling or unable to feed the infant cow's milk based products for&#xD;
             any reason (e.g., religious, cultural);&#xD;
&#xD;
          -  The gestational age of the newborn infant is less than 35 weeks&#xD;
&#xD;
          -  Inability of the family to take part in the study (e.g. the family had no access to&#xD;
             the Study Center or telephone)&#xD;
&#xD;
          -  The newborn infant has a recognizable severe illness such as those due to chromosomal&#xD;
             abnormality, congenital malformation, respiratory failure needing assisted&#xD;
             ventilation, enzyme deficiencies, etc.;&#xD;
&#xD;
          -  The infant receives any infant formula other than study formula or Nutramigen at the&#xD;
             delivery hospital&#xD;
&#xD;
          -  No HLA sample has been drawn before the age of 8 days.&#xD;
      </textblock>
    </criteria>
    <gender>All</gender>
    <minimum_age>N/A</minimum_age>
    <maximum_age>12 Months</maximum_age>
    <healthy_volunteers>Accepts Healthy Volunteers</healthy_volunteers>
  </eligibility>
  <overall_official>
    <last_name>Mikael Knip, M.D.</last_name>
    <role>Principal Investigator</role>
    <affiliation>University of Helsinki</affiliation>
  </overall_official>
  <location>
    <facility>
      <name>Tampere University Hospital</name>
      <address>
        <city>Tampere</city>
        <zip>33521</zip>
        <country>Finland</country>
      </address>
    </facility>
  </location>
  <location_countries>
    <country>Finland</country>
  </location_countries>
  <verification_date>February 2017</verification_date>
  <study_first_submitted>November 24, 2012</study_first_submitted>
  <study_first_submitted_qc>November 24, 2012</study_first_submitted_qc>
  <study_first_posted type="Estimate">November 28, 2012</study_first_posted>
  <last_update_submitted>February 24, 2017</last_update_submitted>
  <last_update_submitted_qc>February 24, 2017</last_update_submitted_qc>
  <last_update_posted type="Actual">February 27, 2017</last_update_posted>
  <responsible_party>
    <responsible_party_type>Principal Investigator</responsible_party_type>
    <investigator_affiliation>University of Helsinki</investigator_affiliation>
    <investigator_full_name>Mikael Knip</investigator_full_name>
    <investigator_title>Professor</investigator_title>
  </responsible_party>
  <keyword>infant formula</keyword>
  <keyword>diet</keyword>
  <keyword>diabetes mellitus, type 1</keyword>
  <keyword>autoimmunity</keyword>
  <condition_browse>
    <!-- CAUTION:  The following MeSH terms are assigned with an imperfect algorithm            -->
    <mesh_term>Diabetes Mellitus</mesh_term>
    <mesh_term>Diabetes Mellitus, Type 1</mesh_term>
    <mesh_term>Autoimmune Diseases</mesh_term>
  </condition_browse>
  <intervention_browse>
    <!-- CAUTION:  The following MeSH terms are assigned with an imperfect algorithm            -->
    <mesh_term>Caseins</mesh_term>
  </intervention_browse>
  <pending_results>
    <submitted>July 9, 2021</submitted>
    <returned>July 30, 2021</returned>
  </pending_results>
  <!-- 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/NCT01735123
org study id: 1DP3DK094338-01
nct id: NCT01735123
lead sponsor: 
collaborator: 
collaborator: 
collaborator: 
has dmc: Yes
The proposed mechanistic formula feeding study sets out to identify the mechanism(s) by which
      an extensively hydrolyzed casein formula is able to protect children at risk for type 1
      diabetes (T1D) from beta-cell autoimmunity.
Based on clinical and experimental observations the study will focus on defining the effects
      of two different formulas on intestinal permeability, IL (interleukin)-17 immunity, serum
      metabolome, and gut microflora. The study will be based on a randomized pilot intervention
      trial using an intention to treat statistical analysis to compare e.g. gut permeability
      between the two treatment groups. The investigators hypothesize that the extensively
      hydrolyzed casein formula decreases intestinal permeability, down-regulates IL-17 immunity
      and proinflammatory lysophosphatidylcholines, and stabilize Lactobacilli levels in the gut
      microflora when compared to the conventional cow's milk formula. The study population
      comprises 120 newborn infants with HLA(Human Leukocyte Antigen)-conferred susceptibility to
      T1D. The mothers will be encouraged to exclusively breast-feed their infants as long as
      possible. The timing of weaning and introduction of study formula will be left to the mother.
      The infants are randomized to be weaned to one of two study formulas: ( i) standard cow's
      milk formula and (ii) an extensively hydrolyzed casein formula. The target will be that the
      infant should be exposed to his/her study formula for at least 90 days before the age of 270
      days. The diet of the infant will be studied with 3-day food records at the age of 3, 6, 9,
      and 12 months of age. To estimate the amount of breast milk received the weight of the infant
      will be measured just before and after each lactation. The HLA genotype will be analyzed from
      cord blood, and the result will be available within 10 days after birth. The family will
      visit the Study Center when the infant is 3, 6, 9, and 12-month-old. Blood samples will be
      obtained on each visit. In addition the families are asked to collect stool samples at home
      once a month during the study. Intestinal permeability will be assessed with the
      lactulose/mannitol test at the age of 3, 6, 9, and 12 months. Gut microflora will be analyzed
      with high-throughput, culture-independent methods and serum metabolome with established
      metabolomics platforms. Il-17 immunity will be studied using peripheral blood mononuclear
      cells. This work will generate novel knowledge of the disease process leading to overt T1D by
      studying potential mechanism(s) mediating the protective effect conferred by an extensively
      hydrolyzed casein formula against beta-cell autoimmunity. The identification of such
      mechanism(s) will most likely facilitate the refinement of effective preventive measures
      based on modifications of early infant nutrition.
allocation: Randomized
intervention model: Parallel Assignment
primary purpose: Prevention
masking: Double (Participant, Outcomes Assessor)
measure: Intestinal permeability will be determined at the age of 3, 6, 9 and 12 months with the lactulose/mannitol test Intestinal permeability at the age of 9 months assessed with the lactulose/mannitol test
time frame: 3, 6, 9 and 12 months
description: Intestinal permeability will be determined at the age of 3, 6, 9 and 12 months with the lactulose/mannitol test
measure: Serum metabolic profile
time frame: 3, 6, 9 and 12 months
description: The serum metabolic profile wil be analyzed with metabolomics at the age of 3, 6, 9, and 12 months
measure: Intestinal microbiome
time frame: 3, 6, 9 and 12 months
description: The intestinal microbiome will be analyzed at the age of 3, 6, 9 , and 12 months
arm group label: extensively hydrolyzed casein formula
arm group type: Experimental
description: The investigators plan to randomize 60 out of 120 infants to be weaned to an extensively hydrolyzed casein formula. Recruited mothers are encouraged to breast-feed. The dietary intervention will be applied until 9 months of age. The minimum exposure time to the study formula should be 90 days. Signs of beta-cell autoimmunity, i.e. diabetes-associated autoantibodies, will be monitored in the study participants, although the study will not have sufficient power to detect statistically significant differences in the seroconversion rate between the groups due to the limited number of infants randomized.
arm group label: cow's milk based infant formula
arm group type: Experimental
description: The investigators plan to randomize 60 out of 120 infants to be weaned to a cow's milk based infant formula. Recruited mothers are encouraged to breast-feed. The dietary intervention will be applied until 9 months of age. The minimum exposure time to the study formula should be 90 days. Signs of beta-cell autoimmunity, i.e. diabetes-associated autoantibodies, will be monitored in the study participants, although the study will not have sufficient power to detect statistically significant differences in the seroconversion rate between the groups due to the limited number of infants randomized.
intervention type: Dietary Supplement
intervention name: dietary intervention
description: hydrolyzed vs. nonhydrolyzed infant formula
arm group label: cow's milk based infant formula
arm group label: extensively hydrolyzed casein formula
other name: An extensively hydrolyzed casein formula
other name: A regular cow's milk based formula
criteria: 
gender: All
minimum age: N/A
maximum age: 12 Months
healthy volunteers: Accepts Healthy Volunteers
last name: Mikael Knip, M.D.
role: Principal Investigator
affiliation: University of Helsinki
facility: 
country: Finland
responsible party type: Principal Investigator
investigator affiliation: University of Helsinki
investigator full name: Mikael Knip
investigator title: Professor
mesh term: Diabetes Mellitus
mesh term: Diabetes Mellitus, Type 1
mesh term: Autoimmune Diseases
mesh term: Caseins
submitted: July 9, 2021
returned: July 30, 2021