<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/NCT03776474</url>
  </required_header>
  <id_info>
    <org_study_id>APHP180057</org_study_id>
    <secondary_id>2018-A01972-53</secondary_id>
    <nct_id>NCT03776474</nct_id>
  </id_info>
  <brief_title>Determine Immunoglobulin G4 (IgG4) Standards for Cow's Milk and Egg in Different Populations of Allergic and Non-allergic Children</brief_title>
  <acronym>IgG4</acronym>
  <official_title>Determine Immunoglobulin G4 (IgG4) Standards for Cow's Milk and Egg in Different Populations of Allergic and Non-allergic Children</official_title>
  <sponsors>
    <lead_sponsor>
      <agency>Assistance Publique - Hôpitaux de Paris</agency>
      <agency_class>Other</agency_class>
    </lead_sponsor>
  </sponsors>
  <source>Assistance Publique - Hôpitaux de Paris</source>
  <oversight_info>
    <has_dmc>No</has_dmc>
    <is_fda_regulated_drug>No</is_fda_regulated_drug>
    <is_fda_regulated_device>No</is_fda_regulated_device>
  </oversight_info>
  <brief_summary>
    <textblock>
      The study objectives are :&#xD;
&#xD;
      Determine standards of plasma levels of casein-specific immunoglobulin G4 (IgG4) and&#xD;
      egg-specific immunoglobulin G4 (IgG4) as a function of age, in non-allergic children, in&#xD;
      allergic children, and in cured former allergic patients.&#xD;
&#xD;
      Analyze the plasma IgG4 / IgE ratio, according to the result of the oral provocation test&#xD;
      (tolerance versus allergy) and, in the event of a reaction, according to the reactogenic dose&#xD;
      (dose which caused the reaction).Determine whether analysis of the plasma metabolome can&#xD;
      identify children with a cured allergy to cow's milk protein or to egg from those with a&#xD;
      persistent allergy.&#xD;
    </textblock>
  </brief_summary>
  <detailed_description>
    <textblock>
      Immunoglobulin E (IgE) mediated allergies to cow's milk and hen's egg affects 2-3% and&#xD;
      0.5-2.5% of children respectively. These allergies expose to the risk of immediate&#xD;
      anaphylactic reaction that may be life-threatening. Approximately 70-80% of children with IgE&#xD;
      mediated allergies to cow's milk and hen's egg will tolerate these foods by the age of 6&#xD;
      years. However, in the absence of reliable biomarker of tolerance, to determine whether oral&#xD;
      tolerance is obtained, it is recommended to perform an oral food challenge (OFC) in a&#xD;
      hospital setting. This procedure is expensive, time consuming, and carries the risk of&#xD;
      anaphylactic reactions. Many studies have tried to find predictive markers of reactivity&#xD;
      during the OFC. Improving the prediction of the response to OFC would be very useful to&#xD;
      better select children in whom an OFC can be performed without risk to confirm the&#xD;
      acquisition of tolerance.&#xD;
&#xD;
      For instance, serum specific IgE positive values beyond which 95% of patients would have an&#xD;
      allergic reaction have been proposed. These values are highly variable from one study to&#xD;
      another because of methodological differences and heterogeneity of populations, and cannot be&#xD;
      used in clinical practice.&#xD;
&#xD;
      The regular dosage of serum specific IgE and its evolution over time is used in clinical&#xD;
      practice to predict a possible persistence of IgE mediated food allergy. Indeed, an initial&#xD;
      high rate and/or elevation of specific IgE levels may be predictive of a persistent allergy,&#xD;
      while initial low rates and a decrease in specific IgE may predict tolerance. When tolerance&#xD;
      develops, there is a decrease in specific IgE levels, however, even if tolerance is obtained,&#xD;
      they can remain positive at pathological levels.&#xD;
&#xD;
      During continuous exposure to an allergen, the specific immunoglobulin G4 (IgG4) response is&#xD;
      physiological. Oral immunotherapy studies in food allergies showed an elevation of specific&#xD;
      IgG4, associated with an elevation in the number of regulatory T lymphocytes (LTreg) and the&#xD;
      production of interleukin (IL)-10. The development of spontaneous oral tolerance, without the&#xD;
      intervention of immunotherapy, also seems to involve IgG4. In a prospective follow-up of a&#xD;
      cohort of children with an IgE-mediated cow's milk allergy, the elevation of specific IgG4&#xD;
      was observed in those who cure of their allergy, with rates higher than those observed in&#xD;
      children whose allergy persists. In children with cow's milk and/or egg allergies, a low&#xD;
      concentration of specific (IgG4 of B-Lactoglobulin or ovalbumin is associated with the need&#xD;
      for a more prolonged exclusion diet. The balance between specific IgE and IgG4 therefore&#xD;
      appears to be important in the development of tolerance and may reflect the balance between&#xD;
      effector T cells and LTreg. However, the normal serum levels of IgG4 to cow's milk and hen's&#xD;
      egg are unknown.&#xD;
&#xD;
      A recently published study of Doctor Guillaume Lezmi and Professor Karine Adel-Patient shows&#xD;
      that children with an IgE-mediated allergy to cow's milk protein and those who outgrew this&#xD;
      allergy, have distinct plasma metabolomic signature. This suggests that plasma metabolomic&#xD;
      analysis may be a useful too to differentiate children with a persistent cow's milk protein&#xD;
      allergy from those who acquired tolerance to cow's milk. If confirmed, the metabolic&#xD;
      signature may be useful to better identify children to whom an oral food challenge with cow's&#xD;
      milk protein could be propose. These results need to be confirmed in a larger population and&#xD;
      in other food allergies.&#xD;
&#xD;
      The study objectives are :&#xD;
&#xD;
      Determine standards of plasma levels of casein-specific immunoglobulin G4 (IgG4) and&#xD;
      egg-specific immunoglobulin G4 (IgG4) as a function of age, in non-allergic children, in&#xD;
      allergic children, and in cured former allergic patients.&#xD;
&#xD;
      Analyze the plasma IgG4 / IgE ratio, according to the result of the oral provocation test&#xD;
      (tolerance versus allergy) and, in the event of a reaction, according to the reactogenic dose&#xD;
      (dose which caused the reaction).&#xD;
&#xD;
      Determine whether analysis of the plasma metabolome can identify children with a cured&#xD;
      allergy to cow's milk protein or to egg from those with a persistent allergy.&#xD;
    </textblock>
  </detailed_description>
  <overall_status>Recruiting</overall_status>
  <start_date type="Actual">November 18, 2020</start_date>
  <completion_date type="Anticipated">November 18, 2023</completion_date>
  <primary_completion_date type="Anticipated">November 18, 2023</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>Plasma concentration of casein-specific immunoglobulin G4 and egg-specific immunoglobulin G4</measure>
    <time_frame>Day 0</time_frame>
  </primary_outcome>
  <secondary_outcome>
    <measure>Plasma concentration of casein-specific immunoglobulin E and egg-specific immunoglobulin E</measure>
    <time_frame>Day 0</time_frame>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Total immunoglobulin E plasma concentration</measure>
    <time_frame>Day 0</time_frame>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Plasma concentration of casein-specific immunoglobulin G4 / plasma concentration of casein-specific immunoglobulin E ratio</measure>
    <time_frame>Day 0</time_frame>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Plasma concentration of egg-specific immunoglobulin G4 / plasma concentration of egg-specific immunoglobulin E ratio</measure>
    <time_frame>Day 0</time_frame>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Plasma concentration of casein-specific immunoglobulin G4 / total immunoglobulin E plasma concentration ratio</measure>
    <time_frame>Day 0</time_frame>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Plasma concentration of egg-specific immunoglobulin G4 / total immunoglobulin E plasma concentration ratio</measure>
    <time_frame>Day 0</time_frame>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Plasma metabolomic analysis</measure>
    <time_frame>Day 0</time_frame>
  </secondary_outcome>
  <number_of_groups>3</number_of_groups>
  <enrollment type="Anticipated">500</enrollment>
  <condition>Food Allergy in Children</condition>
  <arm_group>
    <arm_group_label>Allergic</arm_group_label>
    <description>Minors allergic to cow's milk and/or eggs</description>
  </arm_group>
  <arm_group>
    <arm_group_label>Non-allergic</arm_group_label>
    <description>Minors without history of allergy to cow's milk and/or eggs</description>
  </arm_group>
  <arm_group>
    <arm_group_label>Acquired tolerance</arm_group_label>
    <description>Minors formerly allergic to cow's milk and/or eggs</description>
  </arm_group>
  <intervention>
    <intervention_type>Biological</intervention_type>
    <intervention_name>Blood collection</intervention_name>
    <description>Patients less than 5 kg : 2 ml Patients over 5 kg : 3 ml Patients over 10 kg : 5 ml</description>
    <arm_group_label>Acquired tolerance</arm_group_label>
    <arm_group_label>Allergic</arm_group_label>
    <arm_group_label>Non-allergic</arm_group_label>
  </intervention>
  <biospec_retention>Samples Without DNA</biospec_retention>
  <biospec_descr>
    <textblock>
      Serum&#xD;
    </textblock>
  </biospec_descr>
  <eligibility>
    <study_pop>
      <textblock>
        Minors in consultation or hospitalized at Necker Hospital&#xD;
      </textblock>
    </study_pop>
    <sampling_method>Non-Probability Sample</sampling_method>
    <criteria>
      <textblock>
        Inclusion Criteria:&#xD;
&#xD;
          -  Minors aged 0 to 18&#xD;
&#xD;
          -  In consultation or hospitalized for an oral food challenge for milk or eggs&#xD;
&#xD;
          -  To undergo a blood test&#xD;
&#xD;
        Exclusion Criteria:&#xD;
&#xD;
        Minors with immune deficiency, chronic inflammatory disease or immunosuppressive or&#xD;
        immunomodulator treatment&#xD;
      </textblock>
    </criteria>
    <gender>All</gender>
    <minimum_age>1 Month</minimum_age>
    <maximum_age>18 Years</maximum_age>
    <healthy_volunteers>No</healthy_volunteers>
  </eligibility>
  <overall_official>
    <last_name>Guillaume Lezmi, MD, PhD</last_name>
    <role>Principal Investigator</role>
    <affiliation>Assistance Publique - Hôpitaux de Paris</affiliation>
  </overall_official>
  <overall_contact>
    <last_name>Guillaume Lezmi, MD, PhD</last_name>
    <phone>+33 1 44 49 48 38</phone>
    <email>guillaume.lezmi@aphp.fr</email>
  </overall_contact>
  <overall_contact_backup>
    <last_name>Hélène Morel</last_name>
    <phone>+33 1 71 19 63 46</phone>
    <email>helene.morel@aphp.fr</email>
  </overall_contact_backup>
  <location>
    <facility>
      <name>Hôpital Necker Enfants malades</name>
      <address>
        <city>Paris</city>
        <zip>75015</zip>
        <country>France</country>
      </address>
    </facility>
    <status>Recruiting</status>
    <contact>
      <last_name>Guillaume Lezmi, MD, PhD</last_name>
      <phone>+33 1 44 49 48 38</phone>
      <email>guillaume.lezmi@aphp.fr</email>
    </contact>
    <contact_backup>
      <last_name>Hélène Morel</last_name>
      <phone>+33 1 71 19 63 46</phone>
      <email>helene.morel@aphp.fr</email>
    </contact_backup>
  </location>
  <location_countries>
    <country>France</country>
  </location_countries>
  <reference>
    <citation>Adel-Patient K, Lezmi G, Castelli FA, Blanc S, Bernard H, Soulaines P, Dumond P, Ah-Leung S, Lageix F, de Boissieu D, Cortes-Perez N, Hazebrouck S, Fenaille F, Junot C, Dupont C. Deep analysis of immune response and metabolic signature in children with food protein induced enterocolitis to cow's milk. Clin Transl Allergy. 2018 Sep 28;8:38. doi: 10.1186/s13601-018-0224-9. eCollection 2018.</citation>
    <PMID>30275944</PMID>
  </reference>
  <verification_date>November 2022</verification_date>
  <study_first_submitted>December 6, 2018</study_first_submitted>
  <study_first_submitted_qc>December 13, 2018</study_first_submitted_qc>
  <study_first_posted type="Actual">December 14, 2018</study_first_posted>
  <last_update_submitted>November 7, 2022</last_update_submitted>
  <last_update_submitted_qc>November 7, 2022</last_update_submitted_qc>
  <last_update_posted type="Actual">November 8, 2022</last_update_posted>
  <responsible_party>
    <responsible_party_type>Sponsor</responsible_party_type>
  </responsible_party>
  <keyword>Food allergy in children</keyword>
  <keyword>Immunoglobulin E</keyword>
  <keyword>Immunoglobulin G4</keyword>
  <keyword>Oral food challenge</keyword>
  <keyword>Plasma metabolomic analysis</keyword>
  <condition_browse>
    <!-- CAUTION:  The following MeSH terms are assigned with an imperfect algorithm            -->
    <mesh_term>Food Hypersensitivity</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/NCT03776474
org study id: APHP180057
secondary id: 2018-A01972-53
nct id: NCT03776474
lead sponsor: 
has dmc: No
is fda regulated drug: No
is fda regulated device: No
The study objectives are :

      Determine standards of plasma levels of casein-specific immunoglobulin G4 (IgG4) and
      egg-specific immunoglobulin G4 (IgG4) as a function of age, in non-allergic children, in
      allergic children, and in cured former allergic patients.

      Analyze the plasma IgG4 / IgE ratio, according to the result of the oral provocation test
      (tolerance versus allergy) and, in the event of a reaction, according to the reactogenic dose
      (dose which caused the reaction).Determine whether analysis of the plasma metabolome can
      identify children with a cured allergy to cow's milk protein or to egg from those with a
      persistent allergy.
Immunoglobulin E (IgE) mediated allergies to cow's milk and hen's egg affects 2-3% and
      0.5-2.5% of children respectively. These allergies expose to the risk of immediate
      anaphylactic reaction that may be life-threatening. Approximately 70-80% of children with IgE
      mediated allergies to cow's milk and hen's egg will tolerate these foods by the age of 6
      years. However, in the absence of reliable biomarker of tolerance, to determine whether oral
      tolerance is obtained, it is recommended to perform an oral food challenge (OFC) in a
      hospital setting. This procedure is expensive, time consuming, and carries the risk of
      anaphylactic reactions. Many studies have tried to find predictive markers of reactivity
      during the OFC. Improving the prediction of the response to OFC would be very useful to
      better select children in whom an OFC can be performed without risk to confirm the
      acquisition of tolerance.

      For instance, serum specific IgE positive values beyond which 95% of patients would have an
      allergic reaction have been proposed. These values are highly variable from one study to
      another because of methodological differences and heterogeneity of populations, and cannot be
      used in clinical practice.

      The regular dosage of serum specific IgE and its evolution over time is used in clinical
      practice to predict a possible persistence of IgE mediated food allergy. Indeed, an initial
      high rate and/or elevation of specific IgE levels may be predictive of a persistent allergy,
      while initial low rates and a decrease in specific IgE may predict tolerance. When tolerance
      develops, there is a decrease in specific IgE levels, however, even if tolerance is obtained,
      they can remain positive at pathological levels.

      During continuous exposure to an allergen, the specific immunoglobulin G4 (IgG4) response is
      physiological. Oral immunotherapy studies in food allergies showed an elevation of specific
      IgG4, associated with an elevation in the number of regulatory T lymphocytes (LTreg) and the
      production of interleukin (IL)-10. The development of spontaneous oral tolerance, without the
      intervention of immunotherapy, also seems to involve IgG4. In a prospective follow-up of a
      cohort of children with an IgE-mediated cow's milk allergy, the elevation of specific IgG4
      was observed in those who cure of their allergy, with rates higher than those observed in
      children whose allergy persists. In children with cow's milk and/or egg allergies, a low
      concentration of specific (IgG4 of B-Lactoglobulin or ovalbumin is associated with the need
      for a more prolonged exclusion diet. The balance between specific IgE and IgG4 therefore
      appears to be important in the development of tolerance and may reflect the balance between
      effector T cells and LTreg. However, the normal serum levels of IgG4 to cow's milk and hen's
      egg are unknown.

      A recently published study of Doctor Guillaume Lezmi and Professor Karine Adel-Patient shows
      that children with an IgE-mediated allergy to cow's milk protein and those who outgrew this
      allergy, have distinct plasma metabolomic signature. This suggests that plasma metabolomic
      analysis may be a useful too to differentiate children with a persistent cow's milk protein
      allergy from those who acquired tolerance to cow's milk. If confirmed, the metabolic
      signature may be useful to better identify children to whom an oral food challenge with cow's
      milk protein could be propose. These results need to be confirmed in a larger population and
      in other food allergies.

      The study objectives are :

      Determine standards of plasma levels of casein-specific immunoglobulin G4 (IgG4) and
      egg-specific immunoglobulin G4 (IgG4) as a function of age, in non-allergic children, in
      allergic children, and in cured former allergic patients.

      Analyze the plasma IgG4 / IgE ratio, according to the result of the oral provocation test
      (tolerance versus allergy) and, in the event of a reaction, according to the reactogenic dose
      (dose which caused the reaction).

      Determine whether analysis of the plasma metabolome can identify children with a cured
      allergy to cow's milk protein or to egg from those with a persistent allergy.
observational model: Case-Control
time perspective: Prospective
measure: Plasma concentration of casein-specific immunoglobulin G4 and egg-specific immunoglobulin G4
time frame: Day 0
measure: Plasma concentration of casein-specific immunoglobulin E and egg-specific immunoglobulin E
time frame: Day 0
measure: Total immunoglobulin E plasma concentration
time frame: Day 0
measure: Plasma concentration of casein-specific immunoglobulin G4 / plasma concentration of casein-specific immunoglobulin E ratio
time frame: Day 0
measure: Plasma concentration of egg-specific immunoglobulin G4 / plasma concentration of egg-specific immunoglobulin E ratio
time frame: Day 0
measure: Plasma concentration of casein-specific immunoglobulin G4 / total immunoglobulin E plasma concentration ratio
time frame: Day 0
measure: Plasma concentration of egg-specific immunoglobulin G4 / total immunoglobulin E plasma concentration ratio
time frame: Day 0
measure: Plasma metabolomic analysis
time frame: Day 0
arm group label: Allergic
description: Minors allergic to cow's milk and/or eggs
arm group label: Non-allergic
description: Minors without history of allergy to cow's milk and/or eggs
arm group label: Acquired tolerance
description: Minors formerly allergic to cow's milk and/or eggs
intervention type: Biological
intervention name: Blood collection
description: Patients less than 5 kg : 2 ml Patients over 5 kg : 3 ml Patients over 10 kg : 5 ml
arm group label: Acquired tolerance
arm group label: Allergic
arm group label: Non-allergic
Serum
study pop: 
sampling method: Non-Probability Sample
criteria: 
gender: All
minimum age: 1 Month
maximum age: 18 Years
healthy volunteers: No
last name: Guillaume Lezmi, MD, PhD
role: Principal Investigator
affiliation: Assistance Publique - Hôpitaux de Paris
last name: Guillaume Lezmi, MD, PhD
phone: +33 1 44 49 48 38
email: guillaume.lezmi@aphp.fr
last name: Hélène Morel
phone: +33 1 71 19 63 46
email: helene.morel@aphp.fr
facility: 
status: Recruiting
contact: 
contact backup: 
country: France
citation: Adel-Patient K, Lezmi G, Castelli FA, Blanc S, Bernard H, Soulaines P, Dumond P, Ah-Leung S, Lageix F, de Boissieu D, Cortes-Perez N, Hazebrouck S, Fenaille F, Junot C, Dupont C. Deep analysis of immune response and metabolic signature in children with food protein induced enterocolitis to cow's milk. Clin Transl Allergy. 2018 Sep 28;8:38. doi: 10.1186/s13601-018-0224-9. eCollection 2018.
PMID: 30275944
responsible party type: Sponsor
mesh term: Food Hypersensitivity