<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/NCT04468880</url>
  </required_header>
  <id_info>
    <org_study_id>2020-A00185-34</org_study_id>
    <nct_id>NCT04468880</nct_id>
  </id_info>
  <brief_title>Milk Consumption on Digestive Comfort.</brief_title>
  <acronym>A2-DIGEST</acronym>
  <official_title>Effect of Milk Consumption, Containing A2 β-caseins Only, on Digestive Comfort. A Randomized and Double-blind Study</official_title>
  <sponsors>
    <lead_sponsor>
      <agency>Institut Pasteur de Lille</agency>
      <agency_class>Other</agency_class>
    </lead_sponsor>
  </sponsors>
  <source>Institut Pasteur de Lille</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>
      Lactose, naturally present in milk, can cause digestive discomfort. Delactosed milk is&#xD;
      currently the only one alternative to cow's milk for intolerant people. As some of them do&#xD;
      not digest milk, it was completely remove from their diet. However, are they really&#xD;
      intolerant to lactose or intolerant to milk (or to another of its compounds)? Do β-caseins&#xD;
      play a role in this intolerance? β-caseins are proteins naturally present in milk. Two types&#xD;
      of β-caseins were identified: A1 and A2. These types differ according to the genetic profile&#xD;
      of the cow and depend on the breed. The rare clinical studies interested in this topic&#xD;
      suggest that:&#xD;
&#xD;
        1. consumption of milk A1 versus consumption of milk A2 can lead to: softer stools, delayed&#xD;
           transit, as well as pro-inflammatory effects in some individuals,&#xD;
&#xD;
        2. consumption of A2 milk significantly reduces gastrointestinal symptoms and improves&#xD;
           digestive comfort in lactose intolerant people.&#xD;
&#xD;
      Thus, it would be interesting to be able to assess the effect of a consumption of A2A2 milk&#xD;
      type compared to A1A2 milk type, both on the parameters of digestive comfort and on&#xD;
      inflammatory parameters.&#xD;
    </textblock>
  </brief_summary>
  <detailed_description>
    <textblock>
      The study will be carried out on healthy volunteers, aged 18 to 65 and self-declared&#xD;
      sensitive, even intolerant to the consumption of milk.&#xD;
&#xD;
      The main objective of the study is to assess the impact of milk β-caseins (A2A2 vs A1A2) on&#xD;
      the digestive comfort felt during the consumption of milk in subjects declaring that they do&#xD;
      not tolerate milk.&#xD;
    </textblock>
  </detailed_description>
  <overall_status>Completed</overall_status>
  <start_date type="Actual">July 20, 2020</start_date>
  <completion_date type="Actual">June 1, 2021</completion_date>
  <primary_completion_date type="Actual">April 14, 2021</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>Crossover Assignment</intervention_model>
    <intervention_model_description>monocentric, double-blind, randomized, controlled, cross-over and ambulatory study</intervention_model_description>
    <primary_purpose>Other</primary_purpose>
    <masking>Double (Participant, Investigator)</masking>
  </study_design_info>
  <primary_outcome>
    <measure>Analog visual scales</measure>
    <time_frame>4 weeks</time_frame>
    <description>Digestive comfort will be assessed daily by the average of the following analog visual scales (score : 0 to 10), completed within 30 min to 3 hours after consumption of the daily dose of milk, depending on the usual occurrence of symptoms in individuals:&#xD;
I have bloating&#xD;
I have abdominal pain&#xD;
I have flatulence (gas)&#xD;
I have borborygmas (gurgling)&#xD;
I have reflux (return, rise)&#xD;
Overall, I estimate my digestive comfort.&#xD;
The average of these 6 analog visual scales, called Global Digestive Discomfort (IDG), will therefore be available every day for 14 days; the final variable analyzed will be the average of these 14 IDG values, and will be called Global Average Digestive Discomfort (IDGM).</description>
  </primary_outcome>
  <secondary_outcome>
    <measure>Analysis of the average per period of each analog visual scales independently</measure>
    <time_frame>4 weeks</time_frame>
    <description>The analogue visual scales will be completed daily during each period of milk consumption (4 weeks)</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Difference Calprotectin at the end of the period - Calprotectin at V0 (measured in mg/kg)</measure>
    <time_frame>4 weeks</time_frame>
    <description>Stool collections are made during inclusion visits, V1 follow-up and V3 end of study.</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>For each of the inflammatory markers (CRP us, IL-1β, TNF-α, IL-6) : difference between value at the end of the period and value at V0</measure>
    <time_frame>4 weeks</time_frame>
    <description>Blood samples are taken during inclusion visits, V1 follow-up and V3 end of study.&#xD;
All of the inflammatory markers are measured in pg/ml.</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Average stool frequencies and consistencies</measure>
    <time_frame>4 weeks</time_frame>
    <description>This questionnaires will be completed daily during each period of milk consumption (4 weeks).&#xD;
Bristol scale: stool type 1 (separate hard balls) to stool type 7 (watery, structureless stools)</description>
  </secondary_outcome>
  <number_of_arms>2</number_of_arms>
  <enrollment type="Actual">50</enrollment>
  <condition>Healthy Volunteers</condition>
  <arm_group>
    <arm_group_label>Milk A1A2</arm_group_label>
    <arm_group_type>Other</arm_group_type>
    <description>Group (A1 → A2) receiving control milk A1A2 in period 1 then the milk evaluated A2A2 in period 2</description>
  </arm_group>
  <arm_group>
    <arm_group_label>Milk A2A2</arm_group_label>
    <arm_group_type>Other</arm_group_type>
    <description>Group (A2 → A1) receiving the milk evaluated A2A2 in period 1 then the control milk A1A2 in period 2</description>
  </arm_group>
  <intervention>
    <intervention_type>Other</intervention_type>
    <intervention_name>Group (A1 → A2)</intervention_name>
    <description>Before each start of consumption of the products under study, a wash-out period of 2 weeks (no consumption of milk) must be observed by the subjects.&#xD;
25 subjects will consume A1A2 milk for 2 weeks (period 1), then they will consume A2A2 milk for 2 weeks (period 2).&#xD;
During each consumption period, various questionnaires will be completed by the subjects: frequency and consistency of stool, analog visual scales on digestive comfort and dietary surveys. Stool collections will also be carried out.</description>
    <arm_group_label>Milk A1A2</arm_group_label>
  </intervention>
  <intervention>
    <intervention_type>Other</intervention_type>
    <intervention_name>Group (A2 → A1)</intervention_name>
    <description>Before each start of consumption of the products under study, a wash-out period of 2 weeks (no consumption of milk) must be observed by the subjects.&#xD;
25 subjects will consume A2A2 milk for 2 weeks (period 1), then they will consume A1A2 milk for 2 weeks (period 2).&#xD;
During each consumption period, various questionnaires will be completed by the subjects: frequency and consistency of stool, analog visual scales on digestive comfort and dietary surveys. Stool collections will also be carried out.</description>
    <arm_group_label>Milk A2A2</arm_group_label>
  </intervention>
  <eligibility>
    <criteria>
      <textblock>
        Inclusion Criteria:&#xD;
&#xD;
          -  Man or woman;&#xD;
&#xD;
          -  18 to 65 years old;&#xD;
&#xD;
          -  Declaring to have sensitivity or intolerance when consuming cow's milk;&#xD;
&#xD;
          -  Agreeing to follow the constraints generated by the study;&#xD;
&#xD;
          -  Having signed the informed consent form;&#xD;
&#xD;
          -  Social insured.&#xD;
&#xD;
        Exclusion Criteria:&#xD;
&#xD;
          -  Subject with an allergy to cow's milk proteins;&#xD;
&#xD;
          -  Subject suffering from a severe eating disorder (anorexia, bulimia, binge eating);&#xD;
&#xD;
          -  Subject with chronic pathology interfering with the parameters studied during this&#xD;
             study (inflammatory intestinal disease, celiac disease);&#xD;
&#xD;
          -  Subject suffering from acute intestinal infection at the time of inclusion&#xD;
             (gastroenteritis, etc.);&#xD;
&#xD;
          -  Subject with immunodeficiency or any other serious pathology (cancer, hemopathy);&#xD;
&#xD;
          -  Pregnant or planning to be pregnant during the study period;&#xD;
&#xD;
          -  Subject participating in another clinical study or in period of exclusion from another&#xD;
             study;&#xD;
&#xD;
          -  Subject deprived of liberty;&#xD;
&#xD;
          -  Subject under judicial protection measure;&#xD;
&#xD;
          -  Whose main investigator or a qualified co-investigator judges that the state of health&#xD;
             or the concomitant treatments are not compatible with the good progress of the&#xD;
             clinical study.&#xD;
      </textblock>
    </criteria>
    <gender>All</gender>
    <minimum_age>18 Years</minimum_age>
    <maximum_age>65 Years</maximum_age>
    <healthy_volunteers>Accepts Healthy Volunteers</healthy_volunteers>
  </eligibility>
  <overall_official>
    <last_name>Jean-Michel LECERF, MD</last_name>
    <role>Principal Investigator</role>
    <affiliation>Institut Pasteur de Lille - NutrInvest</affiliation>
  </overall_official>
  <location>
    <facility>
      <name>NutrInvest - Institut Pasteur de Lille</name>
      <address>
        <city>Lille</city>
        <state>Nord</state>
        <zip>59019</zip>
        <country>France</country>
      </address>
    </facility>
  </location>
  <location_countries>
    <country>France</country>
  </location_countries>
  <verification_date>April 2022</verification_date>
  <study_first_submitted>July 9, 2020</study_first_submitted>
  <study_first_submitted_qc>July 9, 2020</study_first_submitted_qc>
  <study_first_posted type="Actual">July 13, 2020</study_first_posted>
  <last_update_submitted>April 5, 2022</last_update_submitted>
  <last_update_submitted_qc>April 5, 2022</last_update_submitted_qc>
  <last_update_posted type="Actual">April 12, 2022</last_update_posted>
  <responsible_party>
    <responsible_party_type>Principal Investigator</responsible_party_type>
    <investigator_affiliation>Institut Pasteur de Lille</investigator_affiliation>
    <investigator_full_name>Jean-Michel Lecerf</investigator_full_name>
    <investigator_title>MD in nutrition and endocrinology</investigator_title>
  </responsible_party>
  <keyword>milk intolerant</keyword>
  <keyword>β-caseins A1 and A2</keyword>
  <keyword>Lactose</keyword>
  <patient_data>
    <sharing_ipd>Undecided</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/NCT04468880
org study id: 2020-A00185-34
nct id: NCT04468880
lead sponsor: 
has dmc: No
is fda regulated drug: No
is fda regulated device: No
Lactose, naturally present in milk, can cause digestive discomfort. Delactosed milk is
      currently the only one alternative to cow's milk for intolerant people. As some of them do
      not digest milk, it was completely remove from their diet. However, are they really
      intolerant to lactose or intolerant to milk (or to another of its compounds)? Do β-caseins
      play a role in this intolerance? β-caseins are proteins naturally present in milk. Two types
      of β-caseins were identified: A1 and A2. These types differ according to the genetic profile
      of the cow and depend on the breed. The rare clinical studies interested in this topic
      suggest that:

        1. consumption of milk A1 versus consumption of milk A2 can lead to: softer stools, delayed
           transit, as well as pro-inflammatory effects in some individuals,

        2. consumption of A2 milk significantly reduces gastrointestinal symptoms and improves
           digestive comfort in lactose intolerant people.

      Thus, it would be interesting to be able to assess the effect of a consumption of A2A2 milk
      type compared to A1A2 milk type, both on the parameters of digestive comfort and on
      inflammatory parameters.
The study will be carried out on healthy volunteers, aged 18 to 65 and self-declared
      sensitive, even intolerant to the consumption of milk.

      The main objective of the study is to assess the impact of milk β-caseins (A2A2 vs A1A2) on
      the digestive comfort felt during the consumption of milk in subjects declaring that they do
      not tolerate milk.
allocation: Randomized
intervention model: Crossover Assignment
intervention model description: monocentric, double-blind, randomized, controlled, cross-over and ambulatory study
primary purpose: Other
masking: Double (Participant, Investigator)
measure: Analog visual scales
time frame: 4 weeks
description: Digestive comfort will be assessed daily by the average of the following analog visual scales (score : 0 to 10), completed within 30 min to 3 hours after consumption of the daily dose of milk, depending on the usual occurrence of symptoms in individuals:
I have bloating
I have abdominal pain
I have flatulence (gas)
I have borborygmas (gurgling)
I have reflux (return, rise)
Overall, I estimate my digestive comfort.
The average of these 6 analog visual scales, called Global Digestive Discomfort (IDG), will therefore be available every day for 14 days; the final variable analyzed will be the average of these 14 IDG values, and will be called Global Average Digestive Discomfort (IDGM).
measure: Analysis of the average per period of each analog visual scales independently
time frame: 4 weeks
description: The analogue visual scales will be completed daily during each period of milk consumption (4 weeks)
measure: Difference Calprotectin at the end of the period - Calprotectin at V0 (measured in mg/kg)
time frame: 4 weeks
description: Stool collections are made during inclusion visits, V1 follow-up and V3 end of study.
measure: For each of the inflammatory markers (CRP us, IL-1β, TNF-α, IL-6) : difference between value at the end of the period and value at V0
time frame: 4 weeks
description: Blood samples are taken during inclusion visits, V1 follow-up and V3 end of study.
All of the inflammatory markers are measured in pg/ml.
measure: Average stool frequencies and consistencies
time frame: 4 weeks
description: This questionnaires will be completed daily during each period of milk consumption (4 weeks).
Bristol scale: stool type 1 (separate hard balls) to stool type 7 (watery, structureless stools)
arm group label: Milk A1A2
arm group type: Other
description: Group (A1 → A2) receiving control milk A1A2 in period 1 then the milk evaluated A2A2 in period 2
arm group label: Milk A2A2
arm group type: Other
description: Group (A2 → A1) receiving the milk evaluated A2A2 in period 1 then the control milk A1A2 in period 2
intervention type: Other
intervention name: Group (A1 → A2)
description: Before each start of consumption of the products under study, a wash-out period of 2 weeks (no consumption of milk) must be observed by the subjects.
25 subjects will consume A1A2 milk for 2 weeks (period 1), then they will consume A2A2 milk for 2 weeks (period 2).
During each consumption period, various questionnaires will be completed by the subjects: frequency and consistency of stool, analog visual scales on digestive comfort and dietary surveys. Stool collections will also be carried out.
arm group label: Milk A1A2
intervention type: Other
intervention name: Group (A2 → A1)
description: Before each start of consumption of the products under study, a wash-out period of 2 weeks (no consumption of milk) must be observed by the subjects.
25 subjects will consume A2A2 milk for 2 weeks (period 1), then they will consume A1A2 milk for 2 weeks (period 2).
During each consumption period, various questionnaires will be completed by the subjects: frequency and consistency of stool, analog visual scales on digestive comfort and dietary surveys. Stool collections will also be carried out.
arm group label: Milk A2A2
criteria: 
gender: All
minimum age: 18 Years
maximum age: 65 Years
healthy volunteers: Accepts Healthy Volunteers
last name: Jean-Michel LECERF, MD
role: Principal Investigator
affiliation: Institut Pasteur de Lille - NutrInvest
facility: 
country: France
responsible party type: Principal Investigator
investigator affiliation: Institut Pasteur de Lille
investigator full name: Jean-Michel Lecerf
investigator title: MD in nutrition and endocrinology
sharing ipd: Undecided