<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/NCT04408443</url>
  </required_header>
  <id_info>
    <org_study_id>IRR_D3</org_study_id>
    <nct_id>NCT04408443</nct_id>
  </id_info>
  <brief_title>Evaluation of Lactobacillus Reuteri DSM 17938 + Vitamin D3 in the Prevention of RRI in Paediatric Patients</brief_title>
  <acronym>LR_D3</acronym>
  <official_title>Evaluation of a Food Supplement Containing Lactobacillus Reuteri DSM 17938 + Vitamin D3 in the Prevention of Recurrent Respiratory Infections in Paediatric Patients</official_title>
  <sponsors>
    <lead_sponsor>
      <agency>Noos S.r.l.</agency>
      <agency_class>Industry</agency_class>
    </lead_sponsor>
  </sponsors>
  <source>Noos S.r.l.</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 aim of this protocol is to evaluate, in a multicenter, randomized, double blind vs&#xD;
      placebo clinical trial the effects of a marketed food supplement containing Lactobacillus&#xD;
      reuteri DSM 17938 and vitamin D3 (Reuterin® D3) in the prevention of recurrent respiratory&#xD;
      infections in pediatric patients suffered from Recurrent Respiratory Infection (RRI) in&#xD;
      previous years.&#xD;
    </textblock>
  </brief_summary>
  <detailed_description>
    <textblock>
      Several clinical trials documented the efficacy of probiotics in the prevention and treatment&#xD;
      of acute gastroenteritis, while there is little evidence on the efficacy of the probiotics in&#xD;
      the prevention of children respiratory infections.&#xD;
&#xD;
      The biological activity of probiotics is linked, partly, to their capacity to adhere to&#xD;
      enterocytes. This would avoid the binding of pathogenic bacteria through a competitive&#xD;
      exclusion mechanism. This inhibition toward pathogen bacteria on epithelial and mucosal level&#xD;
      (substrate), thanks also to the production of antimicrobial substances, can have a beneficial&#xD;
      effect on the balance of the intestinal microflora of the host and improve its immunity.&#xD;
&#xD;
      The adhesion of probiotic bacteria to the enterocyte membrane receptors influences the&#xD;
      activation of second messengers that induces the production of cytokines. The presence of&#xD;
      probiotic bacteria influences the commensal microorganisms in the production of lactic acid&#xD;
      and bacteriocins. These substances inhibit the growth of pathogens and modify the balance of&#xD;
      commensal bacteria of the intestinal bacterial flora.&#xD;
&#xD;
      Numerous controlled clinical trials show that L. reuteri DSM 17938 colonizes the human&#xD;
      gastric and intestinal epithelium and modulates the immune response, particularly through CD4&#xD;
      + T-helper cells in the ileum. These data confirm the pre-clinical evidence obtained in&#xD;
      animal models; furthermore these immunomodulatory effects may explain some clinical&#xD;
      properties of L. reuteri DSM 17938 such as the prevention of diarrhea, inhibition of pathogen&#xD;
      infectionand the following immune system response of the host to these pathogens, as well as&#xD;
      the potential modulation of the immune response by the Th1/Th2 balance in the human&#xD;
      intestinal epithelium, an answer that has been linked to the prevention and treatment of&#xD;
      allergy. In a recent, randomized, double-blind, placebo-controlled clinical trial, L. reuteri&#xD;
      DSM 17938, supplemented for three months to healthy children aged 6-36 months attending&#xD;
      nursery schools, demonstrated not only a significant reduction of episodes and duration of&#xD;
      diarrhea but also of respiratory tract infections with consequent reduction of costs for&#xD;
      society.&#xD;
&#xD;
      Despite the prevalence of food with vitamin D and multivitamin products, reports regarding&#xD;
      non-optimal vitamin D levels in adults and children in the world have increased, in&#xD;
      particular among those subjects overweight and with dark pigmentation of the skin.&#xD;
&#xD;
      In addition to its well-known effects on bone health, vitamin D is indeed an important immune&#xD;
      regulator, because it stimulates innate immunity and modulates inflammation. An analysis of&#xD;
      data from the National Health and Nutrition Examination Survey (NHANES) between 1988 and 1994&#xD;
      showed an inverse relationship between vitamin D levels and the incidence of upper&#xD;
      respiratory tract infections (URTI). These results were supported by other studies showing an&#xD;
      increased risk of acute lower respiratory tract infections in subjects with low levels of&#xD;
      vitamin D.&#xD;
&#xD;
      Historically, the association between rickets and the risk of serious respiratory infections&#xD;
      is well known and vitamin D deficiency has been associated with an increased risk to contract&#xD;
      the flu.&#xD;
&#xD;
      These considerations have led to the hypothesis that supplementation with a probiotic added&#xD;
      with vitamin D3 may influence the composition of intestinal flora by improving the immune&#xD;
      system and therefore reducing episodes of respiratory infections, particularly frequent&#xD;
      during preschool age.&#xD;
    </textblock>
  </detailed_description>
  <overall_status>Terminated</overall_status>
  <why_stopped>
    No enrollment due COVID PANDEMIA&#xD;
  </why_stopped>
  <start_date type="Actual">November 25, 2019</start_date>
  <completion_date type="Actual">September 30, 2021</completion_date>
  <primary_completion_date type="Actual">September 30, 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>Parallel Assignment</intervention_model>
    <primary_purpose>Prevention</primary_purpose>
    <masking>Triple (Participant, Care Provider, Investigator)</masking>
    <masking_description>Triple (Participant, Care Provider, Investigator)</masking_description>
  </study_design_info>
  <primary_outcome>
    <measure>Change of the number of respiratory infection</measure>
    <time_frame>4 months + 2 months of follow up</time_frame>
    <description>Change of the number of respiratory infection respect the previous year</description>
  </primary_outcome>
  <secondary_outcome>
    <measure>Change of number of days with fever</measure>
    <time_frame>4 months + 2 months of follow up</time_frame>
    <description>To evaluate the change of the number of days with fever</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Change of the antibiotic use</measure>
    <time_frame>4 months + 2 months of follow up</time_frame>
    <description>To evaluate the change of the antibiotic use</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Change of number of visit to Pediatrician</measure>
    <time_frame>4 months + 2 months of follow up</time_frame>
    <description>To evaluate the change of the number of visit to Pediatrician</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Change of number of days of absence from the nursery / kindergarten</measure>
    <time_frame>4 months + 2 months of follow up</time_frame>
    <description>To evaluate the change of the number of days of absence from the nursery / kindergarten</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Changes of days of absence from work by parents</measure>
    <time_frame>4 months + 2 months of follow up</time_frame>
    <description>To evaluate the change of days of absence from work by parents</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Modification of intestinal microflora</measure>
    <time_frame>4 months + 2 months of follow up</time_frame>
    <description>To evaluate the modification of intestinal microflora</description>
  </secondary_outcome>
  <number_of_arms>2</number_of_arms>
  <enrollment type="Actual">200</enrollment>
  <condition>Recurrent Respiratory Tract Infections</condition>
  <arm_group>
    <arm_group_label>Reuterin D3</arm_group_label>
    <arm_group_type>Active Comparator</arm_group_type>
    <description>Patients should take 10 drops once a day during meals for 4 months followed by 2 months of follow up.</description>
  </arm_group>
  <arm_group>
    <arm_group_label>Placebo</arm_group_label>
    <arm_group_type>Placebo Comparator</arm_group_type>
    <description>Patients should take 10 drops once a day during meals for 4 months followed by 2 months of follow up.</description>
  </arm_group>
  <intervention>
    <intervention_type>Dietary Supplement</intervention_type>
    <intervention_name>Lactobacillus reuteri DSM 17938 + Vitamine D3</intervention_name>
    <description>Lactobacillus reuteri DSM 17938 (10E8 CFU in 5 drops), Vitamin D3 (400 IU in 5 drops), sunflower oil, medium chain triglycerides, silicon dioxide</description>
    <arm_group_label>Reuterin D3</arm_group_label>
  </intervention>
  <intervention>
    <intervention_type>Dietary Supplement</intervention_type>
    <intervention_name>Placebo</intervention_name>
    <description>sunflower oil, medium chain triglycerides, silicon dioxide</description>
    <arm_group_label>Placebo</arm_group_label>
  </intervention>
  <eligibility>
    <criteria>
      <textblock>
        Inclusion Criteria:&#xD;
&#xD;
          -  Patients between 1 and 6 years of age at the enrollment; both sexes&#xD;
&#xD;
          -  Patients with an history of RRI, according to the definition (The definition of&#xD;
             Recurrent respiratory infections (RRI) is the onset of 8 or more documented airway&#xD;
             infections during the year, in preschool children (up to three years of age) or 6 or&#xD;
             more in children older 3 years, in the absence of any other underlying pathological&#xD;
             condition) in the previous year.&#xD;
&#xD;
          -  Atopic and non-atopic patients&#xD;
&#xD;
          -  Willing and able to give informed consent of participation in the study by parent or&#xD;
             legal guardian.&#xD;
&#xD;
        Exclusion Criteria:&#xD;
&#xD;
          -  Presence of autoimmune diseases, immunodeficiency, neuromuscular diseases, congenital&#xD;
             cardiomyopathies, metabolic diseases&#xD;
&#xD;
          -  Patients in therapy with other drugs for the treatment of RRI&#xD;
&#xD;
          -  Supplementation with probiotics and /or prebiotics in the previous 2 weeks&#xD;
&#xD;
          -  Vitamin D intake in the last 4 weeks&#xD;
&#xD;
          -  IgA deficiency&#xD;
&#xD;
          -  Antibiotic treatment at least 4 week before in inclusion&#xD;
&#xD;
          -  Participation in other clinical trials&#xD;
      </textblock>
    </criteria>
    <gender>All</gender>
    <minimum_age>1 Year</minimum_age>
    <maximum_age>6 Years</maximum_age>
    <healthy_volunteers>Accepts Healthy Volunteers</healthy_volunteers>
  </eligibility>
  <overall_official>
    <last_name>Michele Miraglia del Giudice, Prof.</last_name>
    <role>Principal Investigator</role>
    <affiliation>University of Campania &quot;Luigi Vanvitelli&quot;</affiliation>
  </overall_official>
  <location>
    <facility>
      <name>University of Campania Luigi Vanvitelli</name>
      <address>
        <city>Naples</city>
        <zip>80138</zip>
        <country>Italy</country>
      </address>
    </facility>
  </location>
  <location_countries>
    <country>Italy</country>
  </location_countries>
  <verification_date>March 2023</verification_date>
  <study_first_submitted>May 25, 2020</study_first_submitted>
  <study_first_submitted_qc>May 28, 2020</study_first_submitted_qc>
  <study_first_posted type="Actual">May 29, 2020</study_first_posted>
  <last_update_submitted>March 21, 2023</last_update_submitted>
  <last_update_submitted_qc>March 21, 2023</last_update_submitted_qc>
  <last_update_posted type="Actual">March 23, 2023</last_update_posted>
  <responsible_party>
    <responsible_party_type>Sponsor</responsible_party_type>
  </responsible_party>
  <keyword>RRI, probiotics, vitamin D3, L. reuteri</keyword>
  <condition_browse>
    <!-- CAUTION:  The following MeSH terms are assigned with an imperfect algorithm            -->
    <mesh_term>Infections</mesh_term>
    <mesh_term>Respiratory Tract Infections</mesh_term>
  </condition_browse>
  <intervention_browse>
    <!-- CAUTION:  The following MeSH terms are assigned with an imperfect algorithm            -->
    <mesh_term>Vitamin D</mesh_term>
    <mesh_term>Cholecalciferol</mesh_term>
  </intervention_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/NCT04408443
org study id: IRR_D3
nct id: NCT04408443
lead sponsor: 
has dmc: No
is fda regulated drug: No
is fda regulated device: No
The aim of this protocol is to evaluate, in a multicenter, randomized, double blind vs
      placebo clinical trial the effects of a marketed food supplement containing Lactobacillus
      reuteri DSM 17938 and vitamin D3 (Reuterin® D3) in the prevention of recurrent respiratory
      infections in pediatric patients suffered from Recurrent Respiratory Infection (RRI) in
      previous years.
Several clinical trials documented the efficacy of probiotics in the prevention and treatment
      of acute gastroenteritis, while there is little evidence on the efficacy of the probiotics in
      the prevention of children respiratory infections.

      The biological activity of probiotics is linked, partly, to their capacity to adhere to
      enterocytes. This would avoid the binding of pathogenic bacteria through a competitive
      exclusion mechanism. This inhibition toward pathogen bacteria on epithelial and mucosal level
      (substrate), thanks also to the production of antimicrobial substances, can have a beneficial
      effect on the balance of the intestinal microflora of the host and improve its immunity.

      The adhesion of probiotic bacteria to the enterocyte membrane receptors influences the
      activation of second messengers that induces the production of cytokines. The presence of
      probiotic bacteria influences the commensal microorganisms in the production of lactic acid
      and bacteriocins. These substances inhibit the growth of pathogens and modify the balance of
      commensal bacteria of the intestinal bacterial flora.

      Numerous controlled clinical trials show that L. reuteri DSM 17938 colonizes the human
      gastric and intestinal epithelium and modulates the immune response, particularly through CD4
      + T-helper cells in the ileum. These data confirm the pre-clinical evidence obtained in
      animal models; furthermore these immunomodulatory effects may explain some clinical
      properties of L. reuteri DSM 17938 such as the prevention of diarrhea, inhibition of pathogen
      infectionand the following immune system response of the host to these pathogens, as well as
      the potential modulation of the immune response by the Th1/Th2 balance in the human
      intestinal epithelium, an answer that has been linked to the prevention and treatment of
      allergy. In a recent, randomized, double-blind, placebo-controlled clinical trial, L. reuteri
      DSM 17938, supplemented for three months to healthy children aged 6-36 months attending
      nursery schools, demonstrated not only a significant reduction of episodes and duration of
      diarrhea but also of respiratory tract infections with consequent reduction of costs for
      society.

      Despite the prevalence of food with vitamin D and multivitamin products, reports regarding
      non-optimal vitamin D levels in adults and children in the world have increased, in
      particular among those subjects overweight and with dark pigmentation of the skin.

      In addition to its well-known effects on bone health, vitamin D is indeed an important immune
      regulator, because it stimulates innate immunity and modulates inflammation. An analysis of
      data from the National Health and Nutrition Examination Survey (NHANES) between 1988 and 1994
      showed an inverse relationship between vitamin D levels and the incidence of upper
      respiratory tract infections (URTI). These results were supported by other studies showing an
      increased risk of acute lower respiratory tract infections in subjects with low levels of
      vitamin D.

      Historically, the association between rickets and the risk of serious respiratory infections
      is well known and vitamin D deficiency has been associated with an increased risk to contract
      the flu.

      These considerations have led to the hypothesis that supplementation with a probiotic added
      with vitamin D3 may influence the composition of intestinal flora by improving the immune
      system and therefore reducing episodes of respiratory infections, particularly frequent
      during preschool age.
allocation: Randomized
intervention model: Parallel Assignment
primary purpose: Prevention
masking: Triple (Participant, Care Provider, Investigator)
masking description: Triple (Participant, Care Provider, Investigator)
measure: Change of the number of respiratory infection
time frame: 4 months + 2 months of follow up
description: Change of the number of respiratory infection respect the previous year
measure: Change of number of days with fever
time frame: 4 months + 2 months of follow up
description: To evaluate the change of the number of days with fever
measure: Change of the antibiotic use
time frame: 4 months + 2 months of follow up
description: To evaluate the change of the antibiotic use
measure: Change of number of visit to Pediatrician
time frame: 4 months + 2 months of follow up
description: To evaluate the change of the number of visit to Pediatrician
measure: Change of number of days of absence from the nursery / kindergarten
time frame: 4 months + 2 months of follow up
description: To evaluate the change of the number of days of absence from the nursery / kindergarten
measure: Changes of days of absence from work by parents
time frame: 4 months + 2 months of follow up
description: To evaluate the change of days of absence from work by parents
measure: Modification of intestinal microflora
time frame: 4 months + 2 months of follow up
description: To evaluate the modification of intestinal microflora
arm group label: Reuterin D3
arm group type: Active Comparator
description: Patients should take 10 drops once a day during meals for 4 months followed by 2 months of follow up.
arm group label: Placebo
arm group type: Placebo Comparator
description: Patients should take 10 drops once a day during meals for 4 months followed by 2 months of follow up.
intervention type: Dietary Supplement
intervention name: Lactobacillus reuteri DSM 17938 + Vitamine D3
description: Lactobacillus reuteri DSM 17938 (10E8 CFU in 5 drops), Vitamin D3 (400 IU in 5 drops), sunflower oil, medium chain triglycerides, silicon dioxide
arm group label: Reuterin D3
intervention type: Dietary Supplement
intervention name: Placebo
description: sunflower oil, medium chain triglycerides, silicon dioxide
arm group label: Placebo
criteria: 
gender: All
minimum age: 1 Year
maximum age: 6 Years
healthy volunteers: Accepts Healthy Volunteers
last name: Michele Miraglia del Giudice, Prof.
role: Principal Investigator
affiliation: University of Campania "Luigi Vanvitelli"
facility: 
country: Italy
responsible party type: Sponsor
mesh term: Infections
mesh term: Respiratory Tract Infections
mesh term: Vitamin D
mesh term: Cholecalciferol
sharing ipd: No