<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/NCT02215304</url>
  </required_header>
  <id_info>
    <org_study_id>LALLEM-001</org_study_id>
    <nct_id>NCT02215304</nct_id>
  </id_info>
  <brief_title>Safety and Tolerance Study of Three Probiotic Strains in Infants</brief_title>
  <acronym>PROBINFANT</acronym>
  <official_title>A Randomized, Double-blind, Placebo-controlled Intervention Study to Assess the Safety and Tolerance Effect of Three Probiotic Strains in Infants</official_title>
  <sponsors>
    <lead_sponsor>
      <agency>ProbiSearch SL</agency>
      <agency_class>Industry</agency_class>
    </lead_sponsor>
    <collaborator>
      <agency>Lallemand Health Solutions</agency>
      <agency_class>Industry</agency_class>
    </collaborator>
  </sponsors>
  <source>ProbiSearch SL</source>
  <oversight_info>
    <has_dmc>No</has_dmc>
  </oversight_info>
  <brief_summary>
    <textblock>
      Study to evaluate the safety and tolerance of three probiotic bacteria intake by healthy&#xD;
      infants. Participants are divided at random and unknown to the researchers, in four groups,&#xD;
      three of which receive one of three probiotic bacteria while the fourth group receives&#xD;
      placebo product.&#xD;
    </textblock>
  </brief_summary>
  <detailed_description>
    <textblock>
      Subjects' parents or legal tutors will be contacted for voluntary participation and a written&#xD;
      informed consent will be obtained.&#xD;
&#xD;
      The study visits will take place either in the hospital or primary health center.&#xD;
&#xD;
      During Visit 1, inclusion in- and exclusion criteria will be checked and information on&#xD;
      demographic profile, subject characteristics, feeding option, relevant medical history,&#xD;
      medication and nutritional supplements will be recorded. Weight and length and head&#xD;
      circumference measurements of the infant will be made. The researcher will explain to the&#xD;
      parents that during the first 2 weeks of participation in the study the infant must not&#xD;
      intake any probiotic supplements (run-in ). Parents will be instructed to collect and send&#xD;
      and/or store fecal and urine samples before starting the study. In addition they will be&#xD;
      instructed to collect and send and/or store fecal and urine samples after the initial run-in&#xD;
      period (2 weeks), after the product intake period (8 weeks) and after the final wash out&#xD;
      period (2 weeks).&#xD;
&#xD;
      During Visit 2, subjects will be randomly allocated to receive either one of the test&#xD;
      products or the placebo. Body weight and length will be measure. The researcher will review&#xD;
      with the parents the study diary in detail, how to record data on gastrointestinal tolerance,&#xD;
      stool frequency and stool characteristics, respiratory symptoms, diagnosed infections,&#xD;
      sleeping and crying habits, changes in sleeping pattern, fever episodes, unscheduled visits&#xD;
      resulting from suspected infection or a health problem and antibiotic prescription. The&#xD;
      researcher will explain the procedure of administering the study product to the infant and&#xD;
      anticipated phone calls. The parents will be instructed to start intake of the product as&#xD;
      soon as possible after the collection of fecal and urine samples.&#xD;
&#xD;
      During product intake period (8 weeks) subject's parents will be called weekly by someone&#xD;
      from the Study Team (Phone call 1, 2, 3, 4, 5, 6, 7). During the phone call relevant data&#xD;
      related to possible Adverse Events (AEs) or Serious Adverse Events (SAEs) will be collected.&#xD;
      Parents will be asked about infant's well-being (fever episodes, rashes, diarrhea, visits to&#xD;
      the doctor, antibiotic prescription, etc.). Issues regarding diary completion, if any, will&#xD;
      be discussed. During the Phone call 7 parents will be instructed to collect and send and/or&#xD;
      store fecal and urine samples in one of the days prior to the third visit.&#xD;
&#xD;
      At the third visit (Visit 3, 8 weeks after product intake period), body weight and length&#xD;
      will be measured and relevant data will be collected with respect to health and well-being&#xD;
      aspect of the infant and AE or SAE (fever episodes, rashes, diarrhea, visits to the doctor,&#xD;
      antibiotic prescription, etc.). Completed diaries and fecal and urine samples will be&#xD;
      collected. Parents will be explained that for the last 2 weeks of participation in the study&#xD;
      their infants could not intake any probiotic supplement (final wash out period). Parents will&#xD;
      be instructed to collect and send and/or store fecal and urine samples in one of the days&#xD;
      prior to the next visit (Visit 4).&#xD;
&#xD;
      During visit 4, after the final wash out period, body weight and length will be measured and&#xD;
      relevant data will be collected with respect to health and well-being aspect of the infant&#xD;
      and AEs or SAEs (fever episodes, rashes, diarrhea, visits to the doctor, antibiotic&#xD;
      prescription, etc.). Completed diaries and samples will be collected.&#xD;
    </textblock>
  </detailed_description>
  <overall_status>Completed</overall_status>
  <start_date>June 2014</start_date>
  <completion_date type="Actual">July 2015</completion_date>
  <primary_completion_date type="Actual">July 2015</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>
    <masking>Triple (Participant, Care Provider, Investigator)</masking>
  </study_design_info>
  <primary_outcome>
    <measure>Safety and tolerance will be evaluated according to infant growth (weight, height and head circumference)</measure>
    <time_frame>12 weeks</time_frame>
    <description>growth will be evaluated considering weight, height and head circumference, at four different time points during study: 1st measure will be at screening visit (visit 1/week 0), 2nd measure will be after the run-in period and before starting intervention (visit 2/ week 2), 3rd measure will be after the eight weeks of intervention (visit 3/ week 10) and the 4th measure will be two weeks later (visit 4/week 12).</description>
  </primary_outcome>
  <primary_outcome>
    <measure>Adverse Event and/or Serious Adverse Event</measure>
    <time_frame>10 weeks</time_frame>
    <description>Adverse Event and/or Serious Adverse Event will be recorded daily by parents and notified to investigator within 24hrs., in particular gastro-intestinal symptoms, fever and rashes.</description>
  </primary_outcome>
  <primary_outcome>
    <measure>Fecal characteristics</measure>
    <time_frame>10 weeks</time_frame>
    <description>Fecal characteristics (stool frequency, stool consistency, stool amount and stool color) will be recorded daily by parents according to the &quot;Amsterdam scale&quot; and notified weekly to investigators.</description>
  </primary_outcome>
  <primary_outcome>
    <measure>Use of medication</measure>
    <time_frame>12 weeks</time_frame>
    <description>Medication used (antibiotics, etc) will be recorded daily by parents and notified weekly to investigators.</description>
  </primary_outcome>
  <secondary_outcome>
    <measure>Urine concentration of D-lactic acid.</measure>
    <time_frame>12 weeks</time_frame>
    <description>D-lactic acid will be measured in urine samples at 4 different time points (weeks 0, 2, 10 and 12).</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Changes in sleep and crying patterns</measure>
    <time_frame>10 weeks</time_frame>
    <description>Changes in sleep and crying patterns will be recorded daily by parents and notified weekly to investigators.</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Immune compounds in fecal samples</measure>
    <time_frame>8 weeks</time_frame>
    <description>Immunoglobulins (Ig) A, G1, G2, G3, G4 and M, cytokines, chemokines and growth factors such as interleukins (IL) 1β, 2, 4, 5, 6, 7, 8, 10, 12, 13, and 17, interferon-γ (INF-γ), tumor necrosis factor-α (TNF-α), growth related oncogene-α (GRO-α), macrophages chemoattractant protein-1 (MCP-1), macrophages inflammatory protein-1β (MIP-1β), granulocyte-colony stimulating factor (G-CSF), granulocyte-macrophages colony stimulating factor (GM-CSF) and Calprotectin concentrations will be measured at two time points, before and after the study probiotic intake (weeks 0 and 10).</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Composition of fecal microbiota</measure>
    <time_frame>8 weeks</time_frame>
    <description>Composition of fecal microbiota will be assessed at two different time points, before and after the intervention period</description>
  </secondary_outcome>
  <number_of_arms>4</number_of_arms>
  <enrollment type="Actual">221</enrollment>
  <condition>Body Weight</condition>
  <condition>Body Height</condition>
  <condition>Head Circumference</condition>
  <arm_group>
    <arm_group_label>Bifidobacterium longum R0033</arm_group_label>
    <arm_group_type>Active Comparator</arm_group_type>
    <description>Bifidobacterium longum ssp infantis R0033, 3*10E9 colony forming units (CFU) in 1 sachet per day to be diluted in 10 mL water by mouth for eight weeks</description>
  </arm_group>
  <arm_group>
    <arm_group_label>Lactobacillus helveticus R0052</arm_group_label>
    <arm_group_type>Active Comparator</arm_group_type>
    <description>Lactobacillus helveticus R0052, 3*10E9 colony forming units (CFU) in 1 sachet per day to be diluted in 10 mL water by mouth for eight weeks</description>
  </arm_group>
  <arm_group>
    <arm_group_label>Bifidobacterium bifidum R0071</arm_group_label>
    <arm_group_type>Active Comparator</arm_group_type>
    <description>Bifidobacterium bifidum R0071, 3*10E9 colony forming units (CFU) in 1 sachet per day to be diluted in 10 mL water by mouth for eight weeks</description>
  </arm_group>
  <arm_group>
    <arm_group_label>Placebo</arm_group_label>
    <arm_group_type>Placebo Comparator</arm_group_type>
    <description>potato starch 1 sachet per day to be diluted in 10 mL water by mouth for eight weeks</description>
  </arm_group>
  <intervention>
    <intervention_type>Dietary Supplement</intervention_type>
    <intervention_name>Bifidobacterium longum ssp infantis R0033</intervention_name>
    <description>12 weeks intervention study: A run-in period of two weeks, 8 weeks of intervention (from weeks 2 to 10) and two weeks after intervention finishing time.&#xD;
During the 8 weeks of intervention participants will intake one daily dose of the product which contains 3*10E9 colony forming units (CFU)</description>
    <arm_group_label>Bifidobacterium longum R0033</arm_group_label>
  </intervention>
  <intervention>
    <intervention_type>Dietary Supplement</intervention_type>
    <intervention_name>Lactobacillus helveticus R0052</intervention_name>
    <description>12 weeks intervention study: A run-in period of two weeks, 8 weeks of intervention (from weeks 2 to 10) and two weeks after intervention finishing time.&#xD;
During the 8 weeks of intervention participants will intake one daily dose of the product which contains 3*10E9 colony forming units (CFU)</description>
    <arm_group_label>Lactobacillus helveticus R0052</arm_group_label>
  </intervention>
  <intervention>
    <intervention_type>Dietary Supplement</intervention_type>
    <intervention_name>Bifidobacterium bifidum R0071</intervention_name>
    <description>12 weeks intervention study: A run-in period of two weeks, 8 weeks of intervention (from weeks 2 to 10) and two weeks after intervention finishing time.&#xD;
During the 8 weeks of intervention participants will intake one daily dose of the product which contains 3*10E9 colony forming units (CFU)</description>
    <arm_group_label>Bifidobacterium bifidum R0071</arm_group_label>
  </intervention>
  <intervention>
    <intervention_type>Dietary Supplement</intervention_type>
    <intervention_name>Placebo</intervention_name>
    <description>12 weeks intervention study: A run-in period of two weeks, 8 weeks of intervention (from weeks 2 to 10) and two weeks after intervention finishing time.&#xD;
During the 8 weeks of intervention participants will intake one daily dose of the product which contains 3*10E9 colony forming units (CFU)</description>
    <arm_group_label>Placebo</arm_group_label>
  </intervention>
  <eligibility>
    <criteria>
      <textblock>
        Inclusion Criteria:&#xD;
&#xD;
          -  Healthy term infants between 3-12 months old&#xD;
&#xD;
          -  Written informed consent from at least one parent or the legal tutor.&#xD;
&#xD;
        Exclusion Criteria:&#xD;
&#xD;
          -  Short bowel syndrome or any GI surgery.&#xD;
&#xD;
          -  Impaired intestinal epithelial barrier (e.g. diarrheal illness, intestinal&#xD;
             inflammation).&#xD;
&#xD;
          -  Metabolic disorders (diabetes, lactose intolerance).&#xD;
&#xD;
          -  Immunodeficiency.&#xD;
&#xD;
          -  Heart failure and cardiac medical history (e.g. artificial heart valve, medical&#xD;
             history of infectious endocarditis, cardiac malformation, rheumatic fever).&#xD;
&#xD;
          -  Surgery within one month prior to inclusion (Visit 1/ week 0).&#xD;
&#xD;
          -  Antibiotic prescription 1 week before inclusion (Visit 1/ week 0) and during run-in&#xD;
             period (Visit 2/ week 2).&#xD;
&#xD;
          -  Investigator's uncertainty about the willingness or ability of the infant's parents to&#xD;
             comply with the protocol requirements.&#xD;
&#xD;
          -  Participation in any other clinical trial within two weeks prior to entry into the&#xD;
             study.&#xD;
      </textblock>
    </criteria>
    <gender>All</gender>
    <minimum_age>3 Months</minimum_age>
    <maximum_age>12 Months</maximum_age>
    <healthy_volunteers>Accepts Healthy Volunteers</healthy_volunteers>
  </eligibility>
  <overall_official>
    <last_name>Felix Omeñaca, MD, PhD</last_name>
    <role>Principal Investigator</role>
    <affiliation>Hospital Universitario La Paz</affiliation>
  </overall_official>
  <location>
    <facility>
      <name>Hospital Universitario La Paz</name>
      <address>
        <city>Madrid</city>
        <zip>28046</zip>
        <country>Spain</country>
      </address>
    </facility>
  </location>
  <location_countries>
    <country>Spain</country>
  </location_countries>
  <verification_date>December 2016</verification_date>
  <study_first_submitted>August 11, 2014</study_first_submitted>
  <study_first_submitted_qc>August 12, 2014</study_first_submitted_qc>
  <study_first_posted type="Estimate">August 13, 2014</study_first_posted>
  <last_update_submitted>December 13, 2016</last_update_submitted>
  <last_update_submitted_qc>December 13, 2016</last_update_submitted_qc>
  <last_update_posted type="Estimate">December 14, 2016</last_update_posted>
  <responsible_party>
    <responsible_party_type>Sponsor</responsible_party_type>
  </responsible_party>
  <keyword>Dietary supplementation</keyword>
  <keyword>Probiotics</keyword>
  <keyword>Safety/Efficiency</keyword>
  <keyword>Healthy infants</keyword>
  <condition_browse>
    <!-- CAUTION:  The following MeSH terms are assigned with an imperfect algorithm            -->
    <mesh_term>Body Weight</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/NCT02215304
org study id: LALLEM-001
nct id: NCT02215304
lead sponsor: 
collaborator: 
has dmc: No
Study to evaluate the safety and tolerance of three probiotic bacteria intake by healthy
      infants. Participants are divided at random and unknown to the researchers, in four groups,
      three of which receive one of three probiotic bacteria while the fourth group receives
      placebo product.
Subjects' parents or legal tutors will be contacted for voluntary participation and a written
      informed consent will be obtained.

      The study visits will take place either in the hospital or primary health center.

      During Visit 1, inclusion in- and exclusion criteria will be checked and information on
      demographic profile, subject characteristics, feeding option, relevant medical history,
      medication and nutritional supplements will be recorded. Weight and length and head
      circumference measurements of the infant will be made. The researcher will explain to the
      parents that during the first 2 weeks of participation in the study the infant must not
      intake any probiotic supplements (run-in ). Parents will be instructed to collect and send
      and/or store fecal and urine samples before starting the study. In addition they will be
      instructed to collect and send and/or store fecal and urine samples after the initial run-in
      period (2 weeks), after the product intake period (8 weeks) and after the final wash out
      period (2 weeks).

      During Visit 2, subjects will be randomly allocated to receive either one of the test
      products or the placebo. Body weight and length will be measure. The researcher will review
      with the parents the study diary in detail, how to record data on gastrointestinal tolerance,
      stool frequency and stool characteristics, respiratory symptoms, diagnosed infections,
      sleeping and crying habits, changes in sleeping pattern, fever episodes, unscheduled visits
      resulting from suspected infection or a health problem and antibiotic prescription. The
      researcher will explain the procedure of administering the study product to the infant and
      anticipated phone calls. The parents will be instructed to start intake of the product as
      soon as possible after the collection of fecal and urine samples.

      During product intake period (8 weeks) subject's parents will be called weekly by someone
      from the Study Team (Phone call 1, 2, 3, 4, 5, 6, 7). During the phone call relevant data
      related to possible Adverse Events (AEs) or Serious Adverse Events (SAEs) will be collected.
      Parents will be asked about infant's well-being (fever episodes, rashes, diarrhea, visits to
      the doctor, antibiotic prescription, etc.). Issues regarding diary completion, if any, will
      be discussed. During the Phone call 7 parents will be instructed to collect and send and/or
      store fecal and urine samples in one of the days prior to the third visit.

      At the third visit (Visit 3, 8 weeks after product intake period), body weight and length
      will be measured and relevant data will be collected with respect to health and well-being
      aspect of the infant and AE or SAE (fever episodes, rashes, diarrhea, visits to the doctor,
      antibiotic prescription, etc.). Completed diaries and fecal and urine samples will be
      collected. Parents will be explained that for the last 2 weeks of participation in the study
      their infants could not intake any probiotic supplement (final wash out period). Parents will
      be instructed to collect and send and/or store fecal and urine samples in one of the days
      prior to the next visit (Visit 4).

      During visit 4, after the final wash out period, body weight and length will be measured and
      relevant data will be collected with respect to health and well-being aspect of the infant
      and AEs or SAEs (fever episodes, rashes, diarrhea, visits to the doctor, antibiotic
      prescription, etc.). Completed diaries and samples will be collected.
allocation: Randomized
intervention model: Parallel Assignment
masking: Triple (Participant, Care Provider, Investigator)
measure: Safety and tolerance will be evaluated according to infant growth (weight, height and head circumference)
time frame: 12 weeks
description: growth will be evaluated considering weight, height and head circumference, at four different time points during study: 1st measure will be at screening visit (visit 1/week 0), 2nd measure will be after the run-in period and before starting intervention (visit 2/ week 2), 3rd measure will be after the eight weeks of intervention (visit 3/ week 10) and the 4th measure will be two weeks later (visit 4/week 12).
measure: Adverse Event and/or Serious Adverse Event
time frame: 10 weeks
description: Adverse Event and/or Serious Adverse Event will be recorded daily by parents and notified to investigator within 24hrs., in particular gastro-intestinal symptoms, fever and rashes.
measure: Fecal characteristics
time frame: 10 weeks
description: Fecal characteristics (stool frequency, stool consistency, stool amount and stool color) will be recorded daily by parents according to the "Amsterdam scale" and notified weekly to investigators.
measure: Use of medication
time frame: 12 weeks
description: Medication used (antibiotics, etc) will be recorded daily by parents and notified weekly to investigators.
measure: Urine concentration of D-lactic acid.
time frame: 12 weeks
description: D-lactic acid will be measured in urine samples at 4 different time points (weeks 0, 2, 10 and 12).
measure: Changes in sleep and crying patterns
time frame: 10 weeks
description: Changes in sleep and crying patterns will be recorded daily by parents and notified weekly to investigators.
measure: Immune compounds in fecal samples
time frame: 8 weeks
description: Immunoglobulins (Ig) A, G1, G2, G3, G4 and M, cytokines, chemokines and growth factors such as interleukins (IL) 1β, 2, 4, 5, 6, 7, 8, 10, 12, 13, and 17, interferon-γ (INF-γ), tumor necrosis factor-α (TNF-α), growth related oncogene-α (GRO-α), macrophages chemoattractant protein-1 (MCP-1), macrophages inflammatory protein-1β (MIP-1β), granulocyte-colony stimulating factor (G-CSF), granulocyte-macrophages colony stimulating factor (GM-CSF) and Calprotectin concentrations will be measured at two time points, before and after the study probiotic intake (weeks 0 and 10).
measure: Composition of fecal microbiota
time frame: 8 weeks
description: Composition of fecal microbiota will be assessed at two different time points, before and after the intervention period
arm group label: Bifidobacterium longum R0033
arm group type: Active Comparator
description: Bifidobacterium longum ssp infantis R0033, 3*10E9 colony forming units (CFU) in 1 sachet per day to be diluted in 10 mL water by mouth for eight weeks
arm group label: Lactobacillus helveticus R0052
arm group type: Active Comparator
description: Lactobacillus helveticus R0052, 3*10E9 colony forming units (CFU) in 1 sachet per day to be diluted in 10 mL water by mouth for eight weeks
arm group label: Bifidobacterium bifidum R0071
arm group type: Active Comparator
description: Bifidobacterium bifidum R0071, 3*10E9 colony forming units (CFU) in 1 sachet per day to be diluted in 10 mL water by mouth for eight weeks
arm group label: Placebo
arm group type: Placebo Comparator
description: potato starch 1 sachet per day to be diluted in 10 mL water by mouth for eight weeks
intervention type: Dietary Supplement
intervention name: Bifidobacterium longum ssp infantis R0033
description: 12 weeks intervention study: A run-in period of two weeks, 8 weeks of intervention (from weeks 2 to 10) and two weeks after intervention finishing time.
During the 8 weeks of intervention participants will intake one daily dose of the product which contains 3*10E9 colony forming units (CFU)
arm group label: Bifidobacterium longum R0033
intervention type: Dietary Supplement
intervention name: Lactobacillus helveticus R0052
description: 12 weeks intervention study: A run-in period of two weeks, 8 weeks of intervention (from weeks 2 to 10) and two weeks after intervention finishing time.
During the 8 weeks of intervention participants will intake one daily dose of the product which contains 3*10E9 colony forming units (CFU)
arm group label: Lactobacillus helveticus R0052
intervention type: Dietary Supplement
intervention name: Bifidobacterium bifidum R0071
description: 12 weeks intervention study: A run-in period of two weeks, 8 weeks of intervention (from weeks 2 to 10) and two weeks after intervention finishing time.
During the 8 weeks of intervention participants will intake one daily dose of the product which contains 3*10E9 colony forming units (CFU)
arm group label: Bifidobacterium bifidum R0071
intervention type: Dietary Supplement
intervention name: Placebo
description: 12 weeks intervention study: A run-in period of two weeks, 8 weeks of intervention (from weeks 2 to 10) and two weeks after intervention finishing time.
During the 8 weeks of intervention participants will intake one daily dose of the product which contains 3*10E9 colony forming units (CFU)
arm group label: Placebo
criteria: 
gender: All
minimum age: 3 Months
maximum age: 12 Months
healthy volunteers: Accepts Healthy Volunteers
last name: Felix Omeñaca, MD, PhD
role: Principal Investigator
affiliation: Hospital Universitario La Paz
facility: 
country: Spain
responsible party type: Sponsor
mesh term: Body Weight