<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/NCT04446572</url>
  </required_header>
  <id_info>
    <org_study_id>PREPROBIFERT01</org_study_id>
    <nct_id>NCT04446572</nct_id>
  </id_info>
  <brief_title>Application of Lactobacillus Salivarius CECT5713 in Infertility of Unknown Origin</brief_title>
  <official_title>Application of Lactobacillus Salivarius CECT5713 to Achieve Term Pregnancies in Women With Repetitive Abortion or Infertility of Unknown Origin by Microbiological and Immunological Modulation of the Vaginal Ecosystem</official_title>
  <sponsors>
    <lead_sponsor>
      <agency>Universidad Complutense de Madrid</agency>
      <agency_class>Other</agency_class>
    </lead_sponsor>
    <collaborator>
      <agency>Bisearch Life</agency>
      <agency_class>Other</agency_class>
    </collaborator>
    <collaborator>
      <agency>Centro de Diagnóstico Médico. Ayuntamiento de Madrid.</agency>
      <agency_class>Other</agency_class>
    </collaborator>
  </sponsors>
  <source>Universidad Complutense de Madrid</source>
  <oversight_info>
    <has_dmc>Yes</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>
      In this study, we aimed to assess the cervicovaginal environment (pH, Nugent score, soluble&#xD;
      immune factors and bacterial profile) in women with reproductive failure because of either&#xD;
      repetitive abortion or infertility of unknown origin and compare it to that of healthy&#xD;
      fertile women. The second objective was to evaluate the ability of Lactobacillus salivarius&#xD;
      CECT5713 to modulate such parameters and to increase pregnancy rates in women with&#xD;
      reproductive failure. The administration of L. salivarius CECT5713 (~9 log10 colony-forming&#xD;
      units (CFU)/day) for 6 months or until a diagnosis of pregnancy to women with reproductive&#xD;
      failure resulted in an overall successful (term) pregnancy rate of 56%.&#xD;
    </textblock>
  </brief_summary>
  <detailed_description>
    <textblock>
      In this study, we aimed to assess the cervicovaginal environment (pH, Nugent score, soluble&#xD;
      immune factors and bacterial profile) in women with reproductive failure because of either&#xD;
      repetitive abortion or infertility of unknown origin and compare it to that of healthy&#xD;
      fertile women. The second objective was to evaluate the ability of Lactobacillus salivarius&#xD;
      CECT5713 to modulate such parameters and to increase pregnancy rates in women with&#xD;
      reproductive failure. Vaginal pH and Nugent score were higher in women with reproductive&#xD;
      failure than in fertile women. Differences were also noted regarding soluble immune factors&#xD;
      transforming growth factor beta (TGF-β) and vascular endothelial growth factor (VEGF). Their&#xD;
      concentrations in cervicovaginal lavage samples were reduced by about one-half in women with&#xD;
      reproductive failure compared to fertile women. Lactobacilli were detected in a higher&#xD;
      proportion, and at a higher concentration and having different species profile, in fertile&#xD;
      women than in women with repetitive abortion or infertility. The study of the vaginal&#xD;
      microbiome revealed that samples from fertile women were characterized by the high abundance&#xD;
      of Lactobacillus sequences, while in about one third of samples from women with reproductive&#xD;
      failure DNA from this genus was practically absent while there was an abundance of that of&#xD;
      Gardnerella and Bifidobacterium. Lactobacillus salivarius CECT5713 seemed to be a suitable&#xD;
      candidate to modulate the cervicovaginal microbiota because of its acidifying capacity,&#xD;
      adhesion to vaginal cells and co-aggregation with vaginal pathogens. The administration of L.&#xD;
      salivarius CECT5713 (~9 log10 CFU/day) for 6 months or until a diagnosis of pregnancy to&#xD;
      women with reproductive failure resulted in an overall successful (term) pregnancy rate of&#xD;
      56%. In addition, the probiotic intervention modified significantly key microbiological,&#xD;
      biochemical and immunological parameters in women who got pregnant being their&#xD;
      post-intervention values similar or close to those of fertile women. The high concentrations&#xD;
      of L. salivarius and the detection of L. salivarius DNA in vaginal samples confirmed that the&#xD;
      probiotic was able to reach the vaginal mucosa. In conclusion, L. salivarius CECT5713 has&#xD;
      proved to be a good candidate to improve reproductive success in women with reproductive&#xD;
      failure.&#xD;
    </textblock>
  </detailed_description>
  <overall_status>Completed</overall_status>
  <start_date type="Actual">October 16, 2018</start_date>
  <completion_date type="Actual">November 29, 2019</completion_date>
  <primary_completion_date type="Actual">November 29, 2019</primary_completion_date>
  <phase>Phase 2</phase>
  <study_type>Interventional</study_type>
  <has_expanded_access>No</has_expanded_access>
  <study_design_info>
    <allocation>Non-Randomized</allocation>
    <intervention_model>Parallel Assignment</intervention_model>
    <intervention_model_description>Volunteers were classified into 3 groups. All women in the RA group (n = 21) had a history of recurrent miscarriage with three or more pregnancy losses during the first 12 weeks of pregnancy. All women of the INF group (n = 23) had a history of infertility (inability to conceive) despite being the recipients of assisted-reproduction techniques (ART) for at least three times, including two cycles, at least, of in vitro fertilization (IVF). Finally, the control group (n = 14) included fertile women having at least two children after uncomplicated term pregnancies. Starting at day 0, women of the RA and INF groups consumed (oral route) a daily sachet with ~50 mg of freeze-dried probiotic (~9 log10 CFU of L. salivarius CECT5713) for 6 months or until a diagnosis of pregnancy (whatever happened first).</intervention_model_description>
    <primary_purpose>Basic Science</primary_purpose>
    <masking>None (Open Label)</masking>
  </study_design_info>
  <primary_outcome>
    <measure>Pregnancies and successful pregnancies</measure>
    <time_frame>6 months</time_frame>
    <description>Total number of pregnancies and number of pregnancies with delivery of a healthy baby</description>
  </primary_outcome>
  <secondary_outcome>
    <measure>Modification of the vaginal microbiota</measure>
    <time_frame>6 months</time_frame>
    <description>Variation in the concentration of lactobacilli and other bacteria in cervicovaginal lavage samples</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Vaginal immunomodulation</measure>
    <time_frame>6 months</time_frame>
    <description>Variation in the concentration of TGF-β and VEGF in cervicovaginal lavage</description>
  </secondary_outcome>
  <number_of_arms>3</number_of_arms>
  <enrollment type="Actual">58</enrollment>
  <condition>Abortion, Spontaneous</condition>
  <condition>Abortion in First Trimester</condition>
  <condition>Infertility Unexplained</condition>
  <arm_group>
    <arm_group_label>Repetitive Abortion (RA) group</arm_group_label>
    <arm_group_type>Experimental</arm_group_type>
    <description>Starting at day 0, women of the RA (n=21) group consumed (oral route) a daily sachet with ~50 mg of freeze-dried probiotic (~9 log10 CFU of L. salivarius CECT5713) for 6 months or until a diagnosis of pregnancy (whatever happened first).</description>
  </arm_group>
  <arm_group>
    <arm_group_label>Infertility (INF) group</arm_group_label>
    <arm_group_type>Experimental</arm_group_type>
    <description>Starting at day 0, women of the INF group (n=23) consumed (oral route) a daily sachet with ~50 mg of freeze-dried probiotic (~9 log10 CFU of L. salivarius CECT5713) for 6 months or until a diagnosis of pregnancy (whatever happened first).</description>
  </arm_group>
  <arm_group>
    <arm_group_label>Control group</arm_group_label>
    <arm_group_type>No Intervention</arm_group_type>
    <description>The control group (n = 14) included fertile women having at least two children after uncomplicated term pregnancies.</description>
  </arm_group>
  <intervention>
    <intervention_type>Biological</intervention_type>
    <intervention_name>Lactobacillus salivarius CECT5713</intervention_name>
    <description>Starting at day 0, women of the RA and INF groups consumed (oral route) a daily sachet with ~50 mg of freeze-dried probiotic (~9 log10 CFU of L. salivarius CECT5713) for 6 months or until a diagnosis of pregnancy (whatever happened first).</description>
    <arm_group_label>Infertility (INF) group</arm_group_label>
    <arm_group_label>Repetitive Abortion (RA) group</arm_group_label>
  </intervention>
  <eligibility>
    <criteria>
      <textblock>
        Inclusion Criteria:&#xD;
&#xD;
          -  Recurrent miscarriage with three or more pregnancy losses during the first 12 weeks of&#xD;
             pregnancy (RA group)&#xD;
&#xD;
          -  Infertility (inability to conceive) despite being the recipients of ART for at least&#xD;
             three times, including two cycles, at least, of in vitro fertilization (IVF) (INF&#xD;
             group).&#xD;
&#xD;
          -  Fertile women having at least two children after uncomplicated term pregnancies&#xD;
             (Control group).&#xD;
&#xD;
        Exclusion Criteria:&#xD;
&#xD;
          -  Antiphospholipid syndrome&#xD;
&#xD;
          -  Hormonal therapy, antibiotics or probiotics in the 4 weeks previous to sampling.&#xD;
&#xD;
          -  Lactose intolerance or cow's milk protein allergy (RA and INF groups)&#xD;
      </textblock>
    </criteria>
    <gender>Female</gender>
    <gender_based>Yes</gender_based>
    <gender_description>The targets were abortion or female infertility of unknown origin</gender_description>
    <minimum_age>33 Years</minimum_age>
    <maximum_age>41 Years</maximum_age>
    <healthy_volunteers>No</healthy_volunteers>
  </eligibility>
  <overall_official>
    <last_name>Juan M Rodríguez, PhD</last_name>
    <role>Principal Investigator</role>
    <affiliation>Complutense University Madrid</affiliation>
  </overall_official>
  <location>
    <facility>
      <name>Dpt. Nutricion, Bromatologia y Tecnologia de los Alimentos</name>
      <address>
        <city>Madrid</city>
        <zip>28040</zip>
        <country>Spain</country>
      </address>
    </facility>
  </location>
  <location_countries>
    <country>Spain</country>
  </location_countries>
  <verification_date>June 2020</verification_date>
  <study_first_submitted>June 22, 2020</study_first_submitted>
  <study_first_submitted_qc>June 22, 2020</study_first_submitted_qc>
  <study_first_posted type="Actual">June 25, 2020</study_first_posted>
  <last_update_submitted>June 25, 2020</last_update_submitted>
  <last_update_submitted_qc>June 25, 2020</last_update_submitted_qc>
  <last_update_posted type="Actual">June 26, 2020</last_update_posted>
  <responsible_party>
    <responsible_party_type>Principal Investigator</responsible_party_type>
    <investigator_affiliation>Universidad Complutense de Madrid</investigator_affiliation>
    <investigator_full_name>Juan M. Rodríguez</investigator_full_name>
    <investigator_title>Professor</investigator_title>
  </responsible_party>
  <keyword>Infertility</keyword>
  <keyword>Abortion</keyword>
  <condition_browse>
    <!-- CAUTION:  The following MeSH terms are assigned with an imperfect algorithm            -->
    <mesh_term>Infertility</mesh_term>
    <mesh_term>Abortion, Spontaneous</mesh_term>
  </condition_browse>
  <patient_data>
    <sharing_ipd>Yes</sharing_ipd>
    <ipd_description>Global and individual microbiological and immunological data will be available to other researchers once the study is published.</ipd_description>
    <ipd_info_type>Study Protocol</ipd_info_type>
    <ipd_info_type>Clinical Study Report (CSR)</ipd_info_type>
    <ipd_time_frame>The data will be available to other researchers once the study is published.</ipd_time_frame>
    <ipd_access_criteria>On request</ipd_access_criteria>
  </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/NCT04446572
org study id: PREPROBIFERT01
nct id: NCT04446572
lead sponsor: 
collaborator: 
collaborator: 
has dmc: Yes
is fda regulated drug: No
is fda regulated device: No
In this study, we aimed to assess the cervicovaginal environment (pH, Nugent score, soluble
      immune factors and bacterial profile) in women with reproductive failure because of either
      repetitive abortion or infertility of unknown origin and compare it to that of healthy
      fertile women. The second objective was to evaluate the ability of Lactobacillus salivarius
      CECT5713 to modulate such parameters and to increase pregnancy rates in women with
      reproductive failure. The administration of L. salivarius CECT5713 (~9 log10 colony-forming
      units (CFU)/day) for 6 months or until a diagnosis of pregnancy to women with reproductive
      failure resulted in an overall successful (term) pregnancy rate of 56%.
In this study, we aimed to assess the cervicovaginal environment (pH, Nugent score, soluble
      immune factors and bacterial profile) in women with reproductive failure because of either
      repetitive abortion or infertility of unknown origin and compare it to that of healthy
      fertile women. The second objective was to evaluate the ability of Lactobacillus salivarius
      CECT5713 to modulate such parameters and to increase pregnancy rates in women with
      reproductive failure. Vaginal pH and Nugent score were higher in women with reproductive
      failure than in fertile women. Differences were also noted regarding soluble immune factors
      transforming growth factor beta (TGF-β) and vascular endothelial growth factor (VEGF). Their
      concentrations in cervicovaginal lavage samples were reduced by about one-half in women with
      reproductive failure compared to fertile women. Lactobacilli were detected in a higher
      proportion, and at a higher concentration and having different species profile, in fertile
      women than in women with repetitive abortion or infertility. The study of the vaginal
      microbiome revealed that samples from fertile women were characterized by the high abundance
      of Lactobacillus sequences, while in about one third of samples from women with reproductive
      failure DNA from this genus was practically absent while there was an abundance of that of
      Gardnerella and Bifidobacterium. Lactobacillus salivarius CECT5713 seemed to be a suitable
      candidate to modulate the cervicovaginal microbiota because of its acidifying capacity,
      adhesion to vaginal cells and co-aggregation with vaginal pathogens. The administration of L.
      salivarius CECT5713 (~9 log10 CFU/day) for 6 months or until a diagnosis of pregnancy to
      women with reproductive failure resulted in an overall successful (term) pregnancy rate of
      56%. In addition, the probiotic intervention modified significantly key microbiological,
      biochemical and immunological parameters in women who got pregnant being their
      post-intervention values similar or close to those of fertile women. The high concentrations
      of L. salivarius and the detection of L. salivarius DNA in vaginal samples confirmed that the
      probiotic was able to reach the vaginal mucosa. In conclusion, L. salivarius CECT5713 has
      proved to be a good candidate to improve reproductive success in women with reproductive
      failure.
allocation: Non-Randomized
intervention model: Parallel Assignment
intervention model description: Volunteers were classified into 3 groups. All women in the RA group (n = 21) had a history of recurrent miscarriage with three or more pregnancy losses during the first 12 weeks of pregnancy. All women of the INF group (n = 23) had a history of infertility (inability to conceive) despite being the recipients of assisted-reproduction techniques (ART) for at least three times, including two cycles, at least, of in vitro fertilization (IVF). Finally, the control group (n = 14) included fertile women having at least two children after uncomplicated term pregnancies. Starting at day 0, women of the RA and INF groups consumed (oral route) a daily sachet with ~50 mg of freeze-dried probiotic (~9 log10 CFU of L. salivarius CECT5713) for 6 months or until a diagnosis of pregnancy (whatever happened first).
primary purpose: Basic Science
masking: None (Open Label)
measure: Pregnancies and successful pregnancies
time frame: 6 months
description: Total number of pregnancies and number of pregnancies with delivery of a healthy baby
measure: Modification of the vaginal microbiota
time frame: 6 months
description: Variation in the concentration of lactobacilli and other bacteria in cervicovaginal lavage samples
measure: Vaginal immunomodulation
time frame: 6 months
description: Variation in the concentration of TGF-β and VEGF in cervicovaginal lavage
arm group label: Repetitive Abortion (RA) group
arm group type: Experimental
description: Starting at day 0, women of the RA (n=21) group consumed (oral route) a daily sachet with ~50 mg of freeze-dried probiotic (~9 log10 CFU of L. salivarius CECT5713) for 6 months or until a diagnosis of pregnancy (whatever happened first).
arm group label: Infertility (INF) group
arm group type: Experimental
description: Starting at day 0, women of the INF group (n=23) consumed (oral route) a daily sachet with ~50 mg of freeze-dried probiotic (~9 log10 CFU of L. salivarius CECT5713) for 6 months or until a diagnosis of pregnancy (whatever happened first).
arm group label: Control group
arm group type: No Intervention
description: The control group (n = 14) included fertile women having at least two children after uncomplicated term pregnancies.
intervention type: Biological
intervention name: Lactobacillus salivarius CECT5713
description: Starting at day 0, women of the RA and INF groups consumed (oral route) a daily sachet with ~50 mg of freeze-dried probiotic (~9 log10 CFU of L. salivarius CECT5713) for 6 months or until a diagnosis of pregnancy (whatever happened first).
arm group label: Infertility (INF) group
arm group label: Repetitive Abortion (RA) group
criteria: 
gender: Female
gender based: Yes
gender description: The targets were abortion or female infertility of unknown origin
minimum age: 33 Years
maximum age: 41 Years
healthy volunteers: No
last name: Juan M Rodríguez, PhD
role: Principal Investigator
affiliation: Complutense University Madrid
facility: 
country: Spain
responsible party type: Principal Investigator
investigator affiliation: Universidad Complutense de Madrid
investigator full name: Juan M. Rodríguez
investigator title: Professor
mesh term: Infertility
mesh term: Abortion, Spontaneous
sharing ipd: Yes
ipd description: Global and individual microbiological and immunological data will be available to other researchers once the study is published.
ipd info type: Study Protocol
ipd info type: Clinical Study Report (CSR)
ipd time frame: The data will be available to other researchers once the study is published.
ipd access criteria: On request