<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/NCT04457401</url>
  </required_header>
  <id_info>
    <org_study_id>IRB201901746</org_study_id>
    <nct_id>NCT04457401</nct_id>
  </id_info>
  <brief_title>Probiotic and Gastrointestinal Symptoms Due to Menstruation in Healthy Women</brief_title>
  <official_title>The Effect of a Probiotic on Gastrointestinal Symptoms Due to Menstruation in Healthy Adult Women: a Randomized, Double-blind, Controlled Clinical Trial</official_title>
  <sponsors>
    <lead_sponsor>
      <agency>University of Florida</agency>
      <agency_class>Other</agency_class>
    </lead_sponsor>
    <collaborator>
      <agency>Lallemand Health Solutions</agency>
      <agency_class>Industry</agency_class>
    </collaborator>
  </sponsors>
  <source>University of Florida</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>
      In this double blind, parallel study, female participants who are on an oral contraceptive&#xD;
      will consume either a probiotic or placebo supplement for approximately 8 weeks. Menstrual&#xD;
      cramp and abdominal pain severity, as measured by the visual analog scale, will be assessed&#xD;
      daily. A subgroup of participants will be asked to provide vaginal swab and stool samples to&#xD;
      assess microbial communities.&#xD;
    </textblock>
  </brief_summary>
  <detailed_description>
    <textblock>
      Participants recruited from the university community in the Southeast U.S. will participate&#xD;
      in a randomized, double-blind, placebo-controlled interventional study for approximately 8&#xD;
      weeks following obtainment of informed consent. Participants will be asked to maintain their&#xD;
      usual physical activity level as well as their usual diets with the exception of fermented&#xD;
      foods, food containing added probiotics (e.g. yogurts with live, active cultures or&#xD;
      supplements or probiotic supplements), or foods with added fiber supplements.&#xD;
&#xD;
      After obtaining consent, participants will be randomized to receive either the probiotic or&#xD;
      placebo daily for 8 weeks. All study days will be ± 3 days to account for variation in each&#xD;
      participant's menstrual cycle. The study supplements will be distributed approximately 7 days&#xD;
      before their first menstrual event. Participants will be instructed to begin taking the study&#xD;
      supplement 3 days after they menstruate.&#xD;
&#xD;
      At randomization, participants will be asked to start completing daily questionnaires&#xD;
      inquiring about gastrointestinal symptoms, abdominal pain as measured by a visual analog&#xD;
      scale, duration of abdominal pain, stool form and number, adverse events, and medications&#xD;
      taken, including the dose and administration schedule. On the third day of their menstrual&#xD;
      cycle (day 3/menstruation 1), they will begin consuming their study supplement (start of&#xD;
      intervention). On the days participants experience gastrointestinal symptoms related to the&#xD;
      menstrual cycle, they will answer an additional questionnaire asking about gastrointestinal&#xD;
      symptoms. Approximately seven days prior to the first menstrual cycle (study day -7) and&#xD;
      three days after each menstrual event (study day 3 and 31), participants will answer the&#xD;
      Menstrual Symptom Questionnaire to assess symptoms leading up to and during menstruation.&#xD;
      Seven days after each menstrual event (study days 7 and 35), participants will be&#xD;
      administered the Perceived Stress Scale to assess stress levels over the previous month.&#xD;
      Participants will also answer two validated weekly questionnaires inquiring about&#xD;
      gastrointestinal symptoms and how symptoms affect quality of life each week they are in the&#xD;
      study. Each participant will also complete a 24-hour dietary recall assessment at four points&#xD;
      during the study (study day -7, 21, 28, and 35) in order to determine how dietary patterns&#xD;
      fluctuate throughout the menstrual cycle. A subgroup of participants will be asked to provide&#xD;
      six additional vaginal swab and stool samples and six additional dietary recalls.&#xD;
&#xD;
      A subgroup of 20 participants per arm will also be consented to provide ten stool samples and&#xD;
      vaginal swabs during the study (study day -7, 1, 7, 14, 21, 28, 35, 42, 49, &amp; 56).&#xD;
      Participants will be provided with stool and vaginal swab collection kits. Participants will&#xD;
      self collect both of these samples and may either collect them at home or may use a restroom&#xD;
      in the Food Science and Human Nutrition building to self collect. Coolers will be left&#xD;
      outside of the building and in these restrooms for participants to drop off their samples. If&#xD;
      social distancing is required during this study, participants will be asked to collect the&#xD;
      samples at home and drop them off in a cooler outside of the building to ensure social&#xD;
      distancing. This subgroup will also complete additional 24-hour dietary recalls (study day 1,&#xD;
      42, 49, &amp; 56).&#xD;
&#xD;
      Participants will continue to answer daily questionnaires until the third day of their third&#xD;
      menstrual cycle, at which point they will discontinue answering questionnaires and consuming&#xD;
      the study supplement. At the conclusion of the study, they will complete the final&#xD;
      questionnaire that asks them which supplement they thought they were consuming to assess&#xD;
      blinding efficacy. Participants will be instructed to return any unused supplements to the&#xD;
      study site after the completion of the intervention.&#xD;
    </textblock>
  </detailed_description>
  <overall_status>Active, not recruiting</overall_status>
  <start_date type="Actual">December 1, 2020</start_date>
  <completion_date type="Anticipated">March 18, 2024</completion_date>
  <primary_completion_date type="Actual">March 18, 2022</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>
    <intervention_model_description>A randomized, double-blind, placebo-controlled parallel study in which participants receive one of the study supplements (probiotic or placebo) for an 8-week intervention.</intervention_model_description>
    <primary_purpose>Basic Science</primary_purpose>
    <masking>Triple (Participant, Investigator, Outcomes Assessor)</masking>
    <masking_description>The participants, investigators, and anyone else directly involved with the study will remain blinded for its entirety.</masking_description>
  </study_design_info>
  <primary_outcome>
    <measure>Abdominal Pain</measure>
    <time_frame>28 days</time_frame>
    <description>The primary outcome is the change (average of the first 3 days of the second menstrual cycle during the study when on the intervention minus the average of the first 3 days of the first menstrual cycle during the study prior to initiating the intervention) in the daily Visual Analog Score for abdominal pain between women on the probiotic versus the placebo interventions. The visual analog scale is scored between 0 (not pain at all) - 100 (worst pain imaginable). A higher score is less desirable. While we anticipate that a menstrual cycle should last 28 days, there may be variability in this number due to variability in the length of each participant's menstrual cycle.</description>
  </primary_outcome>
  <secondary_outcome>
    <measure>Menstrual Symptom Questionnaire</measure>
    <time_frame>28 days</time_frame>
    <description>The Menstrual Symptom Questionnaire assesses symptoms related to each menstrual cycle.</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Stool consistency</measure>
    <time_frame>Each day up to 9 weeks</time_frame>
    <description>Compare stool consistency, as measured by the Bristol Stool Form Scale (BSFS), between the probiotic and placebo groups. The BSFS is scored between 1 (hard stool) - 7 (liquid stool). A score of 4 or 5 is ideal.</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Stool frequency</measure>
    <time_frame>Each day up to 9 weeks</time_frame>
    <description>Compare the number of stools between the probiotic and placebo groups.</description>
  </secondary_outcome>
  <other_outcome>
    <measure>Digestive Health</measure>
    <time_frame>Every 7 days up to 9 weeks</time_frame>
    <description>Weekly GI symptoms assessed using the Gastrointestinal Symptom Rating Scale (GSRS). The GSRS consists of 15 questions related to 5 syndromes, constipation, diarrhea, reflux, abdominal pain, and indigestion. Symptoms are scored 1=no discomfort to 7=very severe discomfort. Scores from each of the 15 questions are summed for the total GSRS score.</description>
  </other_outcome>
  <other_outcome>
    <measure>Quality of Life Related to Digestive Health</measure>
    <time_frame>Every 7 days up to 9 weeks</time_frame>
    <description>Weekly GI experiences assessed using an in-house Digestion-Associated Quality of Life questionnaire.</description>
  </other_outcome>
  <other_outcome>
    <measure>Fecal microbial diversity</measure>
    <time_frame>Every 7 days up to 9 weeks</time_frame>
    <description>Changes in fecal microbial composition and diversity (i.e. alpha and beta diversity) will be assessed in a subgroup of participants.</description>
  </other_outcome>
  <other_outcome>
    <measure>Vaginal swab samples</measure>
    <time_frame>Every 7 days up to 9 weeks</time_frame>
    <description>Changes in vaginal microbial composition and diversity will be assessed in a subgroup of participants.</description>
  </other_outcome>
  <number_of_arms>2</number_of_arms>
  <enrollment type="Actual">191</enrollment>
  <condition>Menstrual Discomfort</condition>
  <arm_group>
    <arm_group_label>Probiotic</arm_group_label>
    <arm_group_type>Experimental</arm_group_type>
    <description>1 capsule daily for 8 weeks, containing 3 x 10^9 colony forming units/capsule of a Bifidobacterium strain</description>
  </arm_group>
  <arm_group>
    <arm_group_label>Placebo</arm_group_label>
    <arm_group_type>Placebo Comparator</arm_group_type>
    <description>1 capsule daily for 8 weeks containing the same carrier material and is similar in size, shape and taste to probiotic</description>
  </arm_group>
  <intervention>
    <intervention_type>Dietary Supplement</intervention_type>
    <intervention_name>Probiotic</intervention_name>
    <description>This probiotic is commercially available and contains Bifidobacterium (3 x 10^9 colony forming units/capsule) as the active ingredient and potato starch, magnesium stearate and ascorbic acid as excipients.</description>
    <arm_group_label>Probiotic</arm_group_label>
  </intervention>
  <intervention>
    <intervention_type>Dietary Supplement</intervention_type>
    <intervention_name>Placebo</intervention_name>
    <description>The placebo contains potato starch, magnesium stearate and ascorbic acid.</description>
    <arm_group_label>Placebo</arm_group_label>
  </intervention>
  <eligibility>
    <criteria>
      <textblock>
        Inclusion Criteria:&#xD;
&#xD;
          1. Be a healthy female between the ages of 18 and 35 years who has regular menstrual&#xD;
             cycles (i.e., every 24 to 33 days),&#xD;
&#xD;
          2. On the daily gastrointestinal symptom questionnaire for abdominal pain, participants&#xD;
             must have a score of ≥ 3 for abdominal pain when thinking about their typical average&#xD;
             score during first three days of menstruation,&#xD;
&#xD;
          3. Be on an combination oral contraceptive,&#xD;
&#xD;
          4. Willing and able to consume a probiotic or placebo supplement for approximately 8&#xD;
             weeks,&#xD;
&#xD;
          5. Willing and able to complete daily and weekly questionnaires online regarding dietary&#xD;
             intake and general health and well-being, including gastrointestinal habits (Note: we&#xD;
             will recruit participants who will have Internet access for the duration of the&#xD;
             protocol, but understand that, once enrolled, situations may change. If this is the&#xD;
             case, paper copies of the online forms will be provided.),&#xD;
&#xD;
          6. Willing to discontinue consumption of fermented foods or foods with live active&#xD;
             cultures two weeks prior to beginning the study and throughout the study (This would&#xD;
             include kefir, kombucha, yogurts with live, active cultures, etc.),&#xD;
&#xD;
          7. Willing to discontinue consumption of fiber supplements (This would include Metamucil,&#xD;
             Benefiber, or other products with added fiber supplement.),&#xD;
&#xD;
          8. Willing to complete a pregnancy test before consuming the study supplement,&#xD;
&#xD;
          9. Willingness to complete questionnaires, records, and diaries associated with the study&#xD;
             and to complete all study visits,&#xD;
&#xD;
         10. Able to provide informed consent,&#xD;
&#xD;
         11. Willing to provide a stool and vaginal sample ten times during the study (subgroup),&#xD;
&#xD;
         12. Typically have one stool per day (subgroup).&#xD;
&#xD;
        Exclusion Criteria:&#xD;
&#xD;
          1. Women who have a birth control implant, vaginal ring, shot, or patch or intrauterine&#xD;
             device,&#xD;
&#xD;
          2. Women who are lactating, attempting to become pregnant, know that they are pregnant,&#xD;
             or test positive on a pregnancy test,&#xD;
&#xD;
          3. Women who have consumed probiotic supplements in the last month,&#xD;
&#xD;
          4. Currently being treated for any physician-diagnosed diseases or conditions,&#xD;
&#xD;
          5. Women who have been diagnosed with any gynecological diseases of conditions (fibroma,&#xD;
             endometriosis, etc),&#xD;
&#xD;
          6. Women who have pain that is caused by a disorder in the woman's reproductive organs.&#xD;
             This would include a physician diagnosis such as endometriosis, adenomyosis, uterine&#xD;
             fibroma, or a pelvic infection,&#xD;
&#xD;
          7. Allergy to milk, soy, or yeast,&#xD;
&#xD;
          8. Use of another investigational product within 3 months of the screening visit,&#xD;
&#xD;
          9. Use of any antibiotic drug within 1 month of screening.&#xD;
      </textblock>
    </criteria>
    <gender>Female</gender>
    <gender_based>Yes</gender_based>
    <gender_description>Participant must menstruate regularly and consume an oral contraceptive</gender_description>
    <minimum_age>18 Years</minimum_age>
    <maximum_age>35 Years</maximum_age>
    <healthy_volunteers>Accepts Healthy Volunteers</healthy_volunteers>
  </eligibility>
  <overall_official>
    <last_name>Bobbi Langkamp-Henken, PhD</last_name>
    <role>Principal Investigator</role>
    <affiliation>University of Florida</affiliation>
  </overall_official>
  <location>
    <facility>
      <name>University of Florida</name>
      <address>
        <city>Gainesville</city>
        <state>Florida</state>
        <zip>32611-0370</zip>
        <country>United States</country>
      </address>
    </facility>
  </location>
  <location_countries>
    <country>United States</country>
  </location_countries>
  <verification_date>April 2023</verification_date>
  <study_first_submitted>June 17, 2020</study_first_submitted>
  <study_first_submitted_qc>June 30, 2020</study_first_submitted_qc>
  <study_first_posted type="Actual">July 7, 2020</study_first_posted>
  <last_update_submitted>April 5, 2023</last_update_submitted>
  <last_update_submitted_qc>April 5, 2023</last_update_submitted_qc>
  <last_update_posted type="Actual">April 7, 2023</last_update_posted>
  <responsible_party>
    <responsible_party_type>Sponsor</responsible_party_type>
  </responsible_party>
  <keyword>Gastrointestinal function</keyword>
  <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/NCT04457401
org study id: IRB201901746
nct id: NCT04457401
lead sponsor: 
collaborator: 
has dmc: No
is fda regulated drug: No
is fda regulated device: No
In this double blind, parallel study, female participants who are on an oral contraceptive
      will consume either a probiotic or placebo supplement for approximately 8 weeks. Menstrual
      cramp and abdominal pain severity, as measured by the visual analog scale, will be assessed
      daily. A subgroup of participants will be asked to provide vaginal swab and stool samples to
      assess microbial communities.
Participants recruited from the university community in the Southeast U.S. will participate
      in a randomized, double-blind, placebo-controlled interventional study for approximately 8
      weeks following obtainment of informed consent. Participants will be asked to maintain their
      usual physical activity level as well as their usual diets with the exception of fermented
      foods, food containing added probiotics (e.g. yogurts with live, active cultures or
      supplements or probiotic supplements), or foods with added fiber supplements.

      After obtaining consent, participants will be randomized to receive either the probiotic or
      placebo daily for 8 weeks. All study days will be ± 3 days to account for variation in each
      participant's menstrual cycle. The study supplements will be distributed approximately 7 days
      before their first menstrual event. Participants will be instructed to begin taking the study
      supplement 3 days after they menstruate.

      At randomization, participants will be asked to start completing daily questionnaires
      inquiring about gastrointestinal symptoms, abdominal pain as measured by a visual analog
      scale, duration of abdominal pain, stool form and number, adverse events, and medications
      taken, including the dose and administration schedule. On the third day of their menstrual
      cycle (day 3/menstruation 1), they will begin consuming their study supplement (start of
      intervention). On the days participants experience gastrointestinal symptoms related to the
      menstrual cycle, they will answer an additional questionnaire asking about gastrointestinal
      symptoms. Approximately seven days prior to the first menstrual cycle (study day -7) and
      three days after each menstrual event (study day 3 and 31), participants will answer the
      Menstrual Symptom Questionnaire to assess symptoms leading up to and during menstruation.
      Seven days after each menstrual event (study days 7 and 35), participants will be
      administered the Perceived Stress Scale to assess stress levels over the previous month.
      Participants will also answer two validated weekly questionnaires inquiring about
      gastrointestinal symptoms and how symptoms affect quality of life each week they are in the
      study. Each participant will also complete a 24-hour dietary recall assessment at four points
      during the study (study day -7, 21, 28, and 35) in order to determine how dietary patterns
      fluctuate throughout the menstrual cycle. A subgroup of participants will be asked to provide
      six additional vaginal swab and stool samples and six additional dietary recalls.

      A subgroup of 20 participants per arm will also be consented to provide ten stool samples and
      vaginal swabs during the study (study day -7, 1, 7, 14, 21, 28, 35, 42, 49, & 56).
      Participants will be provided with stool and vaginal swab collection kits. Participants will
      self collect both of these samples and may either collect them at home or may use a restroom
      in the Food Science and Human Nutrition building to self collect. Coolers will be left
      outside of the building and in these restrooms for participants to drop off their samples. If
      social distancing is required during this study, participants will be asked to collect the
      samples at home and drop them off in a cooler outside of the building to ensure social
      distancing. This subgroup will also complete additional 24-hour dietary recalls (study day 1,
      42, 49, & 56).

      Participants will continue to answer daily questionnaires until the third day of their third
      menstrual cycle, at which point they will discontinue answering questionnaires and consuming
      the study supplement. At the conclusion of the study, they will complete the final
      questionnaire that asks them which supplement they thought they were consuming to assess
      blinding efficacy. Participants will be instructed to return any unused supplements to the
      study site after the completion of the intervention.
allocation: Randomized
intervention model: Parallel Assignment
intervention model description: A randomized, double-blind, placebo-controlled parallel study in which participants receive one of the study supplements (probiotic or placebo) for an 8-week intervention.
primary purpose: Basic Science
masking: Triple (Participant, Investigator, Outcomes Assessor)
masking description: The participants, investigators, and anyone else directly involved with the study will remain blinded for its entirety.
measure: Abdominal Pain
time frame: 28 days
description: The primary outcome is the change (average of the first 3 days of the second menstrual cycle during the study when on the intervention minus the average of the first 3 days of the first menstrual cycle during the study prior to initiating the intervention) in the daily Visual Analog Score for abdominal pain between women on the probiotic versus the placebo interventions. The visual analog scale is scored between 0 (not pain at all) - 100 (worst pain imaginable). A higher score is less desirable. While we anticipate that a menstrual cycle should last 28 days, there may be variability in this number due to variability in the length of each participant's menstrual cycle.
measure: Menstrual Symptom Questionnaire
time frame: 28 days
description: The Menstrual Symptom Questionnaire assesses symptoms related to each menstrual cycle.
measure: Stool consistency
time frame: Each day up to 9 weeks
description: Compare stool consistency, as measured by the Bristol Stool Form Scale (BSFS), between the probiotic and placebo groups. The BSFS is scored between 1 (hard stool) - 7 (liquid stool). A score of 4 or 5 is ideal.
measure: Stool frequency
time frame: Each day up to 9 weeks
description: Compare the number of stools between the probiotic and placebo groups.
measure: Digestive Health
time frame: Every 7 days up to 9 weeks
description: Weekly GI symptoms assessed using the Gastrointestinal Symptom Rating Scale (GSRS). The GSRS consists of 15 questions related to 5 syndromes, constipation, diarrhea, reflux, abdominal pain, and indigestion. Symptoms are scored 1=no discomfort to 7=very severe discomfort. Scores from each of the 15 questions are summed for the total GSRS score.
measure: Quality of Life Related to Digestive Health
time frame: Every 7 days up to 9 weeks
description: Weekly GI experiences assessed using an in-house Digestion-Associated Quality of Life questionnaire.
measure: Fecal microbial diversity
time frame: Every 7 days up to 9 weeks
description: Changes in fecal microbial composition and diversity (i.e. alpha and beta diversity) will be assessed in a subgroup of participants.
measure: Vaginal swab samples
time frame: Every 7 days up to 9 weeks
description: Changes in vaginal microbial composition and diversity will be assessed in a subgroup of participants.
arm group label: Probiotic
arm group type: Experimental
description: 1 capsule daily for 8 weeks, containing 3 x 10^9 colony forming units/capsule of a Bifidobacterium strain
arm group label: Placebo
arm group type: Placebo Comparator
description: 1 capsule daily for 8 weeks containing the same carrier material and is similar in size, shape and taste to probiotic
intervention type: Dietary Supplement
intervention name: Probiotic
description: This probiotic is commercially available and contains Bifidobacterium (3 x 10^9 colony forming units/capsule) as the active ingredient and potato starch, magnesium stearate and ascorbic acid as excipients.
arm group label: Probiotic
intervention type: Dietary Supplement
intervention name: Placebo
description: The placebo contains potato starch, magnesium stearate and ascorbic acid.
arm group label: Placebo
criteria: 
gender: Female
gender based: Yes
gender description: Participant must menstruate regularly and consume an oral contraceptive
minimum age: 18 Years
maximum age: 35 Years
healthy volunteers: Accepts Healthy Volunteers
last name: Bobbi Langkamp-Henken, PhD
role: Principal Investigator
affiliation: University of Florida
facility: 
country: United States
responsible party type: Sponsor
sharing ipd: No