<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/NCT03837015</url>
  </required_header>
  <id_info>
    <org_study_id>CTN308</org_study_id>
    <nct_id>NCT03837015</nct_id>
  </id_info>
  <brief_title>Estrogen, Probiotics and Vaginal Health to Prevent HIV Infection in ACB Women</brief_title>
  <official_title>Improving Vaginal Health to Decrease Biological Risk of HIV-1 Infection in Canadian African, Caribbean and Black (ACB) Women: Estrogen and Probiotic Treatment for Vaginal Health</official_title>
  <sponsors>
    <lead_sponsor>
      <agency>McMaster University</agency>
      <agency_class>Other</agency_class>
    </lead_sponsor>
    <collaborator>
      <agency>CIHR Canadian HIV Trials Network</agency>
      <agency_class>Other</agency_class>
    </collaborator>
  </sponsors>
  <source>McMaster University</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>
    <is_us_export>No</is_us_export>
  </oversight_info>
  <brief_summary>
    <textblock>
      This study will enrol African, Caribbean and Black (ACB) women who are known to have a more&#xD;
      diverse vaginal microbiome, higher rates of bacterial vaginosis with lower numbers of&#xD;
      protective lactobacilli, and are at increased risk for HIV. The investigators will evaluate&#xD;
      the safety, feasibility, effect on the vaginal bacterial microbiome and changes in local&#xD;
      immune and inflammatory responses with the administration of vaginal estrogen alone, vaginal&#xD;
      estrogen in combination with oral or vaginally administered probiotics, or vaginal probiotics&#xD;
      alone.&#xD;
    </textblock>
  </brief_summary>
  <detailed_description>
    <textblock>
      Women are at increased risk of HIV acquisition compared with men. A number of biological&#xD;
      factors are associated with increased risk, many of which likely enhance risk by increasing&#xD;
      inflammation in the female genital tract. Susceptibility to infections and immune responses&#xD;
      in the female genital tract are regulated by hormones: progesterone increases inflammation&#xD;
      and HIV susceptibility and estrogen decreases inflammation and enhances colonization with&#xD;
      Lactobacilli.&#xD;
&#xD;
      A Lactobacillus dominant vaginal microbiome is associated with increased protection against&#xD;
      HIV, while a polymicrobial vaginal flora, as seen in bacterial vaginosis, is associated with&#xD;
      increased risk. About 40% of ACB women have a polymicrobial flora.&#xD;
&#xD;
      The goal of this study is to establish a Lactobacillus dominant vaginal microbiome in ACB&#xD;
      women, that will be associated with decreased inflammation and decreased susceptibility to&#xD;
      HIV, by administering a low level of intravaginal estrogen to increase colonization with&#xD;
      Lactobacilli together with a Lactobacillus-containing probiotic.&#xD;
    </textblock>
  </detailed_description>
  <overall_status>Completed</overall_status>
  <start_date type="Actual">November 4, 2019</start_date>
  <completion_date type="Actual">December 14, 2021</completion_date>
  <primary_completion_date type="Actual">December 14, 2021</primary_completion_date>
  <phase>Phase 1</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>None (Open Label)</masking>
  </study_design_info>
  <primary_outcome>
    <measure>Refusal rate</measure>
    <time_frame>12 months</time_frame>
    <description>Number of eligible participants approached who do not consent to be enrolled</description>
  </primary_outcome>
  <primary_outcome>
    <measure>Participant retention rate</measure>
    <time_frame>12 months</time_frame>
    <description>Number of participants who complete the study as proportion of total number of participants enrolled</description>
  </primary_outcome>
  <primary_outcome>
    <measure>Incidence of treatment emergent adverse events</measure>
    <time_frame>2 months</time_frame>
    <description>The incidence of adverse events, including serious adverse events, their severity and their relationship to study intervention assessed by reviewing case report forms and participant diaries.</description>
  </primary_outcome>
  <primary_outcome>
    <measure>Rate of adherence</measure>
    <time_frame>30 days</time_frame>
    <description>Adherence will be measured by calculating the total probiotic used/total dispensed and for Estring by total days used/total time period</description>
  </primary_outcome>
  <secondary_outcome>
    <measure>Changes in proportion of Lactobacillus species in the vaginal microbiota</measure>
    <time_frame>30 days</time_frame>
    <description>Aliquots of cervico-vaginal lavage (CVL) fluids will undergo microbiome analysis using a modified Illumina sequencing method for bacterial community profiling of 16S rRNA to measure changes from baseline at follow-up sampling.</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Change in innate inflammatory cytokine/chemokine levels</measure>
    <time_frame>30 days</time_frame>
    <description>Changes from baseline in levels of cytokine/chemokines will be measured in CVL by a 22-plex multiplex assay at 2 and 4 weeks</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Changes in number of HIV target cells in the genital tract</measure>
    <time_frame>30 days</time_frame>
    <description>Changes from baseline in level of HIV susceptible CD4+ T cells will be quantified using a lab developed HIV pseudovirus assay at 2 and 4 weeks.</description>
  </secondary_outcome>
  <number_of_arms>4</number_of_arms>
  <enrollment type="Actual">50</enrollment>
  <condition>HIV-1-infection</condition>
  <condition>Bacterial Vaginoses</condition>
  <arm_group>
    <arm_group_label>Estring alone</arm_group_label>
    <arm_group_type>Active Comparator</arm_group_type>
    <description>Participants will be given a single packet containing one Estring vaginal ring. Participants will begin using the vaginal ring on day 0 and keep it in place until day 30. Estring should not be removed during the one-month study intervention.</description>
  </arm_group>
  <arm_group>
    <arm_group_label>Estring and vaginal RepHresh Pro-B</arm_group_label>
    <arm_group_type>Active Comparator</arm_group_type>
    <description>Participants will be given a single packet containing one Estring vaginal ring. Participants will begin using the vaginal ring on day 0 and keep it in place until day 30. Estring should not be removed during the one-month study intervention. Participants will also be instructed to insert one RepHresh Pro-B capsule vaginally twice daily, morning and night, until day 30</description>
  </arm_group>
  <arm_group>
    <arm_group_label>Estring and oral RepHresh Pro-B</arm_group_label>
    <arm_group_type>Active Comparator</arm_group_type>
    <description>Participants will be given a single packet containing one Estring vaginal ring. Participants will begin using the vaginal ring on day 0 and keep it in place until day 30. Estring should not be removed during the one-month study intervention. Participants will be instructed to take one RepHresh Pro-B capsule orally twice daily until day 30.</description>
  </arm_group>
  <arm_group>
    <arm_group_label>Vaginal RepHresh Pro-B</arm_group_label>
    <arm_group_type>Active Comparator</arm_group_type>
    <description>Participants will be given a 30 days supply of RepHresh Pro-B and instructed to insert one capsule vaginally twice daily until day 30.</description>
  </arm_group>
  <intervention>
    <intervention_type>Drug</intervention_type>
    <intervention_name>Estring Vaginal Ring</intervention_name>
    <description>Estradiol vaginal ring, containing 2mg estradiol designed for slow release over 30 days</description>
    <arm_group_label>Estring alone</arm_group_label>
    <arm_group_label>Estring and oral RepHresh Pro-B</arm_group_label>
    <arm_group_label>Estring and vaginal RepHresh Pro-B</arm_group_label>
    <other_name>17 beta-estradiol</other_name>
  </intervention>
  <intervention>
    <intervention_type>Other</intervention_type>
    <intervention_name>RepHresh Pro-B</intervention_name>
    <description>Probiotic supplement containing 2.5 billion CFU of Lactobacilli reuteri RC-14 and Lactobacilli rhamnosus GR-1, administered vaginally or orally</description>
    <arm_group_label>Estring and oral RepHresh Pro-B</arm_group_label>
    <arm_group_label>Estring and vaginal RepHresh Pro-B</arm_group_label>
    <arm_group_label>Vaginal RepHresh Pro-B</arm_group_label>
  </intervention>
  <eligibility>
    <criteria>
      <textblock>
        Inclusion Criteria:&#xD;
&#xD;
          -  African, Caribbean, Black&#xD;
&#xD;
          -  Pre-menopausal women in good general health, as determined by the investigator&#xD;
&#xD;
          -  Uterus and cervix present&#xD;
&#xD;
          -  Negative pregnancy test&#xD;
&#xD;
          -  Currently practicing barrier or non-hormonal forms of contraception, and planning to&#xD;
             continue, for the duration of the study (barrier contraceptive, abstinence)&#xD;
&#xD;
          -  Willing to undergo a pelvic exam by a female nurse/female doctor&#xD;
&#xD;
          -  Willing to abstain from vaginal intercourse for 48 hours prior to sampling, over the&#xD;
             entire course of the study&#xD;
&#xD;
          -  Able to understand, comply and consent to protocol requirements and instructions&#xD;
&#xD;
          -  Able to attend scheduled study visits and complete required investigations&#xD;
&#xD;
        Exclusion Criteria:&#xD;
&#xD;
          -  Currently lactating&#xD;
&#xD;
          -  Pregnant: suspected, current or in the last 12 months&#xD;
&#xD;
          -  Irregular menstrual cycle (less than 6 periods in a year) not related to contraceptive&#xD;
             use, pregnancy or breastfeeding&#xD;
&#xD;
          -  Post-menopausal&#xD;
&#xD;
          -  Hormonal Contraceptive use or other hormonal treatment in the past 3 months&#xD;
&#xD;
          -  Current Intra-Uterine Device (IUD) use&#xD;
&#xD;
          -  Positive test result for Gonorrhea and/or Chlamydia&#xD;
&#xD;
          -  Clinically obvious genital ulceration/lesions&#xD;
&#xD;
          -  Symptomatic vaginal yeast infection or clinically significant vaginal discharge&#xD;
&#xD;
          -  HIV-positive&#xD;
&#xD;
          -  Any clinically significant abnormality on screening safety blood tests, that in the&#xD;
             opinion of the investigator would preclude enrolment.&#xD;
&#xD;
          -  Diagnosed blood clotting disorder&#xD;
&#xD;
          -  Any genital tract procedure (e.g. biopsy) within the past 6 months&#xD;
&#xD;
          -  Use of oral probiotic supplement, oral antibiotics or oral steroids within the past 30&#xD;
             days&#xD;
&#xD;
          -  Current use of any vaginal products (except tampons) such as spermicides,&#xD;
             microbicides, douching or drying products, antifungals, or steroids.&#xD;
&#xD;
          -  Known intolerance of Lactobacillus-containing probiotic supplements&#xD;
&#xD;
          -  Undiagnosed abnormal genital bleeding&#xD;
&#xD;
          -  Known, suspected, or history of breast cancer&#xD;
&#xD;
          -  Known or suspected estrogen-dependent malignant neoplasia (e.g. endometrial cancer)&#xD;
&#xD;
          -  Currently taking immunosuppressive drugs&#xD;
&#xD;
          -  Known or suspected hypersensitivity to any component of the Estring or RepHresh Pro-B&#xD;
             products&#xD;
&#xD;
          -  Diagnosis of endometrial hyperplasia&#xD;
&#xD;
          -  Known liver dysfunction or disease; as long as liver function tests have failed to&#xD;
             return to normal&#xD;
&#xD;
          -  Active or past history of arterial thromboembolic disease (e.g. stroke, myocardial&#xD;
             infarction, coronary heart disease)&#xD;
&#xD;
          -  Partial or complete loss of vision due to ophthalmic vascular disease&#xD;
&#xD;
          -  Porphyria&#xD;
&#xD;
          -  Concomitant medication which in the opinion of the investigator may be associated with&#xD;
             a significant drug interaction with the estrogen in Estring.&#xD;
&#xD;
          -  The conditions below are grounds for exclusion based on the opinion of the&#xD;
             investigator:&#xD;
&#xD;
               1. Risk factors for estrogen dependent tumours, e.g. first degree heredity for&#xD;
                  breast cancer&#xD;
&#xD;
               2. Diabetes mellitus with or without vascular involvement&#xD;
&#xD;
               3. Migraine or (severe) headache&#xD;
&#xD;
               4. Epilepsy&#xD;
&#xD;
               5. A history of, or risk factors for, thromboembolic disorders&#xD;
&#xD;
               6. Systemic lupus erythematosus&#xD;
&#xD;
               7. Otosclerosis&#xD;
&#xD;
               8. Cholelithiasis&#xD;
&#xD;
               9. Leiomyoma (uterine fibroids)&#xD;
&#xD;
              10. Endometriosis&#xD;
&#xD;
              11. A history of endometrial hyperplasia&#xD;
&#xD;
              12. Hypertension&#xD;
&#xD;
              13. Asthma&#xD;
&#xD;
              14. Diagnosed anemia&#xD;
      </textblock>
    </criteria>
    <gender>Female</gender>
    <minimum_age>18 Years</minimum_age>
    <maximum_age>49 Years</maximum_age>
    <healthy_volunteers>Accepts Healthy Volunteers</healthy_volunteers>
  </eligibility>
  <location>
    <facility>
      <name>Women's Health in Women's Hands</name>
      <address>
        <city>Toronto</city>
        <state>Ontario</state>
        <zip>M5B1J3</zip>
        <country>Canada</country>
      </address>
    </facility>
  </location>
  <location_countries>
    <country>Canada</country>
  </location_countries>
  <verification_date>December 2021</verification_date>
  <study_first_submitted>February 8, 2019</study_first_submitted>
  <study_first_submitted_qc>February 8, 2019</study_first_submitted_qc>
  <study_first_posted type="Actual">February 11, 2019</study_first_posted>
  <last_update_submitted>December 16, 2021</last_update_submitted>
  <last_update_submitted_qc>December 16, 2021</last_update_submitted_qc>
  <last_update_posted type="Actual">December 17, 2021</last_update_posted>
  <responsible_party>
    <responsible_party_type>Sponsor</responsible_party_type>
  </responsible_party>
  <condition_browse>
    <!-- CAUTION:  The following MeSH terms are assigned with an imperfect algorithm            -->
    <mesh_term>Infections</mesh_term>
    <mesh_term>Communicable Diseases</mesh_term>
    <mesh_term>Vaginosis, Bacterial</mesh_term>
  </condition_browse>
  <intervention_browse>
    <!-- CAUTION:  The following MeSH terms are assigned with an imperfect algorithm            -->
    <mesh_term>Estradiol</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/NCT03837015
org study id: CTN308
nct id: NCT03837015
lead sponsor: 
collaborator: 
has dmc: Yes
is fda regulated drug: No
is fda regulated device: No
is us export: No
This study will enrol African, Caribbean and Black (ACB) women who are known to have a more
      diverse vaginal microbiome, higher rates of bacterial vaginosis with lower numbers of
      protective lactobacilli, and are at increased risk for HIV. The investigators will evaluate
      the safety, feasibility, effect on the vaginal bacterial microbiome and changes in local
      immune and inflammatory responses with the administration of vaginal estrogen alone, vaginal
      estrogen in combination with oral or vaginally administered probiotics, or vaginal probiotics
      alone.
Women are at increased risk of HIV acquisition compared with men. A number of biological
      factors are associated with increased risk, many of which likely enhance risk by increasing
      inflammation in the female genital tract. Susceptibility to infections and immune responses
      in the female genital tract are regulated by hormones: progesterone increases inflammation
      and HIV susceptibility and estrogen decreases inflammation and enhances colonization with
      Lactobacilli.

      A Lactobacillus dominant vaginal microbiome is associated with increased protection against
      HIV, while a polymicrobial vaginal flora, as seen in bacterial vaginosis, is associated with
      increased risk. About 40% of ACB women have a polymicrobial flora.

      The goal of this study is to establish a Lactobacillus dominant vaginal microbiome in ACB
      women, that will be associated with decreased inflammation and decreased susceptibility to
      HIV, by administering a low level of intravaginal estrogen to increase colonization with
      Lactobacilli together with a Lactobacillus-containing probiotic.
allocation: Randomized
intervention model: Parallel Assignment
primary purpose: Prevention
masking: None (Open Label)
measure: Refusal rate
time frame: 12 months
description: Number of eligible participants approached who do not consent to be enrolled
measure: Participant retention rate
time frame: 12 months
description: Number of participants who complete the study as proportion of total number of participants enrolled
measure: Incidence of treatment emergent adverse events
time frame: 2 months
description: The incidence of adverse events, including serious adverse events, their severity and their relationship to study intervention assessed by reviewing case report forms and participant diaries.
measure: Rate of adherence
time frame: 30 days
description: Adherence will be measured by calculating the total probiotic used/total dispensed and for Estring by total days used/total time period
measure: Changes in proportion of Lactobacillus species in the vaginal microbiota
time frame: 30 days
description: Aliquots of cervico-vaginal lavage (CVL) fluids will undergo microbiome analysis using a modified Illumina sequencing method for bacterial community profiling of 16S rRNA to measure changes from baseline at follow-up sampling.
measure: Change in innate inflammatory cytokine/chemokine levels
time frame: 30 days
description: Changes from baseline in levels of cytokine/chemokines will be measured in CVL by a 22-plex multiplex assay at 2 and 4 weeks
measure: Changes in number of HIV target cells in the genital tract
time frame: 30 days
description: Changes from baseline in level of HIV susceptible CD4+ T cells will be quantified using a lab developed HIV pseudovirus assay at 2 and 4 weeks.
arm group label: Estring alone
arm group type: Active Comparator
description: Participants will be given a single packet containing one Estring vaginal ring. Participants will begin using the vaginal ring on day 0 and keep it in place until day 30. Estring should not be removed during the one-month study intervention.
arm group label: Estring and vaginal RepHresh Pro-B
arm group type: Active Comparator
description: Participants will be given a single packet containing one Estring vaginal ring. Participants will begin using the vaginal ring on day 0 and keep it in place until day 30. Estring should not be removed during the one-month study intervention. Participants will also be instructed to insert one RepHresh Pro-B capsule vaginally twice daily, morning and night, until day 30
arm group label: Estring and oral RepHresh Pro-B
arm group type: Active Comparator
description: Participants will be given a single packet containing one Estring vaginal ring. Participants will begin using the vaginal ring on day 0 and keep it in place until day 30. Estring should not be removed during the one-month study intervention. Participants will be instructed to take one RepHresh Pro-B capsule orally twice daily until day 30.
arm group label: Vaginal RepHresh Pro-B
arm group type: Active Comparator
description: Participants will be given a 30 days supply of RepHresh Pro-B and instructed to insert one capsule vaginally twice daily until day 30.
intervention type: Drug
intervention name: Estring Vaginal Ring
description: Estradiol vaginal ring, containing 2mg estradiol designed for slow release over 30 days
arm group label: Estring alone
arm group label: Estring and oral RepHresh Pro-B
arm group label: Estring and vaginal RepHresh Pro-B
other name: 17 beta-estradiol
intervention type: Other
intervention name: RepHresh Pro-B
description: Probiotic supplement containing 2.5 billion CFU of Lactobacilli reuteri RC-14 and Lactobacilli rhamnosus GR-1, administered vaginally or orally
arm group label: Estring and oral RepHresh Pro-B
arm group label: Estring and vaginal RepHresh Pro-B
arm group label: Vaginal RepHresh Pro-B
criteria: 
gender: Female
minimum age: 18 Years
maximum age: 49 Years
healthy volunteers: Accepts Healthy Volunteers
facility: 
country: Canada
responsible party type: Sponsor
mesh term: Infections
mesh term: Communicable Diseases
mesh term: Vaginosis, Bacterial
mesh term: Estradiol
sharing ipd: No