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Estrogen, Probiotics and Vaginal Health to Prevent HIV Infection in ACB Women

Primary Purpose

HIV-1-infection, Bacterial Vaginoses

Status
Completed
Phase
Phase 1
Locations
Canada
Study Type
Interventional
Intervention
Estring Vaginal Ring
RepHresh Pro-B
Sponsored by
McMaster University
About
Eligibility
Locations
Arms
Outcomes
Full info

About this trial

This is an interventional prevention trial for HIV-1-infection

Eligibility Criteria

18 Years - 49 Years (Adult)FemaleAccepts Healthy Volunteers

Inclusion Criteria:

  • African, Caribbean, Black
  • Pre-menopausal women in good general health, as determined by the investigator
  • Uterus and cervix present
  • Negative pregnancy test
  • Currently practicing barrier or non-hormonal forms of contraception, and planning to continue, for the duration of the study (barrier contraceptive, abstinence)
  • Willing to undergo a pelvic exam by a female nurse/female doctor
  • Willing to abstain from vaginal intercourse for 48 hours prior to sampling, over the entire course of the study
  • Able to understand, comply and consent to protocol requirements and instructions
  • Able to attend scheduled study visits and complete required investigations

Exclusion Criteria:

  • Currently lactating
  • Pregnant: suspected, current or in the last 12 months
  • Irregular menstrual cycle (less than 6 periods in a year) not related to contraceptive use, pregnancy or breastfeeding
  • Post-menopausal
  • Hormonal Contraceptive use or other hormonal treatment in the past 3 months
  • Current Intra-Uterine Device (IUD) use
  • Positive test result for Gonorrhea and/or Chlamydia
  • Clinically obvious genital ulceration/lesions
  • Symptomatic vaginal yeast infection or clinically significant vaginal discharge
  • HIV-positive
  • Any clinically significant abnormality on screening safety blood tests, that in the opinion of the investigator would preclude enrolment.
  • Diagnosed blood clotting disorder
  • Any genital tract procedure (e.g. biopsy) within the past 6 months
  • Use of oral probiotic supplement, oral antibiotics or oral steroids within the past 30 days
  • Current use of any vaginal products (except tampons) such as spermicides, microbicides, douching or drying products, antifungals, or steroids.
  • Known intolerance of Lactobacillus-containing probiotic supplements
  • Undiagnosed abnormal genital bleeding
  • Known, suspected, or history of breast cancer
  • Known or suspected estrogen-dependent malignant neoplasia (e.g. endometrial cancer)
  • Currently taking immunosuppressive drugs
  • Known or suspected hypersensitivity to any component of the Estring or RepHresh Pro-B products
  • Diagnosis of endometrial hyperplasia
  • Known liver dysfunction or disease; as long as liver function tests have failed to return to normal
  • Active or past history of arterial thromboembolic disease (e.g. stroke, myocardial infarction, coronary heart disease)
  • Partial or complete loss of vision due to ophthalmic vascular disease
  • Porphyria
  • Concomitant medication which in the opinion of the investigator may be associated with a significant drug interaction with the estrogen in Estring.

  • The conditions below are grounds for exclusion based on the opinion of the investigator:

    1. Risk factors for estrogen dependent tumours, e.g. first degree heredity for breast cancer
    2. Diabetes mellitus with or without vascular involvement
    3. Migraine or (severe) headache
    4. Epilepsy
    5. A history of, or risk factors for, thromboembolic disorders
    6. Systemic lupus erythematosus
    7. Otosclerosis
    8. Cholelithiasis
    9. Leiomyoma (uterine fibroids)
    10. Endometriosis
    11. A history of endometrial hyperplasia
    12. Hypertension
    13. Asthma
    14. Diagnosed anemia

Sites / Locations

  • Women's Health in Women's Hands

Arms of the Study

Arm 1

Arm 2

Arm 3

Arm 4

Arm Type

Active Comparator

Active Comparator

Active Comparator

Active Comparator

Arm Label

Estring alone

Estring and vaginal RepHresh Pro-B

Estring and oral RepHresh Pro-B

Vaginal RepHresh Pro-B

Arm 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 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

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.

Participants will be given a 30 days supply of RepHresh Pro-B and instructed to insert one capsule vaginally twice daily until day 30.

Outcomes

Primary Outcome Measures

Refusal rate
Number of eligible participants approached who do not consent to be enrolled
Participant retention rate
Number of participants who complete the study as proportion of total number of participants enrolled
Incidence of treatment emergent adverse events
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.
Rate of adherence
Adherence will be measured by calculating the total probiotic used/total dispensed and for Estring by total days used/total time period

Secondary Outcome Measures

Changes in proportion of Lactobacillus species in the vaginal microbiota
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.
Change in innate inflammatory cytokine/chemokine levels
Changes from baseline in levels of cytokine/chemokines will be measured in CVL by a 22-plex multiplex assay at 2 and 4 weeks
Changes in number of HIV target cells in the genital tract
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.

Full Information

First Posted
February 8, 2019
Last Updated
December 16, 2021
Sponsor
McMaster University
Collaborators
CIHR Canadian HIV Trials Network
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1. Study Identification

Unique Protocol Identification Number
NCT03837015
Brief Title
Estrogen, Probiotics and Vaginal Health to Prevent HIV Infection in ACB Women
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
Study Type
Interventional

2. Study Status

Record Verification Date
December 2021
Overall Recruitment Status
Completed
Study Start Date
November 4, 2019 (Actual)
Primary Completion Date
December 14, 2021 (Actual)
Study Completion Date
December 14, 2021 (Actual)

3. Sponsor/Collaborators

Responsible Party, by Official Title
Sponsor
Name of the Sponsor
McMaster University
Collaborators
CIHR Canadian HIV Trials Network

4. Oversight

Studies a U.S. FDA-regulated Drug Product
No
Studies a U.S. FDA-regulated Device Product
No
Product Manufactured in and Exported from the U.S.
No
Data Monitoring Committee
Yes

5. Study Description

Brief Summary
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.
Detailed Description
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.

6. Conditions and Keywords

Primary Disease or Condition Being Studied in the Trial, or the Focus of the Study
HIV-1-infection, Bacterial Vaginoses

7. Study Design

Primary Purpose
Prevention
Study Phase
Phase 1
Interventional Study Model
Parallel Assignment
Masking
None (Open Label)
Allocation
Randomized
Enrollment
50 (Actual)

8. Arms, Groups, and Interventions

Arm Title
Estring alone
Arm Type
Active Comparator
Arm 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 Title
Estring and vaginal RepHresh Pro-B
Arm Type
Active Comparator
Arm 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 Title
Estring and oral RepHresh Pro-B
Arm Type
Active Comparator
Arm 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 Title
Vaginal RepHresh Pro-B
Arm Type
Active Comparator
Arm 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(s)
Estring Vaginal Ring
Other Intervention Name(s)
17 beta-estradiol
Intervention Description
Estradiol vaginal ring, containing 2mg estradiol designed for slow release over 30 days
Intervention Type
Other
Intervention Name(s)
RepHresh Pro-B
Intervention Description
Probiotic supplement containing 2.5 billion CFU of Lactobacilli reuteri RC-14 and Lactobacilli rhamnosus GR-1, administered vaginally or orally
Primary Outcome Measure Information:
Title
Refusal rate
Description
Number of eligible participants approached who do not consent to be enrolled
Time Frame
12 months
Title
Participant retention rate
Description
Number of participants who complete the study as proportion of total number of participants enrolled
Time Frame
12 months
Title
Incidence of treatment emergent adverse events
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.
Time Frame
2 months
Title
Rate of adherence
Description
Adherence will be measured by calculating the total probiotic used/total dispensed and for Estring by total days used/total time period
Time Frame
30 days
Secondary Outcome Measure Information:
Title
Changes in proportion of Lactobacillus species in the vaginal microbiota
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.
Time Frame
30 days
Title
Change in innate inflammatory cytokine/chemokine levels
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
Time Frame
30 days
Title
Changes in number of HIV target cells in the genital tract
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.
Time Frame
30 days

10. Eligibility

Sex
Female
Minimum Age & Unit of Time
18 Years
Maximum Age & Unit of Time
49 Years
Accepts Healthy Volunteers
Accepts Healthy Volunteers
Eligibility Criteria
Inclusion Criteria: African, Caribbean, Black Pre-menopausal women in good general health, as determined by the investigator Uterus and cervix present Negative pregnancy test Currently practicing barrier or non-hormonal forms of contraception, and planning to continue, for the duration of the study (barrier contraceptive, abstinence) Willing to undergo a pelvic exam by a female nurse/female doctor Willing to abstain from vaginal intercourse for 48 hours prior to sampling, over the entire course of the study Able to understand, comply and consent to protocol requirements and instructions Able to attend scheduled study visits and complete required investigations Exclusion Criteria: Currently lactating Pregnant: suspected, current or in the last 12 months Irregular menstrual cycle (less than 6 periods in a year) not related to contraceptive use, pregnancy or breastfeeding Post-menopausal Hormonal Contraceptive use or other hormonal treatment in the past 3 months Current Intra-Uterine Device (IUD) use Positive test result for Gonorrhea and/or Chlamydia Clinically obvious genital ulceration/lesions Symptomatic vaginal yeast infection or clinically significant vaginal discharge HIV-positive Any clinically significant abnormality on screening safety blood tests, that in the opinion of the investigator would preclude enrolment. Diagnosed blood clotting disorder Any genital tract procedure (e.g. biopsy) within the past 6 months Use of oral probiotic supplement, oral antibiotics or oral steroids within the past 30 days Current use of any vaginal products (except tampons) such as spermicides, microbicides, douching or drying products, antifungals, or steroids. Known intolerance of Lactobacillus-containing probiotic supplements Undiagnosed abnormal genital bleeding Known, suspected, or history of breast cancer Known or suspected estrogen-dependent malignant neoplasia (e.g. endometrial cancer) Currently taking immunosuppressive drugs Known or suspected hypersensitivity to any component of the Estring or RepHresh Pro-B products Diagnosis of endometrial hyperplasia Known liver dysfunction or disease; as long as liver function tests have failed to return to normal Active or past history of arterial thromboembolic disease (e.g. stroke, myocardial infarction, coronary heart disease) Partial or complete loss of vision due to ophthalmic vascular disease Porphyria Concomitant medication which in the opinion of the investigator may be associated with a significant drug interaction with the estrogen in Estring. The conditions below are grounds for exclusion based on the opinion of the investigator: Risk factors for estrogen dependent tumours, e.g. first degree heredity for breast cancer Diabetes mellitus with or without vascular involvement Migraine or (severe) headache Epilepsy A history of, or risk factors for, thromboembolic disorders Systemic lupus erythematosus Otosclerosis Cholelithiasis Leiomyoma (uterine fibroids) Endometriosis A history of endometrial hyperplasia Hypertension Asthma Diagnosed anemia
Facility Information:
Facility Name
Women's Health in Women's Hands
City
Toronto
State/Province
Ontario
ZIP/Postal Code
M5B1J3
Country
Canada

12. IPD Sharing Statement

Plan to Share IPD
No

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Estrogen, Probiotics and Vaginal Health to Prevent HIV Infection in ACB Women

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