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

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

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.

Study Overview

• Status: Completed
• Conditions: HIV-1-infection; Bacterial Vaginoses
• Intervention / Treatment: Drug: Estring Vaginal Ring; Other: RepHresh Pro-B

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.

• Study Type: Interventional
• Enrollment (Actual): 50
• Phase: Phase 1

Contacts and Locations

Study Locations

• Canada
  • Ontario
    • Toronto, Ontario, Canada, M5B1J3
      • Women's Health in Women's Hands

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years to 49 years (Adult)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: Female

Description

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

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Prevention
• Allocation: Randomized
• Interventional Model: Parallel Assignment
• Masking: None (Open Label)

Number of Arms

4

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Active Comparator: Estring alone; 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.	Drug: Estring Vaginal Ring; Estradiol vaginal ring, containing 2mg estradiol designed for slow release over 30 days; Other Names: 17 beta-estradiol
Active Comparator: Estring and vaginal RepHresh Pro-B; 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	Drug: Estring Vaginal Ring; Estradiol vaginal ring, containing 2mg estradiol designed for slow release over 30 days; Other Names: 17 beta-estradiol; Other: RepHresh Pro-B; Probiotic supplement containing 2.5 billion CFU of Lactobacilli reuteri RC-14 and Lactobacilli rhamnosus GR-1, administered vaginally or orally
Active Comparator: Estring and oral RepHresh Pro-B; 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.	Drug: Estring Vaginal Ring; Estradiol vaginal ring, containing 2mg estradiol designed for slow release over 30 days; Other Names: 17 beta-estradiol; Other: RepHresh Pro-B; Probiotic supplement containing 2.5 billion CFU of Lactobacilli reuteri RC-14 and Lactobacilli rhamnosus GR-1, administered vaginally or orally
Active Comparator: Vaginal RepHresh Pro-B; Participants will be given a 30 days supply of RepHresh Pro-B and instructed to insert one capsule vaginally twice daily until day 30.	Other: RepHresh Pro-B; Probiotic supplement containing 2.5 billion CFU of Lactobacilli reuteri RC-14 and Lactobacilli rhamnosus GR-1, administered vaginally or orally

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Refusal rate	Number of eligible participants approached who do not consent to be enrolled	12 months
Participant retention rate	Number of participants who complete the study as proportion of total number of participants enrolled	12 months
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.	2 months
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	30 days

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
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.	30 days
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	30 days
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.	30 days

Collaborators and Investigators

• Sponsor: McMaster University
• Collaborators: CIHR Canadian HIV Trials Network

Study record dates

Study Major Dates

• Study Start (Actual): November 4, 2019
• Primary Completion (Actual): December 14, 2021
• Study Completion (Actual): December 14, 2021

Study Registration Dates

• First Submitted: February 8, 2019
• First Submitted That Met QC Criteria: February 8, 2019
• First Posted (Actual): February 11, 2019

Study Record Updates

• Last Update Posted (Actual): December 17, 2021
• Last Update Submitted That Met QC Criteria: December 16, 2021
• Last Verified: December 1, 2021

More Information

Terms related to this study

• Additional Relevant MeSH Terms: Pathologic Processes; Disease Attributes; Bacterial Infections; Bacterial Infections and Mycoses; Vaginal Diseases; Vaginitis; Infections; Communicable Diseases; Vaginosis, Bacterial; Physiological Effects of Drugs; Hormones; Hormones, Hormone Substitutes, and Hormone Antagonists; Estrogens; Estradiol
• Other Study ID Numbers: CTN308

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: No

Drug and device information, study documents

• 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