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

Phase 1

Completed

• Conditions: Bacterial Vaginoses; HIV-1-infection
• Interventions: Drug: Estring Vaginal Ring; Other: RepHresh Pro-B

• Registration Number: NCT03837015
• Lead Sponsor: McMaster University

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.

Study Timeline

• Study First Submitted: 2019-02-08
• Study First Submitted QC: 2019-02-08
• Study First Posted: 2019-02-11
• Study Start: 2019-11-04
• Status Verified: 2021-12
• Primary Completion: 2021-12-14
• Study Completion: 2021-12-14
• Last Update Submitted: 2021-12-16
• Last Update Posted: 2021-12-17

Recruitment & Eligibility

• Status: COMPLETED
• Sex: Female
• Target Recruitment: 50

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 & Design

• Study Type: INTERVENTIONAL
• Study Design: PARALLEL

Arm && Interventions

Group	Intervention	Description
Estring alone	Estring Vaginal Ring	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.
Estring and vaginal RepHresh Pro-B	Estring Vaginal Ring	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
Estring and oral RepHresh Pro-B	Estring Vaginal Ring	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.
Estring and vaginal RepHresh Pro-B	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
Estring and oral RepHresh Pro-B	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.
Vaginal RepHresh Pro-B	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.

Primary Outcome Measures

Name	Time	Method
Incidence of treatment emergent adverse events	2 months	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.
Participant retention rate	12 months	Number of participants who complete the study as proportion of total number of participants enrolled
Refusal rate	12 months	Number of eligible participants approached who do not consent to be enrolled
Rate of adherence	30 days	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

Name	Time	Method
Changes in proportion of Lactobacillus species in the vaginal microbiota	30 days	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	30 days	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	30 days	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.

Trial Locations

Locations (1)

Women's Health in Women's Hands; 🇨🇦 Toronto, Ontario, Canada