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

HIV-1-infection Clinical Trial

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

Clinical Trial Details — Status: Completed

Administrative data

• NCT number: NCT03837015
• Other study ID #: CTN308
• Status: Completed
• Phase: Phase 1
• Start date: November 4, 2019
• Est. completion date: December 14, 2021

Study information

• Verified date: December 2021
• Source: McMaster University
• Contact: n/a
• Is FDA regulated: No
• Study type: Interventional

Clinical Trial 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.

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.

Recruitment information / eligibility

• Status: Completed
• Enrollment: 50
• Est. completion date: December 14, 2021
• Est. primary completion date: December 14, 2021
• Accepts healthy volunteers: Accepts Healthy Volunteers
• Gender: Female
• Age group: 18 Years to 49 Years

Eligibility

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

Related Conditions & MeSH terms

• Bacterial Vaginoses
• Communicable Diseases
• HIV-1-infection
• Infections
• Vaginosis, Bacterial

Intervention

Drug:
• Estring Vaginal Ring
Estradiol vaginal ring, containing 2mg estradiol designed for slow release over 30 days

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

Locations

Country	Name	City	State
Canada	Women's Health in Women's Hands	Toronto	Ontario

Sponsors (2)

Lead Sponsor	Collaborator
McMaster University	CIHR Canadian HIV Trials Network

Country where clinical trial is conducted

Canada, 

Outcome

Type	Measure	Description	Time frame	Safety issue
Primary	Refusal rate	Number of eligible participants approached who do not consent to be enrolled	12 months
Primary	Participant retention rate	Number of participants who complete the study as proportion of total number of participants enrolled	12 months
Primary	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
Primary	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	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
Secondary	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
Secondary	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