Accelerated Genital Tract Aging in HIV: Estradiol Clinical Trial

Study Overview
=================
Brief Summary
-----------------
During menopause, there is a decrease in a hormone estrogen, which leads to aging of the vagina. Vaginal aging includes changes in the type and amount of healthy bacteria in the vagina, inflammation and a breakdown of natural barriers that keep the vagina healthy and protected from infections. Some menopausal women develop a condition called vaginal atrophy, which causes vaginal dryness, irritation, pain with sex, and itching. We are testing whether an estradiol tablet placed inside the vagina will lead to fewer changes in the types of bacteria present in the vagina, improve vaginal atrophy symptoms and ultimately keep the vagina healthier for a longer. This is important for women with HIV as they are living longer, healthier, sexually active lives due to successful treatment with antiretrovirals.

Detailed Description
-----------------
HIV may be associated with premature aging in the female genital tract including alterations in the vaginal microbiome and mucosal inflammation, which may increase risk for vaginal atrophy, urinary tract infections (UTI) and other genital tract infections. This study will determine whether use of vaginal estradiol for 12 weeks in menopausal women living with HIV with symptomatic vaginal atrophy will improve atrophy symptoms and the vaginal microbiome and reduce mucosal inflammation thereby improving vaginal health. This study will include 50 participants randomized to treatment with a vaginal estradiol insert or no therapy for 12 weeks and will have 4 study visits.

Official Title
-----------------
The Impact of HIV on Accelerated Aging in the Female Genital Tract: a Pilot Trial of Topical Estradiol to Improve the Vaginal Microbiome and Symptoms of Vaginal Atrophy in Menopausal Women With HIV

Conditions
-----------------
HIV Infection, Vaginal Atrophy, Menopause, Menopause Related Conditions, Aging, Premature Aging, Atrophic Vaginitis, Dysbiosis, Vaginitis

Intervention / Treatment
-----------------
* Drug: Estradiol Vaginal Insert


Participation Criteria
=================
Eligibility Criteria
-----------------
Inclusion Criteria: HIV infection Females aged 45-70 Menopause defined by having no menstrual periods for 12 consecutive months, confirmed with serum follicle-stimulating hormone (FSH) level >40 IU/ml and serum estradiol level <20 pg/ml Symptomatic vaginal atrophy defined as reporting at least once per week in the past 30 days, 1 or more of the following symptoms of moderate or severe intensity: Dryness, Itching, Irritation, Soreness or pain OR Pain associated with sexual activity at least once Evidence of atrophy on exam, including thin, pale and dry vaginal and vulvar surfaces Agrees not to use vaginal products other than vaginal estradiol tablet during the clinical trial Exclusion Criteria: Current or previous history of breast cancer or estrogen dependent neoplasia Current or past thromboembolic disease (deep vein thrombosis or pulmonary embolism, not including thrombophlebitis) Current or previous history of myocardial infarction or stroke Known blood clotting disorders including Protein C, Protein S and antithrombin deficiency, Factor V Leiden or prothrombin mutations Known severe liver disease including cirrhosis or active Hepatitis B History of adverse reaction to vaginal estradiol Current unexplained or unevaluated abnormal genital bleeding Current or suspected pregnancy If < age 55, had a hysterectomy and has at least one ovary Pelvic or vaginal surgery in the prior 60 days Use of systemic reproductive hormones in the past 2 months Antibiotic use in the past 30 days Use of immunosuppressive medications in the prior 60 days including biologics, chemotherapeutics or post-transplant immunosuppressive medications Use of any vaginal or vulvar preparations 1 month prior to enrollment Current active vaginal infection (diagnosed by wet mount at Visit 1 or 2) Any serious disease or chronic condition that might interfere with study compliance Unwilling to agree to the provisions of the protocol

Ages Eligible for Study
-----------------
Minimum Age: 45 Years
Maximum Age: 70 Years

Sexes Eligible for Study
-----------------
Female

Accepts Healthy Volunteers
-----------------
Accepts Healthy Volunteers

Study Plan
=================
How is the study designed?
-----------------

Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Parallel Assignment
Interventional Model Description: Participants will be randomly assigned to receive treatment with estradiol vaginal tablets or no treatment.
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Estradiol Vaginal Insert<br>Using a pre-loaded single-use plastic applicator, participants will insert one 10 microgram estradiol tablet intravaginally daily for 2 weeks and then one tablet twice weekly for the remainder of the study for a total of 12 weeks. | Drug: Estradiol Vaginal Insert<br>* Using a pre-loaded single-use plastic applicator, participants will insert one 10 microgram estradiol tablet intravaginally daily for 2 weeks and then one tablet twice weekly for the remainder of the study for a total of 12 weeks.<br>* Other names: Vagifem (estradiol vaginal tablet);|
| No Intervention: No treatment<br>No intervention | |

What is the study measuring?
-----------------
Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Vaginal Atrophy Symptoms | Change in clinical symptoms measured by most bothersome symptom (MBS) of vaginal atrophy after estradiol treatment | Between baseline and 6 and 12 weeks | 
| Vaginal Microbiome | Changes in the vaginal microbiome, specifically the relative abundance of protective lactobacillus species L. crispatus as measured by lllumina sequencing and quantities of protective lactobacilli species (L. crispatus, L. jensenii and L. gasseri) as measured by quantitative PCR (qPCR) | Between baseline and 6 and 12 weeks | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Vaginal Microbiome | Changes in relative abundance and quantities of bacterial vaginosis associated species | Between baseline and 6 and 12 weeks | 
| Vaginal cytokines and chemokines | Changes in concentrations of cytokines and chemokines in cervicovaginal lavage (CVL) | Between baseline and 6 and 12 weeks | 
| Immunoglobulin (Ig)A and IgG coated bacteria | Differences in levels of live IgA+IgG+ coated, live IgA+IgG- coated, live IgA-IgG-coated and dead bacteria | Baseline and 6 and 12 weeks | 
| HIV-1 RNA levels in the genital tract | HIV-1 RNA testing from cervicovaginal lavage fluid | Baseline and 6 and 12 weeks | 

 Terms related to the study
=================
Keywords Provided by Centre Hospitalier Valida
-----------------
HIV Infection, Vaginal Atrophy, Menopause, Vaginal Microbiome, Microbiome, Dysbiosis, Aging, Premature Aging, Atrophic Vaginitis