Clinical trial NCT04079218: Accelerated Genital Tract Aging in HIV: Estradiol Clinical Trial
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
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: PHASE4
Conditions: HIV Infection
Vaginal Atrophy
Menopause
Menopause Related Conditions
Aging
Premature Aging
Atrophic Vaginitis
Dysbiosis
Vaginitis
Keywords: HIV Infection
Vaginal Atrophy
Menopause
Vaginal Microbiome
Microbiome
Dysbiosis
Aging
Premature Aging
Atrophic Vaginitis
Lead sponsor: Albert Einstein College of Medicine
Sponsor class: OTHER
Collaborators: name: National Institute on Aging (NIA)
name: Novo Nordisk A/S
name: Irma L and Abram S Croll Charitable Trust
First posted: 2019-09-06
Enrollment: 60
Sex: FEMALE
Minimum age (years): 45
Maximum age (years): 70
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: yes
Allocation: RANDOMIZED
Intervention model: PARALLEL
Intervention model description: Participants will be randomly assigned to receive treatment with estradiol vaginal tablets or no treatment.
Primary purpose: TREATMENT

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.

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

Primary outcomes:
measure: Change in Most Bothersome Symptom (MBS) of Vaginal Atrophy
timeFrame: Between baseline (Visit 2) and 12 weeks (Visit 5)
measure: Vaginal Microbiome - Relative Abundance of Lactobacillus Crispatus (L. Crispatus)
timeFrame: Between baseline (Visit 2) and 6 weeks and 12 weeks (Visit 5)
measure: Vaginal Microbiome - Quantitative Determination of Protective Lactobacilli Species
timeFrame: Between baseline (Visit 2) and 6 weeks and 12 weeks (Visit 5)
Secondary outcomes:
measure: Vaginal Microbiome - Relative Abundance of Bacterial Vaginosis Associated Species
timeFrame: Between baseline (Visit 2) and 6 weeks and 12 weeks (Visit 5)
measure: Vaginal Microbiome - Quantitative Determination of Bacterial Vaginosis Associated Species
timeFrame: Between baseline (Visit 2) and 6 weeks and 12 weeks (Visit 5)
measure: Change in Vaginal Cytokine and Chemokine Concentrations
timeFrame: Between baseline (Visit 2) and 6 weeks and 12 weeks (Visit 5)
Other outcomes:
measure: HIV-1 RNA Levels in the Genital Tract
timeFrame: Baseline and 6 and 12 weeks
measure: Immunoglobulin (Ig)A and IgG Coated Bacteria
timeFrame: Baseline and 6 and 12 weeks
Locations:
city: Bronx
country: United States
facility: Albert Einstein College of Medicine
state: New York
Study officials:
affiliation: Albert Einstein College of Medicine
name: Kerry J Murphy, MD
role: PRINCIPAL_INVESTIGATOR
References:
citation: Murphy K, Keller MJ, Anastos K, Sinclair S, Devlin JC, Shi Q, Hoover DR, Starkman B, McGillick J, Mullis C, Minkoff H, Dominguez-Bello MG, Herold BC. Impact of reproductive aging on the vaginal microbiome and soluble immune mediators in women living with and at-risk for HIV infection. PLoS One. 2019 Apr 26;14(4):e0216049. doi: 10.1371/journal.pone.0216049. eCollection 2019.
citation: Shen J, Song N, Williams CJ, Brown CJ, Yan Z, Xu C, Forney LJ. Effects of low dose estrogen therapy on the vaginal microbiomes of women with atrophic vaginitis. Sci Rep. 2016 Apr 22;6:24380. doi: 10.1038/srep24380.
citation: Hummelen R, Macklaim JM, Bisanz JE, Hammond JA, McMillan A, Vongsa R, Koenig D, Gloor GB, Reid G. Vaginal microbiome and epithelial gene array in post-menopausal women with moderate to severe dryness. PLoS One. 2011;6(11):e26602. doi: 10.1371/journal.pone.0026602. Epub 2011 Nov 2.
citation: Brotman RM, Shardell MD, Gajer P, Fadrosh D, Chang K, Silver MI, Viscidi RP, Burke AE, Ravel J, Gravitt PE. Association between the vaginal microbiota, menopause status, and signs of vulvovaginal atrophy. Menopause. 2018 Nov;25(11):1321-1330. doi: 10.1097/GME.0000000000001236.
citation: Mitchell CM, Reed SD, Diem S, Larson JC, Newton KM, Ensrud KE, LaCroix AZ, Caan B, Guthrie KA. Efficacy of Vaginal Estradiol or Vaginal Moisturizer vs Placebo for Treating Postmenopausal Vulvovaginal Symptoms: A Randomized Clinical Trial. JAMA Intern Med. 2018 May 1;178(5):681-690. doi: 10.1001/jamainternmed.2018.0116.