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Accelerated Genital Tract Aging in HIV: Estradiol Clinical Trial

Primary Purpose

HIV Infection, Vaginal Atrophy, Menopause

Status

Active

Phase

Phase 4

Locations

United States

Study Type

Interventional

Intervention

Estradiol Vaginal Insert

About this trial

This is an interventional treatment trial for HIV Infection focused on measuring HIV Infection, Vaginal Atrophy, Menopause, Vaginal Microbiome, Microbiome, Dysbiosis, Aging, Premature Aging, Atrophic Vaginitis

Eligibility Criteria

45 Years - 70 Years (Adult, Older Adult)FemaleAccepts Healthy Volunteers

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

Sites / Locations

Albert Einstein College of Medicine

Arms of the Study

Arm 1

Arm 2

Arm Type

Experimental

No Intervention

Arm Label

Estradiol Vaginal Insert

No treatment

Arm Description

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.

No intervention

Outcomes

Primary Outcome Measures

Vaginal Atrophy Symptoms

Change in clinical symptoms measured by most bothersome symptom (MBS) of vaginal atrophy after estradiol treatment

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)

Secondary Outcome Measures

Vaginal Microbiome

Changes in relative abundance and quantities of bacterial vaginosis associated species

Vaginal cytokines and chemokines

Changes in concentrations of cytokines and chemokines in cervicovaginal lavage (CVL)

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

HIV-1 RNA levels in the genital tract

HIV-1 RNA testing from cervicovaginal lavage fluid

Full Information

NCT ID

NCT04079218

First Posted

September 3, 2019

Last Updated

September 8, 2023

Sponsor

Albert Einstein College of Medicine

Collaborators

National Institute on Aging (NIA), Novo Nordisk A/S

1. Study Identification

Unique Protocol Identification Number

NCT04079218

Brief Title

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

2. Study Status

Record Verification Date

September 2023

Overall Recruitment Status

Active, not recruiting

Study Start Date

September 1, 2020 (Actual)

Primary Completion Date

August 9, 2023 (Actual)

Study Completion Date

December 31, 2023 (Anticipated)

3. Sponsor/Collaborators

Responsible Party, by Official Title

Principal Investigator

Name of the Sponsor

Albert Einstein College of Medicine

Collaborators

National Institute on Aging (NIA), Novo Nordisk A/S

4. Oversight

Studies a U.S. FDA-regulated Drug Product

Yes

Studies a U.S. FDA-regulated Device Product

Product Manufactured in and Exported from the U.S.

Yes

Data Monitoring Committee

Yes

5. Study Description

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.

6. Conditions and Keywords

Primary Disease or Condition Being Studied in the Trial, or the Focus of the Study

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

7. Study Design

Primary Purpose

Treatment

Study Phase

Phase 4

Interventional Study Model

Parallel Assignment

Model Description

Participants will be randomly assigned to receive treatment with estradiol vaginal tablets or no treatment.

Masking

None (Open Label)

Allocation

Randomized

Enrollment

51 (Actual)

8. Arms, Groups, and Interventions

Arm Title

Estradiol Vaginal Insert

Arm Type

Experimental

Arm Description

Arm Title

No treatment

Arm Type

No Intervention

Arm Description

No intervention

Intervention Type

Drug

Intervention Name(s)

Estradiol Vaginal Insert

Other Intervention Name(s)

Vagifem®, Vagifem (estradiol vaginal tablet)

Intervention Description

Primary Outcome Measure Information:

Title

Vaginal Atrophy Symptoms

Description

Change in clinical symptoms measured by most bothersome symptom (MBS) of vaginal atrophy after estradiol treatment

Time Frame

Between baseline and 6 and 12 weeks

Title

Vaginal Microbiome

Description

Time Frame

Between baseline and 6 and 12 weeks

Secondary Outcome Measure Information:

Title

Vaginal Microbiome

Description

Changes in relative abundance and quantities of bacterial vaginosis associated species

Time Frame

Between baseline and 6 and 12 weeks

Title

Vaginal cytokines and chemokines

Description

Changes in concentrations of cytokines and chemokines in cervicovaginal lavage (CVL)

Time Frame

Between baseline and 6 and 12 weeks

Title

Immunoglobulin (Ig)A and IgG coated bacteria

Description

Differences in levels of live IgA+IgG+ coated, live IgA+IgG- coated, live IgA-IgG-coated and dead bacteria

Time Frame

Baseline and 6 and 12 weeks

Title

HIV-1 RNA levels in the genital tract

Description

HIV-1 RNA testing from cervicovaginal lavage fluid

Time Frame

Baseline and 6 and 12 weeks

10. Eligibility

Sex

Female

Minimum Age & Unit of Time

45 Years

Maximum Age & Unit of Time

70 Years

Accepts Healthy Volunteers

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

Overall Study Officials:

First Name & Middle Initial & Last Name & Degree

Kerry J Murphy, MD

Organizational Affiliation

Albert Einstein College of Medicine

Official's Role

Principal Investigator

Facility Information:

Facility Name

Albert Einstein College of Medicine

City

Bronx

State/Province

New York

ZIP/Postal Code

10461

Country

United States

12. IPD Sharing Statement

Plan to Share IPD

Yes

IPD Sharing Plan Description

After publication of the main study findings, external investigators may contact the Principal Investigator Dr. Kerry Murphy for de-identified datasets.

IPD Sharing Time Frame

Within 12 months after publication

IPD Sharing Access Criteria

De-identified electronic datasets of published results will be made available to external investigators in a format in which subsequent statistical analyses can be performed.

Citations:

PubMed Identifier

31026271

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.

Results Reference

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PubMed Identifier

27103314

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. Erratum In: Sci Rep. 2016 Nov 29;6:34119.

Results Reference

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PubMed Identifier

22073175

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.

Results Reference

background

PubMed Identifier

30358729

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.

Results Reference

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PubMed Identifier

29554173

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.

Results Reference

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Accelerated Genital Tract Aging in HIV: Estradiol Clinical Trial

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