Accelerated Genital Tract Aging in HIV: Estradiol Clinical Trial

NCT04079218 | Completed Phase 4 Results DMC FDA Drug

• 2 other identifiers: 2019-105291K23AG062400-01A1
• Study Type: interventional
• Target: 60
• Locations: 1 country
• Sites: 1

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.

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

Outcome Measures

Primary Outcomes (3)

• Change in Most Bothersome Symptom (MBS) of Vaginal Atrophy

  Change in the severity of MBS of vaginal atrophy as reported during the baseline visit was assessed at 12 weeks (Visit 5). During the baseline visit, participants were asked to identify their MBS and assess the severity of the MBS on an ordinal scale of "None," "Mild," "Moderate," or "Severe." During the follow-up visit at 12 weeks participants were again asked to identify and assess the severity of their MBS. The degree of severity of the MBS reported at baseline was then compared to the severity of the MBS reported at 12 weeks and categorically summarized and reported as either "Severity Increased" "Severity Decreased" or "No change in Severity" for the given MBS. Participants whose MBS reported at baseline changed during the follow-up visit at 12 weeks were excluded from the analysis. Participants who did not report an MBS during the baseline visit were also excluded. Data for each possible type of MBS is summarized by study arm.

  Between baseline (Visit 2) and 12 weeks (Visit 5)

• Vaginal Microbiome - Relative Abundance of Lactobacillus Crispatus (L. Crispatus)

  The relative abundance of the protective Lactobacillus species, L. crispatus, as quantified by lllumina MiSeq sequencing will be calculated by dividing the total number of L crispatus sequences detected in a sample by the total number of sequences from all bacterial species detected in the same sample. This proportion will be expressed as a percentage. The change in relative abundance between baseline (visit 2) and 12 weeks (visit 5) will be summarized by study arm.

  Between baseline (Visit 2) and 6 weeks and 12 weeks (Visit 5)

• Vaginal Microbiome - Quantitative Determination of Protective Lactobacilli Species

  Changes in the vaginal microbiome, specifically the quantities of protective Lactobacilli species (L. crispatus, L. jensenii and L. gasseri) as measured by quantitative PCR (qPCR) will be determined. The three Lactobacilli species will be identified and quantified in colony forming units per milliliter of sample (CFU/mL). Changes in abundance from baseline will be summarized by study arm using basic descriptive statistics.

  Between baseline (Visit 2) and 6 weeks and 12 weeks (Visit 5)

Secondary Outcomes (3)

• Vaginal Microbiome - Relative Abundance of Bacterial Vaginosis Associated Species

  Between baseline (Visit 2) and 6 weeks and 12 weeks (Visit 5)

• Vaginal Microbiome - Quantitative Determination of Bacterial Vaginosis Associated Species

  Between baseline (Visit 2) and 6 weeks and 12 weeks (Visit 5)

• Change in Vaginal Cytokine and Chemokine Concentrations

  Between baseline (Visit 2) and 6 weeks and 12 weeks (Visit 5)

Other Outcomes (2)

• HIV-1 RNA Levels in the Genital Tract

  Baseline and 6 and 12 weeks

• Immunoglobulin (Ig)A and IgG Coated Bacteria

  Baseline and 6 and 12 weeks

Study Arms (2)

Estradiol Vaginal Insert

EXPERIMENTAL

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

No treatment

NO INTERVENTION

No intervention

Interventions

Estradiol Vaginal Insert DRUG

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.

Also known as: Vagifem®, Vagifem (estradiol vaginal tablet)

Estradiol Vaginal Insert

Eligibility Criteria

• Age: 45 Years - 70 Years
• Sex: female
• Healthy Volunteers: Yes
• Age Groups: Adult (18-64), Older Adult (65+)

You may qualify if:

• 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

You may not qualify if:

• 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)

Sponsors & Collaborators

• Kerry Murphy: lead
• National Institute on Aging (NIA): collaborator
• Novo Nordisk A/S: collaborator
• Irma L and Abram S Croll Charitable Trust: collaborator

Study Sites (1)

Albert Einstein College of Medicine

The Bronx, New York, 10461, United States

Location

Related Publications (5)

• 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.

  PMID: 31026271 BACKGROUND

• 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.

  PMID: 27103314 BACKGROUND

• 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.

  PMID: 22073175 BACKGROUND

• 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.

  PMID: 30358729 BACKGROUND

• 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.

  PMID: 29554173 BACKGROUND

MeSH Terms

Conditions

HIV Infections; Aging, Premature; Atrophic Vaginitis; Dysbiosis; Vaginitis

Interventions

Estradiol

Condition Hierarchy (Ancestors)

Blood-Borne Infections; Communicable Diseases; Infections; Sexually Transmitted Diseases, Viral; Sexually Transmitted Diseases; Lentivirus Infections; Retroviridae Infections; RNA Virus Infections; Virus Diseases; Genital Diseases; Urogenital Diseases; Immunologic Deficiency Syndromes; Immune System Diseases; Signs and Symptoms; Pathological Conditions, Signs and Symptoms; Vaginal Diseases; Genital Diseases, Female; Female Urogenital Diseases; Female Urogenital Diseases and Pregnancy Complications; Pathologic Processes

Intervention Hierarchy (Ancestors)

Estrenes; Estranes; Steroids; Fused-Ring Compounds; Polycyclic Compounds; Estradiol Congeners; Gonadal Steroid Hormones; Gonadal Hormones; Hormones; Hormones, Hormone Substitutes, and Hormone Antagonists

Results Point of Contact

• Title: Dr. Kerry Murphy
• Organization: Albert Einstein College of Medicine

kerry.murphy@einsteinmed.edu

718-839-7885

Study Officials

• Kerry J Murphy, MD

  Albert Einstein College of Medicine

  PRINCIPAL INVESTIGATOR

Publication Agreements

• PI is Sponsor Employee: Yes

Study Design

• Study Type: interventional
• Phase: phase 4
• Allocation: RANDOMIZED
• Masking: NONE
• Purpose: TREATMENT
• Intervention Model: PARALLEL
• Sponsor Type: OTHER
• Responsible Party: SPONSOR INVESTIGATOR
• PI Title: Assistant Professor, Department of Medicine (Infectious Diseases)

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

Study Record Dates

• First Submitted: September 3, 2019
• First Posted: September 6, 2019
• Study Start: September 1, 2020
• Primary Completion: August 9, 2023
• Study Completion: August 9, 2023
• Last Updated: March 14, 2025
• Results First Posted: March 14, 2025

Record last verified: 2025-02

Data Sharing

• IPD Sharing: Will share
• Shared Documents: STUDY PROTOCOL, SAP, ICF
• Time Frame: Within 12 months after publication
• 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.

Locations

US (1)