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
Allocation: RANDOMIZED | Intervention model: PARALLEL
Enrollment: 60
Healthy volunteers: yes

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.

Arms:
arm 1: 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. arm 2: No intervention

Interventions: intervention 1: Estradiol Vaginal Insert
Intervention descriptions: intervention 1: 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.

Protocol document:
Prot_SAP_000.pdf: 
Study Title: Accelerated Genital Tract Aging in HIV: Estradiol Clinical Trial
NCT04079218
IRB Number: 2019-10529
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Accelerated genital tract aging in HIV: estradiol clinical trial
1. Background
HIV is associated with accelerated and accentuated aging as evidenced by earlier onset 
and increased prevalence of several age-related conditions including cardiovascular, 
neurocognitive and bone disease1-4. Chronic HIV infection and aging may be linked by a common 
mechanism: inflammation5, which is fueled by ongoing low-level viral replication, microbial 
translocation, immunosenescence, immune activation and ART use6. However, the link between 
HIV infection and genital tract aging in women is understudied and has important clinical 
implications. The phenotype of female genital tract (FGT) aging is characterized by vaginal 
dysbiosis (increase in diverse anaerobes and decrease in acid-producing lactobacilli) and 
mucosal inflammation. These changes are associated with an increased risk for urinary tract and 
sexually transmitted infections (STI), vaginal atrophy, HIV acquisition and shedding7,8,9. Among 
incident US HIV infections in 2015, 17% occurred in persons >50 years of age. Approximately 
45% of people living with HIV in the US are aged ≥5010,11, and by 2030 an estimated 70% will be 
over age 50, underscoring the importance of studying the effects of aging on the FGT and genital 
health as well as HIV acquisition and shedding. 
This proposal will test the hypothesis that HIV is associated with earlier onset and more 
pronounced changes in the FGT characterized by vaginal dysbiosis and mucosal inflammation. I 
propose a cross-sectional study to compare a phenotype of FGT aging in HIV-infected (HIV+) and 
HIV-uninfected (HIV-) menopausal women aged 45-70 years and predict that younger HIV+ 
menopausal women (45-55 years) will have a phenotype similar to older (56-70 years) HIV- 
menopausal women. I will also explore whether topical estradiol therapy in HIV+ women with 
vaginal atrophy will improve symptoms and the age-related phenotype of dysbiosis and 
inflammation. Results of these studies have important clinical implications and could lead to 
recommendations for earlier and/or more aggressive treatment of vaginal atrophy in HIV+ women. 
Menopause is associated with vaginal dysbiosis, inflammation, and atrophy: hydrogen 
peroxide, lactic acid-producing lactobacilli (L. crispatus, L.  jensenii and L. gasseri) are protective 
by maintaining an acidic vaginal pH <4.7 and producing antimicrobial molecules such as 
bacteriocins. In contrast, dysbiosis, defined as a decrease in protective lactobacilli and increase 
in diverse anaerobes, is associated with a greater risk for HIV and other infections. Among the 
clinical conditions associated with dysbiosis are the estrogen deficient states of menopause and 
associated vaginal atrophy. These conditions are associated with increases in proinflammatory 
molecules and disruption of epithelial integrity12,13. A study comparing the vaginal microbiome of 
HIV- pre- and postmenopausal women showed that premenopausal women were more often in 
community state type (CST)-I (predominance of L. crispatus), whereas postmenopausal women 
were most often in CST-IV (dominated by diverse anaerobes). Limited data suggest that 
symptoms of vaginal atrophy may be at least partly mediated by vaginal dysbiosis. 
Postmenopausal participants with symptoms of vaginal atrophy had 25X greater odds of having 
CST-IV vs. CST-I13. Moreover, postmenopausal women reporting moderate to severe dryness 
had more Prevotella and other anaerobes, whereas women with little or no dryness had a 
predominance of lactobacilli12. Further, women with atrophy and dryness had increased 
expression of proinflammatory genes and decreased expression of genes associated with 
epithelial integrity. The findings of dysbiosis and inflammation may be linked mechanistically as 
studies have shown that bacteria commonly found in CST-IV (e.g. Prevotella, Mobiluncus and 
Sneathia) induce higher levels of proinflammatory cytokines including interleukin (IL)-1, IL-1 
and IL-8 compared to L. crispatus (CST-I)14,15. Similar shifts in the vaginal microbiome and 
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concomitant inflammation are associated with increased risk of HIV shedding and transmission16-
20. However, there are no studies that specifically address changes in the FGT in postmenopausal 
HIV+ women. I propose to address this knowledge gap and to study whether HIV+ menopausal 
women develop an earlier and greater degree of dysbiosis and mucosal inflammation compared 
to HIV- menopausal women and to evaluate the impact of vaginal estradiol treatment in HIV+ 
women with vaginal atrophy.
Vaginal atrophy is common but undertreated especially in women living with HIV (WLWH). 
Vaginal atrophy affects up to 45% of menopausal women21 and presents with symptoms of vaginal 
dryness and  dyspareunia, as well as urinary symptoms. Although the systemic vasomotor 
symptoms of menopause (e.g. hot flashes) often improve with time, atrophy symptoms persist. 
Intravaginal estrogen is effective for the treatment of vaginal atrophy with a favorable safety 
profile22-25,26-29 compared to systemic preparations. However, it is estimated that only 25% of 
symptomatic women seek medical attention21 and even in these women it is undertreated. With 
the increased availability of antiretroviral therapy (ART) and associated aging of the HIV 
population30,31, large numbers of WLWH will enter menopause, placing them at risk for vaginal 
atrophy. Topical estrogen therapy has not been studied in WLWH, despite the findings that they 
experience and report menopausal symptoms at an earlier age than HIV- women32-35. Moreover, 
severe menopausal symptoms have been associated with reduced adherence to ART placing 
menopausal WLWH at risk for possible drug resistance and adverse HIV related health 
outcomes36. Low dose intravaginal estrogen (Vagifem 10 g) is safe, effective and FDA approved 
for the treatment of symptomatic vaginal atrophy. Because of low systemic absorption (3-11 
pg/ml)37,38, there is little risk of complications nor need for progesterone supplementation22,23,39. 
The boxed warning for risk for endometrial cancer and cardiovascular disease (CVD) is based on 
extrapolations of data from clinical trials of systemic hormonal therapy, with substantially higher 
levels of exposure. There is no randomized trial or consistent observational evidence linking low-
dose vaginal estrogen to cancer, CVD, dementia, or thromboembolism. A Working Group on 
Women’s Health and Well-Being in Menopause has proposed to the FDA a labeling change40. 
2. Innovation
This is the first study specifically designed to test an intervention to restore local 
estrogen in HIV+ menopausal women with the goal of improving symptoms of atrophy, 
promoting an optimal vaginal microbiome and reducing GT inflammation. Previous studies 
have demonstrated a reduction in symptoms of vaginal atrophy and increased lactobacilli after 
oral estrogen replacement in HIV- menopausal women41. However, the effect of topical estradiol 
on the vaginal microbiome has not been studied nor has local estradiol treatment been 
systematically assessed in HIV+ women with vaginal atrophy. We will fill this research gap in this 
pilot randomized clinical trial. In addition to assessing improvement in clinical symptoms, we will 
explore the effects of topical estradiol on the vaginal microbiome, markers of mucosal 
inflammation, and HIV shedding.
Despite numerous studies documenting the composition of the vaginal microbiome in 
various disease states, our understanding of the functional relationship between the vaginal 
microbiome and mucosal health is limited. In order to fill this knowledge gap, we will evaluate the 
vaginal microbiome with Illumina MiSEq and quantitative PCR for select bacteria, and also 
propose to apply a more novel technique of Ig-SEQ, which combines flow cytometry-based 
bacterial cell sorting and 16S sequencing to identify subpopulations of IgA and/or IgG 
coated bacteria, with the goal of understanding the link between bacterial species, 
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mucosal inflammation and genital tract aging. We hypothesize that functional consequences 
of differences in the microbiome may link to immunoglobulin (Ig) coating.
3. Approach
We propose to test the hypothesis that menopausal women living with HIV (WLWH) develop 
genital tract aging earlier than HIV- menopausal women and that the magnitude of changes in 
microbiome and mucosal inflammation will be greater in HIV+ versus HIV- women. We will also 
test whether vaginal estradiol treatment in menopausal WLWH with vaginal atrophy will result in 
improvement of symptoms and an increase in Ig-coated, lactobacillus-dominant vaginal 
microbiota and reduction in mucosal inflammation. If the hypothesis is supported by this pilot 
interventional study, results would provide the foundation for a future study to evaluate the efficacy 
of earlier use of topical estradiol and generate new testable hypotheses to link aging, the vaginal 
microbiome and host mucosal immunity to HIV care. 
4. Objectives and Study Design
A. To determine if HIV is associated with earlier and more significant age-associated 
changes in FGT by comparing the vaginal microbiome and mucosal inflammation in 
menopausal WLWH and HIV- menopausal women.
B. To conduct a pilot randomized clinical trial in menopausal WLWH with symptomatic 
vaginal atrophy to evaluate the impact of vaginal estradiol treatment on symptoms and 
biomarkers of FGT aging.
We propose a study nested in the Bronx Women’s Interagency HIV Study (WIHS) to compare a 
phenotype of FGT aging between menopausal WLWH and HIV- women. We will use the following 
biomarkers of aging: lower levels of lactobacilli (primary outcome), increased dysbiosis, less Ig 
bacterial coating, and higher levels of mucosal inflammatory mediators. We will also assess 
bacterial and host cell gene expression using metatranscriptomics (vaginal swabs) and RNAseq 
(vaginal biopsies). These exploratory “omic” studies may provide insights into the functional 
significance of observed differences in the composition and Ig coating of vaginal microbiota and 
their link to vaginal health.
In the first part of the study (Aim 1), 50 HIV+ and 50 HIV- participants aged 45-70 will have 2 
study visits one month apart to assess reproducibility of findings. Participants will be frequency 
matched by age, race and ethnicity into 4 groups: (i) HIV+ aged 45-55; (ii) HIV+ aged 56-70; (iii) 
HIV- aged 45-55; and (iv) HIV- aged 56-70 years. We have chosen to dichotomize into these age 
groups based on differences in the taxonomic composition of the microbiome in a recently 
published study42 and potential eligible participants in WIHS. Figure 1 illustrates the overall study 
design. Sampling at both study visits will include vaginal swabs for pH, microbiome assessment 
and evaluation for vaginal infections (candida, bacterial vaginosis [BV], trichomonas), 
cervicovaginal lavage (CVL) for soluble immune mediators, glycogen, and HIV CVL RNA 
(shedding), blood for HIV RNA (plasma viral load), CD4 count, estradiol and follicular stimulating 
hormone (FSH), and vaginal biopsies for exploratory RNAseq (Visit 2 only).
At Visit 2, 50 HIV+ participants with vaginal atrophy will be offered immediate enrollment into a 
1:1 randomized trial of vaginal estradiol (n=25) versus no treatment (n=25) to assess whether 
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estradiol will improve vaginal symptoms and modify the genital tract aging phenotype. HIV+ 
women who agree to participate in the trial will have 3 additional study visits: randomization (Visit 
3), 6 weeks after randomization (Visit 4) and 12 weeks after randomization (Visit 5). HIV- women 
can only participate in Aim 1 and will have 2 study visits. HIV+ women can elect to participate in 
Aim 1 and/or Aim 2 (2 study visits if only Aim 1 is completed; 4 study visits if only Aim 2 is 
completed; 5 visits if both Aims 1 and 2 are completed).     
Inclusion criteria for Aim 1 (first 2 study visits):
-
HIV infection or HIV negative
-
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
In the second part of the study (Aim 2), we propose a pilot randomized clinical trial nested in the 
Bronx WIHS in 50 menopausal WLWH with symptomatic vaginal atrophy to assess the impact of 
12 weeks of a topical low-dose estradiol vaginal tablet (Vagifem® 10 μg) on symptoms of atrophy 
and measures of the vaginal microbiome. Participants will be randomized 1:1 to estradiol (n=25) 
or no therapy (n=25) and will be followed for 12 weeks. The dosing of Vagifem® will be 1 tablet 
inserted using a plastic applicator (similar to a tampon) in the vagina daily for 2 weeks followed 
by 1 tablet inserted twice weekly (i.e., Tuesday and Friday). If we find benefit among women 
assigned to the estradiol arm, participants randomized to the no therapy arm will be offered 
vaginal estradiol treatment at the end of the study by their primary care doctor. If participants 
assigned to Vagifem are symptomatic beyond the 12-week study period and wish to continue 
Vagifem®, it can be prescribed by their primary care physician. Women will have 3 visits before 
(Visits 1, 2 and 3) and 2 visits following Vagifem® treatment (Visits 4 and 5). Adherence to 
Vagifem will be assessed with the use of participant diaries of Vagifem use and counting of used 
Vagifem applicators. 
Inclusion criteria for Aim 2 (randomized clinical trial for HIV+ participants only):
-
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 Vagifem during the clinical trial
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Exclusion criteria for Aims 1 & 2:
-
Current unexplained or unevaluated abnormal genital bleeding
-
Current or suspected pregnancy
-
If < age 55, hysterectomy and has at least one ovary
-
Pelvic or vaginal surgery in the 60 days prior to enrollment
-
Use of systemic reproductive hormones in the 2 months prior to study enrollment
-
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 acute vaginal infection (diagnosed by wet mount at Visit 1 or 2)
-
Any serious disease or chronic condition that might interfere with study compliance
-
Participants who are unwilling to agree to the provisions of the protocol
Additional Exclusion Criteria for Aim 2 only:
-
Current or previous history of breast cancer or estrogen dependent neoplasia
-
Known current or past thromboembolic disease (deep vein thrombosis or pulmonary 
embolism, not including thrombophlebitis), 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
5. Recruitment
The study is nested in Bronx WIHS, which is an NIH-funded prospective observational cohort 
study of HIV+ and at-risk HIV- women. We have identified 90 HIV- and 248 HIV+ Bronx and 
Brooklyn WIHS participants who are potentially eligible for this study. Potential participants will be 
invited to discuss this study at semiannual Core WIHS visits. We will recruit participants from the 
Bronx and Brooklyn WIHS for this study. Bronx WIHS staff will call potentially eligible participants 
and schedule them to come in to the Clinical Research Center at the Albert Einstein College of 
Medicine or the  Bronx WIHS site for a screening visit. As we have done for prior studies, Brooklyn 
WIHS participants who are interested in participating in the study, will be contacted by the Bronx 
WIHS staff and seen at the Bronx WIHS site for all visits. Additional participants may be recruited 
HIV+ Vaginal Atrophy 
Randomization (n=50)
Estradiol
(n=25)
6 
weeks
12 
weeks
No Treatment
(n=25)
6 
weeks
12 weeks
• Aged 45-55 (n=25)
• Aged 56-70 (n=25)
HIV+
(n=50)
• Aged 45-55 (n=25)
• Aged 56-70 (n=25)
HIV-
(n=50)
Groups will be frequency 
matched by age, race, ethnicity
Groups will be frequency 
matched by age, race, ethnicity
Visit 1
Visit 2
Visit 3
Visit 4
Visit 5
                       Aim 2  
           Aim 1
Figure 1. Study Design
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from Montefiore Medical center, and may be identified using the Center for AIDS Research 
Clinical Database.
6. Study procedures
Study visits will occur at the Einstein Clinical Research Center or the Bronx WIHS clinical study 
site. The study clinicians or study coordinator will screen participants for eligibility, discuss the 
study, answer any questions, and obtain written informed consent. At each scheduled research 
visit, a pelvic examination will be performed for the collection of the following specimens: vaginal 
swabs for pH, and microbiome studies; CVL; vaginal swabs to assess for infection (Visits 1 and 
2 only) and vaginal biopsies and a vaginal scraping (VMI) to assess for vaginal aging at (Visits 2 
and 5 only) (Table 1). If candida, BV, or trichomonas is diagnosed, participants will be notified 
and referred to their primary doctor for treatment prior to enrollment in the study. After 
treatment, participants may return for repeat testing and if the infection has resolved, they may 
be enrolled in the study.  
At Visit 2 blood will be collected for estradiol and follicular stimulating hormone (FSH) levels, 
aging biomarkers and future studies and for HIV positive participants, CD4 and HIV-1 RNA. At 
Visit 5, blood will be collected for aging biomarkers and future studies. Participants will be asked 
at Visits 2-5 to complete a questionnaire about the presence and severity of the most 
bothersome symptom of atrophy, defined as vulvovaginal itching, pain, dryness, irritation or pain 
with penetration (dyspareunia)43. 
Participants will rate the severity of symptoms based on a four-point scale (0=none, 1=mild, 
2=moderate, 3=severe). Presence or absence of atrophy will also be assessed via clinical exam 
at Visits 2-5 and at Visits 2 and 5 with the Vaginal Maturation Index (VMI) which is done by 
lightly scraping the upper 1/3rd of the vaginal wall with a saline dipped vaginal spatula to 
examine cells under the microscope to assess for vaginal aging43. Following placement of a 
speculum into the vaginal vault, swabs will be collected from the lateral vaginal walls. CVL is 
collected using a small syringe to place 10 cc of normal saline in the vaginal area. The fluid is 
immediately removed and sent to the Herold lab for storage and analysis. Vaginal biopsies will 
be collected at Visits 2 and 5 only. Women will be counseled to abstain from vaginal product use 
and sexual intercourse for one week after biopsy collection to allow adequate time for healing. In 
our experience, re-epithelialization occurs within one to two days, and the biopsy sites are 
completely healed within seven days. Adult women who decline or state that they are unlikely to 
abstain from sexual activity for one week after biopsy visits will not undergo biopsy collection. 
Tissue samples are typically ~3 x 5 mm. Biopsies are obtained with a Tischler or other biopsy 
forceps. All participants will receive a follow-up phone call the day after the vaginal biopsies 
from the study clinician to ensure they are feeling well. The specimens will be obtained strictly 
for research purposes and used only for the specific objectives outlined in the study. At all 
scheduled return visits or at any visit initiated by the participant due to genitourinary symptoms, 
an appropriate examination for the evaluation of specific symptoms and adverse events will be 
performed (for example, performance of a pelvic examination in women with complaints of 
abnormal vaginal discharge or bleeding). If any examination findings warrant further diagnostic 
evaluation for clinical management, participants will be referred to their medical provider for 
appropriate diagnostic studies and treatment.
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7. Potential Risks:
There is a small risk of bruising, blood clots or infection from blood draws. Sometimes the area 
of needle insertion becomes sore or red. A woman may experience mild discomfort at the time 
of speculum placement and sample collection. There is a very small risk of injury to the lining of 
the vagina from the speculum or from the vaginal scraping. There is no discomfort or risk to 
placement or removal of sterile saline into the vaginal area. There is no risk to CVL or vaginal 
swab collection. Women may experience a sharp pinch or have pain when vaginal biopsies are 
performed. In order to minimize the pain and discomfort of the biopsy, we will apply a topical 
numbing medication (benzocaine gel) to the tissue. There may be stinging, burning, redness, or 
itching associated with local anesthesia (topical benzocaine gel) which is rare. Biopsies may 
cause light bleeding, Rarely, a biopsy can cause infection and/or prolonged bleeding. 
Sometimes a medication is needed to stop the bleeding, which would be applied directly to the 
Aim 1
Study of Menopausal HIV- and 
WLWH
Aim 2
Pilot Randomized Clinical Trial of 
Topical Estradiol in Menopausal WLWH
Visit 1
Screening
Visit 2
2nd visit and/or 
Screening for Trial
Visit 3
Randomized
Estradiol vs. 
No therapy
Visit 4
6 weeks 
Estradiol vs. 
No therapy
Visit 5 
12 weeks 
Estradiol vs. No 
therapy
Safety Call
2, 8, 13 weeks
Eligibility/Informed consent
X
X
X
Randomization to Estradiol vs. No 
treatment
X
WIHS database extraction
Demographics, CD4 count, plasma HIV-
1 RNA, ART regimen and reported 
adherence, etc.
X
X
Vaginal atrophy symptom 
questionnaire
X
X
X
X
X
Adverse event assessment
X
X
X
X
X
X
Vaginal swabs (n=4-5 per visit)
pH, microbiome studies
X
X
X
X
X
Cervicovaginal lavage (CVL) 
supernatant
Immune mediators, HIV-1 RNA, RSID, 
saline/KOH, glycogen
X
X
X
X
X
CVL cell pellet
Nugent score, additional microbiome 
di
X
X
X
X
X
Wet mount (candida, trichomonas, 
bacterial vaginosis)
X
X
Vaginal biopsies (2)
RNA seq, future immunohistochemistry 
studies
X
X
Blood collection
Estradiol/FSH levels, HIV-1 RNA, CD4,  
plasma for future aging biomarkers
X
X
Clinical Exam to assess for Vaginal 
Atrophy (VMI)
X
X
Table 1. Timeline of Study Visits, Procedures, & Sample Collection
ART=antiretroviral therapy; RSID=rapid semen identification; FSH=follicle stimulating hormone; VMI=vaginal maturation index
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site. This medication can cause a temporary dark-colored discharge from the vagina. In rare 
cases a stitch might be needed or a machine (cautery) may be used to stop the bleeding. 
Potential risks of vaginal estrogen tablets (Vagifem® 10 μg) include back pain, diarrhea, 
vulvovaginal mycotic infection, and vulvovaginal pruritus (treatment emergent adverse reactions 
reported at a frequency of ≥5 percent in a 12-month randomized, double-blind, placebo-
controlled study in which 309 postmenopausal women received either placebo or Vagifem® 10 
μg). Vagifem applicator may cause vaginal abrasion. The Division of AIDS (DAIDS) Female 
Genital Grading Table for Use in Microbicide Studies will be the primary tool for grading adverse 
events available at https://rsc.niaid.nih.gov/sites/default/files/addendum-1-female-genital-
grading-table-v1-nov-2007.pdf. AEs will be reported to the IRB. 
Women who use systemic forms of unopposed estradiol who have an intact uterus may have an 
increased risk of endometrial hyperplasia, which in some women may be a precursor to 
endometrial cancer after prolonged use. Women in this study will be using a low-dose topical 
estradiol vaginal tablet, which does not increase serum levels of estradiol beyond the baseline 
menopausal levels and has been proven to be safe for the treatment of vaginal atrophy without 
adverse effects on the endometrium, including endometrial hyperplasia. Further, low-dose vaginal 
estrogen has not been shown to increase risk for coronary heart disease, stroke, venous 
thromboembolism or dementia. The proposed study will test the effect of 6 and 12 weeks of 
vaginal estrogen on clinical symptoms, the vaginal microbiome, and soluble markers of 
inflammation. Participants will be followed closely by the study team and will be instructed to 
report immediately any vaginal bleeding or spotting while using Vagifem®. Women may remain 
symptomatic beyond the 3-month study period and may elect to continue Vagifem® with close 
medical follow-up by their primary clinician. If benefit is determined in the estradiol arm of the 
study, participants randomized to the no treatment group, will be offered Vagifem® by their 
primary care physicians. The study team will contact participants’ medical provider if the decision 
is made to continue treatment or initiate Vagifem®.
8. Adequacy of Protection Against Risks:
The consent will contain the following: investigators’ statement identifying the study; purpose 
and benefits; procedures; risk, benefits, stress, and discomfort associated with the study; 
request for permission for future use of samples (as a separate checkbox, so that participants 
may be in the study and not agree to storage of samples for future use) and other information 
deemed necessary. The consent will also identify the investigators and provide contact 
information. The participant must verbally assent that they understand the nature of the study, 
its inherent risks and benefits, other treatment alternatives, their right to terminate participation 
in the study without affecting their health care or involvement in the core WIHS cohort study, 
and that they have freely given informed consent to participate in the study. A signed copy of 
the informed consent form will be given to the participant. The participants are informed that all 
medical records are kept confidential. Participants will be compensated for time and travel. 
Participants will receive a total of $125 ($50 for Visit 1 and $75 for Visit 2) if they complete only 
the first part of the study (Aim 1, 2 visits). Participants with HIV who complete both parts of the 
study (Aims 1 and 2, 5 visits), will receive a total of $300 ($50 at Visits 1, 3 and 4 and $75 at 
Visits 2 and 5). HIV+ participants who enroll only in the second part of the study (Aim 2, 
randomized trial) will receive a total of $250 ($50 at Visits 3 and 4 and $75 at Visits 2 and 5).
All specimens and study forms are labeled with a unique study identifier that has no relationship 
to participant’s identifying information (such as name, initials, or date of birth). All records and 
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data are kept in locked offices and a secure computer database. The Bronx site of the WIHS has 
a long history of participation in many sub-studies and the staff is very familiar with the need to 
maintain participant confidentiality and security of study data. Samples will be stored in Dr. Betsy 
Herold’s lab and will not be destroyed at the end of the study, unless participants do not agree to 
use of remaining samples for related studies. A secure, web-based application, REDCap 
(Research Electronic Data Capture), will be used to collect and store data from questionnaires 
obtained in this study. REDCap is designed exclusively to support data capture for research 
studies. REDCap servers are housed in a data center at Einstein and all web-based information 
transmission is encrypted. REDCap was developed specifically around HIPAA-security guidelines 
and it includes full audit trail.
Participants will receive telephone calls at 2 and 8 weeks after initiation of estradiol and 1 week 
after completion of therapy to assess for safety. Participants will also receive telephone calls a 
day after vaginal biopsies are performed. If symptoms are reported, participants will be 
instructed to return to the study site for evaluation. Participants will receive local anesthesia with 
topical benzocaine gel prior to each biopsy procedure and will be advised that they may take a 
mild pain reliever (Tylenol) before and after each biopsy procedure. Women who have any 
history of estrogen responsive cancer including breast cancer, endometrial cancer or vaginal 
bleeding will be excluded from this study to minimize risk for adverse events. In the event of an 
injury resulting from participation in this study, participants will be instructed to seek immediate 
appropriate medical care and inform the study doctor. In the event of an emergency they will be 
instructed to go to the emergency room. Participants will be provided with a 24-hour telephone 
number to call to contact a study clinician at any time. Appropriate blood and secretion 
precautions will be employed by all personnel in the drawing of blood and handling of all 
specimens, as currently recommended by the US Centers for Disease Control and Prevention 
(CDC). Universal precautions will be observed at all times.
9. Potential Benefits:
Women with HIV infection experience menopausal symptoms at an earlier age and are more 
likely to report symptoms compared to women who do not have HIV. Participants may benefit 
from study participation because the use of low dose topical estradiol, which has been FDA 
approved since 2009 for the treatment of vaginal atrophy in menopausal women, may relieve 
symptoms of vaginal dryness, itching, soreness, pain and urinary symptoms in women with HIV. 
Participants and others may benefit in the future from information learned from this study. 
Specifically, if we find that HIV accelerates genital tract aging, this may prompt 
recommendations for earlier treatment of vaginal atrophy in menopausal women with HIV.
10. Data analysis and sample size:
Aim 1: The primary exposure variables are HIV infection and age. The primary outcome is the 
vaginal microbiome, specifically the relative abundance and quantities of lactobacillus species as 
measured by llumina MiSeq and qPCR respectively. Secondary outcomes are relative abundance 
and quantities of specific BV associated bacteria and quantities of CVL cytokine/chemokines. 
Exploratory outcomes are quantities and composition of Ig coated bacteria and levels of HIV-1 in 
the genital tract. Multivariate linear regression will be applied for our analysis. General form of the 
linear regression model will be: yi = μ+ βagei + HIVi + agei × HIVi + 1Covariatesi+…+ ej, in which 
yi is the outcome variables subject to necessary transformation as necessary. Age will be 
analyzed as a continuous variable to examine the slope or rate of change in lactobacillus and as 
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a dichotomous variable (e.g. age 45-55 vs. 56-70) to examine the magnitude of difference 
between younger and older HIV+ and HIV- menopausal participants. We have chosen the age 
cut offs above given the significant differences observed in the taxonomic composition of the 
microbiome in pilot studies when comparing HIV+ menopausal participants in these age ranges 
and the distribution of eligible participants in WIHS. We will adjust the regression analysis for 
important covariates including years since menopause, time since HIV diagnosis, HIV plasma 
viral load, CD4 count, ART use, and HSV-2 serostatus. Both raw p values and the false discovery 
rate (FDR) according to Benjamini and Hochberg will be examined. To limit the false positive rate 
in our analysis of secondary outcomes, an arbitrary cutoff of 0.05 for FDR will used.  
Power Considerations: We estimated the power of the proposed study using software PASS 
(Power and Sample Size Analysis, version 11). Given the sample size of 50 HIV- and 50 HIV+ 
menopausal participants, we will have >80% power for the minimal detectable difference of 0.6SD 
and 0.9SD between HIV (or age) group with the significance level of 0.05 and 0.0005 (a 
conservative Bonferroni correction for 100 independent tests). Data from preliminary studies in 
our lab investigating the impact of menopause and HIV status on the vaginal microbiome indicated 
51 HIV+ menopausal participants had a significantly lower relative abundance of lactobacillus 
species of 7.3% compared to 23% for 19 HIV- menopausal participants, equivalent to about 0.8SD 
change. Further when comparing upper and lower age ranges of HIV+ menopausal participants, 
HIV+ participants age 56-70 (n=28) had significantly lower relative proportions of L. iners 7.4% 
compared to 44.7% in HIV+ menopausal participants aged 47-55.9 (n=23), equivalent to about 
1.2SD change. Based on the preliminary data, we are confident that this study will have excellent 
power to detect effects of age and HIV.
Aim 2: The primary outcomes are clinical symptoms measured by most bothersome symptom of 
vaginal atrophy and changes in the vaginal microbiome, specifically the relative abundance of 
protective lactobacillus species L. crispatus as measured by llumina MiSeq and quantities of 
protective lactobacilli species (L. crispatus, L. jensenii and L. gasseri) as measured by qPCR 
between baseline and 6 and 12 weeks within individual participants and between participants 
randomized to estradiol vs. no drug at baseline, 6 and 12 weeks. The 12-week time frame was 
chosen as this was the endpoint utilized in several clinical trials demonstrating Vagifem efficacy 
and is recommended in FDA guidelines22,43. The secondary outcomes are changes relative 
abundance and quantities of specific BV associated bacteria and levels CVL cytokine/chemokines 
between baseline, 6 and 12 weeks. Exploratory outcomes are the quantities and composition of 
Ig coated bacteria and levels of HIV-1 in the genital tract. Spearman’s correlation coefficients 
(SCC) will be calculated to evaluate associations between pairs of quantitative outcome variables 
and covariates, such as levels of protective lactobacilli species and MBS of atrophy, quantity of 
Ig coated bacteria, inflammatory mediators, CVL HIV-1 RNA, levels of estradiol in the blood. 
Linear mixed effects models or generalized linear mixed models will be used to examine effects 
of time and estradiol use on outcomes (bacterial communities, vaginal bacterial quantities, 
symptoms) after adjustment for factors such as ART, duration of HIV, plasma viral load, and CD4+ 
T cell count. We will also address the variability of the microbiome and inflammatory mediators 
over time in the absence of an intervention by comparing these measures at the screening (Visit 
2) and enrollment visits (Visit 3).
Power Considerations: We have increased our sample size and added randomization for this 
clinical trial based on feedback from the NIH reviewers. If we assume an attrition rate of 15%, a 
sample of 50 HIV+ women randomized to estradiol (Vagifem) vs. no treatment will have >80% 
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power for the minimal detectable difference in lactobacilli of 0.85 SD and 1.4 SD with the 
significance level of 0.05 and 0.0005 (a conservative Bonferroni correction for 100 independent 
tests), respectively, at 12 weeks post treatment. Although data is lacking in HIV+ women treated 
with Vagifem, a previous study with a smaller sample size (30 HIV-) investigating the use of low 
dose (0.3mg) oral conjugated estrogens for treatment of vaginal atrophy in demonstrated a 
significant increase in the relative abundance of Lactobacillus from 11.2% to 71% (p<0.0001) 
comparing baseline to 4 weeks estrogen treatment. Further the vaginal symptom score decreased 
from 3.93 vs. 1.00 (p<0.0001) at the same time points41, suggesting this proposed study may 
have adequate power for detecting a realistic difference of candidate Lactobacillus and symptom 
score. It should be noted that this is a pilot study and as such we acknowledge that it may be 
underpowered for testing interaction effects of time and estradiol use. However, the goal of the 
study is to determine an effect size of topical estradiol in planning for a future large-scale 
randomized controlled trial.
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Wing EJ. HIV and aging. International journal of infectious diseases : IJID : official publication of 
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Martin HL, Richardson BA, Nyange PM, et al. Vaginal lactobacilli, microbial flora, and risk of 
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Hummelen R, Macklaim JM, Bisanz JE, et al. Vaginal microbiome and epithelial gene array in 
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Brotman RM, Shardell MD, Gajer P, et al. Association between the vaginal microbiota, 
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Anahtar MN, Byrne EH, Doherty KE, et al. Cervicovaginal bacteria are a major modulator of host 
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15.
Masson L, Mlisana K, Little F, et al. Defining genital tract cytokine signatures of sexually 
transmitted infections and bacterial vaginosis in women at high risk of HIV infection: a cross-
sectional study. Sexually transmitted infections. 2014;90(8):580-587.
16.
Mauck C, Chen PL, Morrison CS, et al. Biomarkers of Cervical Inflammation and Immunity 
Associated with Cervical Shedding of HIV-1. AIDS research and human retroviruses. 
2016;32(5):443-451.
17.
Sha BE, Zariffard MR, Wang QJ, et al. Female genital-tract HIV load correlates inversely with 
Lactobacillus species but positively with bacterial vaginosis and Mycoplasma hominis. The 
Journal of infectious diseases. 2005;191(1):25-32.
18.
Mitchell C, Balkus JE, Fredricks D, et al. Interaction between lactobacilli, bacterial vaginosis-
associated bacteria, and HIV Type 1 RNA and DNA Genital shedding in U.S. and Kenyan women. 
AIDS research and human retroviruses. 2013;29(1):13-19.
19.
Mitchell C, Hitti J, Paul K, et al. Cervicovaginal shedding of HIV type 1 is related to genital tract 
inflammation independent of changes in vaginal microbiota. AIDS research and human 
retroviruses. 2011;27(1):35-39.
20.
Baeten JM, Kahle E, Lingappa JR, et al. Genital HIV-1 RNA predicts risk of heterosexual HIV-1 
transmission. Science translational medicine. 2011;3(77):77ra29.
21.
Lindahl SH. Reviewing the options for local estrogen treatment of vaginal atrophy. International 
journal of women's health. 2014;6:307-312.
22.
Simon J, Nachtigall L, Gut R, Lang E, Archer DF, Utian W. Effective treatment of vaginal atrophy 
with an ultra-low-dose estradiol vaginal tablet. Obstetrics and gynecology. 2008;112(5):1053-
1060.
23.
Ulrich LS, Naessen T, Elia D, Goldstein JA, Eugster-Hausmann M. Endometrial safety of ultra-low-
dose Vagifem 10 microg in postmenopausal women with vaginal atrophy. Climacteric : the 
journal of the International Menopause Society. 2010;13(3):228-237.
24.
Rahn DD, Carberry C, Sanses TV, et al. Vaginal estrogen for genitourinary syndrome of 
menopause: a systematic review. Obstetrics and gynecology. 2014;124(6):1147-1156.
25.
Santoro N, Fan M, Maslow B, Schoenbaum E. Women and HIV infection: the makings of a midlife 
crisis. Maturitas. 2009;64(3):160-164.
26.
Bachmann G, Lobo RA, Gut R, Nachtigall L, Notelovitz M. Efficacy of low-dose estradiol vaginal 
tablets in the treatment of atrophic vaginitis: a randomized controlled trial. Obstetrics and 
gynecology. 2008;111(1):67-76.
27.
Eriksen PS, Rasmussen H. Low-dose 17 beta-estradiol vaginal tablets in the treatment of 
atrophic vaginitis: a double-blind placebo controlled study. European journal of obstetrics, 
gynecology, and reproductive biology. 1992;44(2):137-144.
28.
Simunic V, Banovic I, Ciglar S, Jeren L, Pavicic Baldani D, Sprem M. Local estrogen treatment in 
patients with urogenital symptoms. International journal of gynaecology and obstetrics: the 
official organ of the International Federation of Gynaecology and Obstetrics. 2003;82(2):187-
197.
29.
Lethaby A, Ayeleke RO, Roberts H. Local oestrogen for vaginal atrophy in postmenopausal 
women. The Cochrane database of systematic reviews. 2016(8):Cd001500.
30.
Nakagawa F, Lodwick RK, Smith CJ, et al. Projected life expectancy of people with HIV according 
to timing of diagnosis. AIDS (London, England). 2012;26(3):335-343.
31.
Nakagawa F, May M, Phillips A. Life expectancy living with HIV: recent estimates and future 
implications. Current opinion in infectious diseases. 2013;26(1):17-25.
32.
Miller SA, Santoro N, Lo Y, et al. Menopause symptoms in HIV-infected and drug-using women. 
Menopause (New York, NY). 2005;12(3):348-356.
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33.
Schoenbaum EE, Hartel D, Lo Y, et al. HIV infection, drug use, and onset of natural menopause. 
Clinical infectious diseases : an official publication of the Infectious Diseases Society of America. 
2005;41(10):1517-1524.
34.
Ferreira CE, Pinto-Neto AM, Conde DM, Costa-Paiva L, Morais SS, Magalhaes J. Menopause 
symptoms in women infected with HIV: prevalence and associated factors. Gynecological 
endocrinology : the official journal of the International Society of Gynecological Endocrinology. 
2007;23(4):198-205.
35.
Clark RA, Cohn SE, Jarek C, et al. Perimenopausal symptomatology among HIV-infected women 
at least 40 years of age. Journal of acquired immune deficiency syndromes (1999). 
2000;23(1):99-100.
36.
Duff PK, Money DM, Ogilvie GS, et al. Severe menopausal symptoms associated with reduced 
adherence to antiretroviral therapy among perimenopausal and menopausal women living with 
HIV in Metro Vancouver. Menopause (New York, NY). 2017.
37.
Santen RJ, Pinkerton JV, Conaway M, et al. Treatment of urogenital atrophy with low-dose 
estradiol: preliminary results. Menopause (New York, NY). 2002;9(3):179-187.
38.
Eugster-Hausmann M, Waitzinger J, Lehnick D. Minimized estradiol absorption with ultra-low-
dose 10 microg 17beta-estradiol vaginal tablets. Climacteric : the journal of the International 
Menopause Society. 2010;13(3):219-227.
39.
Weisberg E, Ayton R, Darling G, et al. Endometrial and vaginal effects of low-dose estradiol 
delivered by vaginal ring or vaginal tablet. Climacteric : the journal of the International 
Menopause Society. 2005;8(1):83-92.
40.
Manson JE, Goldstein SR, Kagan R, et al. Why the product labeling for low-dose vaginal estrogen 
should be changed. Menopause (New York, NY). 2014;21(9):911-916.
41.
Shen J, Song N, Williams CJ, et al. Effects of low dose estrogen therapy on the vaginal 
microbiomes of women with atrophic vaginitis. Scientific reports. 2016;6:24380.
42.
Murphy K, Keller MJ, Anastos K, et al. 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;14(4):e0216049.
43.
US Food and Drug Administration. Guidance for industry: estrogen and estrogen/progestin drug 
products to treat vasomotor symptoms and vulvar and vaginal atrophy symptoms—
recommendationsfor clinical evaluation. Rockville, MD: US Food and Drug Administration; 2003.
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ICF_001.pdf: 
The study has two parts. Part 1 is for menopausal women with and without HIV. It consists of 2 visits over 4 weeks (Table 1 Option 1). At the first 
visit, a clinician will perform a pelvic exam to examine the vagina and collect swabs and fluid. At the second visit, a questionnaire will be used to 
assess symptoms of vaginal aging, blood will be drawn to measure hormone levels that indicate menopause and CD4 count and HIV viral load for 
women with HIV and a pelvic exam will be done, including 2 vaginal biopsies. We will apply numbing medication (a gel) before a small piece of 
skin from inside the vagina is removed. Typically, there is a little bleeding and it may feel like a pinch. Part 2 of the study is only for menopausal 
women with HIV. If you participate in Part 1 of the study (2 visits), you will have 3 additional visits for a total of 5 study visits (Table 1, Option 2). If 
you do not participate in Part 1 of the study, you will have a total of 4 study visits (Table 1 Option 3). Each participant will be randomly assigned 
(like flipping a coin) to the treatment group (estradiol vaginal tablet) or the non-treatment group. The visits are the same for both groups. There will 
be pelvic exams and questionnaires at each visit as well as vaginal biopsies at the first visit (if you do not participate in Part 1 of the study) and the 
last visit. All participants will receive 3 phone calls during the study in addition to the study visits.
Table 1: Study Participation Options
WHAT ARE KEY REASONS YOU MIGHT CHOOSE TO VOLUNTEER FOR THIS STUDY?
Women with HIV who participate in the trial may have direct benefit of vaginal estradiol as symptoms of vaginal atrophy such as itching, burning, 
and dryness may resolve. Some participants appreciate knowing they have contributed to research that may benefit others in the future. For a 
complete description of benefits, refer to the Consent Document below.
WHAT ARE KEY REASONS YOU MIGHT CHOOSE NOT TO VOLUNTEER FOR THIS STUDY?
Some people feel that a women’s health study is too personal for them, due to the pelvic exam. We also ask detailed questions about your medical 
history and sexual practices. There may also be discomfort associated with blood draws, pelvic exams, and vaginal biopsies. You will not lose any 
services, benefits or rights or access to care you would normally have if you choose not to volunteer.
DO YOU HAVE TO TAKE PART IN THE STUDY?
You are not obligated to take part in the study.  If you decide to take part in the study, it should be because you really want to volunteer. 
WHAT IF YOU HAVE QUESTIONS, SUGGESTIONS OR CONCERNS?
The person in charge of the study is Kerry Murphy, MD. If you have questions, suggestions, or concerns regarding this study or want to withdraw 
from the study, you can reach Dr. Murphy at 718-839-7885. Her office address is 1225 Morris Park Ave., Van Etten Building, 6A-04C, Bronx, NY 
10461. If you have any questions, suggestions or concerns about your rights as a volunteer in this research, contact staff in the Einstein Institutional 
Review Board (IRB) between the business hours of 9am and 5pm EST, Monday-Friday at 718-430-2253 or irb@einstein.yu.edu. 
Part 1
Study of Menopausal HIV- 
and HIV+ women
Part 2
Pilot Randomized Clinical Trial of 
Topical Estradiol in Menopausal Women with HIV
Visit 1
Screening
Visit 2
(4 week 
follow up)
Visit 3
Randomized
Estradiol vs. No therapy
Visit 4
6 weeks Estradiol vs.
 No therapy
Visit 5 
12 weeks Estradiol vs.
 No therapy
HIV+ and HIV- Participants 
Option 1  2 visits
X
X
HIV+ Participants Option 2
5 visits
X
X
X
X
HIV+ Participants Option 3
4 visits
X
X
X
IRB NUMBER: 2019-10529
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IRB EXPIRATION DATE: 06/13/2024
KEY INFORMATION FOR ACCELERATED GENITAL TRACT AGING IN HIV: ESTRADIOL CLINICAL TRIAL 
We are asking you to choose whether or not to volunteer for a research study that aims to understand how aging of the female genital tract differs in 
menopausal women living with HIV compared to HIV- menopausal women. Women with and without HIV will participate in 2 study visits (Table 1, 
Option 1). If you have HIV and vaginal symptoms (dryness, irritation, itching, pain with sex), you will also be asked to participate in a clinical trial to 
examine the effect of vaginal estradiol on these symptoms. If you participate in Part 1 of the study (2 visits), you will have 3 additional visits for a 
total of 5 study visits (Table 1, Option 2). If you have HIV and vaginal symptoms and do not participate in Part 1, you will have a total of 4 visits 
(Table 1, Option 3). This page is designed to give you key information to help you decide whether to participate. We have included detailed 
information after this page. Ask the research team questions. If you have questions later, the contact information for the research investigator in 
charge of the study is below.  
WHAT IS THE STUDY ABOUT AND HOW LONG WILL IT LAST?
Estrogen is a hormone that has many effects on the body. It keeps the vagina healthy, moist, with good blood supply and helps to maintain healthy 
vaginal bacteria, which protect women from infection. During menopause, this hormone decreases, causing undesirable side effects, including aging 
of the vagina. This aging process can lead to changes in the types and amount of healthy bacteria in the vagina, inflammation and a breakdown of 
natural barriers that keep the vagina healthy. Some menopausal women develop a condition known as vaginal atrophy, which causes uncomfortable 
symptoms such as dryness, irrita
tion, pain with sex, and itching. We hope to determ
 
 
ine if vaginal aging occurs earlier in women with HIV compared
ithout HIV of the same age. We are also testing the effects of vaginal estradiol on this aging process in women with HIV. An estradiol 
tablet placed inside the vagina may prevent the aging process, 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 period of time. This is especially important for women with HIV as they are 
living longer, healthier, sexually active lives because the virus is controlled with medication. We will explain the study visits and possible risks and 
benefits to you.  After all of your questions have been answered, you can decide if you want to take part in the study. If you decide to take part, we 
will ask questions about your medical and sexual history. 


2
ALBERT EINSTEIN COLLEGE OF MEDICINE
MONTEFIORE MEDICAL CENTER
DOCUMENTATION OF INFORMED CONSENT AND HIPAA AUTHORIZATION
Introduction
You are being asked to participate in a research study called Accelerated Genital Tract Aging 
in HIV: Estradiol Clinical Trial. Your participation is voluntary -- it is up to you whether you 
would like to participate. It is fine to say “no” now or at any time after you have started the study. 
If you say “no,” your decision will not affect any of your rights or benefits or your access to care.
The researcher in charge of this project is called the 
“Principal Investigator.” Her name is Kerry Murphy, 
MD. You can reach Dr. Murphy at:
Office Address:
1225 Morris Park Ave.
Van Etten Building, 6A-04C
Bronx, NY 10461
Telephone #: (718) 839-7885
For questions about the research study, or if you 
believe you have an injury, contact the Principal 
Investigator or the IRB.
Support for this research study is provided by the 
National Institutes of Health and NovoNordisk
The Institutional Review Board (IRB) of the 
Albert Einstein College of Medicine and 
Montefiore Medical Center has approved this 
research study. The IRB # is in the stamp in 
the upper right-hand corner. If you have 
questions regarding your rights as a research 
subject you may contact the IRB office at 
718-430-2253, by e-mail at
irb@einstein.yu.edu, or by mail:
Einstein IRB 
Albert Einstein College of Medicine
1300 Morris Park Ave., Belfer Bldg #1002
Bronx, New York 10461
Why is this study being done?
Why am I being asked to participate? 
You are being asked to participate in this study because you are a woman 45-70 years of age 
and menopausal, defined as having no periods in the last 12 months. For Part 1 of the study 
you may or may not have HIV infection. For Part 2 of the study, you must have HIV infection 
and symptomatic vaginal atrophy. Symptomatic vaginal atrophy will be 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: vaginal dryness, itching, irritation, soreness/pain or pain associated with sexual 
activity at least once. Study visits will take place at the Clinic Research Center at the Albert 
Einstein College of Medicine or the Bronx Women’s Interagency HIV Study (WIHS) site at 
IRB NUMBER: 2019-10529
IRB APPROVAL DATE: 06/14/2023
IRB EXPIRATION DATE: 06/13/2024
The study has two major goals. The first goal is to compare changes that occur with aging in the 
vagina between menopausal women with and without HIV. This includes changes in the amount 
and types of bacteria and the amount of inflammation present in vagina. We want to determine if 
having HIV is associated with accelerated vaginal aging including earlier changes in the amount 
and types of vaginal bacteria and inflammation. Some menopausal women develop a condition 
known as vaginal atrophy, which causes uncomfortab
le symptoms such as irritation, pain with sex, 
dryness and itching. The second goal is to study in menopausal women with HIV if use of a 
vaginal estradiol tablet (Vagifem® 10 μg) for 12 weeks improves vaginal atrophy symptoms and 
aging associated changes in the vagina (bacteria, inflammation). Vagifem is safe, effective and 
FDA approved for the treatment of symptomatic vaginal atrophy. Little is known about the use of 
Vagifem in women with HIV.


3
Montefiore Medical Center, which is an ongoing study of HIV+ and HIV- women. If you are a 
WIHS participant, you may be invited to discuss this study at your semiannual Core WIHS visit. 
If you are not a WIHS participant, you may be invited to discuss the study through clinics at 
Montefiore Medical Center.
You do not qualify to take part in either part of the study if you have any of the following:

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

Used systemic reproductive hormones in the last 2 months

Used antibiotics in the last 30 days

Used immunosuppressive medications in the prior 60 days including biologics,
chemotherapeutics or post-transplant immunosuppressive medications.

Used any vaginal or vulvar preparations in the last month

Current active vaginal infection diagnosed at study entry

Any serious disease or condition that may interfere with study compliance
You do not qualify for Part 2 of the study (Clinical Trial) if you have any of the following 
additional conditions:

Current or previous history of breast cancer or estrogen-dependent cancer (e.g. ovarian,
endometrial)

Current or previous history of deep vein thrombosis or pulmonary embolism

Current or previous history of myocardial infarction or stroke

Known clotting disorder including Protein C, Protein S and antithrombin deficiency,
Factor V Leiden or prothrombin mutations

Known severe liver disease including cirrhosis or active Hepatitis BKnown allergic
reaction to Vagifem (estradiol vaginal tablet)
How many people will take part in the research study?
You will be one of about 150 people participating in this study. The first part of the study will 
include 100 menopausal women, 50 with HIV and 50 without HIV. Enrollment in the second part 
of the study will include 50 HIV+ menopausal women with vaginal atrophy who will be asked to 
join a clinical trial where 25 women will receive vaginal estradiol tablet and 25 women will 
receive no treatment for 12 weeks. Women with HIV can choose to participate in the first, 
second, or both parts of the study.
IRB NUMBER: 2019-10529
IRB APPROVAL DATE: 06/14/2023
IRB EXPIRATION DATE: 06/13/2024


4
How long will I take part in this research?
or non-treatment group (no therapy). The chance of you being assigned to either group is 
exactly the same. We do not know ahead of time which group you will be assigned to, and you 
will not be able to choose or change your group.
CHECK 1 (ONE) OF THE FOLLOWING OPTIONS:
  I do not have HIV and agree to participate in the first part of the study. I understand that I 
may not participate in the trial. The second visit will be my final visit.
  I have HIV and agree to participate only in the first part of the study. I will not participate in 
the trial. The second visit will be my final visit. 
  I have HIV and agree to participate only in the trial. I agree to return for a total of four visits. I 
understand that I will be assigned at random to either the vaginal estradiol treatment group or to 
the group with no treatment.
  I have HIV and agree to participate in the both parts of the study, including the trial. I agree 
to return for a total of five study visits. I understand that I will be assigned at random to either 
the vaginal estradiol treatment group or to the group with no treatment.
Visit 1
The screening visit for the first part of the study (Visit 1) will take about one hour to complete. 
During this visit, we will do some tests and procedures to see if you eligible to take part in this 
research study. The study doctor will review the results of these tests and procedures. If you are 
not eligible, the study doctor will tell you why. 
At this visit:

You will be asked questions about your background (e.g. age, education, etc.), your medical
and sexual history.

You will have a pelvic exam. A speculum (small plastic instrument) will be inserted into your
vagina by the clinician to view the vagina. You will have samples collected from your vagina 
using a swab (like a Q-tip®). Swabs will be collected to measure the pH (how acidic the 
IRB NUMBER: 2019-10529
IRB APPROVAL DATE: 06/14/2023
IRB EXPIRATION DATE: 06/13/2024
Depending on your HIV status and enrollment group, the study may take from four weeks up to 
17 weeks to complete. 
What will happen if I participate in the study?
The first visit will take about one hour to complete. During this visit you will have a pelvic exam 
and will fill out a questionnaire about your medical history and sexual practices. If you are 
determined to be eligible, you will return for a second study visit in 4 weeks. At the second visit 
we will repeat the pelvic exam and perform vaginal biopsies, blood tests and ask additional 
questions regarding any changes to your medical history. If you have HIV and symptoms of 
vaginal atrophy you will be asked to participate in a clinical trial, which will consist of 3 additional 
visits over a 12-w
eek period. Symptomatic vaginal atrophy will be 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/pain or pain associated with sexual activity at least once. If 
you do not have HIV or have HIV but do not want to continue with the second part of the study, 
the second visit will be your final study visit. If you have HIV, are eligible, and wish to continue, 
you will be assigned randomly (like flipping a coin) to the treatment (vaginal estradiol) 


5
vaginal fluid is), to measure types and quantity of vaginal bacteria present and to examine 
your fluid under a microscope to look for vaginal infections, including bacterial vaginosis, 
candida (yeast) and trichomonas. If you have a vaginal infection, you will be notified and 
referred to your primary doctor for treatment prior to enrollment in the study. After treatment, 
you may return for repeat testing and if the infection has resolved, you may be enrolled in 
the study.  

Cervical fluid will be collected by using a small syringe to rinse the vaginal area with saline
and then immediately collect the fluid. The fluid will be used in the laboratory to measure the 
amount of cytokines present in the genital tract (cytokines are substances produced by cells 
to fight infection).

If you are determined to be eligible, you will return for a second study visit in 4 weeks.
Visit 2
The following will take place at Visit 2 for participants who do not have HIV or 
participants with HIV who are not participating in the clinical trial: 

The study staff will draw a blood sample for hormone levels (estradiol and follicular
stimulating hormone) to confirm you are menopausal. For participants with HIV, blood will 
also be drawn for CD4 count and HIV viral load. Test results will be drawn for research 
purposes only. To obtain the blood sample, we will wipe the skin on your arm with alcohol to 
clean it. Then, we will insert a small needle into a vein and three tubes of blood will be 
drawn, which is less than three tablespoons of blood.

You will have a pelvic exam. A speculum (small plastic instrument) will be inserted into your
vagina by the clinician to view the vagina. You will have samples collected from your vagina 
using a swab (like a Q-tip®). Swabs will be collected to measure the pH (how acidic the 
vaginal fluid is) and to measure types and quantity of vaginal bacteria present. 

Cervical fluid will be collected by using a small syringe to rinse the vaginal area with saline
and then immediately collect the fluid. The fluid will be used in the laboratory to measure 
cytokines and other substances in the genital tract that fight infection.

Two small samples of tissue will be taken from the vagina in a procedure called a biopsy.
The areas where the biopsies will be taken will first be cleaned with saline. A gel 
(benzocaine) will be put on the biopsy areas to numb them. The small pieces of tissue are 
taken with forceps (similar to tweezers). You may feel a pinch when the tissue is taken. You 
may also take Tylenol up to one hour before the procedure if you wish. Instructions on how 
to care for your biopsies will be reviewed. You will be instructed not to have sex or to use 
any vaginal products for one week after this visit to give your biopsy sites time to heal. You 
will be told to contact the study staff if you have any bleeding, more than spotting, and/or 
pain.

To measure vaginal atrophy, a visual exam will be done to assess for thin, pale and dry
vaginal and vulvar surfaces and a light scraping of the vaginal wall will be performed to 
collect cells to examine under the microscope.
IRB NUMBER: 2019-10529
IRB APPROVAL DATE: 06/14/2023
IRB EXPIRATION DATE: 06/13/2024


6
The following will take place at Visit 2 for participants with HIV who are participating in 
the clinical trial and will serve as the screening visit for the trial:

You will be asked questions about your background (e.g. age, education, etc.), your medical
and sexual history and whether you have symptoms of vaginal atrophy.


you may return for repeat testing and if the infection has resolved, you may be enrolled in 
the trial. 

Cervical fluid will be collected by using a small syringe to rinse the vaginal area with saline
and then immediately collect the fluid. The fluid will be used in the laboratory to measure 
certain substances in the genital tract that fight infection.

Two small samples of tissue will be taken from the vagina in a procedure called a biopsy.
The areas where the biopsies will be taken will first be cleaned with saline. A gel 
(benzocaine) will be put on the biopsy areas to numb them. The small pieces of tissue are 
taken with forceps (similar to tweezers). You may feel a pinch when the tissue is taken. You 
may also take Tylenol up to one hour before the procedure if you wish. Instructions on how 
to care for your biopsies will be reviewed. You will be instructed not to have sex or to use 
any vaginal products for one week after this visit to give your biopsy sites time to heal. You 
will be told to contact the study staff if you have any bleeding, more than spotting, and/or 
pain.

To measure vaginal atrophy, a visual exam will be done to assess for thin, pale and dry 
vaginal and vulvar surfaces and a light scraping of the vaginal wall will be performed to 
collect cells to examine under the microscope.

If you have HIV and symptoms of vaginal atrophy (e.g. irritation, pain with sex, dryness,
itching) and are determined to be eligible, you will be asked to participate in clinical trial of 
vaginal estradiol which will consist of 3 additional visits (Visits 3, 4 and 5) over a 12 week 
period. The chance of you being assigned to either the estradiol treatment group or the no 
treatment group is exactly the same. We do not know ahead of time which group you will be 
assigned to, and you will not be able to choose or change your group.
IRB NUMBER: 2019-10529
IRB APPROVAL DATE: 06/14/2023
IRB EXPIRATION DATE: 06/13/2024
The study staff will draw a blood sample for hormone levels (estradiol and follicular 
stimulating hormones) to confirm you are menopausal. Blood will also be drawn for CD4 
count and HIV viral load. Test results will be drawn for research purposes only. We will wipe 
the skin on your arm with alcohol to clean it. Then, we will insert a small needle into a vein 
and three tubes of blood will be drawn, which is less than three tablespoons of blood.
You will have a pelvic exam. A speculum (small plastic instrument) will be inserted into your 
vagina by t
he clinician to view the vagina. You will have samples collected from your vagina using a 
swab (like a Q-tip®). Swabs will be collected to measure the pH (how acidic the vaginal fluid 
is), to measure types and quantity of vaginal bacteria present and to examine your fluid 
under a microscope to look for vaginal infections, including bacterial vaginosis, candida 
(yeast) and trichomonas. If you have a vaginal infection, you will be notified and referred to 
your primary doctor for treatment prior to enrollment in the trial. After treatment,


7
Visit 3
At this visit:
You will be given a questionnaire and a pelvic exam will be performed including vaginal
swabs, the saline wash and a visual exam to assess for vaginal atrophy as described for
Visit 2. Vaginal biopsies will not be done at this visit.
You will be randomized to vaginal estradiol treatment group or the non-treatment group.
If you are assigned to receive Vagifem, you will be instructed by research staff on how to
insert the vaginal estradiol tablet using a plastic applicator which is similar to a tampon. 
The dosing of Vagifem® will be 1 tablet placed in the vagina once daily for 2 weeks 
followed by 1 tablet inserted twice weekly (i.e., Tuesday and Friday) for a total of 12 
weeks. Each dose of Vagifem is packaged with a single plastic applicator. At this visit, 
you will be given a 6-week supply of Vagifem (22 single dose tablets and applicators). 
You will be instructed to use Vagifem the same time daily for all applications. It is 
important that you not use any other vaginal product while using this medication. You will 
be instructed to keep a diary of the date and time of Vagifem insertion and to return used 
applicators at your next study visit. 
Visit 4
This visit will take place 6 weeks after visit 3. At this visit:
You will be given the same questionnaire as the last visit.
You will have another pelvic exam, during which the clinician will collect the same samples
described at Visit 2 in addition to the same visual exam of the vagina. There will be no 
vaginal biopsies at this visit.
If you are assigned to receive Vagifem, you will be given a 6 week supply of Vagifem (12
single dose tablets and applicators). You will be instructed to use Vagifem the same time 
daily for all applications. It is important that you not use any other vaginal product while 
using this medication. You will be instructed to keep a diary of the date and time of 
Vagifem insertion and to return used applicators at your next study visit.
Visit 5
This visit will take place 12 weeks after visit 3 and will involve the same tests, biopsies, exams 
and questionnaires as Visit 2.
There will be three phone calls during the study. They will occur at 2 and 8 weeks after starting 
Vagifem and 1 week after conclusion of the trial. You will be asked questions about dosing and 
any discomfort or issues related to the use of the estradiol vaginal insert.
A description of this clinical trial will be available on www.ClinicalTrials.gov, as required by U.S. 
law. This Web site will not include information that can identify you. At most, the Web site will 
include a summary of the results. You can search this Web site at any time.
Will there be testing for HIV?

Prior to study enrollment, most participants will be aware of their HIV status. If you are
unaware of your HIV status, you will be tested for HIV as part of the study.

If as a result of participation in this study you are diagnosed with HIV, you will be given
HIV counseling or a referral for HIV counseling and you will be connected with care.
IRB NUMBER: 2019-10529
IRB APPROVAL DATE: 06/14/2023
IRB EXPIRATION DATE: 06/13/2024


8

The law protects the confidentiality of HIV related test results.

The law prohibits discrimination based on your HIV status and services are available to
address any discrimination.

If as a result of participation in this study you are INITIALLY diagnosed with HIV, the
results must be reported to the New York State Department of Health for contact tracing
purposes.
Genetic Testing
This study will not involve genetic research or genetic testing.
Specimen Banking (Future Use and Storage)
We will store your specimens and information about you in a “biobank”, which is a library of 
information and specimens (tissue, blood, vaginal washes) from many studies. These 
specimens and information can be linked to you. In the future, researchers can apply for 
permission to use the specimens and information for new studies to prevent, diagnose or treat 
disease, including genetic research. If you agree to the future use, some of your de-identified 
genetic and health information (not linked to you) may be placed into one or more scientific 
databases. These may include databases maintained by the federal government. Your 
specimens and information may be kept for a long time, perhaps longer than 50 years. You may 
remove your consent for future research at any time by contacting the Principal Investigator 
named on the first page of the consent or the IRB office at 718-430-2237. If you do, we will 
destroy remaining specimens and information but if these were already shared with other 
researchers, we cannot get them back.
You can choose not to participate in the biobank and still be part of the main study and this will 
not affect your treatment at this facility. 
INITIAL ONE (1) OF THE FOLLOWING OPTIONS
_______ I consent to have my specimens and information about me used for future research 
studies.
_______ I do NOT consent to have my specimens and information about me used for future 
research studies. Information about me will be kept as long as required by regulations and 
institutional policy, but will not be used for future studies.
INITIAL YOUR CHOICE BELOW
_______ I consent to be contacted in the future to learn about:
_______ New research protocols that I may wish to join.
_______ General information about research findings.
_______ I do not want to be contacted at all.
Will I be paid for being in this research study? 
You will receive compensation to help cover your time and travel expenses related to 
participating in this study. You will receive reimbursement only for visits that you complete.
IRB NUMBER: 2019-10529
IRB APPROVAL DATE: 06/14/2023
IRB EXPIRATION DATE: 06/13/2024


9
You will receive a total of $125 ($50 for Visit 1 and $75 for Visit 2) if you complete only the first 
part of the study (2 visits). 
If you have HIV and complete both parts of the study (five visits), you will receive a total of $300 
($50 at Visits 1, 3 and 4 and $75 at Visits 2 and 5). If you have HIV and complete only the 
second part of the study (clinical trial) you will receive a total of $250 ($50 at Visits 3 and 4 and 
$75 at Visits 2 and 5).
You will receive cash reimbursement for your participation in the study. If you choose to 
withdraw from the study before all visits are completed, you will be paid only for the visits you 
completed.
If any new products, tests, or discoveries resulting from the research have potential commercial 
value, you will not be compensated or benefit financially. 
Some researchers may develop tests, treatments or products that are worth money. You will not 
receive payment of any kind for your specimens and information or for any tests, treatments, 
products or other things of value that may result from the research.
Will it cost me anything to participate in this study? 
There will be no cost to you to participate in the study.
What will happen if I am injured because I took part in this study?
Taking part in this research study may result in injury or harm to you. In the event of an injury 
resulting from your participation in this study, you should seek appropriate medical care and 
inform the study doctor. In the event of an emergency you should go to an emergency room. 
If you are injured or harmed as a result of participating in the study and receive medical care 
through the Montefiore Medical Center, a Montefiore doctor, or any other health provider, you 
will be sent a bill for whatever medical care you receive. All or part of your bill may be paid by 
your health insurance. 
Albert Einstein College of Medicine and Montefiore Medical Center are not offering to provide 
you the drug/device after the termination of the study or to pay you for pain, worry, lost income, 
the cost of your medical care or non-medical care costs that might occur as a result of your 
taking part in this study. However, you do not waive any of your legal rights in signing this form.
Immediately report any discomforts, problems or injuries you experience during the course of 
your participation in the study to Dr. Kerry Murphy at (718) 839-7885.
What else do I have to do?

You must tell the research study doctor about any past and present diseases or allergies
you are aware of and about all medications you are taking including “over-the-counter” 
remedies and nutritional supplements or herbs.

You must take your study drug as instructed, returning any unused study drug (including
any empty bottles), at every visit.

If you do not feel well at any time, call your doctor or the research study doctor
immediately. 
IRB NUMBER: 2019-10529
IRB APPROVAL DATE: 06/14/2023
IRB EXPIRATION DATE: 06/13/2024


10

Drugs may cause a reaction that, if not treated promptly, could be life-threatening.
It is important that you report all symptoms, reactions and other complaints to the
research study doctor.

If any other doctor recommends that you take any medicine, please inform him/her that
you are taking part in a research study. You should give the other doctor the research
study doctor’s name and phone number.

You may carry out all your normal daily activities.
Confidentiality
The researchers and study staff follow federal and state laws to protect your privacy. This part 
of the consent form tells you what information about you may be used and shared in the 
research described in this form. You do not have to sign this form but, if you do not, you may not 
participate in the research. 
The health information that we may use or disclose for the research described in this form 
includes information from your entire medical record, such as your name, phone number, email, 
medical diagnoses, dates, test results, social security number, medical record numbers, etc. In 
addition, the researchers wish to review information pertaining to your HIV records. By law, you 
must specifically authorize access to these records.
  Yes, I authorize the use and disclosure of my information pertaining to HIV testing and HIV 
status. 
Initial: ________ 
Date: _______ 
Your information and research records will be kept confidential. Your study information will be 
kept as long as they are useful for the research described in this form.
The only people who can see your research records are:

Researchers and other individuals who work with the researchers

Organizations and institutions involved in this research, including the National Institutes
of Health and NovoNordisk.

Groups that review research such as Einstein Institutional Review Board, Montefiore
Medical Center, the Office for Human Research Protections, the US Food and Drug 
Administration, and the National Institutes of Health
The purposes of these uses and disclosures are to (1) conduct the study and (2) make sure the 
study is being done correctly. The information covered under this form may no longer be 
protected by federal privacy laws (such as HIPAA) once disclosed, and those persons who 
receive your health information may share your information with others without your additional 
permission. All of these groups have been asked to keep your information confidential. 
Medical information collected during the research, such as test results, may be entered into your 
Montefiore electronic medical record and will be available to clinicians and other staff at 
Montefiore who provide care to you. 
To maintain the integrity of this research study, you generally will not have access to your 
research-related personal health information. If it is necessary for your care, your research-
related health information will be provided to you or your physician.
Certificate of Confidentiality
IRB NUMBER: 2019-10529
IRB APPROVAL DATE: 06/14/2023
IRB EXPIRATION DATE: 06/13/2024


11
As a way to protect your privacy, we have obtained a Certificate of Confidentiality from the 
National Institutes of Health, which is funding this study. If information from this study were 
requested or subpoenaed by government agencies or the courts, we would use the Certificate 
to attempt to legally refuse to provide that information. These requests are rare – in only a few 
cases did researchers have to use the Certificate, and it was honored most of the time, but not 
every time. There are several kinds of situations to which the Certificate does not apply. For 
example, we are still required to report child abuse and some diseases, and we must make data 
available to the government for review or evaluation of our research. The Certificate does not 
prevent you or a member of your family from voluntarily sharing information. Similarly, if an 
insurer, employer, or other person obtains your written consent to receive research information, 
then the researchers may not use the Certificate to withhold that information.
Are there any risks to me? 
Blood Draw
Rarely, the vein where we inserted the needle will become sore or red. Sometimes, a 
temporary harmless “black and blue” may develop. There is a small risk of blood clots or 
infection from drawing blood. Very rarely, fainting may occur. 
Pelvic/Speculum Exam and Procedures
Having a pelvic/speculum exam may cause some discomfort. You may feel some discomfort 
when the vaginal speculum is inserted. There is a very small risk of injury to the lining inside 
your vagina from the speculum or vaginal scraping. There is no risk to cervicovaginal lavage or 
vaginal swab collection. 
Vaginal Biopsies 
spotting), foul smelling vaginal discharge, fever, chills or severe pain in your lower belly or 
pelvis.
Risks of taking Vagifem® 10 μg
Common Side Effects:

Back pain (7 out of 100)

Diarrhea (5 out of 100)

Vulvovaginal fungal infection (8 out of 100)
Vulvovaginal itching (8 out of 100)
IRB NUMBER: 2019-10529
IRB APPROVAL DATE: 06/14/2023
IRB EXPIRATION DATE: 06/13/2024
You may feel a sharp pinch or have pain when the samples are taken. In order to minimize the 
pain and discomfort of the biopsy, we will apply a topical numbing medication (benzocaine gel) 
to the tissue. Benzocaine gel can cause burning, redness, and itching at the application site, 
which is rare. You may also choose to take Tylenol® up to one hour before the biopsy. The 
biopsies may also cause light bleeding, which we will make sure is under control before you 
leave. Sometimes a medication is needed to stop the bleeding, which would be applied directly 
to the site. This medication can cause a dark- discharge from your vagina, which is temporary. 
In rare cases a stitch might be needed or a machine (cautery) may be used. You may feel 
soreness or discomfort for one or two days after the biopsy. You may have some vaginal 
spotting or bleeding and a slight discharge for up to a week after a biopsy. If needed, you can 
use a sanitary pad for the bleeding. Rarely, a biopsy can cause infection and/or prolonged 
bleeding. You should call the study staff if you have vaginal bleeding (more than 


12
Less Common Side Effects:

Vagifem applicator may cause vaginal abrasion
Women who use systemic forms (e.g. pills) of estradiol (without progesterone added) who have 
a uterus may have an increased risk of endometrial hyperplasia, which in some women may be 
a precursor to endometrial cancer after prolonged use. In this study, you will be using a low-
dose topical estradiol vaginal tablet, which does not increase blood levels of estradiol beyond 
the baseline menopausal levels and has been proven to be safe for the treatment of vaginal 
atrophy without adverse effects on the uterus lining, including endometrial hyperplasia. Further, 
low-dose vaginal estrogen has not been shown to increase risk for coronary heart disease, 
stroke, venous thromboembolism or dementia. 
Risks to Women Who Are or May Become Pregnant
The effect of Vagifem on an embryo or fetus (developing baby still in the womb), or on a 
breastfeeding infant, is unknown and may be harmful.  Because of these unknown risks, women 
cannot take part in this study if they are:

Pregnant

Trying to become pregnant

Breastfeeding or sharing breast milk
Allergic Reaction to Study Drug
Any drug can cause an allergic reaction which could be mild or more serious and can even 
result in death. Common symptoms of an allergic reaction are rash, itching, skin problems, 
swelling of the face and throat, or trouble breathing. If you are having trouble breathing, call 911 
immediately.
Psychological/Emotional
You may become embarrassed, worried, or anxious during the physical examinations, or when 
discussing your sexual history. Although the study team makes every effort to protect your 
privacy and confidentiality, a risk of taking part in this study is the possibility of a loss of 
confidentiality or privacy. Loss of privacy means having your personal information shared with 
someone who is not on the study team and was not supposed to see or know about your 
information. As a result, it is possible that social harms may occur such as difficulties in personal 
relationships or discrimination from your family or community. If you experience these kinds of 
problems during the study, a trained counselor will work with you to address the problem and 
provide referrals to other service providers if needed. The study team plans to protect your 
privacy – see the Confidentiality section above for details.
Inconvenience
Participation in the study may cause an inconvenience to your daily schedule because you will 
need to come to the study clinic for 2-5 visits. You will be asked not to use any vaginal products 
other than the study vaginal estradiol tablet.
IRB NUMBER: 2019-10529
IRB APPROVAL DATE: 06/14/2023
IRB EXPIRATION DATE: 06/13/2024


13
New Findings
If we learn any significant new findings during the study that might influence your decision to 
continue, we will contact you and explain them.
Unknown Risks
There is always the possibility that you will have a reaction that is currently not known and not 
expected. All drugs may have the risk of causing an allergic reaction that, if not treated 
promptly, could be life threatening. It is important that you report any and all symptoms or 
possible reactions to your doctor. You will be monitored for side effects by the research study 
staff, and the research study doctor may decide that you should be withdrawn from the research 
study.
Are there possible benefits to me? 
Women with HIV infection experience menopausal symptoms at an earlier age and are more 
likely to report symptoms compared to women who do not have HIV. Participants may benefit 
from study participation because the use of low dose topical estradiol, which has been FDA 
approved since 2009 for the treatment of vaginal atrophy in menopausal women, may relieve 
symptoms of vaginal dryness, itching, soreness, pain and urinary symptoms in women with HIV. 
Participants and others may benefit in the future from information learned from this study. 
Specifically, if we find that HIV accelerates genital tract aging, this may prompt 
recommendations for earlier treatment of vaginal atrophy in menopausal women with HIV.
What choices do I have other than participating in this study?
You can refuse to participate in the study. 
Are there any consequences to me if I decide to stop participating in this study?
No. If you decide to take part, you are free to stop participating at any time without giving a 
reason. This will not affect your care and you will continue to be treated by your regular 
providers. However, some of the information may have already been entered into the study and 
that will not be removed. The researchers and the sponsor may continue to use and share the 
information they have already collected. If you decide to stop taking part in the study for any 
reason, we will ask you to make a final study visit. You will need to return all unused study drug.
To revoke (take back) your consent and authorization, you must contact the Principal 
Investigator in writing at the address on page 1 of this form. However, you may first call or 
speak to the Principal Investigator and she will stop collecting new information about you.  If you 
take back your consent and authorization, you will not be allowed to continue to participate in 
this research study. 
Can the study end my participation early?
We will not let you participate in the study any more if you are unable to follow study 
instructions, you become ineligible, or if it is unsafe for you to continue your participation in the 
study. In addition, your participation will end if the investigator or study sponsor stops the study 
earlier than expected.
IRB NUMBER: 2019-10529
IRB APPROVAL DATE: 06/14/2023
IRB EXPIRATION DATE: 06/13/2024


14
CONSENT TO PARTICIPATE
I have read the consent form and I understand that it is up to me whether or not I participate. I know 
enough about the purpose, methods, risks and benefits of the research study to decide that I want to 
take part in it. I understand that I am not waiving any of my legal rights by signing this informed consent 
document. I will be given a signed copy of this consent form.
Printed name of participant
Signature of participant
Date
Time
Printed name of the person 
conducting the consent 
process
Signature
Date
Time
IRB NUMBER: 2019-10529
IRB APPROVAL DATE: 06/14/2023
IRB EXPIRATION DATE: 06/13/2024