Conditions: Vaginal Atrophy Postmenopausal Symptoms Breast Cancer Female Long-term Survivors
Keywords: Postmenopausal Breast Cancer Survivor Vaginal
Allocation: RANDOMIZED | Intervention model: PARALLEL
Enrollment: 8
Healthy volunteers: no

Brief summary:
The purpose of this research is to gather information on the safety and effectiveness of Intrarosa®, also known as Dehydroepiandrosterone (DHEA), and prasterone. By doing this study, the investigators hope to learn if Intrarosa® can improve vaginal discomfort. Participants will be assigned to one of two groups. One group will use Intrarosa® once a day. The other group will use Replens™ two times a week.

Detailed description:
This will be a two-armed, randomized Phase II trial. All study subjects will be asked to fill out a simple 5-question sexual functioning survey. If any concern about sexual functioning is noted, the subject will also be asked to fill out a more extensive Sexual functioning tool, to help determine which domain of sexual functioning is the most bothersome.

Subjects who complete the initial screening will be randomly assigned to the Intrarosa® or Replens™ arm by a 1:1 ratio. Subjects randomized to the Intrarosa® arm will use 6.5 mg daily for 12 weeks (±1 week). Subjects randomized to the Replens™ arm will use a vaginal applicator two times per week for 12 weeks.

At baseline and at 12 weeks, subjects will undergo a physical exam including clinical breast and gynecological exam. During gynecologic exams, the vaginal Potential of Hydrogen (pH) will be determined and a swab of vaginal epithelium sent for determination of the Vaginal Maturation Index (VMI) and Maturation Value (MV). These will be used as objective physiologic markers to determine the improvement in vaginal atrophy. The cytologist's reading specimens will be blinded.

Additionally, all study subjects will be asked to fill out questionnaires at baseline and again in 12 weeks.

Arms:
arm 1: Vaginal insert with 6.5 mg vaginal DHEA self-administered once daily at bedtime for 12 weeks arm 2: Prefilled vaginal applicator with 2.5 g of polycarbophil vaginal moisturizing gel, self-administered two times per week at night for 12 weeks

Interventions: intervention 1: Vaginal Dehydroepiandrosterone intervention 2: Vaginal Polycarbophil Moisturizer
Intervention descriptions: intervention 1: This is a vaginally administered suppository steroid indicated for the treatment of moderate to severe dyspareunia, a frequent symptom of vulvovaginal atrophy due to menopause or genitourinary syndrome of menopause. intervention 2: This is an FDA cleared, over-the-counter personal lubricant for vaginal application, intended to moisturize and lubricate, to enhance the ease and comfort of intimate sexual activity and supplement the body's natural lubrication. It is non-sterile, water-based, non-irritating, non-greasy, non-staining vaginal gel delivered as a long-lasting moisturizer for vaginal dryness.

Protocol document:
Prot_SAP_000.pdf: 
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Study Title: Comparison of Vaginal Dehydroepiandrosterone (DHEA) to Control 
for Treatment of Vaginal Symptoms in Postmenopausal Breast Cancer 
Survivors on Aromatase Inhibitors: A Phase II Randomized Trial 
 
Principal Investigator: 
Gloria Richard-Davis, MD 
University of Arkansas for Medical Sciences 
4301 W. Markham Street, Slot 518 
Little Rock, AR 72205 
Telephone: 501.614.2047 
Email: GARichardDavis@uams.edu 
 
Sub-Investigators: 
Sindhu Malapati, MD 
University of Arkansas for Medical Sciences 
4301 W. Markham Street, Slot 508 
Little Rock, AR 72205 
Telephone: 501.686.8530 
Email: SMalapati@uams.edu 
 
Sam Makhoul, MD 
Medical Director of Clinical Research 
CARTI Cancer Center 
8901 CARTI Way 
Little Rock, AR 72205-6523 
Telephone: 501.906.3000 
Email: Sam.Makhoul@carti.com 
 
Study Statistician: 
Eric R. Siegel, MS, M.Ap.Stat 
University of Arkansas for Medical Sciences 
4301 W. Markham Street, Slot 781 
Little Rock, AR 72205 
Telephone: 501.526.6717 
Email: SiegelEricR@uams.edu 
 
Medical Monitor: 
Konstantinos Arnaoutakis, MD 
University of Arkansas for Medical Sciences 
4301 W. Markham Street, Slot 508 
Little Rock, AR 72205 
Telephone: 501.526.6990 x8064 
Email: KArnaoutakis@uams.edu 
 
Study location: 
University of Arkansas for Medical Sciences 
 
NCT Number: 
NCT04493333 
 


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Table of Contents 
Abbreviations ............................................................................................................................. 3 
Background and Rationale ......................................................................................................... 4 
Objectives and Rationale ........................................................................................................... 5 
Study Population ........................................................................................................................ 6 
Eligibility Criteria ........................................................................................................................ 6 
Inclusion Criteria .................................................................................................................. 6 
Exclusion Criteria ................................................................................................................. 6 
Study Design and Procedures .................................................................................................... 7 
Randomization ........................................................................................................................... 9 
Investigational Product ............................................................................................................... 9 
Intrarosa® (Vaginal DHEA) Description ................................................................................. 9 
Replens™ Description .........................................................................................................10 
Investigational Product Accountability .................................................................................10 
Risks and Benefits ....................................................................................................................10 
Data Handling and Recordkeeping............................................................................................11 
Adverse Events .........................................................................................................................12 
Definitions ...........................................................................................................................12 
Monitoring, Recording and Reporting of AEs .......................................................................13 
Expedited Reporting of AEs ................................................................................................14 
Monitoring .................................................................................................................................15 
Study Discontinuation ...............................................................................................................15 
Individual Subject Stopping Rules .......................................................................................15 
Study Stopping Rules ..........................................................................................................15 
Protocol Deviations and Violations ............................................................................................16 
Deviations ...........................................................................................................................16 
Violations ............................................................................................................................16 
Compliance ...............................................................................................................................16 
Subject Withdrawal ...................................................................................................................16 
Subject Termination ..................................................................................................................17 
Specimen Handling and Storage ...............................................................................................17 
Data Analysis ............................................................................................................................17 
Efficacy and Safety Populations ..........................................................................................17 
Efficacy Endpoints ...............................................................................................................17 
Analysis Plan.......................................................................................................................18 
Ethical Considerations ..............................................................................................................19 
Dissemination of Data ...............................................................................................................19 
References ...............................................................................................................................20 
Appendices ...............................................................................................................................21 
Appendix A: Study Calendar ...............................................................................................21 
Appendix B. Eligibility Flow Diagram ...................................................................................22 
 
 


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Abbreviations 
AE 
Adverse Event 
AI 
Aromatase Inhibitors 
AIS 
Adenocarcinoma in situ 
APR 
Annual Progress Report 
AR-AERS 
AR-Adverse Events Reporting System 
BSSC-W 
Brief Sexual Symptom Checklist for Women 
CFR 
Code of Federal Regulations 
CI 
Confidence Interval 
CIN 
Cervical Intra-Epithelial Neoplasia 
CTCAE 
Common Terminology Criteria for Adverse Events 
DCIS 
Ductal carcinoma in situ 
DHEA 
Dehydroepiandrosterone 
F 
Fahrenheit 
FDA 
Food and Drug Administration 
FSFI 
Female Sexual Function Index 
FSH 
Follicle-stimulating hormone 
g 
gram 
HER2 
Human Epidermal Growth Factor Receptor 2 
HSIL 
High Grade Squamous Intraepithelial Lesion 
I 
Intermediate 
ICH GCP 
International Conference on Harmonisation Good Clinical Practice 
IRB 
Institutional Review Board 
IU/L 
International Units per Liter 
mg 
milligram 
mL 
milliliter 
mm 
millimeter 
MAR 
Missing at Random 
MCAR 
Missing Completely at Random 
MNAR 
Missing Not at Random 
NCI 
National Cancer Institute 
ORRA 
Office of Research Regulatory Affairs 
P 
Parabasal 
QOL-CSV 
Quality of Life-Cancer Survivor Version 
RPRS 
Research Participant Registry System 
S 
Superficial 
SAE 
Serious Adverse Event 
SD 
Standard Deviation 
SEM 
Standard Error of the Mean 
UAMS 
University of Arkansas for Medical Sciences 
UPIRTSO 
Unanticipated Problem Involving Risks to Subjects or Others 
VMI 
Vaginal Maturation Index 
 
 


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Background and Rationale 
Aromatase inhibitors (AI) are the preferred adjuvant treatment for postmenopausal females with 
hormone receptor-positive breast cancer for a duration of five to ten years to reduce the risk of 
recurrence and death, but rates of poor adherence and early discontinuation of AI therapy are 
high due to side effects [1]. Genitourinary symptoms, which arise from estrogen deprivation, are 
especially prevalent. In one study of females on AI, 74% reported insufficient lubrication and 56% 
reported dyspareunia [2]. Treatment with estrogen is the most efficacious treatment in the general 
population, but systemic estrogen therapy is contraindicated in patients with hormone receptor-
positive breast cancer. Additionally, patients with breast cancer and their clinicians are reluctant 
to use vaginal estrogen [3], despite data that low dose vaginal estradiol can significantly improve 
symptoms and does not raise serum estradiol levels above the menopausal range [4]. Treatment 
of vaginal symptoms has been limited to vaginal moisturizers and lifestyle modification, providing 
only marginal improvements. More recently, vaginal dehydroepiandrosterone (DHEA, prasterone, 
Intrarosa®) was FDA approved to treat moderate to severe dyspareunia, which is a symptom of 
vulvar and vaginal atrophy due to menopause. Vaginal DHEA allows intracellular production of 
estrogen and testosterone in genital tissues with relatively little systemic effect [5]. Serum 
concentrations of metabolites of both estrogens and androgens remain within the normal 
postmenopausal range following daily intravaginal administration of 6.5mg prasterone at 12, 26 
and 52 weeks of use. [6] Barton et al. demonstrated no effect on serum estrogen concentrations 
when it was used in females with breast cancer on AI [7]. Prior studies have demonstrated 
clinically and statistically significant improvement of patient-reported vulvovaginal atrophy 
symptoms and dyspareunia, which correlated with findings of decreased vaginal pH and 
improvement in the vaginal maturation index (VMI) after treatment with vaginal DHEA [8]. 
 
The VMI and vaginal pH have been well studied as indicators of the degree of vaginal atrophy, 
which is the end result of treatment with AI that leads to vaginal dryness and dyspareunia. VMI is 
the proportional relationship of parabasal (P) cells to intermediate (I) and superficial (S) cells in 
the vaginal epithelium (see Figure 1 below). A normal premenopausal vaginal mucosa is 
dominated by S cells, which makes it thicker. The VMI is a clinical measure of vaginal 
estrogenization derived from the maturation index. VMI = 1.0 x %S + 0.5 x %I + 0.0 x %P cells, 
which is the same as VMI = %S + (0.5 x %I) when simplified, with a potential range of 0-100. A 
VMI of 65-100 suggests a normal premenopausal environment, 50-64 indicates a moderate 
estrogenic effect, and < 50 indicates atrophy [9]. As the vaginal epithelium becomes thinner and 
more atrophic, the mucosa has less glycogen content and less lactobacilli to convert the glycogen 
into lactic acid, which results in an increase in the vaginal pH. A normal healthy vaginal pH is 4.5 
[9]. 
 
Figure 1: Estrogenized Vaginal Epithelium vs Atrophic Vaginal Epithelium 
 
 


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The VMI will be used as an objective physiologic marker to determine the improvement in vaginal 
atrophy, which is the end result of treatment with AI that leads to vaginal dryness and dyspareunia. 
The more estrogen that the vaginal epithelium receives, the thicker it becomes, resulting in 
increased presence of I and S cells. Since VMI is a weighted sum of the percentage of I and S 
cells, a higher VMI suggests a healthier vaginal epithelium. 
 
Significantly atrophied vaginal tissue has a higher percentage of P cells, a reduced percentage of 
I+S cells on the VMI, and an increase in pH compared to normal pre-menopausal vaginal tissue. 
The VMI is determined from the percentages of P, I, and S cells in vaginal scrapings and provides 
an approximate idea about status of vaginal walls. The approximate percentages of the P, I, and 
S cells in premenopausal and postmenopausal females are provided in Table 1 below. 
  
Table 1. Percentages of P, I, and S cells in Premenopausal and Postmenopausal Females 
 
Components of VMI 
Premenopausal (%) 
Postmenopausal (%) 
Parabasal (P) cells 
5-10 
70-75 
Intermediate (I) cells 
40 
25 
Superficial (S) cells 
50-55 
< 5 
 
Breast cancer survivors are living longer and quality of life, including sexual health, is important. 
Females with estrogen deficiencies may suffer from vaginal dryness and atrophy that negatively 
impact sexual health. Chemoprevention treatment with AIs blocks estrogen production and 
compounds the problem. Vaginal DHEA, a non-estrogen product, is known to improve vaginal 
atrophy and sexual health. This study will evaluate the use of vaginal DHEA in breast cancer 
survivors on AIs. 
 
Objectives and Rationale 
The primary objective is to determine change in vaginal atrophy as assessed by the VMI after 12 
weeks (±1 week) of treatment with vaginal DHEA 6.5 mg inserted nightly (Intrarosa®) when 
compared to a prefilled applicator of a polycarbophil vaginal moisturizing gel (6.7 g) (Replens™), 
into the vagina two times per week at night. 
 
The secondary objectives are to 1) determine change in vaginal pH 2) determine improvement of 
vaginal symptoms and sexual function as assessed by the Brief Sexual Symptom Checklist for 
Women (BSSC-W) and the Female Sexual Function Index (FSFI) [10-11] and 3) determine 
improvement in quality of life using the Quality of Life - Cancer Survivor Version (QOL-CSV) [12] 
after 12 weeks (±1 week) of treatment with vaginal DHEA (Intrarosa®) when compared to 
polycarbophil vaginal moisturizer (Replens™) in breast cancer survivors on AI, and to compare 
side effects in each group that may impact patient acceptability. 
 
It is hypothesized that the Intrarosa® arm will exhibit greater improvement in the VMI and decrease 
in vaginal pH when compared to Replens™ after 12 weeks (±1 week) of treatment. It is also 
hypothesized that the Intrarosa® arm will have improvement in vaginal and sexual symptoms as 
indicated by the validated symptom inventories to be administered both pre and post study period. 
 
Of note, the BSSC-W, the FSFI, and the QOL-CSV have all been validated for use in a study 
population such as this one [10-12]. 


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Study Population 
Subjects will be postmenopausal breast cancer survivors, stage I-III, hormone receptor positive 
breast cancer (ER+, PR+) regardless of human epidermal growth factor receptor 2 (HER2) status, 
ages 18 to 70 years old, on AIs identified at UAMS Cancer Institute and Women’s Health clinics 
and at CARTI Cancer Center. Up to 120 subjects will be screened for a total of 60 subjects 
enrolled, 30 in each arm of the study. See Appendix B. 
 
Eligibility Criteria 
Inclusion Criteria 
 
Females, ages 18-70 
 
Postmenopausal patients with a history of breast cancer who have completed primary 
treatment with curative intent and currently are on an AI and have been for at least 6 months 
 
Ductal carcinoma in situ (DCIS) or Stage I-III, hormone receptor-positive breast cancer 
regardless of HER2 status 
 
Postmenopause defined as ≥ 12 months spontaneous amenorrhea, ≥ 6 months spontaneous 
amenorrhea with serum FSH levels > 40 mIU/mL, or ≥ 6 weeks postsurgical bilateral 
oophorectomy with or without hysterectomy. FSH level will be documented on all subjects. 
 
Reported dissatisfaction with sexual function on Question 1 of the BSSC-W No planned 
changes in AI during the study period 
 
Mammogram within the 12 months prior to study entry (if appropriate, as determined by the 
treating physician) 
 
Normal Pap within the 12 months prior to study entry (i.e., negative Pap results consistent 
with American Cancer Society (ACS) guidelines). Females whose cervix has been removed 
by surgery for reasons not related to cervical cancer or serious cervical pre-cancer [e.g., CIN 
2 or 3 (HSIL, moderate or severe dysplasia) or AIS] may be excluded from this requirement. 
 
Exclusion Criteria 
 
Use of any estrogen or progesterone depot-preparation drug or progestin implant in the last 6 
months before study entry. 
 
Use of any androgen or anabolic steroids in the last 6 months before study entry. 
 
Use of any oral or transdermal hormonal products (estrogen, progestin, or DHEA) within the 
last 8 weeks prior to study entry; however, a subject can elect to wait for an 8-week washout 
period before study entry. 
 
Use of any vaginal or intrauterine hormonal products in the last 8 weeks; however, a subject 
can elect to wait for an 8-week washout before study entry. 
 
Use of any natural over-the-counter estrogenic products in the last 6 months; however, a 
subject can elect to wait for a 6-month washout before study entry. 
 
Concomitant vulvar and vaginal surgical or laser treatments 
 
Vaginal infection or confounding vulvar or active vaginal disease process 
 
Active malignant breast or gynecologic disease 
 
History of prior radiation to the pelvis or prior gynecologic cancer or pre-cancer 
 
Inability to tolerate a vaginal/speculum exam 
 
Undiagnosed, persistent or recurring genital bleeding or other indication of active pelvic 
disease process that has not been evaluated to determine the cause [6] 
 
Clinically significant uncontrolled depression or severe psychiatric symptoms 
 
If subject has an established routine of inert vaginal lubricant use for routine or occasional 
relief of vulvar or vaginal symptoms prior to the study period, it may be continued during the 


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study period along with the study drug. 
 
Study Design and Procedures 
This will be a two-armed, randomized, open-label Phase II trial. All study subjects will be asked 
to fill out the simple 5-question BSSC-W. If any concern about sexual functioning is noted with 
the BSSC-W question 1 as a no answer to “are you satisfied with sexual function”, the subject will 
also be asked to fill out the more extensive FSFI tool, to help determine which domain of sexual 
functioning is the most bothersome. Questions 7-10 on FSFI specifically assess degree of vaginal 
dryness while questions 17-19 assess pain with sex, which are both commonly associated with 
vaginal atrophy. Subjects who indicate that they are satisfied with their sexual function on BSSC-
W in question 1 will be deemed ineligible for the study and will not complete the FSFI. All 
questionnaires will be administered in paper format. 
 
Potential research subjects will be identified in the UAMS Cancer Institute and UAMS Women’s 
Health clinics (e.g. Women’s Cancer and Cancer Survivorship clinics, and Gynecology/Fertility 
clinics, etc.) and from the CARTI Cancer Center, during routine clinic appointments by the 
provider or research staff. For potential subjects being seen in the UAMS clinics, the study team 
will review daily clinic schedules to assess for possibly eligible subjects. If an individual is found, 
a request to the clinical team will be made to allow access to the patient to discuss the study. 
Potential research subjects may also contact the UAMS Cancer Institute’s Clinical Trials Office 
regarding participation based on the information found within the IRB-approved DHEA flyer that 
is to be distributed amongst UAMS and the CARTI medical clinics. No individual at CARTI will be 
involved with the recruitment, consenting, or treatment process; however, clinicians at CARTI 
whose patients may qualify for the research may inform the potential subjects of the study and 
refer them to the UAMS study team for more information. Interested research subjects who are 
referred to UAMS will subsequently interact with the UAMS study team for study treatment and 
consent. Postmenopausal patients on AIs, ages 18 to 70, who have had stage I-III, hormone 
receptor-positive breast cancer (ER+, PR+) regardless of HER2 status will be invited to enroll in 
the study after they have completed all adjuvant chemotherapy, radiation therapy and HER2-
targeted therapy. All potential subjects will be referred to the UAMS Cancer Institute for consent 
and study treatment. Patients should have been on at least six months of an AI after the 
completion of all their adjuvant therapies before enrollment. Prior to any research activities, the 
research subject will provide informed consent. 
 
Potential research subjects have the ability to review the informed consent and DHEA flyer 
through MyChart prior to any clinic visit.  The flyer provides a description of the program and its 
processes in layman’s terms.  These items are intended to augment the consenting process and 
provide a useful tool for the consenter and consentee to communicate.  The potential subject will 
also have the option within MyChart to indicate whether they are interested in consenting to the 
study prior to their visit. The Arkansas Clinical Data Repository (AR-CDR) will be utilized to find 
and recruit subjects who may meet eligibility criteria. Information requested from AR-CDR will be 
a list of female patients between the ages of 18 and 70 years old with a history of breast cancer 
who are currently on an aromatase inhibitor and have been for at least 6 months. Patients who fit 
these criteria will be contacted via email, phone, or patient portal and asked if they are interested 
in learning more about the study. If they are, a study staff member may contact the patient via 
email, phone or patient portal to discuss further. If a patient prefers to not be contacted, they can 
opt out of further communications by responding via email, phone or patient portal to notify the 
research team.  
 
Females of childbearing age and potential must have negative pregnancy test at screening. 
Subjects who are post-menopausal (as defined in the inclusion criteria) will not require a 


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pregnancy test. 
 
At baseline, subjects will undergo a physical exam including clinical breast and gynecological 
exam. During gynecologic exams, the vaginal pH will be determined and a swab of vaginal 
epithelium will be sent to pathology to calculate the VMI. These will be used as objective 
physiologic markers to determine the improvement in vaginal atrophy. The cytologists reading the 
specimens will be blinded.  If the VMI results are “unsatisfactory”, the swab of vaginal epithelium 
will need to be recollected within 4 weeks of Day 1, Week 1 to calculate a new VMI.  
 
Additionally, at baseline, all study subjects will be asked to fill out the BSSC-W, QOL-CSV, and 
DHEA Trial Supplemental Clinical Survey.  FSFI will also be completed at baseline by all subjects 
who indicate sexual complaints on Question 1 of the BSSC-W at baseline; any consented 
individuals who do not indicate sexual complaints on Question 1 of the BSSC-W at baseline will 
be considered a screen fail and will not complete the FSFI or continue in the study. Questionnaires 
will be administered in paper format. Subjects will be instructed not to use vaginal products other 
than water-based lubricants during intercourse throughout the duration of the study period. 
Subjects will be given a paper diary to record the dates and approximate times the treatment was 
used. Subjects will be advised to complete this at home. These diaries will be used to track 
compliance with study treatment. All adverse events (AEs) will be analyzed, tabulated and 
organized by organ-system and included in the primary analysis. 
 
At 1 week (±3 days) from Day 1, Week 1, subjects will be followed up with via phone call to ensure 
study drug was received, emphasize study compliance with study treatment, remind subjects to 
correctly complete diary entries, and assess any changes in the subject’s health.   
 
At 6 weeks (±1 week) from Day 1, Week 1, subjects will be followed up with via phone call to 
emphasize study compliance with study treatment, remind subjects to correctly complete diary 
entries, and assess any changes in the subject’s health.  
 
Both follow-ups (1 week and 6 week) will be recorded/documented in eMR. 
 
At 12 weeks (±1 week), from Day 1, Week 1, subjects will undergo a physical exam including 
clinical breast and gynecological exam. During gynecologic exams, the vaginal pH will be 
determined and a swab of vaginal epithelium sent to pathology to calculate the VMI. These will 
be used as objective physiologic markers to determine the improvement in vaginal atrophy. The 
cytologist’s reading the specimens will be blinded. 
 
Additionally, at 12 weeks (±1 week) from Day 1, Week 1, all study subjects will be asked to fill out 
the BSSC-W, QOL-CSV, and FSFI. Questionnaires will be administered in paper format. Diaries 
will be collected at the completion of study treatment, 12 weeks (±1 week) from Day 1, Week 1, 
or if treatment is not completed per protocol, when treatment is stopped. 
 
All AEs will be analyzed, tabulated and organized by organ-system based on NCI CTCAE v5 and 
included in the primary analysis. 
 
Diary progress should be submitted after Week 4 (±1 week), Week 8 (±1 week), and Week 12 (±1 
week) of treatment.  Diaries can be submitted in person, via self-addressed envelope to the cancer 
clinical trials office, text photos to the research nurse cellphone, email photos to the research 
nurse email, sent photos through MyChart, or faxed to the cancer clinical trials office. There will 
be no deviation for subjects who do not submit diary progress at Week 4 or Week 8. There will be 
a deviation for subjects who do not submit diary progress at Week 12 (or by the end of study 


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participation, if they end treatment early).    
 
Compensation is available to subjects upon submission of diaries and completion of study-related 
activities. The first payment of $25 will be made to the subject upon submission of diary at Week 
4 and completion of the Week 6 phone call. The second payment of $50 will be made to the 
subject upon completion of the Week 12 visit, which includes clinic attendance for physical exam, 
estradiol 
level, 
and 
return 
of 
questionnaires/survey, 
diaries, 
drug 
boxes, 
unused 
products/packaging.  Subjects will be issued a Greenphire Clincard, which will be used to receive 
payment and funds will be available for use within 1 business day once approved to be released 
to the card.   
See Appendix A: Study Calendar for summary of study protocol and procedures. 
 
Randomization 
Subjects who complete the screening will be randomly assigned to either the Intrarosa® or 
Replens™ arm in a 1:1 ratio. Subjects randomized to the Intrarosa® arm will use 6.5 mg daily for 
12 weeks (±1 week). Subjects randomized to the Replens™ arm will use a vaginal applicator two 
times per week for 12 weeks (±1 week). 
 
The study coordinator will use the Research Participant Registry System (RPRS) to randomize 
subjects to either the Intrarosa® arm or the Replens™ arm. Once a subject is registered in RPRS, 
the computer system will generate a randomly assigned arm. The UAMS Research Pharmacy will 
dispense study drugs after the subject has been randomized. 
 
Investigational Product 
Intrarosa® (Vaginal DHEA) Description 
Intrarosa® (prasterone) is vaginally administered steroid indicated for the treatment of moderate 
to severe dyspareunia, a frequent symptom of vulvovaginal atrophy due to menopause or 
genitourinary syndrome of menopause. The mechanism of action of Intrarosa® in postmenopausal 
females with vulvar and vaginal atrophy is not fully established [13]. Intrarosa® presumably acts 
like endogenous DHEA, which is an inactive steroid secreted by the human adrenal glands that 
is converted into small quantities of active androgens and/or estrogens. However, prior studies of 
normal postmenopausal females and those on AIs have shown that serum estrogen and 
testosterone concentrations were maintained in the normal postmenopausal ranges after use of 
Intrarosa® with no detectible change in metabolism with up to 52 weeks of treatment [6-7]. 
 
Prasterone is identified chemically as 3β-hydroxyandrost-5-en-17-one. It has the empirical 
formula C19H28O2 with a molecular weight of 288.424 g/mol. Prasterone is a white to off-white 
crystalline powder insoluble in water and soluble in sodium lauryl sulfate (SLS). Each Intrarosa® 
(prasterone) vaginal insert contains 6.5 mg of prasterone in 1.3 mL of off-white hard fat (Witepsol), 
which is formed into a smooth, white to off-white solid bullet-shaped suppository measuring 28 
mm in length, 9 mm in width at its wider end, and weighing 1.2 g. 
 
Intrarosa® is manufactured for Endoceutics, Inc. (Quebec City, Canada) and distributed by 
Millicent Pharma (East Hanover, NJ, USA). It will be provided to the UAMS Research Pharmacy 
in sterile packaging. It will be supplied, from the commercial line, in boxes containing 28 
applicators and small boxes of 4 blister packs containing 7 vaginal inserts (28 vaginal inserts per 
box). It may be stored either at room temperature or in refrigeration (5°C-30°C). 
 
One Intrarosa® vaginal insert will be self-administered with the provided applicator once daily at 
bedtime for 12 weeks (±1 week). 


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Replens™ Description 
Replens™ is cleared (K101098) for over-the-counter use as a personal lubricant for vaginal 
application, intended to moisturize and lubricate, to enhance the ease and comfort of intimate 
sexual activity and supplement the body's natural lubrication. Replens™ is non-sterile, water-
based, white to off-white, non-irritating, non-greasy, non-staining vaginal gel delivered as a long-
lasting moisturizer for vaginal dryness Replens Vaginal Moisturizer contains ingredients 
commonly used in other products for vaginal use sold as medical devices and cosmetics (purified 
water, glycerin, mineral oil, polycarbophil, carbomer homopolymer type B, hydrogenated palm oil 
glyceride, sorbic acid, sodium hydroxide). All ingredients are either NF, USP, or are considered 
“generally recognized as safe” for their intended use. 
 
Replens™ is manufactured for Dwight and Church Co. Inc., (Ewing, NJ USA). Replens™ will be 
obtained from commercial supply in packages of 8 prefilled applicators by the UAMS Research 
Pharmacy. It should be stored at room temperature (15°C-30°C). 
 
Replens™ personal lubricant will be self-administered with the prefilled applicator two times per 
week on non-consecutive days as prescribed at bedtime for 12 weeks (±1 week). 
 
Investigational Product Accountability 
Intrarosa® and Replens™ will be stored in the UAMS Research Pharmacy under the supervision 
of the research pharmacist who will be responsible for receiving the investigational product, 
storing the supply according to the manufacturers’ specifications, dispensing the investigational 
product for administration and maintaining all accountability logs. Standard UAMS accountability 
logs will be used. Investigational product accountability records will be maintained per Pharmacy, 
Institutional, FDA, and other applicable policies. 
 
Intrarosa® and Replens™ Dosing Delays 
If there are any delays or missed doses in the subjects’ usage of Intrarosa® or Replens™, subjects 
are to notify the clinical research nurse immediately.  Subjects are to also notify the clinical 
research nurse when they begin usage of Intrarosa® or Replens™ again.   
 
Subject will be terminated from the study due to non-compliance (see “Subject Termination” 
section below) for either of the following dosing delays: 
 
Missing >1 week of consecutive treatment (seven consecutive doses of Intrarosa® or two 
consecutive doses of Replens™). 
 
OR 
 
 
If at any point it is discovered that the subject has missed ≥25% of the total prescribed 
treatment doses (21 doses of Intrarosa® or 6 doses of Replens™). 
 
Risks and Benefits 
Although prior trials have not reported serious physical side effects with DHEA, there is a risk of 
possible side effects from DHEA. The most significant side effect reported in prior studies was an 
increase in vaginal discharge, reported in 6% of users [14-15]. In an extended 52-week trial, 
changes in Pap smear were reported in 2.1% (11 of 521) subjects. None of the reported abnormal 
Pap results were high-grade lesions [14-15]. During the final gynecologic exam, a Pap smear may 
be done at the treating physician’s discretion if abnormal cervical changes are suspected. 
 


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Intrarosa® package insert lists the following adverse reactions from clinical trials experience [6]: 
 
Vaginal discharge (incidence of ≥ 2%, and greater than reported in the placebo group) 
 
Abnormal Pap smear (incidence of 2.1%) 
 
Under a “warnings and precautions” section, the package insert lists “current or past history of 
breast cancer,” noting that exogenously-administered estrogen is contraindicated in females with 
history of breast cancer, and that estrogen is a metabolite of prasterone. Additionally, it states, 
“Intrarosa® has not been studied in women with breast cancer.” [6] However, since publication of 
the package insert in 2016, high-quality studies have concluded that serum estrogen and 
testosterone concentrations were maintained in the normal postmenopausal ranges in breast 
cancer survivors on AI’s after extended use of Intrarosa® [7,13,16] mitigating concern for this 
subgroup, who are the focus of the study proposed here. 
 
There is a risk of minor discomfort with the pelvic exams proposed in this study. Subjects will 
undergo a physical exam outside of the scheduled visits if a subject experiences distress from 
side effects she perceives to be resulting from the study treatment. 
 
There is a risk of psychological distress due to subjects filling out questionnaires about sexual 
health and quality of life. These questionnaires will be assessed and subject’s feelings about 
sexual health and quality of life will be monitored for the duration of the study. 
Another risk to study subjects is the potential for loss of confidentiality. Measures to protect the 
confidentiality of study subjects will be implemented as described in the Data Handling and 
Recordkeeping section below. No social or economic harms are anticipated. 
 
Data Handling and Recordkeeping 
The Principal Investigator will carefully monitor study procedures to protect the safety of research 
subjects, the quality of the data and the integrity of the study. All study subject material will be 
assigned a unique identifying number. The key to the code will be kept in a locked file in the 
principal investigator’s office. Only Investigators and study staff shall have access to the code and 
information that identifies the subject in this study. At the conclusion of the study, the data will be 
permanently de-identified. Per UAMS Admin Guide, the data will be retained for seven years after 
final reporting. The data will be destroyed after it has been retained for the appropriate time. 
 
Though not expected, any AEs experienced will be captured in the medical record. In addition to 
AEs, the following will also be collected from the subject or subject’s medical record: 
 
Age 
 
Race 
 
History of disease (including stage and treatments) 
 
Menopause - natural 
 
Menopause - surgical (i.e. removal of ovaries) 
 
Weight 
 
Height 
 
Which AI (anastrozole/letrozole vs exemestane) 
 
# of months on current AI 
 
Previous (not current) endocrine therapy (tamoxifen, anastrozole/letrozole, exemestane) and 
duration of each in months 
 
Previous adjuvant chemotherapy (yes/no) 
 
Most bothersome vaginal symptom (dyspareunia vs vaginal dryness/discomfort) 
 
Duration of dyspareunia (# of months) 
 
Duration of vaginal dryness/discomfort (# of months) 


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 
Cigarette smoking (current, past or never) 
 
Medical conditions (e.g. diabetes, hypertension, cardiac disease, stroke, etc.) 
 
Adverse Events (AEs) 
Following consent, safety will be measured by assessment of AEs throughout the duration of the 
study, which is approximately 12 weeks (±1 week) from Day 1, Week 1 of treatment. AEs will be 
documented at every visit by the study staff or clinic nurses. Subjects may report AEs at any point 
during the study (clinic visits, on diaries, by phone or email, etc.) The PI and/or delegated 
designee will evaluate and assess all AEs based on NCI CTCAE v5. 
 
Definitions 
Adverse Event (AE) 
An AE is any symptom, sign, illness or experience that develops or worsens in severity during the 
course of the study, whether or not it has a causal relationship to the study treatment. Concurrent 
illnesses or injuries should be regarded as AEs. Abnormal results of diagnostic procedures are 
considered AEs if the abnormality: 
 
results in study withdrawal 
 
is associated with a serious AE 
 
is associated with clinical signs or symptoms 
 
leads to additional treatment or to further diagnostic tests 
 
is considered by the investigator to be of clinical significance 
 
Serious Adverse Event (SAE) 
An event is “serious” if it involves considerable detriment or harm to one or more persons (who 
may or may not be subjects), or required intervention to prevent one or more persons from 
experiencing considerable detriment or harm. SAEs include: 
 
Death 
 
Life-threatening experience - Disease or condition where the likelihood of death is high unless 
the course of the disease/condition is interrupted or diseases/conditions with potentially fatal 
outcomes where the end point of the clinical trial analysis is survival 
 
Inpatient hospitalization or prolongation of hospitalization 
 
Persistent or significant disability/incapacity 
 
Congenital anomaly/birth defect in subject’s offspring 
 
Any other important medical event that, based upon appropriate medical judgment, may 
jeopardize the subject and may require medical or surgical intervention to prevent one of the 
outcomes listed above. Examples include allergic bronchospasm requiring intensive treatment 
in an emergency room or at home, blood dyscrasias or convulsions that do not result in 
inpatient hospitalization, the development of drug dependency or drug abuse, suicidal ideation 
or attempts, or the unintentional revealing of some genetic information to insurers. 
 
To avoid confusion, as the terms “serious” and “severe” are not synonymous, the following 
clarification is given: The term “severe” is often used to describe the intensity (severity) of a 
specific event (as in mild, moderate or severe myocardial infarction); the event itself, however, 
may be of relatively minor medical significance (such as severe headache). This is not the same 
as “serious,” which is based on subject/event outcome or action usually associated with events 
that pose a threat to a subject’s life or functioning. Seriousness (not severity) serves as a guide 
for defining regulatory reporting obligations. [ICH-E2A(II)(B)] 
 
Related 
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Unexpected 
An event is “unexpected” when its specificity, nature, severity, or incidence is not accurately 
reflected in the consent form, protocol, or investigator’s brochure previously reviewed and 
approved by the IRB. Examples include a lower rate of response to treatment or a side effect that 
is more severe than initially expected. 
 
Study Period 
Following consent (i.e. study entry), baselines/pre-existing conditions will be assessed until 
initiation of study treatment. All AEs will then be recorded through the end of the designated follow-
up period (i.e. week 12, ±1 week). All AEs will be recorded within the research database AR-
Adverse Events Reporting System (AR-AERS). 
 
Abnormal Laboratory Values Defined as AEs 
An abnormal laboratory value is considered an AE if the laboratory abnormality is characterized 
by any of the following, for test done as part of the research protocol: 
 
Results in discontinuation from the study 
 
Requires treatment, modification of study treatment dose, or other therapeutic intervention 
 
Is judged by the Investigator to be of significant clinical impact/importance 
 
Grade 3 or Grade 4 lab abnormalities regardless of significance 
If a laboratory abnormality is one component of a diagnosis or syndrome, then only the diagnosis 
or syndrome should be recorded as an AE. If the laboratory abnormality was not a part of a 
diagnosis or syndrome, then the abnormality should be recorded as the AE. 
 
Estradiol levels will be measured at baseline and 12 weeks (±1 week) from Day 1, Week 1 of 
treatment. A report will be sent to FDA for any subject with an estradiol level out of the normal 
postmenopausal range at 12 weeks (±1 week) from Day 1, Week 1 of treatment. 
 
Monitoring, Recording and Reporting of AEs 
All relevant historical medical conditions, laboratory abnormalities, or physical findings with an 
onset date prior to the subject signing consent (present at Baseline) are considered to be pre-
existing in nature and will be recorded as part of the subject’s medical history (not as AEs). All 
AEs, which completely resolve and then recur, should be recorded as a new AE, regardless of 
whether it is related or not. In addition to new events, any increase in the severity or frequency of 
a pre-existing condition that occurs after the first administration of the study drug is considered 
an AE. If the study subject’s condition deteriorates or exacerbates at any time during the study, it 
will be recorded as an AE. 
 
All AEs occurring during the study period must be recorded. The clinical course of each event 
should be followed until resolution, stabilization, or until it has been determined that the study 
treatment or participation is not the cause. SAEs that are still ongoing at the end of the study 
period must be followed for up to 30 days to determine the final outcome. Any SAE that occurs 
after the study period and is considered to be definitely/probably/possibly related to the study 
treatment or study participation should be recorded and reported immediately to the Sponsor. 
 
All AEs and SAEs will be captured on the appropriate case report form (CRF). Information to be 
collected includes event description, time of onset, clinician’s assessment of severity, relationship 
to study product (assessed only by those with the training and authority to make a diagnosis), and 
time of resolution/ stabilization of the event. All AEs occurring while on study must be documented 
appropriately regardless of relationship. All AEs will be followed until adequate resolution or to 
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All subjects will be monitored for AEs during the study. Assessments may include monitoring the 
subject’s clinical symptoms; laboratory, pathological, radiological, or surgical findings; physical 
examination; or other appropriate tests and procedures. 
 
AE data collection and reporting, which are required as part of every study, are done to ensure 
the safety of subjects enrolled in the studies and those who will enroll in future protocols. AEs are 
to be reported in a routine fashion at scheduled times during the trial, such as with the annual 
continuing review to the IRB. Certain AEs must be reported in an expedited fashion to allow for 
timely monitoring of subject safety and care. 
 
The reporting of these events depends on the characteristics of the event: 
1. Seriousness (grading of event) 
2. Relatedness to study therapy 
3. Expectedness 
 
Steps to Determine if the Event Requires Expedited Reporting: 
1. Identify the type of event using NCI CTCAE version 5.0 
2. Grade the event using NCI CTCAE version 5.0 
3. Determine whether the AE is related to the investigational drug. Attribution categories are as 
follows: 
 
Unrelated 
 
Unlikely 
 
Possible 
 
Probable 
 
Definite 
4. Determine expectedness of event. Expected events are those previously identified resulting 
from administration of the agent. An AE is considered unexpected when the type or severity 
of the event is not listed in the: 
 
Package inserts 
 
Protocol 
 
Note: This includes all events that occur within 30 days of the last dose of protocol treatment. Any 
event occurring more than 30 days after the last dose that is possible, probably, or definitely 
attributable to the investigational drug must be reported according to the instructions above. 
 
Expedited Reporting of AEs 
Institutional Review Board Reporting 
Only AEs meeting the UPIRTSO (Unanticipated Problem Involving Risks to Subjects or Others) 
will need to be reported to the UAMS IRB within the required 10-day allotment of being notified of 
the event. UPIRTSO requires that an unanticipated problem meet the following qualifications: a) 
unanticipated or unexpected; b) related to the research; and c) involves new or increased risk to 
the subject(s). All other AEs should be recorded and reported to the UAMS IRB at continuing 
review. 
 
Sponsor Reporting 
The Sponsor will be promptly notified of all SAEs that are definitely/probably/possibly related to 
the study intervention. These SAEs will be reported to the Sponsor using the FDA MedWatch 
3500A. SAEs that are definitely/probably/possibly related and unanticipated/unexpected will be 
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report all events to FDA in accordance with 21 CFR 312. 
 
All other SAEs will be reported to the Sponsor and FDA in the Annual Progress Report. 
 
Deaths that are related to research will be reported to the Sponsor immediately upon Investigator 
notification. A death due to a terminal condition of the research subject would be considered 
anticipated and not related to the research. 
 
THE SPONSOR WILL REPORT DEATHS TO FDA IN ACCORDANCE WITH 21 CFR 312. 
 
Monitoring 
The PI will have the overall responsibility for assuring safety and gathering the data for the study 
with assistance from the sub-investigators, and research staff, under the guidance of the 
Institutional Review Board (IRB) and the study Sponsor. Clinical site monitoring will be conducted 
on behalf of the Sponsor, UAMS, by the Office of Research Regulatory Affairs (ORRA), to ensure 
that the rights and well-being of human subjects are protected; the trial data are accurate, 
complete and verifiable from source documents; and the trial is conducted in compliance with 
currently approved protocol/amendment(s), ICH GCP, and applicable regulatory requirements. 
 
Monitoring specialists from ORRA will conduct periodic on-site, comprehensive monitoring as 
determined by a protocol-specific monitoring plan, as provided by the ORRA Monitoring Unit. 
 
Study Discontinuation 
The Medical Monitor will review ALL Grade 3 or higher AEs, using the NCI CTCAE v5.0. Grade 
3 AEs are severe or medically significant events (but not immediately life-threatening), 
hospitalization, or prolongation of hospitalization. The Medical Monitor may choose to halt the 
study temporarily if serious concerns arise regarding subject safety. 
 
Individual Subject Stopping Rules 
Any subject who experiences a grade 3 or higher related AE will discontinue study treatment. The 
study will be suspended if any subject experiences grade IV or higher related AE. These activities 
can re-start only after notifying the applicable regulatory authorities and with a permission to 
resume from the Medical Monitor and Sponsor. 
 
Study Stopping Rules 
After accrual of the first six subjects who have been randomly assigned to the Intrarosa® arm, 
enrollment will be paused until the Medical Monitor has reviewed all Grade 3 or higher AEs in this 
cohort. The Medical Monitor may begin reviewing the AEs as soon as enrollment is paused; 
however, review of AEs will continue until each subject in the cohort has either completed study 
treatment or has otherwise stopped study treatment (see Subject Withdrawal and Subject 
Termination sections below). If two or fewer subjects (total, regardless of assigned treatment arm) 
experience a Grade 3 or higher related AE, the study will reopen to enrollment until six more 
subjects have been randomly assigned to the Intrarosa® arm. Enrollment will once again be 
paused until the Medical Monitor has reviewed all Grade 3 or higher AEs and approves additional 
enrollment. Enrollment will continue in cohorts in this manner until either all 60 subjects have been 
accrued or the study is terminated. If at any point in the study, three or more subjects (cumulative, 
including both arms) experience Grade 3 or higher related AEs, the study will be terminated. 
 
If the study is prematurely terminated or suspended, the Principal Investigator (PI) will promptly 
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suspension. Study subjects will be contacted, as applicable, and be informed of changes to study 
visit schedule. If only suspended the study may resume once all concerns have been addressed, 
and satisfy the Sponsor, IRB, and/or the FDA. 
 
Protocol Deviations and Violations 
Deviations 
Protocol Deviation: any unintentional change, divergence, or departure from the study design or 
procedures defined in the protocol. Protocol deviations will be tracked and compiled in a Protocol 
Deviation Log. Deviations should be reported to the IRB at the time of Continuing Review and at 
the time of the Annual Progress Report (APR). Deviations that potentially cause concern for the 
subject health, safety, or rights will be reported to ORRA, the Sponsor, as soon as possible for 
guidance on reporting. Deviations will be made available for Monitors to check against source 
data at each monitoring visit. 
 
Violations 
Protocol violation: a change to, or non-compliance with the IRB-approved procedures without 
prior Sponsor and IRB approval. Violation may affect health, safety, or rights of a subject. Any 
violation will be reported immediately to the Sponsor for guidance on reporting. Violations will be 
made available for Monitors to check against source data at each monitoring visit. 
 
If the protocol deviation/protocol violation does not represent a significant alteration in the 
approved protocol and/or affect the safety or welfare of the subject, it will be reported to the UAMS 
IRB at the time of Continuing Review. If the protocol deviation or protocol violation represents a 
significant alteration in the approved protocol and/or if it affects the safety or welfare of the subject, 
it must be reported to the UAMS IRB immediately. 
 
Compliance 
All drug boxes and unused product will be collected from subject at last visit by research staff and 
will be given to the research pharmacy to log for compliance. No serious harm is anticipated from 
non-adherence or cessation of use of the investigational products. 
 
Subject Withdrawal 
Subjects may withdraw from treatment or consent from the study at any time for any reason, 
without penalty.  
 
Subjects who voluntarily withdraw from study treatment will stop taking the study drug but will still 
participate in the research-related assessments. These research-related assessments include 
physical exam (including clinical breast and gynecological exam for pH and VMI), estradiol level, 
completion of BSSC-W, QOL-CSV, and FSFI, and reporting of AEs until the end of the study 
duration [i.e., Week 12 (±1 week)].   
 
Subjects who withdraw consent from the study will stop taking the study drug and all research-
related assessments will be ceased.  Any data previously collected will be used but no further 
data will be collected following the subject’s withdrawal of consent. Subjects will be encouraged 
to report AEs thought to be possibly/probably related to the study drug for 30 days after 
discontinuation. 
 
For evaluation and reporting purposes, reasons for early withdrawal may be discussed with willing 
subjects for purposes of identifying potential problems with the drug or study design. When 
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result of the study intervention may recede and a return to the pre-study baseline can be expected. 
 
Subject Termination 
An investigator may terminate a subject’s participation from the study drug treatment to protect 
the subject from excessive risk without demonstrated benefit (e.g., a side effect such an allergic 
response making symptoms worsen instead of improve).   
 
Additionally, in the interest of protecting the integrity of the data, an investigator may terminate a 
subject’s participation from the study all together if the subject is not following procedures or is 
deliberately falsifying information. In the event of termination, the investigator will explain the 
reasons to the subject and discuss other available treatment options. The subject will refrain from 
using the study drug and return unused product and packaging for drug accountability. The 
subject will be instructed to return the completed diary and refrain from using the study drug for 
30 days after discontinuation. The subject will also be instructed to report any AEs that occur 
during the 30 days following drug discontinuation via phone or email to the clinical research nurse. 
Subjects will be contacted 30 days (+3 days) from the date of drug discontinuation by the clinical 
research nurse for final safety evaluation.  The subject’s study status will be listed as ‘Withdrawn’ 
and the date of withdrawal will be 30 days (+3 days) after discontinuation. Subjects may obtain 
drug (Intrarosa® or Replens™) and resume use at their own discretion after the 30-day time period 
has elapsed after discontinuation. 
 
Specimen Handling and Storage 
Vaginal smears will be obtained by scraping the second third of the sidewall of the vagina. A 100-
cell count will be performed to classify cells as S, I, and P. Vaginal pH will be measured using a 
pH indicator strip directly applied to the lateral wall of the vagina. The swab of the vaginal mucosa 
will be collected during the gynecologic exam, labeled and placed in sterile solution, sent for 
determination of VMI, then discarded per the usual cytology lab protocol. 
 
Data Analysis 
Efficacy and Safety Populations 
The efficacy population will include all subjects with a baseline assessment who have received at 
least two weeks of treatment with either Intrarosa® or Replens™. Subjects who discontinue 
participation in the study (stop the assigned treatment, withdraw consent, etc.) before 2 weeks of 
treatment will not be included in the efficacy population. Subjects who discontinue participation in 
the study after 2 weeks but prior to 12 weeks will be included in the efficacy analysis. These 
subjects will be invited to complete the end of study evaluation at the time of discontinuation; 
these evaluation values will be included in the efficacy analyses. 
 
The safety population will include all subjects who received at least one administration of either 
Intrarosa® or Replens™. 
 
Efficacy Endpoints 
The primary efficacy endpoint is VMI Response, which is defined as the change in the subject’s 
calculated VMI from baseline to the end of treatment at 12 (±1 week). 
 
Secondary efficacy endpoints: Secondary efficacy endpoints for all study subjects will be 
determined both at baseline and at the end of treatment. They consist of the following: 
 
Vaginal pH, 
 
Dyspareunia and vaginal dryness scores on the BSSC-W and the FSFI, 
 
Quality of life using the QOL-CSV. 


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Analysis Plan 
Descriptive Analysis: Each efficacy endpoint will be summarized by treatment group and time 
point as the mean, standard deviation (SD), minimum, 1st quartile, median, 3rd quartile, and 
maximum. Within each subject, the endpoint’s response to treatment will be defined (and 
calculated) as the endpoint’s value at 12 weeks minus its value at baseline; the resulting endpoint 
responses will be summarized by treatment group as the mean, SD, minimum, 1st quartile, 
median, 3rd quartile, and maximum. Graphical displays will consist of box plots and scatter plots 
along with profile plots, a.k.a. “spaghetti plots”, that show how the individual subjects respond 
over time to their assigned treatment. Adherence to distributional assumptions will be assessed, 
and data transformation to increase such adherence will be implemented, if warranted. 
 
Primary Efficacy Analyses: To determine each treatment arm’s VMI response to treatment, the 
Intrarosa® arm will be compared to the Replens™ arm for the difference in their VMI responses 
using Student’s t-test if group variances are equal, Welch’s t-test if group variances are unequal, 
or Wilcoxon’s rank-sum test if data violate normality assumptions. In keeping with the research 
hypothesis that the Intrarosa® arm will exhibit greater improvement in the VMI when compared to 
the Replens™ arm after 12 weeks (±1 week) of treatment, this primary-efficacy comparison will 
be conducted using a one-sided test at an α = 0.05 significance level to look specifically for 
increased VMI response in the Intrarosa® arm. The follow-up of this primary-efficacy comparison 
will be analyzed using an ANCOVA model that has 12-week VMI as the outcome variable, 
treatment arm as the factor of interest, and baseline VMI as the continuous covariate. 
 
Secondary Efficacy Analyses: For each secondary endpoint, the treatment arms will be compared 
for a difference in the endpoint at baseline, a difference in the endpoint at 12 weeks (±1 week), 
and a difference in the endpoint’s response to treatment. All comparisons will be conducted using 
1-sided tests that employ a multiple-comparison-adjusted α = 0.01 significance level to look 
specifically for improvements with Intrarosa® compared to Replens™. The tests will consist of 
Student’s t-test, Welch’s t-test, or Wilcoxon’s rank-sum test depending on the endpoint’s 
adherence to distributional assumptions. In follow-up analysis, each secondary endpoint will be 
analyzed using an ANCOVA model that has the endpoint’s 12-week value as the outcome, 
treatment arm as the factor of interest, and endpoint’s baseline value as the continuous covariate. 
 
Sample Size and Power: The study is powered to detect an effect size of 0.8 SDs for the expected 
improvement in VMI response among subjects on the Intrarosa® arm compared to subjects on 
the Replens™ arm. Specifically, if the study meets its enrollment goal of 60 subjects (30 in each 
treatment arm), then 30 subjects per arm provide Student’s t-test and Wilcoxon’s rank-sum test 
(both 1-sided at α = 0.05) with 92.2% power and 91.2% power, respectively, to detect an effect 
size of 0.8 SDs in VMI response. Moreover, even if the study were to suffer an attrition rate of 
20%, then the remaining 24 subjects per arm (48 subjects that remain) still provide Student’s t-
test and Wilcoxon’s rank-sum test (both 1-sided at α = 0.05) with 86.1% power and 84.9% power, 
respectively, to detect an effect size of 0.8 SDs in VMI response. 
 
To see that a 0.8-SD effect size is reasonable for VMI response, we call attention to the studies 
of Archer et al. [14] and Labrie et al. [8]. Although neither study utilized VMI itself as the outcome, 
both studies utilized the percentages of P and S cells as outcomes when reporting the 12-week 
differences they observed between their DHEA (6.5mg) arms and their placebo arms. Archer et 
al. [14] observed treatment-arm differences of 1.52 SDs in %P cells and 1.02 SDs in %S cells at 
12 weeks, whereas Labrie et al. [8] observed treatment-arm differences of 1.11 SDs in %P cells 
and 0.99 SDs in %S cells at 12 weeks. These prior observations of ≥ 1-SD effect sizes for VMI-
related endpoints show that it is reasonable to expect an effect size of 0.8 SDs for VMI response, 


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and thus that our study has sufficient power to achieve its research objectives. 
 
Ethical Considerations 
This study will be conducted in accordance with all applicable government regulations and 
University of Arkansas for Medical Sciences research policies and procedures. This protocol and 
any amendments will be submitted and approved by the UAMS Institutional Review Board (IRB) 
to conduct the study. 
 
A Partial HIPAA Waiver for Recruitment will permit study staff to prescreen potential subjects prior 
to obtaining consent/HIPAA authorization to determine use of prohibited medical products 
requiring either an 8-week or 6-month washout in order to meet eligibility. 
 
The formal consent of each subject will be obtained at UAMS before that subject is submitted to 
any study procedure using an IRB-approved consent form, which will describe this study and 
provide sufficient information in language suitable for subjects to make an informed decision about 
their participation in this study. The person obtaining consent will thoroughly explain each element 
of the document and outline the risks and benefits, alternate treatment(s), and requirements of 
the study. The consent process will take place in a quiet and private room, and subjects may take 
as much time as needed to make a decision about their participation. Participation privacy will be 
maintained and questions regarding participation will be answered. No coercion or undue 
influence will be used in the consent process. This consent form will be signed by the subject or 
legally authorized representative, and the individual obtaining the consent. A copy of the signed 
consent will be given to the subject, and the informed consent process will be documented in 
each subject’s research record. 
 
Dissemination of Data 
Results of this study may be used for presentations, posters, or publications. The publications will 
not contain any identifiable information that could be linked to a subject. The study will be listed 
on clinicaltrials.gov in accordance with FDA requirements. 
 
 


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2. Baumgart, Juliane, et al. “Sexual Dysfunction in Women on Adjuvant Endocrine Therapy after 
Breast Cancer.” Menopause: The Journal of The North American Menopause Society, 2012, p. 1, 
doi:10.1097/gme.0b013e31826560da. 
3. Sinha, A., and A. A. A. Ewies. “Non-Hormonal Topical Treatment of Vulvovaginal Atrophy: an up-
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5. Chollet, Janet A. “Efficacy and Safety of Ultra-Low-Dose Vagifem (10 Mcg).” Patient Preference 
and Adherence, 2011, p. 571, doi:10.2147/ppa.s22940. 
6. Basson R. Pharmacotherapy for women's sexual dysfunction. Expert Opin Pharmacother. 2009 
Jul;10(10):1631-48. doi: 10.1517/14656560903004184. 
7. Ke, Y, Gonthier R, Simard, Archer D, Lavoie L, Martel C, Vaillancourt M, Labrie F. Serum steroids 
remain within the same normal postmenopausal values during 12-month intravaginal 0.50% 
DHEA. Horm Mol Biol Clin Investig. 2015 Dec;24(3):117-29. doi: 10.1515/hmbci-2015-0035. 
8. Barton, Debra L., et al. “Evaluating the Efficacy of Vaginal Dehydroepiandrosterone for Vaginal 
Symptoms in Postmenopausal Cancer Survivors: NCCTG N10C1 (Alliance).” Supportive Care in 
Cancer, vol. 26, no. 2, 2018, pp. 643-650., doi:10.1007/s00520-017-3878-2. 
9. Labrie F, Fernand, et al. “Efficacy of Intravaginal Dehydroepiandrosterone (DHEA) on Moderate 
to Severe Dyspareunia and Vaginal Dryness, Symptoms of Vulvovaginal Atrophy, and of the 
Genitourinary Syndrome of Menopause.” Menopause, vol. 25, no. 11, 2018, pp. 1339–1353., 
doi:10.1097/gme.0000000000001238. 
10. Lester, Joanne, et al. “Atrophic Vaginitis in Breast Cancer Survivors: A Difficult Survivorship Issue.” 
Journal of Personalized Medicine, 2015, vol. 5, pp. 50-66. doi: 10.3390/jpm5020050. 
11. Hatzichristou D, Rosen RC, et al. “Recommendations for the clinical evaluation of men and women 
with sexual dysfunction.” Journal of Sexual Medicine, vol. 7, pp. 337-48. doi: 10.1111/j.1743-
6109.2009.01619.x. 
12. Rosen R, et al. “The Female Sexual Function Index (FSFI): a multidimensional self- report 
instrument for the assessment of female function.” J Sex Marital Ther. 2000;26(2):191. 
13. Ferrell, B. R., Hassey-Dow, K., Grant, M. (2012). Quality of Life Patient/Cancer Survivor Version 
(QOL-CSV) Measurement Instrument Database for the Social Science. Retrieved from 
www.midss.ie 
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2019 from www.accessdata.fda.gov/drugsatfda_docs/label/2016/208470s000lbl.pdf 
15. Archer DF, Labrie F, et al. “Treatment of pain at sexual activity (dyspareunia) with intravaginal 
dehydroepiandrosterone (prasterone).” Menopause, vol 22(9), Sep 2015, pp. 950-63. 
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JM, 
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Apr;26(4):1335-1343. doi: 10.1007/s00520-017-3960-9. Epub 2017 Nov 21. 


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Appendices 
Appendix A: Study Calendar 
 
Pre-
Study/Baselinea Day1, Week 1b Week 2-12 
End of 
Treatmentc  
Determine eligibility for study: 
x 
 
 
 
Study consent discussed and signed 
x 
 
 
 
Pregnancy testd 
x 
 
 
 
Collect relevant disease-related data (mammogram, Pap 
smear)e, FSH levelf, baseline conditions, height, weight, and 
medical history 
x 
 
 
 
Complete BSSC-W 
 xg 
 
 
xg 
Complete FSFIh 
 xg 
 
 
xg 
Complete DHEA Trial Clinical Supplemental Survey 
 xg 
 
 
 
Physical exam (including gynecologici and breast exams) 
x 
 
 
xj 
Vaginal pH to be determined 
x 
 
 
x 
Swab of vaginal epithelium collected and sent to pathology 
to calculate VMIk 
x 
 
 
x 
Estradiol levell 
x 
 
 
x 
Complete QOL-CSV 
 xg 
 
 
xg 
Randomize to treatment arm 
x 
 
 
 
Assigned treatment and study diaries dispensed to subject 
 
x 
 
 
Self-administration (starts same day as dispensed) 
 Intrarosa® 6.5 mg insert nightly 
 
~OR~ 
 Replens™ 6.7 g prefilled applicator intravaginal two non-
consecutive nights weekly 
 
x 
x 
 
Collect AEsm 
 
x 
x 
x 
Diary Submissions 
 
 
Xn 
Xo 
Drug boxes and unused products collected from subject 
 
 
 
x 
Follow up call  
 
 
     xp,q 
 
                                                          
a   Pre-study/Baseline should be completed within 28 days prior to Day 1, Week 1. 
b  Day 1, Week 1 visit may be done the same day as Pre-Study/Baseline visit if all Pre-Study/Baseline activities are completed and eligibility has been  
     confirmed prior to Day 1, Week 1 activities. 
c    End of Treatment should be completed at week 12 from Day 1, Week 1, i.e., Week 12 ±1 week). 
d  Subjects who are post-menopausal will not require a pregnancy test. SoC pregnancy test results may be used if completed within 7 days of Day 1,  
     Week 1. 
e  Mammogram (if deemed appropriate by the treating physician) and normal Pap must be documented within 12 months prior to study entry. If these  
     are not documented in the medical history, they will be obtained for the study. SoC Pap and mammogram (if appropriate) may be used if completed  
     within 28 days of Day 1, Week 1. Pap is not required for females whose cervix has been removed by surgery for reasons not related to cervical cancer  
     or serious cervical pre-cancer. 
f    If  FSH level is not documented in the medical history, one will be obtained prior to study entry. 
g   Should be completed in-person but can be completed over the phone, if necessary. 
h   FSFI is to be completed only if participant answers no to question 1 on the coinciding BSSC-W.  
i    Gynecologic exam, including vaginal pH and VMI activities can take place on the same day as consent and Day 1, Week 1 as long they are completed  
     after consent, all other eligibility criteria have been met, and prior to Day 1, Week 1 activities. SoC breast and pelvic exams may be used if completed  
     within 28 days of Day 1, Week 1. 
j    During the gynecologic exam, a Pap smear may be performed at the treating physician’s discretion if abnormal cervical changes are suspected. 
k   If the VMI results are “unsatisfactory”, the swab of vaginal epithelium will need to be recollected within 4 weeks of Day 1, Week 1 to calculate a new  
     VMI. 
l    A report will be sent to FDA for any subject with an estradiol level out of the normal postmenopausal range at week 12 (±1 week). 
m  All AEs reported during clinic visits, on diaries, by phone or email, etc. are to be documented, assessed by the PI or designee, and tabulated. 
n  Diary progress should be submitted after Week 4 (±1 week), Week 8 (±1 week) of treatment.  Diaries can be submitted in person, via self-addressed  
     envelope to CTO, text photos to the research nurse cellphone, email photos to the research nurse email, sent photos through MyChart, or faxed to  
     CTO.  There will be no deviation for subjects who do not submit diary progress at Week 4 or Week 8. 
o  Diary progress should be submitted after Week 12 (±1 week) of treatment, or end of treatment.  Diaries can be submitted in person, via self-addressed  
     envelope to CTO, text photos to the research nurse cellphone, email photos to the research nurse email, sent photos through MyChart, or faxed to  
    CTO. There will be a deviation for subjects who do not submit diary progress at Week 12 or if they come off treatment early.    
p  Follow-up call should occur at 1 week ±3 days after Day 1, Week 1. 
q  Follow-up call should occur at 6 weeks ±1 week after Day 1, Week 1. 


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Appendix B. Eligibility Flow Diagram 
 
INCLUSION CRITERIA: 
 Females, ages 18-70 
 Postmenopausal patients with a history of breast cancer 
who have completed primary treatment with curative intent 
and currently are on an AI and have been for ≥6 months 
 DCIS or Stage I-III, hormone-receptor positive breast 
cancer regardless of HER2 status 
 Postmenopause defined as ≥ 12 months spontaneous 
amenorrhea, ≥ 6 months spontaneous amenorrhea with 
serum FSH levels > 40 mIU/mL, or ≥ 6 weeks postsurgical 
bilateral oophorectomy with or without hysterectomy 
 Reported dissatisfaction with sexual function on Question 1 
of the BSSC-W 
 No planned changes in AI during the study period 
 Mammogram within 12 months prior to study entry 
(if deemed appropriate by the treating physician) 
 Normal Pap within 12 months prior to study entry 
(i.e. negative Pap results consistent with ACS guidelines). 
Females whose cervix has been removed by surgery for 
reasons not related to cervical cancer or serious cervical 
pre-cancer (e.g., CIN 2 or 3 (HSIL, moderate or severe 
dysplasia) or AIS) may be excluded from this requirement. 
EXCLUSION CRITERIA: 
 Use of any estrogen or progesterone depot preparation or 
progestin implant, androgen or anabolic steroids, or natural 
over-the-counter 
estrogenic 
products 
without 
6-month washout period 
 Use of any oral or transdermal hormonal products 
(estrogen, progestin, or DHEA), or vaginal or intrauterine 
hormonal products without 6-month washout period 
 Concomitant vulvar and vaginal surgical or laser treatments 
 Vaginal infection or confounding vulvar or active vaginal 
disease process 
 Active malignant breast or gynecologic disease 
 History of radiation to the pelvis or prior gynecologic cancer 
or pre-cancer 
 Inability to tolerate a vaginal/speculum exam 
 Undiagnosed persistent or recurring genital bleeding or 
other indication of active pelvic disease process 
 Clinically significant uncontrolled depression or severe 
psychiatric symptoms 
60 patients who meet study criteria 
30 subjects in active control group: 
Replens™ 6.7 g vaginal prefilled applicator two nights 
weekly for 12 weeks (±1 week) from Day 1, Week1 
Note: Thirty subjects/arm (60 subjects) give the 1-sided Student’s t-test 92.2% power at α = 0.05 to detect 
a 0.8-SD increase in VMI Response with Intrarosa® compared to Replens™. Under 20% attrition, 
the remaining 24 subject/arm (48 subjects) still provide the 1-sided Student’s t-test with 86.1% 
power at α = 0.05 to detect the 0.8-SD increase in VMI Response. 
Randomization 
Postmenopausal breast cancer survivors who have completed primary treatment with 
curative intent and are on AI for > 6 months with vaginal symptoms identified at UAMS 
Cancer and Women’s Health Clinics and CARTI Cancer Center. 
30 subjects in the investigational group: 
Intrarosa® 6.5 mg vaginal insert nightly for 12 
weeks (±1 week) from Day 1, Week1