Clinical trial NCT04544475
Conditions: Genitourinary Syndrome of Menopause (GSM)
Sponsor: NYU Langone Health
Start date: 2021-09-01; Completion date: 2022-10-03
Enrollment: 49 participants; Allocation: RANDOMIZED; Intervention model: PARALLEL

Brief summary:
Non-hormonal alternatives for the treatment of genitourinary syndrome of menopause (GSM) are needed. In this proposed trial, patients who are diagnosed with GSM will be randomized to receive either a hyaluronic acid (HLA) vaginal insert or vaginal estrogen topical cream for 12 weeks. There will be a baseline visit and an 12 week follow up visit, at which points the patient will undergo a detailed history and physical examination including a pelvic exam, vaginal pH sampling, vaginal cell sample for microscopic analysis, and will fill out a vulvovaginal symptom questionnaire (VSQ). These study arms will be analyzed to assess the efficacy of HLA as compared to the gold standard of vaginal estrogen to treat GSM symptoms.

Detailed description:

Arms: arm 1: None arm 2: None
Interventions: intervention 1: Revaree intervention 2: Estrace
Intervention descriptions: intervention 1: Hyaluronic Acid Vaginal Insert (Revaree). A 2g vaginal insert that contains 5mg of HLA sodium salt and a base of semi-synthetic glycerides. It is an insert that does not require an applicator and should be placed in the vagina while laying down twice weekly. intervention 2: Vaginal estrogen cream, estradiol: 100mcg

Protocol documents:
Prot_SAP_000.pdf: 
 
 
Official Title: 
A Randomized, Single Center Pilot Study Comparing Hyaluronic Acid to 
Vaginal Estrogen for Treatment of Genitourinary Syndrome of 
Menopause   
NCT Number: 
NCT04544475 
Study Number: 
19-01922 
Document Type:  
Study Protocol and Statistical Analysis Plan 
Date of the 
Document: 
• 
August 1, 2022 
 
 


 
 
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authorized in writing by the study sponsor 
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Tool Revision History: 
 
Version Number Version Date 
Summary of Revisions Made 
1.0 
08/26/20 
Original version 
1.1 
7/6/21 
Modification Request 
1.2 
9/26/21 
Modification Request 
1.3 
7/21/22 
Modification Request 
 
 


 
 
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A randomized, single center pilot study comparing hyaluronic acid 
to vaginal estrogen for treatment of genitourinary syndrome of 
menopause 
 
Principal Investigator: 
 
Dr. Lila Nachtigall 
Gynecology 
251 E 33rd St, New York, NY 10016 
Lila.Nachtigall@nyulangone.org 
212-263-6361 
Additional Investigators: 
 
Dr. Benjamin Brucker 
Female Pelvic Medicine and Reconstructive Surgery 
222 E. 41st 11th Floor  
Benjamin.Brucker@nyulangone.org 
(646) 754-2404  
 
Dr. Christina Escobar 
Female Pelvic Medicine and Reconstructive Surgery 
222 E. 41st 11th Floor  
Christina.Escobar@nyulangone.org 
(646) 825-6324 
 
Dr. Zoe Lapier 
Female Pelvic Medicine and Reconstructive Surgery 
222 E. 41st 11th Floor  
Zoe.lapier@nyulangone.org 
(646) 825-6324 
 
Dr. Surbhi Agrawal (Collaborator) 
Female Pelvic and Reconstructive Surgery 
University of Pennsylvania, Philadelphia, PA 
Surbhi.agrawal14@gmail.com 
(240) 418-9399 
Due to her previous knowledge of the study as part of the 
research team, she will now be an outside collaborator from the 
University of Pennsylvania. She will participate in non-PHI data 
analysis. She will have no access to PHI; nor will she have a 
hands-on role at any NYU location. 
 
Dr. Antoinette Oot 
Obstetrics & Gynecology 
462 1st Avenue, New York, NY 10016 
antoinette.oot@nyulangone.org 
(603) 689-4907 


 
 
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Dr. Maria Smith 
Obstetrics & Gynecology 
462 1st Avenue, New York, NY 10016 
Maria.Smith@nyulangone.org 
(715) 559-5448 
 
Dr. Shavy Nagpal 
Female Pelvic Medicine and Reconstructive Surgery 
222 E. 41st 11th Floor  
Shavy.nagpal@nyulangone.org 
(646) 825-6324 
 
Dr. Erinn Hade 
Biostatistics, Department of Population Health 
180 Madison Avenue, Suite 5-53 
Erinn.Hade@nyulangone.org 
(646) 501-3742 
 
Steven Friedman 
Biostatistics, Department of Population Health 
180 Madison Avenue, Suite 5-53 
Steven.Friedman2@nyulangone.org  
(646) 501-3737 
 
 
 
NYULMC Study 
Number: 
s19-01922 
Funding Sponsor: 
JDS Therapeutics 
1 Manhattanville Road, Suite 104, Purchase, NY 10577 
(914) 701-4508 
IND/IDE Number:  
N/A 
Regulatory Sponsor:  
N/A 
Study Product: 
Hyaluronic acid vaginal insert, Revaree 
Study Product Provider:  JDS Therapeutics 
ClinicalTrials.gov 
Number                 
NCT04544475 
 
Initial version: 08/07/2020 
 
 


Study number: s19-01922 
 
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Statement of Compliance 
 
This study will be conducted in accordance with the Code of Federal Regulations on the 
Protection of Human Subjects (45 CFR Part 46), 21 CFR Parts 50, 56, 312, and 812 as 
applicable, any other applicable US government research regulations, and institutional research 
policies and procedures. The International Conference on Harmonisation (“ICH”) Guideline for 
Good Clinical Practice (“GCP”) (sometimes referred to as “ICH-GCP” or “E6”) will be applied 
only to the extent that it is compatible with FDA and DHHS regulations. The Principal 
Investigator will assure that no deviation from, or changes to the protocol will take place without 
prior agreement from the sponsor and documented approval from the Institutional Review Board 
(IRB), except where necessary to eliminate an immediate hazard(s) to the trial participants. All 
personnel involved in the conduct of this study have completed Human Subjects Protection 
Training. 
 
 


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Table of Contents 
 
STATEMENT OF COMPLIANCE ................................................................................................................ IV 
LIST OF ABBREVIATIONS....................................................................................................................... VIII 
PROTOCOL SUMMARY .............................................................................................................................. 1 
SCHEMATIC OF STUDY DESIGN ............................................................................................................... 3 
1 
KEY ROLES ......................................................................................................................................... 4 
2 
INTRODUCTION, BACKGROUND INFORMATION AND SCIENTIFIC RATIONALE ....................... 5 
2.1 
BACKGROUND INFORMATION AND RELEVANT LITERATURE ................................................................ 5 
2.2 
NAME AND DESCRIPTION OF THE INVESTIGATIONAL AGENT .............................................................. 8 
2.2.1 
Preclinical Data........................................................................................................................ 8 
2.2.2 
Clinical Data to Date ................................................................................................................ 8 
2.2.3 
Dose Rationale (if applicable) ................................................................................................. 9 
2.3 
RATIONALE .................................................................................................................................... 9 
2.4 
POTENTIAL RISKS & BENEFITS ...................................................................................................... 10 
2.4.1 
Known Potential Risks ........................................................................................................... 10 
2.4.2 
Known Potential Benefits ...................................................................................................... 11 
3 
OBJECTIVES AND PURPOSE ......................................................................................................... 11 
3.1 
PRIMARY OBJECTIVE .................................................................................................................... 11 
3.2 
SECONDARY OBJECTIVES (IF APPLICABLE) .................................................................................... 11 
4 
STUDY DESIGN AND ENDPOINTS .................................................................................................. 11 
4.1 
DESCRIPTION OF STUDY DESIGN .................................................................................................. 11 
4.2 
STUDY ENDPOINTS....................................................................................................................... 11 
4.2.1 
Primary Study Endpoints ....................................................................................................... 11 
4.2.2 
Secondary Study Endpoints .................................................................................................. 12 
4.2.3 
Exploratory Endpoints ........................................................................................................... 12 
5 
STUDY ENROLLMENT AND WITHDRAWAL .................................................................................. 12 
5.1 
INCLUSION CRITERIA .................................................................................................................... 12 
5.2 
EXCLUSION CRITERIA ................................................................................................................... 13 
5.3 
VULNERABLE SUBJECTS ............................................................................................................... 13 
5.4 
STRATEGIES FOR RECRUITMENT AND RETENTION .......................................................................... 13 
5.4.1 
Use of DataCore/Epic Information for Recruitment Purposes .............................................. 13 
5.5 
DURATION OF STUDY PARTICIPATION ............................................................................................ 13 
5.6 
TOTAL NUMBER OF PARTICIPANTS AND SITES ................................................................................ 13 
5.7 
PARTICIPANT WITHDRAWAL OR TERMINATION ................................................................................ 14 
5.7.1 
Reasons for Withdrawal or Termination ................................................................................ 14 
5.7.2 
Handling of Participant Withdrawals or Termination ............................................................. 14 
5.8 
PREMATURE TERMINATION OR SUSPENSION OF STUDY .................................................................. 14 
6 
STUDY AGENT (STUDY DRUG, DEVICE, BIOLOGIC, VACCINE ETC.) AND/OR PROCEDURAL 
INTERVENTION ......................................................................................................................................... 14 
6.1 
STUDY AGENT(S) AND CONTROL DESCRIPTION .............................................................................. 14 
6.1.1 
Acquisition ............................................................................................................................. 15 
6.1.2 
Formulation, Appearance, Packaging, and Labeling ............................................................ 15 
6.1.3 
Product Storage and Stability ................................................................................................ 15 
6.1.4 
Preparation ............................................................................................................................ 15 
6.1.5 
Dosing and Administration .................................................................................................... 15 
6.1.6 
Route of Administration ......................................................................................................... 16 
6.1.7 
Starting Dose and Dose Escalation Schedule ...................................................................... 16 
6.1.8 
Dose Adjustments/Modifications/Delays ............................................................................... 16 


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6.1.9 
Duration of Therapy ............................................................................................................... 16 
6.1.10 
Tracking of Dose ............................................................................................................... 16 
6.1.11 
Device Specific Considerations ........................................................................................ 16 
6.2 
STUDY AGENT ACCOUNTABILITY PROCEDURES ............................................................................. 16 
7 
STUDY PROCEDURES AND SCHEDULE ....................................................................................... 16 
7.1 
STUDY PROCEDURES/EVALUATIONS ............................................................................................. 16 
7.1.1 
Study Specific Procedures .................................................................................................... 16 
7.1.2 
Standard of Care Study Procedures ..................................................................................... 17 
7.2 
LABORATORY PROCEDURES/EVALUATIONS ................................................................................... 17 
7.2.1 
Clinical Laboratory Evaluations ............................................................................................. 17 
7.2.2 
Screening .............................................................................................................................. 17 
7.2.3 
Enrollment/Baseline .............................................................................................................. 17 
7.2.4 
Final Study Visit ..................................................................................................................... 18 
7.2.5 
Withdrawal/Early Termination Visit........................................................................................ 18 
7.2.6 
Unscheduled Visit .................................................................................................................. 18 
CONCOMITANT MEDICATIONS, TREATMENTS, AND PROCEDURES ................................................................. 19 
PROHIBITED MEDICATIONS, TREATMENTS, AND PROCEDURES ..................................................................... 19 
PARTICIPANT ACCESS TO STUDY AGENT AT STUDY CLOSURE ..................................................................... 19 
8 
ASSESSMENT OF SAFETY ............................................................................................................. 19 
8.1 
SPECIFICATION OF SAFETY PARAMETERS ...................................................................................... 19 
8.1.1 
Definition of Adverse Events (AE) ......................................................................................... 19 
8.1.2 
Definition of Serious Adverse Events (SAE) ......................................................................... 19 
8.1.3 
Definition of Unanticipated Problems (UP) ............................................................................ 20 
8.2 
CLASSIFICATION OF AN ADVERSE EVENT ....................................................................................... 20 
8.2.1 
Severity of Event ................................................................................................................... 20 
8.2.2 
Relationship to Study Agent .................................................................................................. 20 
8.2.3 
Expectedness ........................................................................................................................ 21 
8.3 
TIME PERIOD AND FREQUENCY FOR EVENT ASSESSMENT AND FOLLOW-UP .................................... 21 
8.4 
REPORTING PROCEDURES – NOTIFYING THE IRB .......................................................................... 22 
8.4.1 
Adverse Event Reporting ...................................................................................................... 22 
8.4.2 
Serious Adverse Event Reporting ......................................................................................... 22 
8.4.3 
Unanticipated Problem Reporting ......................................................................................... 22 
8.4.4 
Reporting of Pregnancy ......................................................................................................... 23 
8.5 
REPORTING PROCEDURES – NOTIFYING THE STUDY SPONSOR ...................................................... 23 
8.6 
STUDY HALTING RULES ................................................................................................................ 23 
8.7 
SAFETY OVERSIGHT ..................................................................................................................... 24 
9 
CLINICAL MONITORING .................................................................................................................. 24 
10 
STATISTICAL CONSIDERATIONS .................................................................................................. 24 
10.1 
STATISTICAL AND ANALYTICAL PLANS (SAP) ................................................................................. 24 
10.2 
STATISTICAL HYPOTHESES ........................................................................................................... 24 
10.3 
ANALYSIS DATASETS .................................................................................................................... 25 
10.4 
DESCRIPTION OF STATISTICAL METHODS ...................................................................................... 25 
10.4.1 
General Approach ............................................................... Error! Bookmark not defined. 
10.4.2 
Analysis of the Primary Efficacy Endpoint(s) .................................................................... 25 
10.4.3 
Analysis of the Secondary Endpoint(s) ............................................................................. 25 
10.4.4 
Safety Analyses ................................................................................................................ 26 
10.4.5 
Adherence and Retention Analyses .................................................................................. 26 
10.4.6 
Baseline Descriptive Statistics ............................................ Error! Bookmark not defined. 
10.4.7 
Planned Interim Analysis .................................................................................................. 26 
10.4.8 
Additional Sub-Group Analyses ........................................................................................ 26 
10.4.9 
Exploratory Analyses ........................................................................................................ 26 
10.5 
SAMPLE SIZE ............................................................................................................................... 27 
10.6 
MEASURES TO MINIMIZE BIAS ....................................................................................................... 27 


Study number: s19-01922 
 
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10.6.1 
Enrollment/Randomization/Masking Procedures .............................................................. 27 
11 
SOURCE DOCUMENTS AND ACCESS TO SOURCE DATA/DOCUMENTS ................................. 27 
12 
QUALITY ASSURANCE AND QUALITY CONTROL ....................................................................... 28 
13 
ETHICS/PROTECTION OF HUMAN SUBJECTS ............................................................................. 29 
13.1 
ETHICAL STANDARD ..................................................................................................................... 29 
13.2 
INSTITUTIONAL REVIEW BOARD ..................................................................................................... 29 
13.3 
INFORMED CONSENT PROCESS .................................................................................................... 29 
13.3.1 
Consent/Assent and Other Informational Documents Provided to Participants ............... 29 
13.3.2 
Consent Procedures and Documentation ......................................................................... 29 
13.4 
POSTING OF CLINICAL TRIAL CONSENT FORM ................................................................................ 30 
13.5 
PARTICIPANT AND DATA CONFIDENTIALITY .................................................................................... 30 
13.5.1 
Research Use of Stored Human Samples, Specimens, or Data ...................................... 30 
13.6 
FUTURE USE OF STORED SPECIMENS ........................................... ERROR! BOOKMARK NOT DEFINED. 
14 
DATA HANDLING AND RECORD KEEPING ................................................................................... 31 
14.1 
DATA COLLECTION AND MANAGEMENT RESPONSIBILITIES .............................................................. 31 
14.2 
STUDY RECORDS RETENTION ....................................................................................................... 31 
14.3 
PROTOCOL DEVIATIONS ............................................................................................................... 32 
14.4 
PUBLICATION AND DATA SHARING POLICY ..................................................................................... 32 
15 
STUDY FINANCES ............................................................................................................................ 33 
15.1 
FUNDING SOURCE ........................................................................................................................ 33 
15.2 
COSTS TO THE PARTICIPANT ......................................................................................................... 33 
16 
STUDY ADMINISTRATION ............................................................................................................... 33 
16.1 
STUDY LEADERSHIP ..................................................................................................................... 33 
17 
CONFLICT OF INTEREST POLICY .................................................................................................. 33 
18 
REFERENCES ................................................................................................................................... 34 
19 
ATTACHMENTS ................................................................................................................................ 36 
20 
SCHEDULE OF EVENTS .................................................................................................................. 41 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 


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List of Abbreviations 
 
AE 
Adverse Event/Adverse Experience 
SAE 
Serious Adverse Event 
GSM 
Genitourinary syndrome of menopause 
HLA 
Hyaluronic acid 
VSQ 
Vulvovaginal symptom questionnaire 
VSI 
Vaginal Symptom Index 
FSFI 
Female Sexual Function Index 
VMI 
Vaginal maturation index 
MCG 
Micrograms 
ASCCP 
American Society of Colposcopy and Cervical Pathology 
VAS 
Visual analog scale 
PGI-I 
Patient global impression of improvement 
HIPAA 
Health Insurance Portability and Accountability Act 
IRB 
Institutional Review Board 
N 
Number (typically refers to participants) 
NIH 
National Institutes of Health 
OHRP 
Office for Human Research Protections 
OHSR 
Office of Human Subjects Research 
PI 
Principal Investigator 
QA 
Quality Assurance 
QC 
Quality Control 
US 
United States 
 
 


Study number:  
 
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Protocol Summary 
Title 
A randomized, single center study comparing hyaluronic acid to 
vaginal estrogen for treatment of genitourinary syndrome of 
menopause 
Short Title 
HLA vs vaginal estrogen for treatment of GSM 
Brief Summary 
Non-hormonal alternatives for the treatment of genitourinary syndrome 
of menopause (GSM) are needed. In this proposed trial, patients who 
are diagnosed with GSM will be randomized to receive either a 
hyaluronic acid (HLA) vaginal insert or vaginal estrogen topical cream 
for 12 weeks. There will be a baseline visit and a 12 week follow up 
visit, at which points the patient will undergo a detailed history and 
physical examination including a pelvic exam, vaginal pH sampling, 
vaginal cell sample for microscopic analysis, and will fill out 
questionnaires (vulvovaginal symptom questionnaire (VSQ), vaginal 
symptom index (VSI), and female sexual function index (FSFI)). These 
study arms will be analyzed to assess the efficacy of HLA as compared 
to the gold standard of vaginal estrogen to treat GSM symptoms.  
Phase 
Pilot 
Objectives 
The primary objective is to assess the feasibility and acceptability of 
the proposed intervention of HLA insert as measured by the 
vulvovaginal system questionnaire (VSQ). Secondary objectives 
include the assessment of preliminary effectiveness of the HLA insert 
to improve GSM symptoms and GSM physical exam measures, as 
compared to vaginal estrogen.  
Methodology 
This is an open label, randomized, active control, parallel group study.  
Endpoint 
The primary endpoint is the VSQ – 21 item questionnaire that 
measures patient quality of life via GSM symptoms, their emotional 
impact, sexual impact, and life impact.  
 
Secondary endpoints include study treatment compliance and retention 
through 12 weeks, vaginal maturation index (VMI), vaginal pH, 
vaginal rugal folds, and subjective changes in the visual analog scale 
(VAS) scores for dyspareunia, vaginal itching, and dryness in 
participants receiving HLA insert as compared to those receiving 
vaginal estrogen.  
Study Duration 
1 year  
Participant Duration 
12 weeks 
Duration of IP 
administration 
12 weeks  
Population 
Post-menopausal women in New York  


Study number: s19-01922 
 
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Study Sites 
222 E 41st St, 11th floor, New York, NY 10017  
Number of 
participants 
40 
Description of Study 
Agent/Procedure 
HLA Vaginal insert: 5mg of active medication in 2g vaginal insert 
Reference Therapy 
Vaginal estrogen cream, estradiol: 100mcg 
Key Procedures 
Sampling of vaginal tissue, sampling of vaginal pH 
Statistical Analysis 
Primary and secondary outcome measures will be summarized and 
described overall and by treatment group. Analysis will focus on the 
quality of life as well as objective measures of vaginal health 
improvement obtained in the HLA group, rather than hypothesis 
testing to compare outcomes to those receiving estrogen. Overall, and 
by treatment group, compliance and retention will be similarly 
described.    
 
 
 


Study number: s19-01922 
 
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Schematic of Study Design 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 


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1 Key Roles 
Lila Nachtigall, MD, principal investigator 
Gynecology 
251 E 33rd St, New York, NY 10016 
Lila.Nachtigall@nyulangone.org 
212-263-6361 
 
Benjamin Brucker, MD, site investigator 
Female Pelvic Medicine and Reconstructive Surgery 
222 E. 41st 11th Floor  
Benjamin.Brucker@nyulangone.org 
646-754-2404  
 
Christina Escobar, MD, site investigator 
Female Pelvic Medicine and Reconstructive Surgery 
222 E. 41st 11th Floor  
Christina.Escobar@nyulangone.org 
646-825-6324 
 
Zoe Lapier, MD, site investigator 
Female Pelvic Medicine and Reconstructive Surgery 
222 E. 41st 11th Floor  
Zoe.lapier@nyulangone.org 
(646) 825-6324 
 
Antoinette Oot, MD, site investigator 
Obstetrics & Gynecology 
462 1st Avenue, New York, NY 10016 
antoinette.oot@nyulangone.org 
(603) 689-4907 
 
Surbhi Agrawal, MD, collaborator 
Female Pelvic Medicine and Reconstructive SurgeryUniversity of Pennsylvania, Philadelphia, 
PA 
Surbhi.agrawal14@gmail.com240-418-9399 
 
Maria Smith, MD, site investigator 
Obstetrics & Gynecology 
462 1st Avenue, New York, NY 10016 
Maria.Smith@nyulangone.org 
715-559-5448 
 
Shavy Nagpal, MD, site investigator 
Female Pelvic Medicine and Reconstructive Surgery 
222 E. 41st 11th Floor  
Shavy.nagpal@nyulangone.org 


Study number: s19-01922 
 
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(646) 825-6324 
 
Erinn Hade, PhD, statistician 
Biostatistics, Department of Population Health 
180 Madison Avenue, Suite 5-53 
Erinn.Hade@nyulangone.org 
(646) 501-3742 
 
Steven Friedman, MS, statistician 
Biostatistics, Department of Population Health 
180 Madison Avenue, Suite 5-53 
Steven.Friedman2@nyulangone.org  
(646) 501-3737 
 
 
JDS Therapeutics, sponsor 
1 Manhattanville Road, Suite 104, Purchase, NY 10577 
914-701-4508 
2 Introduction, Background Information and Scientific Rationale 
2.1 Background Information and Relevant Literature 
Genitourinary syndrome of menopause (also referred to as vulvovaginal atrophy, urogenital 
atrophy, and atrophic vaginitis) is a collection of vulvovaginal and urinary signs and symptoms 
that result from a decrease in estrogen (1). The most common symptoms include dryness, 
burning, dyspareunia, and urinary incontinence in menopausal women (2). The impact of these 
symptoms is widespread with 85% of women over the age of 40 who endorse vaginal dryness 
(3). Further, over half of the women with symptoms report that their quality of life is negatively 
impacted (4). Due to the deeply impactful effects of GSM, it is worthwhile to assess the 
mainstays of treatment and examine novel therapies in order to positively improve the quality of 
life of these women.  
 
For many years, topical estrogen therapy has been the standard of care for GSM, after over-the-
counter vaginal moisturizers and lubricants have failed (5). In many ways, estrogen is a logical 
treatment choice due to the fact that it replaces what is lost in post-menopausal women. The 
topical estrogen functions to maintain the collagen content in the epithelium, optimize genital 
blood flow, and maintain levels of acid mucopolysaccharides and hyaluronic acid (HLA) within 
the epithelium.  
 
However, some patients may be uncomfortable with hormonal therapies or in certain 
circumstances hormonal therapies may be contraindicated, even in topical form. Therefore, it is 
important to explore non-hormonal alternatives for the treatment of this common condition. 
 
One such novel therapy is topical HLA. HLA is a large non-sulfated glycosaminoglycan that 
forms in the plasma membrane of cells and serves three major functions (6). First, it helps 
maintain the extracellular matrix. Second, it contributes to cell proliferation and turn over. Third, 


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it modulates moisture in the epithelium. Currently, HLA is FDA approved for use in 
osteoarthritis (albeit with limited efficacy), and is used in the treatment of dry skin, dry eye, and 
youth-promoting cosmetic products. Recently, the potential role for HLA in the treatment of 
GSM has been uncovered.  
 
In a study of rats randomly assigned to oophorectomy plus placebo, oophorectomy plus vaginal 
HLA gel, or sham oophorectomy, it was found that HLA resulted in a reversal of vaginal atrophy 
with no associated increase in uterine weight (7). This study is particularly promising because it 
not only shows the reversal of atrophy, but also it suggests that HLA has no effect on uterine 
weight (a proxy for endometrial lining) which is a feared complication of unopposed systemic 
estrogen therapy.  
 
One of the earliest human studies examining the potential application of HLA for GSM 
symptoms as a non-hormonal alternative comes from Italy in 2006 (8). A pilot study of just 10 
patients was initially performed to assess the safety profile of use of HLA gel on the vulva for 
GSM symptoms for 30 days. No side effects or adverse events were noted between the start and 
end of the usage period. No lab abnormalities were found aside from a ‘slight increase’ in 
monocyte percentage (9 to 13%) between the start and end, which the investigators deemed to be 
unrelated to the HLA treatment. Subsequently, a larger trial of 100 post-menopausal women was 
conducted by the same group of investigators. In this cohort, HLA was applied vaginally and 
studied over a period of 12 weeks. Using the visual analog scale (VAS) for GSM symptoms—
specifically vaginal dryness, itching, burning, and dyspareunia—clinically significant 
improvement was noted from baseline to the end of the study period. Again, no adverse events or 
side-effects were noted for the gel usage.  
 
In a similar study from Italy, an open trial of 150 post-menopausal women were given a vaginal 
insert that contained HLA, vitamin E, and vitamin A to use for four weeks (9). Subjective and 
objective vaginal markers were compared over the four weeks and significant improvement was 
observed in the primary endpoint of vaginal dryness as compared to baseline with no side-effects 
to the HLA insert reported. 
 
An open RCT conducted in China in 2013 comparing vaginal HLA gel to vaginal estriol cream 
confirmed HLA’s overall efficacy and safety profile (10). Only mild adverse events were noted 
relating to HLA gel use. On laboratory testing, two patients were found to have vulvovaginal 
candidiasis and one patient was found to have bacterial vaginosis. These three patients had no 
symptoms, required no intervention, and the infections self-resolved. Only one patient was found 
to have symptomatic vulvovaginal candidiasis and was treated with no subsequent 
complications.  
 
A small, recent study in Iran also noted the non-inferiority of vaginal HLA as compared to 
vaginal estrogen cream for symptomatic GSM (11). The study found that both treatment groups 
improved compared to baseline in dryness, itch, maturation index, pH, and a composite score of 
vaginal symptoms. However, only the HLA group showed improvement in symptoms of urinary 
incontinence. Further, improvement in the HLA group was significantly greater than the estrogen 
group for dryness, maturation index, and composite score. Meanwhile, a Turkish study found the 
opposite—vaginal estradiol tablets were more effective on improving vaginal symptoms as 


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compared to vaginal HLA tablets, but both treatments still significantly improved all vaginal 
symptoms studied (12).   
 
Most studies above examined the individual parameters that make up the composite ‘vaginal 
health index score’ (13). The vaginal health index score is a tool that evaluates five parameters to 
establish the degree of vaginal atrophy: vaginal elasticity, vaginal secretions, pH, epithelial 
mucous membrane, and vaginal hydration. In congruence with the above studies, vaginal HLA 
use led to significant vaginal health index score improvements over time. In sum, the results of 
these international studies are promising in that they suggest a potential role for HLA use in the 
treatment of GSM as a non-hormonal alternative.  
 
This study proposes comparing a HLA vaginal insert available in the US, Revaree, to the 
commonly used vaginal estrogen cream, estradiol, for the treatment of GSM. Not only would this 
be one of the first randomized controlled trials conducted in the US examining this non-
hormonal alternative to the standard of care for GSM, but also the vulvovaginal system 
questionnaire (VSQ), would be the first to be used in a study on this issue.  
 
The studies cited earlier primarily use some combination of the following measurement tools: 
VAS for vaginal symptoms (dryness, itching, burning, and dyspareunia), physical exam findings, 
and vaginal maturation index (VMI). Vaginal maturation index is a qualitative measure of 
hormonal influences on the vaginal epithelium. It measures the percentage of parabasal, 
intermediate, and squamous cells appearing on a smear and is a valuable tool when comparing 
the changes in two samples of the same patient (14).  
 
While this study proposes using these aforementioned evaluation tools for GSM, we propose to 
use the VSQ as the primary outcome to globally assess quality of life as reported by the patient. 
The VSQ is a 21-question survey developed in 2012 that specifically asks about GSM 
symptoms, their emotional impact, sexual impact, and life impact. Among 120 post-menopausal 
women, this questionnaire was found to have reliability and internal consistency (15). Most 
importantly, in the absence of a gold standard instrument to assess the quality of life impact of 
GSM, this questionnaire is a critical new tool. It is more nuanced and disease-specific than VAS 
scoring, and thus far, an underutilized tool to understand the significant psychological impact of 
this disease. Because GSM is a symptom-driven disease and patients will likely adhere to a 
treatment plan if they perceive symptomatic improvement, this study’s primary endpoint of 
treatment success will be measured by improvement in VSQ scoring.  
 
In summary, the goal of this study is to compare and assess the acceptance and effectiveness of 
the non-hormonal alternative, HLA, to the standard of care, vaginal estrogen, for the treatment of 
GSM using a randomized, controlled, parallel trial. The primary objective will be assessed by the 
disease-specific, quality-of-life VSQ score that no study on this investigational product has used 
thus far.  Further, this pilot randomized trial will be the basis for the protocol for assessment of 
effectiveness in a larger randomized trial. 


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2.2 Name and Description of the Investigational Agent  
2.2.1 Preclinical Data 
The investigational treatment in this study, HLA vaginal insert, Revaree (brand name), is a FDA-
approved class II medical device. It is a 2g vaginal insert that contains 5mg of HLA sodium salt 
and a base of semi-synthetic glycerides. It is an insert that does not require an applicator and 
should be placed in the vagina while laying down twice weekly. HLA in different formulations is 
currently used in disciplines such as ophthalmology and orthopedic surgery. As explained below, 
it is an extremely well tolerated medication with little to no side effects.  
 
In a study of rats randomly assigned to oophorectomy plus placebo, oophorectomy plus vaginal 
HLA gel, or sham oophorectomy, it was found that HLA resulted in a reversal of vaginal atrophy 
with no associated increase in uterine weight (7). This study is particularly promising because it 
not only shows the reversal of atrophy but also it suggests that HLA has no effect on uterine 
weight (a proxy for endometrial lining) which is a feared complication of unopposed systemic 
estrogen therapy.  
2.2.2 Clinical Data to Date 
One of the earliest human studies examining the potential application of HLA for GSM 
symptoms as a non-hormonal alternative comes from Italy in 2006 (8). A pilot study of just 10 
patients was initially performed to assess the safety profile of use of HLA gel on the vulva for 
GSM symptoms for 30 days. No side effects or adverse events were noted between the start and 
end of the usage period. No lab abnormalities were found aside from a ‘slight increase’ in 
monocyte percentage (9 to 13%) between the start and end, which the investigators deemed to be 
unrelated to the HLA treatment. Subsequently, a larger trial of 100 post-menopausal women was 
conducted by the same group of investigators. In this cohort, HLA was applied vaginally and 
studied over a period of 12 weeks. Using the visual analog scale (VAS) for GSM symptoms—
specifically vaginal dryness, itching, burning, and dyspareunia—clinically significant 
improvement was noted from baseline to the end of the study period. Again, no adverse events or 
even side-effects were noted for the gel usage.  
 
In a similar study from Italy, an open trial of 150 post-menopausal women were given a vaginal 
insert that contained HLA, vitamin E, and vitamin A to use for four weeks (9). Subjective and 
objective vaginal markers were compared over the four weeks and significant improvement was 
observed in the primary endpoint of vaginal dryness as compared to baseline with no side-effects 
to the HLA insert reported. It is important to note that while the HLA insert used in the cited 
study is different than the one proposed for this study, it used the same dose of HLA, 5mg, as 
found in this study’s HLA formulation.  
 
An open RCT conducted in China in 2013 comparing vaginal HLA gel to vaginal estriol cream 
confirmed HLA’s overall efficacy and safety profile (10). Four mild adverse events were noted 
relating to HLA gel use. On laboratory testing, two patients were found to have vulvovaginal 
candidiasis and one patient was found to have bacterial vaginosis. These three patients had no 
symptoms, required no intervention, and the infections self-resolved. Only one patient was found 
to have symptomatic vulvovaginal candidiasis and was treated with no complications.  
 


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A small, recent study in Iran also noted the non-inferiority of vaginal HLA as compared to 
vaginal estrogen cream for symptomatic GSM (11). The study found that both treatment groups 
improved compared to baseline in dryness, itch, maturation index, pH, and a composite score of 
vaginal symptoms. However, only the HLA group showed improvement in symptoms of urinary 
incontinence. Further, improvement in the HLA group was significantly greater than the estrogen 
group for dryness, maturation index, and composite score. Meanwhile, a Turkish study found the 
opposite—vaginal estradiol tablets were more effective on improving vaginal symptoms as 
compared to vaginal HLA tablets, but both treatments still significantly improved all vaginal 
symptoms studied (12).   
 
In summary, the clinical data to date on this topic comes from international studies comparing 
different vaginal HLA formulations to different vaginal estrogen formulations. However, all 
studies showed a safe usage profile of vaginal HLA, with only one clinically symptomatic fungal 
infection that required treatment.  
2.2.3 Dose Rationale (if applicable)  
In the US, the only dosage available for a vaginal insert preparation of HLA is 5mg, to the 
author’s best knowledge. As noted above, some international studies have used this dosage with 
good safety profiles. 
2.3 Rationale 
GSM is a condition whose current standard of care is primarily hormone-based treatment. With 
patients being weary of using hormonal-based therapies and some patients being unable to 
receive such therapies even if willing, non-hormonal, safe alternatives must be explored. As 
noted earlier, there are a few preliminary international studies that have shown that HLA may be 
a promising new therapy for GSM. HLA alone has been shown in multiple studies to improve 
GSM symptoms.  
 
This study proposes comparing HLA to vaginal estrogen cream because if the goal is to offer 
non-hormonal alternatives to all GSM patients, new therapies must be weighed against the 
standard of care. Additionally, no studies to date have used the VSQ proposed in this study as a 
tool to assess symptomatic and quality-of-life improvement. The hypothesis of this study is that 
HLA will be equal to estrogen in improving symptoms, quality of life, and physical attributes of 
GSM as compared to vaginal estrogen cream. 
 
Both vaginal HLA and vaginal estrogen cream will be dosed and administered as recommended 
by the manufacturer to allow for reliable and realistic comparison of both therapies.  
 
As mentioned above, HLA is associated with infrequent and usually mild side effects. The 
control in this study, vaginal estrogen cream, while also considered safe and FDA-approved for 
GSM, may be associated with certain side effects that would warrant further medical treatment. 
For example, if a patient starts to experience vaginal bleeding while on vaginal estrogen, the 
normal work-up for post-menopausal bleeding will be initiated.  
 
Last, the intervention period of 12 weeks was chosen to allow for adequate time for therapeutic 
effect. Vaginal estrogen therapy can offer symptomatic improvement after just three weeks of 


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use, but can take four to six weeks in some patients (16). Thus, 12 weeks will maximize vaginal 
estrogen’s therapeutic effect, allowing for a proper comparison of a novel therapy.  
2.4 Potential Risks & Benefits 
2.4.1 Known Potential Risks 
Regarding vaginal HLA usage, the only observed risk thus far has been a fungal or bacterial 
infection in four patients, three of which were asymptomatic and did not require intervention and 
the remaining one was treated with no complication (10). Otherwise no other adverse events 
have been noted in studies.  
 
Regarding the vaginal estrogen cream in this study, on the package insert for Estrace (see 
attached hyperlink), the risks of local vaginal estrogen are not separated from oral hormone 
replacement therapy (HRT). The package insert states that the risks include thromboembolism, 
retinal thrombosis, heart attack, stroke, breast cancer, ovarian cancer, endometrial cancer, 
endometrial hyperplasia, hypercalcemia, gallbladder disease, and probable dementia. It also 
includes possible exacerbation of the following conditions: hereditary angioedema, 
hypothyroidism, asthma, endometriosis, diabetes mellitus, epilepsy, migraine, 
hypertriglyclideremia leading to pancreatitis, hypoparathyroidism, porphyria, systemic lupus 
erythematosus, and hepatic hemangiomas (19). 
 
However, when examining vaginal dosing of estrogen formulations, first, the dose is 
significantly less than oral HRT. Second, the risks associated with oral HRT, as mentioned 
above, have not been found in studies examining different—comparable to Estrace—vaginal 
estrogens. The reported cases of endometrial hyperplasia, breast or endometrial cancer were no 
different than those prior to initiation of therapy (20-24). Third, circulating levels of estradiol 
have been shown to be minimal with low-dose vaginal estrogen creams, tablets and the estrogen 
ring (25). Thus, systemic effects from these low-dose topical therapies are felt to be extremely 
rare. The other concern with any unopposed estrogen is endometrial safety. There have been 
several large studies that have established endometrial safety of various low-dose formulations of 
vaginal estrogen (Vagifem™, Estring™ and conjugated estrogen cream at a dose of 0.3mg) (20-
22). Therefore, with low systemic absorption and no significant increase in endometrial 
pathology with low-dose vaginal estrogen, it is generally thought that the use of progestins is not 
necessary to protect the endometrium (23). 
 
Reactions reported in randomized controlled trials of vaginal estrogen include application site 
reaction, vaginal bleeding/spotting, breast changes/pain, abdominal bloating/cramps, 
nausea/vomiting, cervical secretion changes, headache/migraine, fluid retention, elevated blood 
pressure, mood changes, candidiasis, glucose intolerance, weight changes, libido changes, 
contact lens intolerance, vision changes, rash, melasma/choasma, hair loss and hirsutism. Despite 
this risk profile, vaginal estrogen is well tolerated in most patients and is the recommended 
treatment if first-line over-the-counter vaginal moisturizers and lubricants do not work.   
 
Regarding the office visit, the only potential risk of vaginal tissue sampling may be minimal 
bleeding, for which local pressure will be applied. If a patient is on oral HRT within 6 weeks of 
the study, she will not be able to participate in this study.  


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2.4.2 Known Potential Benefits 
The potential physical benefits of vaginal HLA insert discussed in detail above come from 
multiple international studies. They include improvement in symptoms (dyspareunia, itching, 
dryness, vaginal bleeding), vaginal maturation index, vaginal pH, and urinary symptoms 
secondary to GSM (8-13). Regarding the vaginal estrogen cream to be used in this study, estrace, 
is FDA approved for the treatment of vulvovaginal atrophy secondary to menopause. 
Additionally, studies examining similar formulations of vaginal estrogen have showed 
improvement in GSM symptoms (20-22).  
Regarding potential psychological benefits, no study to date has examined vaginal HLA’s impact 
on quality of life; it is included in the primary objective of this study. A study that compared a 
vaginal moisturizer to vaginal estrogen tablets—very similar to the control being used in this 
study—found there was significant improvement in the overall sexual function domain and 
overall Menopause Quality of Life scores in the vaginal estrogen group (17).  
 
3 Objectives and Purpose 
3.1 Primary Objective 
The primary objective is to measure symptoms and quality of life for GSM in those randomized 
to vaginal HLA versus vaginal estrogen cream  in a contemporary cohort.  
3.2 Secondary Objectives (if applicable) 
The secondary objective is to measure objective and physical attributes of GSM, as well as 
treatment compliance and retention in those receiving vaginal HLA or vaginal estrogen cream.  
4 Study Design and Endpoints 
4.1 Description of Study Design 
This will be an open, randomized, active control, parallel design study. This is a pilot 
randomized trial to gain understanding of symptom and quality of life, physical measurements, 
and overall protocol administration. There are two study arms, HLA vaginal insert 
(investigational) and vaginal estrogen cream (standard of care). Participants will be recruited and 
treated at a single-center study. Both interventions will last for 12 weeks. There will be no 
protocol changes to either medication in this study. Randomization will not be stratified.  
4.2 Study Endpoints 
4.2.1 Primary Study Endpoints 
The primary endpoint will be the change in the VSQ score, between the baseline visit and 12 
week follow-up. 
 
The VSQ is a 21-question survey developed in 2012 that specifically asks about GSM 
symptoms, their emotional impact, sexual impact, and life impact. Among 120 post-menopausal 
women, this questionnaire was found to have reliability and internal consistency (15). Most 
importantly, in the absence of a gold standard instrument to assess the quality of life impact of 


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GSM, this questionnaire is critical. It is more nuanced and disease-specific than VAS scoring, 
and thus far, an underutilized tool to understand the significant psychological impact of this 
disease. Because GSM is a symptom-driven disease and patients will likely adhere to a treatment 
plan if they perceive symptomatic improvement, this study’s primary endpoint of treatment 
success will be measured by improvement in VSQ scoring.  
4.2.2 Secondary Study Endpoints 
The secondary study endpoints will include: the change in the FSFI and VSI score from baseline 
to the 12 week visit, the change in the percentage of superficial squamous cells in the vaginal 
maturation index, the change in vaginal pH, the qualitative change in rugal fold appearance, and 
the change in VAS scoring for vaginal dyspareunia, itching, and dryness. These are well-studied 
measurement tools for GSM research and have been used in some combination in all of the 
studies cited earlier.  
 
Vaginal pH in a postmenopausal woman is generally between 6.0 and 8.0, while an estrogenized 
vagina will have a pH of 3.5 to 4.5 (18). Thus, the change in pH can be a surrogate marker for 
the hormonal influence on vaginal epithelium. 
 
VMI is a qualitative measure of hormonal influences on the vaginal epithelium. It measures the 
percentage of parabasal, intermediate, and superficial squamous cells appearing on a smear and 
is a valuable tool when comparing the changes in two samples of the same patient (14).  
 
Patient global impression of improvement (PGI-I), a one question assessment, will also be asked 
at the follow up visit for overall patient satisfaction assessment. 
4.2.3 Exploratory Endpoints 
N/A 
5 Study Enrollment and Withdrawal 
5.1 Inclusion Criteria 
In order to be eligible to participate in this study, an individual must meet all of the following 
criteria: 
1. Postmenopausal status as defined by amenorrhea for >12 months or history of bilateral 
salpingo-oophrectomy or if the patient has had a hysterectomy and menopausal 
symptoms for >1 year or FSH > 40  
2. Symptoms of GSM  
3. Pap smear screening as per ASCCP (American Society of Colposcopy and Cervical 
Pathology) guidelines. If Pap smear was indicated in last three to five years, it must be 
negative. 
4. Capable of giving informed consent 
5. Ambulatory 
6. Capable and willing to follow all study-relation procedures  


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5.2 Exclusion Criteria 
An individual who meets any of the following criteria will be excluded from participation in this 
study: 
1. Use of any HRT (systemic or local) or raloxifene within six weeks of proposed start date 
2. History of estrogen-sensitive tumor  
3. Undiagnosed vaginal bleeding in the past 12 months  
4. History of thromboembolic event  
5. Currently have or have had liver problem 
6. Bleeding disorder 
7. Impaired mental status  
8. Prior pelvic irradiation  
9. Active vaginal infection 
10. Any medical reason the investigator deems incompatible with treatment with vaginal 
estrogen 
5.3 Vulnerable Subjects 
No vulnerable subject populations based on federal regulations are included in this trial. Children 
and fetuses are not affected by this disease, pregnant women by definition are not post-
menopausal, and prisoners are not treated as outpatients at any of the study sites. The elderly are 
potential vulnerable subjects; however they need to be included in our study population to make 
the results useful in clinical practice as the average age of menopause is 51.2 years old. 
However, those who are no longer able to provide consent for themselves will be excluded. 
5.4 Strategies for Recruitment and Retention 
All patients seen at Dr. Brucker’s office will be offered participation in this randomized 
controlled trial. 
 
Informed consent will take place at Dr. Brucker’s office. Patients will be asked personal 
demographic information. Only staff (attendings, fellows, residents, medical students,) involved 
in the study will have access to this information.  
5.4.1 Use of DataCore/Epic Information for Recruitment Purposes 
This study will not utilize EPIC or Data Core to identify subjects.  
5.5 Duration of Study Participation 
There is no pre-screening to visit one. After visit one, the patient will have a follow-up visit 
approximately 12 weeks later. There is no follow up required after the 12 week visit. Thus, the 
duration of study participation is 12 weeks.  
5.6 Total Number of Participants and Sites  
Recruitment will end when approximately 60 participants are enrolled at this single site at 
NYUMC. It is expected that approximately 60 participants will need to be enrolled in order to 
retain 40 evaluable participants at 12 weeks of follow up (an overall 33% drop out rate). 


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5.7 Participant Withdrawal or Termination 
5.7.1 Reasons for Withdrawal or Termination 
Participants are free to withdraw from participation in the study at any time upon request. An 
investigator may terminate participation in the study if: 
• 
Any clinical adverse event (AE), laboratory abnormality, or other medical condition or situation 
occurs such that continued participation in the study would not be in the best interest of the 
participant 
• 
The participant meets an exclusion criterion (either newly developed or not previously 
recognized) that precludes further study participation 
5.7.2 Handling of Participant Withdrawals or Termination 
Patients who withdraw or terminate participation in this study will be called and a follow-up 
office visit will be set up at 12 weeks regardless of their participation. If the patient refuses to 
come in, a phone call will be made to discuss adverse events or unanticipated problems over the 
phone. If a patient is lost to follow-up, two phone calls to the patient and subsequently two phone 
calls to next-of-kin will be made in an attempt to reach the patient. There is low concern for 
long-term and short-term safety with either study agent, particularly for the duration of eight 
weeks only. 
5.8 Premature Termination or Suspension of Study 
This study may be temporarily suspended or prematurely terminated if there is sufficient 
reasonable cause. Written notification, documenting the reason for study suspension or 
termination, will be provided by the suspending or terminating party to Dr. Nachtigall JDS 
Therapeutics, NYU medical center, and regulatory authorities. If the study is prematurely 
terminated or suspended, the PI will promptly inform the IRB and will provide the reason(s) for 
the termination or suspension. 
Circumstances that may warrant termination or suspension include, but are not limited to: 
• 
Determination of unexpected, significant, or unacceptable risk to participants 
• 
Demonstration of efficacy that would warrant stopping 
• 
Insufficient compliance to protocol requirements 
• 
Data that are not sufficiently complete and/or evaluable 
• 
Determination of futility 
 
Study may resume once concerns about safety, protocol compliance, data quality are addressed 
and satisfy the sponsor, IRB and/or FDA. 
6 Study Agent (Study drug, device, biologic, vaccine etc.) and/or 
Procedural Intervention  
6.1 Study Agent(s) and Control Description 
The study agent is the HLA vaginal insert, Revaree (brand name). It is a FDA-approved class II 
medical device. It is a 2g insert that contains 5mg of HLA sodium salt and a base of semi-
synthetic glycerides. The off-label use of this device for GSM is considered non-significant risk 
(NSR) as it does not meet the criteria for significant risk device set forth in 21 CFR 812.3(m). 
This device is approved as a personal lubricant for vaginal application. This device does not pose 
significant risk because as mentioned earlier, multiple international trials have shown no side 


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effects and the only adverse event noted that required treatment was one episode of vulvovaginal 
candidiasis (10).  
 
The control agent is vaginal estradiol cream, Estrace (brand name). It is a cream composed of 
100mcg estradiol in a non-liquefying 1g base containing purified water, propylene glycol, stearyl 
alcohol, white ceresin wax, mono- and di-glycerides, hypromellose 2208 (4000 cps), sodium 
lauryl sulfate, methylparaben, edetate di-sodium and tertiary-butylhydroquinone. It is FDA 
approved for GSM treatment.  
6.1.1 Acquisition 
Both study agents will be acquired and shipped to Dr. Brucker’s Manhattan office by JDS 
Therapeutics. 
6.1.2 Formulation, Appearance, Packaging, and Labeling 
The study agent, Revaree, is manufactured by JDS Therapeutics. It is a semi-solid, off-white 
suppository for the vagina. The suppository must be removed from its packaging by pulling two 
pre-cut flyers of the plastic strip. This is a commercially marketed medical ‘device,’ available for 
human use in the form, route, and dose planned in this trial.  
 
The control agent, Estrace, is manufactured by Allergan. It is a white cream that must be 
squeezed onto a calibrated applicator to dose it. This is a commercially marketed medication, 
available for human use in the form, route, and dose planned in this trial.  
6.1.3 Product Storage and Stability 
Revaree should be stored at 39°F to 77°F, avoiding void heat over 86°F. Estrace should be stored 
at 68°F to 77°F with excursions permitted to 59°F to 86°F.  
6.1.4 Preparation 
No preparation of the study agents is needed. 
6.1.5 Dosing and Administration 
The study agent, Revaree, has only one dose. As per the manufacturer, the suppository should be 
placed in the vagina at bed time. It should be removed from the packaging before insertion, 
inserted into the vagina while laying down with knees bent, and then pushed further into the 
vagina gently, as far as tolerated. It should be placed twice weekly.  
 
The control agent, Estrace, is dosed by the amount of cream applied to the vagina. The patient 
will need to attach the applicator to the tube and squeeze the cream into the calibrated applicator 
accordingly before application at bed time. The dosing will be 100mcg of estradiol (1g of cream) 
inserted into the vagina twice a week. This dosing is consistent with the manufacturer 
recommended maintenance dosing for Estrace and it mimics the usage pattern of the other study 
agent, HLA. Additionally, a study of a similar vaginal cream, Premarin, showed that twice 
weekly dosing was as efficacious and safe as using the cream daily for 21 days and 7 days off for 
GSM symptoms (22). 


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6.1.6 Route of Administration 
Vaginal for both study agents. 
6.1.7 Starting Dose and Dose Escalation Schedule 
The starting doses are mentioned above. There will be no escalation.  
6.1.8 Dose Adjustments/Modifications/Delays 
There will be no dose adjustments for the study agent, Revaree. It is not physically possible with 
this formulation of the drug. 
 
Dose modification for the vaginal estrogen cream, Estrace, may occur if a patient exhibits side 
effects. If a patient starts to exhibit the most common side effects of breast pain, vaginal spotting, 
or headache, the dose may be decreased or the treatment may be discontinued depending on the 
clinical context. If there is any concern for an AE, the treatment may be discontinued. If the 
patient is responding positively to treatment, the dosing will not be increased.  
6.1.9 Duration of Therapy 
The duration of therapy will be 12 weeks. This is based on evidence that vaginal estrogen 
therapy can can take up to six weeks to offer symptomatic relief in some patients (16). 
Additionally, with four weeks of usage, vaginal administration of HLA has shown to have 
significant impact on GSM symptoms.   
6.1.10 Tracking of Dose 
Subject diary will be used to track date/time of dosing of vaginal estrogen or HLA insert.  
6.1.11 Device Specific Considerations 
N/A 
6.2 Study Agent Accountability Procedures 
NYU Investigational pharmacy will be used to ensure the drug and device are stored and 
dispensed in a regulated manner through the faculty group practice study site. Unused product 
will be returned to JDS Therapeutics (1 Manhattanville Road, Suite 104, Purchase, NY 10577). 
Both medications will be stored at the office in a locked cabinet. There will be no additional 
interventions.  
 
Regular study drug reconciliation will be performed to document drug assigned, drug consumed, 
and drug remaining. This reconciliation will be logged on the drug reconciliation form, and 
signed and dated by the study team. 
7 Study Procedures and Schedule 
7.1 Study Procedures/Evaluations 
7.1.1 Study Specific Procedures 
• 
Medical history: will be obtained by interview 
o 
Included: genitourinary symptoms  
• 
Medication history: 


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o 
All history of HRT use currently or in the past 
 
Any usage of HRT in the last six weeks would prohibit participation until six 
weeks off HRT 
• 
Physical Exam:  
o 
Pelvic:  
 
Vaginal pH sample 
 
Vaginal tissue sample via scraping for VMI  
• 
VSQ, FSFI, VSI 
• 
Counseling on usage of medication depending on the study arm randomization 
• 
Patient report of medication compliance at twelve week follow-up 
7.1.2 Standard of Care Study Procedures 
• 
Demographic information 
• 
Medical history: will be obtained by interview 
o 
Included: obstetrical, gynecologic, medical, and surgical history  
• 
Medication history: 
o 
All current medications (prescription and over the counter) usage and dosages 
• 
Physical Exam:  
o 
Vitals: blood pressure, heart rate, respiratory rate, temperature, height, weight 
o 
Cardiovascular exam: lung and heart auscultation  
o 
Abdominal exam: skin, surgical scars, distention, tenderness 
o 
Pelvic:  
 
Speculum: external genitalia and urethral opening, vulva, vaginal, cervix 
• 
Bimanual: cervical os, uterine size (if present), adnexal fullness, adnexal tenderness 
7.2 Laboratory Procedures/Evaluations 
N/A 
7.2.1 Clinical Laboratory Evaluations 
• 
After enrollment 
o 
Vaginal pH test: will be checked at office at visit one and two 
o 
Vaginal scraping for microscopy analysis for VMI: will be checked at the office at visit one 
and two 
o 
Urine analysis: dipstick urinalysis, including protein, hemoglobin and glucose; if dipstick is 
abnormal, complete urinalysis with microscopic evaluation is required. 
7.2.2 Screening  
There will be no screening visit separate from the enrollment visit.  
7.2.3 Enrollment/Baseline 
 
Screening/Enrollment/Baseline Visit (Visit 1, Day 0) 
• 
Obtain informed consent of potential participant verified by signature on study informed consent 
form  
• 
Obtain demographic information, history of present illness, medical history, surgical history, 
obstetrical history, gynecologic history, medication history, HRT usage history 
• 
Perform physical exam: vitals, cardiovascular, abdominal, pelvic 
• 
Diagnose GSM  
• 
If GSM diagnosis, explain study and verify inclusion and exclusion criteria 
• 
Obtain urine pregnancy test: result must be negative and available prior to administration of study 
agents 


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• 
Obtain urine analysis: result must be negative and available prior to administration of study 
agents 
• 
Record VAS scores for dyspareunia, itching, and dryness 
• 
Record rugal fold analysis 
• 
Collect pelvic samples for vaginal pH and vaginal tissue scraping for VMI 
• 
Have patient fill out VSQ, FSFI, VSI 
• 
Perform randomization and determine patient study arm 
• 
Give patient appropriate prescription (HLA vs vaginal estrogen) 
• 
Counsel on medication dosage, usage, and application 
• 
Counsel on communication routes to inform research team about side effects and/or AE 
7.2.4 Final Study Visit 
 
Final Study Visit (Visit 2, Week 12 +/- 3 to 5 days )  
• 
Record AE as reported by participant or observed by investigator 
• 
Record participant’s adherence to treatment regimen 
• 
Record VAS scores for dyspareunia, itching, and dryness 
• 
Record vital signs, results of physical exam including pelvic 
• 
Collect pelvic samples for vaginal pH and vaginal tissue scraping for VMI 
• 
Have patient fill out VSQ, FSFI, VSI, PGI-I 
• 
Discuss the preliminary changes in their symptoms, if any exist  
• 
Provide contact information for Dr. Shavy Nagpal to communicate any AE or side-effect 
experienced after the end of the study if patient believes it is related to the study  
7.2.5 Withdrawal/Early Termination Visit 
If 12 weeks of study agent usage:  
• 
Record AE as reported by participant or observed by investigator 
• 
Record participant’s adherence to treatment regimen 
• 
Obtain GSM symptom history, and record VAS scores for dyspareunia, itching, and dryness 
• 
Record vital signs, results of physical exam including pelvic 
• 
Collect pelvic samples for vaginal pH and vaginal tissue scraping for vaginal maturation index 
• 
Have patient fill out VSQ  
• 
Discuss the obvious, preliminary changes in their symptoms, if any exist  
• 
Provide contact information for Dr. Shavy Nagpal to communicate any AE or side-effect 
experienced after the end of the study if patient believes it is related to the study  
 
If <12 weeks of study agent usage: 
• 
Record AE as reported by participant or observed by investigator 
• 
Record participant’s adherence to treatment regimen 
• 
Record vital signs, results of physical exam including pelvic 
• 
Provide contact information for Dr. Shavy Nagpal to communicate any AE or side-effect 
experienced after the end of the study if patient believes it is related to the study  
7.2.6 Unscheduled Visit 
• 
Obtain patient’s reason for visit  
• 
Perform relevant physical exam 
• 
Based on the clinical context, determine whether study agent should be continued or 
discontinued or modified 
• 
Discuss plan with patient  
• 
Based on the clinical context, document whether patient will continue in study or be removed 


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Concomitant Medications, Treatments, and Procedures 
All concomitant prescription medications taken during study participation will be recorded on 
the case report forms (CRFs). For this protocol, a prescription medication is defined as a 
medication that can be prescribed only by a properly authorized/licensed clinician. Medications 
to be reported in the CRF are concomitant prescription medications, over-the-counter 
medications and non-prescription medications. 
Prohibited Medications, Treatments, and Procedures 
Treatment with systemic HRT will not be permitted during or within 6 weeks of starting this 
study.  
Participant Access to Study Agent at Study Closure 
HLA is an over the counter medication so patients will have access to the study agent after 
closure. However, the cost will not be covered after study closure and will be the subject’s 
responsibility, so purchasing the study agent may be cost prohibitive.  
8 Assessment of Safety 
8.1 Specification of Safety Parameters  
8.1.1 Definition of Adverse Events (AE) 
An adverse event (AE) is any symptom, sign, illness or experience that develops or worsens in 
severity during the course of the study.  Intercurrent illnesses or injuries should be regarded as 
adverse events.  Abnormal results of diagnostic procedures are considered to be adverse events if 
the abnormality: 
• results in study withdrawal 
• is associated with a serious adverse event 
• 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 
8.1.2 Definition of Serious Adverse Events (SAE) 
Serious Adverse Event 
Adverse events are classified as serious or non-serious.  A serious adverse event is any AE that 
is:  
• fatal 
• life-threatening 
• requires or prolongs hospital stay 
• results in persistent or significant disability or incapacity 
• a congenital anomaly or birth defect 
• an important medical event 
 
Important medical events are those that may not be immediately life threatening, but are clearly 
of major clinical significance. They may jeopardize the subject, and may require intervention to 
prevent one of the other serious outcomes noted above. For example, drug overdose or abuse, a 


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seizure that did not result in in-patient hospitalization, or intensive treatment of bronchospasm in 
an emergency department would typically be considered serious.  
 
All adverse events that do not meet any of the criteria for serious should be regarded as non-
serious adverse events.  
8.1.3 Definition of Unanticipated Problems (UP) 
Unanticipated Problems Involving Risk to Subjects or Others 
Any incident, experience, or outcome that meets all of the following criteria:  
• Unexpected in nature, severity, or frequency  (i.e. not described in study-related 
documents such as the IRB-approved protocol or consent form, the investigators brochure, 
etc) 
• Related or possibly related to participation in the research (i.e. possibly related means 
there is a reasonable possibility that the incident experience, or outcome may have been 
caused by the procedures involved in the research) 
• Suggests that the research places subjects or others at greater risk of harm (including 
physical, psychological, economic, or social harm). 
This definition could include an unanticipated adverse device effect, any serious adverse effect 
on health or safety or any life-threatening problem or death caused by, or associated with, a 
device, if that effect, problem, or death was not previously identified in nature, severity, or 
degree of incidence in the investigational plan or application (including a supplementary plan or 
application), or any other unanticipated serious problem associated with a device that relates to 
the rights, safety, or welfare of subjects (21 CFR 812.3(s)). 
8.2 Classification of an Adverse Event 
8.2.1 Severity of Event 
For AEs not included in the protocol defined grading system, the following guidelines will be 
used to describe severity. 
 
• Mild – Events require minimal or no treatment and do not interfere with the participant’s daily 
activities. 
• Moderate – Events result in a low level of inconvenience or concern with the therapeutic 
measures. Moderate events may cause some interference with functioning. 
• Severe – Events interrupt a participant’s usual daily activity and may require systemic drug 
therapy or other treatment. Severe events are usually potentially life-threatening or incapacitating. 
8.2.2 Relationship to Study Agent 
For all collected AEs, the clinician who examines and evaluates the participant will determine 
the AE’s causality based on temporal relationship and his/her clinical judgment. The degree of 
certainty about causality will be graded using the categories below. 
• Definitely Related – There is clear evidence to suggest a causal relationship, and other possible 
contributing factors can be ruled out. The clinical event, including an abnormal laboratory test 
result, occurs in a plausible time relationship to drug administration and cannot be explained by 
concurrent disease or other drugs or chemicals. The response to withdrawal of the drug 
(dechallenge) should be clinically plausible. The event must be pharmacologically or 
phenomenologically definitive, with use of a satisfactory rechallenge procedure if necessary. 


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• Probably Related – There is evidence to suggest a causal relationship, and the influence of other 
factors is unlikely. The clinical event, including an abnormal laboratory test result, occurs within a 
reasonable time after administration of the drug, is unlikely to be attributed to concurrent disease 
or other drugs or chemicals, and follows a clinically reasonable response on withdrawal 
(dechallenge). Rechallenge information is not required to fulfill this definition. 
• Possibly Related – There is some evidence to suggest a causal relationship (e.g., the event 
occurred within a reasonable time after administration of the trial medication). However, other 
factors may have contributed to the event (e.g., the participant’s clinical condition, other 
concomitant events). Although an AE may rate only as “possibly related” soon after discovery, it 
can be flagged as requiring more information and later be upgraded to “probably related” or 
“definitely related,” as appropriate. 
• Unlikely to be related – A clinical event, including an abnormal laboratory test result, whose 
temporal relationship to drug administration makes a causal relationship improbable (e.g., the 
event did not occur within a reasonable time after administration of the trial medication) and in 
which other drugs or chemicals or underlying disease provides plausible explanations (e.g., the 
participant’s clinical condition, other concomitant treatments). 
• Not Related – The AE is completely independent of study drug administration, and/or evidence 
exists that the event is definitely related to another etiology. There must be an alternative, 
definitive etiology documented by the clinician. 
8.2.3 Expectedness 
Dr. Nachtigall will be responsible for determining whether an AE is expected or unexpected. An 
AE will be considered unexpected if the nature, severity, or frequency of the event is not 
consistent with the risk information previously described for the study agent. 
8.3 Time Period and Frequency for Event Assessment and Follow-Up 
The occurrence of an AE or SAE may come to the attention of study personnel during study 
visits and interviews of a study participant presenting for medical care, or upon review by a 
study monitor. All AEs including local and systemic reactions not meeting the criteria for SAEs 
will be captured on the appropriate RF. 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 to adequate resolution. 
 
Any medical condition that is present at the time that the participant is screened will be 
considered as baseline and not reported as an AE. However, if the study participant’s condition 
deteriorates at any time during the study, it will be recorded as an AE. UPs will be recorded in 
the data collection system throughout the study. 
 
Changes in the severity of an AE will be documented to allow an assessment of the duration of 
the event at each level of severity to be performed. AEs characterized as intermittent require 
documentation of onset and duration of each episode. 
 
The PI will record all reportable events with start dates occurring any time after informed 
consent is obtained until 7 (for non-serious AEs) or 30 days (for SAEs) after the last day of study 
participation. At each study visit, the investigator will inquire about the occurrence of AE/SAEs 
since the last visit. Events will be followed for outcome information until resolution or 
stabilization.  


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All unresolved adverse events should be followed by the investigator until the events are 
resolved, the subject is lost to follow-up, or the adverse event is otherwise explained.  At the last 
scheduled visit, the investigator should instruct each subject to report any subsequent event(s) 
that the subject, or the subject’s personal physician, believes might reasonably be related to 
participation in this study.  The investigator should notify the study sponsor of any death or 
adverse event occurring at any time after a subject has discontinued or terminated study 
participation that may reasonably be related to this study.  The sponsor should also be notified if 
the investigator should become aware of the development of cancer or of a congenital anomaly 
in a subsequently conceived offspring of a subject that has participated in this study.  
8.4 Reporting Procedures – Notifying the IRB    
8.4.1 Adverse Event Reporting 
The patient will be given Dr. Shavy Nagpal, Dr. Christina Escobar, and Dr. Lila Nachtigall’s 
contact to report any AE. AE’s deemed to be related to the study will be reported to the IRB 
within 7 days of the investigator becoming aware of the event. Dr.Nachtigall, the principal 
investigator, will be responsible for completing and signing off on AE reports.  
8.4.2 Serious Adverse Event Reporting 
The patient will be given Dr. Shavy Nagpal, Dr. Christina Escobar, Dr. Lila Nachtigall’s contact 
to report any SAE. SAE deemed to be related to the study will be reported to the IRB within 3 
days of the investigator becoming aware of the event. Dr. Nachtigall, the principal investigator, 
will be responsible for completing and signing off on SAE reports.  
8.4.3 Unanticipated Problem Reporting 
Incidents or events that meet the OHRP criteria for UPs require the creation and completion of 
an UP report form. It is the site investigator’s responsibility to report UPs to their IRB. The UP 
report will include the following information: 
• Protocol identifying information: protocol title and number, PI’s name, and the IRB project number; 
• A detailed description of the event, incident, experience, or outcome; 
• An explanation of the basis for determining that the event, incident, experience, or outcome 
represents an UP; 
• A description of any changes to the protocol or other corrective actions that have been taken or 
are proposed in response to the UP. 
 
To satisfy the requirement for prompt reporting, UPs will be reported using the following 
timeline: 
• UPs that are SAEs will be reported to the IRB within 3 days of the investigator becoming aware of 
the event. 
• Any other UP will be reported to the IRB within 7 days of the investigator becoming aware of the 
problem. 
• All UPs should be reported to appropriate institutional officials (as required by an institution’s 
written reporting procedures), the supporting agency head (or designee), and OHRP within 7 days 
of the IR’s receipt of the report of the problem from the investigator. 


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8.4.4 Reporting of Pregnancy 
This study is being conducted in post-menopausal women. But in the rare circumstance that a 
patient becomes pregnant while in this study, the treatment (either arm) will be discontinued, 
follow-up visit will be scheduled to assess for safety, and a request will be made to follow the 
patient through her pregnancy to the pregnancy outcome.  
8.5 Reporting Procedures – Notifying the Study Sponsor 
The study clinician will complete a SAE Form within the following timelines: 
 
• All deaths and immediately life-threatening events, whether related or unrelated, will be recorded 
on the SAE Form and submitted within 24 hours of site awareness. See Section 1, Key Roles for 
contact information. 
• Other SAEs regardless of relationship will be submitted within 72 hours of site awareness. 
 
All SAEs will be followed until satisfactory resolution or until the investigator deems the event 
to be chronic or the adherence to be stable.  
 
As a follow-up to the initial report, within the following 48 hours of awareness of the event, the 
investigator shall provide further information, as applicable, on the unanticipated event or the 
unanticipated problem in the form of a written narrative.  This should include a copy of the 
completed Unanticipated Problem form, and any other diagnostic information that will assist the 
understanding of the event.  Significant new information on ongoing unanticipated adverse 
effects shall be provided promptly to the study sponsor. 
 
The study investigator shall complete an Unanticipated Adverse Device Effect Form and submit 
to the study sponsor and to the reviewing IRB as soon as possible, but in no event later than 10 
working days after the investigator first learns of the effect. The study sponsor contact 
information is provided in Section 1, Key Roles. 
 
As a follow-up to the initial report, within the following 48 hours of awareness of the event, the 
investigator shall provide further information, as applicable, on the unanticipated event or the 
unanticipated problem in the form of a written narrative.  This should include a copy of the 
completed Unanticipated Problem form, and any other diagnostic information that will assist the 
understanding of the event.  Significant new information on ongoing unanticipated adverse 
effects shall be provided promptly to the study sponsor. 
 
The study sponsor is responsible for conducting an evaluation of an unanticipated adverse device 
effect and shall report the results of such evaluation to FDA and to all reviewing IRBs and 
participating investigators within 10 working days after the sponsor first receives notice of the 
effect. Thereafter the sponsor shall submit such additional reports concerning the effect as FDA 
requests. 
8.6 Study Halting Rules 
Administration of study agent will be halted when three grade 3 AEs determined to be “probably 
related” are reported to the PI. There are no predicted grade 3 AE’s for either study agent. The PI 
will inform the FDA of the temporary halt and the disposition of the study. 


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8.7 Safety Oversight 
It is the responsibility of the Principal Investigator to oversee the safety of the study at his/her 
site.  This safety monitoring will include careful assessment and appropriate reporting of adverse 
events as noted above, as well as the construction and implementation of a site data and safety-
monitoring plan. Medical monitoring will include a regular assessment of the number and type of 
serious adverse events. The monitoring plan includes two official review time points of all AE’s 
noted by patients within the time frame of the study. Since the planned time frame of the study is 
one year, there will be one review at the 6 month mark and one at the end, 12 month mark. The 
outcomes of the data safety monitoring and AE’s will be summarized and submitted as a 
progress report to the IRB with the Continuing Review Submission. 
9 Clinical Monitoring 
Clinical site monitoring is conducted to ensure that the rights and well-being of human subjects 
are protected, that the reported trial data are accurate, complete, and verifiable, and that the 
conduct of the trial is in compliance with the currently approved protocol/amendment(s), with 
GCP, and with applicable regulatory requirement(s). 
• Dr. Shavy Nagpal will monitor the data for accuracy and completeness and the safety review will 
be performed by Dr. Nachtigall. The monitoring reports will be distributed to all study investigators. 
• Independent audits will not be conducted. 
• Each clinical site will perform internal quality management of study conduct, data collection, 
documentation and completion. An individualized quality management plan will be developed to 
describe a site’s quality management. 
10 Statistical Considerations 
10.1 Statistical and Analytical Plans (SAP) 
As the study is a pilot randomized trial, the results are expected to inform the overall protocol 
design for a larger effectiveness evaluation, including the statistical analysis plan. Our overall 
strategy will be to estimate the primary and secondary outcomes for those randomized to HLA, 
along with the contemporary cohort randomized to vaginal estrogen. Formal comparisons 
between randomized groups are not of focus, but we will estimate treatment effects along with 
measures of variability in these measures (95% CI).  
   
10.2 Statistical Hypotheses 
We expect no clinically meaningful differences in baseline characteristics or baseline assessment 
of outcomes between those randomized to HLA or to vaginal estrogen, however this is possible 
given the limited pilot trial sample size. These differences will be assessed and considered in the 
evaluation of outcomes for primary and secondary endpoints.  
 
We expect a clinically meaningful improvement in the change measured at 12 weeks 
(comparison of VSQ at 12 weeks, adjusted for baseline) in VSQ in the HLA group, and expect 
this to be greater as compared to those randomized to vaginal estrogen. Similarly, we expect to 
observe clinically meaningful improvements in the HLA group at 12 weeks, beyond those 
observed in those randomized to the vaginal estrogen cohort. These include VSI, FSFI, VAS for 
dyspareunia, itching, and dryness, vaginal pH, and presence of rugal folds.  


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These estimates will provide estimates for establishing effectiveness in future trials.  
10.3 Analysis Datasets 
The analysis dataset will include the intent to treat cohort, to include all those randomized to 
treatment, as well as a per protocol set to include who used either the control or investigational 
product for at least 12 weeks.  
10.4 Description of Statistical Methods 
 
Baseline (pre-randomization) participant demographics and clinical characteristics will be 
summarized through descriptive statistics overall, and by randomized group. Clinical 
characteristics will include past HRT use, uterus present or not, and components of their medical 
and gynecologic history. Details of each outcome measure is provided below. Analysis of the 
primary and secondary measures will include summarizing each by the mean and standard 
deviation at baseline and all measured time points, including at the primary outcome time of 12 
weeks. For continuous measures, a linear mixed effects regression model will estimate the mean 
outcome at 12 weeks, both unadjusted and adjusted for baseline measurement. No further 
adjustment for participant characteristics is expected given the limited trial size. The linear 
mixed effects regression model will allow all participants to be included in analysis, regardless 
of completion of study follow up at 12 weeks, under the assumption of this assessment being 
missing at random.  
 
Missing outcome data will be summarized by participant characteristics to understand how to 
better retain individuals in treatment.  
10.4.1 Analysis of the Primary Endpoint 
• 
VSQ score (see attached below): 
o 
Definition: 21 question survey 
o 
Interval variable overall (binary responses; a ‘yes’ equates to one point, a ‘no’ equates to 
zero points for each question which is then added up to a sum) 
o 
Single endpoint measure with a score that can range from 0 to 21 
10.4.2 Analysis of the Secondary Endpoint(s) 
• 
FSFI score (see attached below): 
o 
Definition: 19 question survey 
o 
Graded responses from 0 to 5 
o 
Single endpoint measure with a score that can range from 0 to 95 
• 
VSI score (see attached below): 
o 
Definition: 19 question survey 
o 
Graded responses from 0 to 3 
o 
Single endpoint measure with a score that can range from 0 to 15 
• 
Vaginal pH 
o 
Definition: pH number 
o 
Interval variable ranging from 0 to 14 
o 
Single endpoint 
• 
Vaginal maturation index (VMI) 
o 
Definition: microscopic analysis of vaginal tissue that assigns a percentage to the amount 
of parabasal, intermediate, and squamous cells visualized that add up to 100% 


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o 
Ratio variable ranging from 0 to 100 
o 
Single endpoint (only the % of squamous cells will be reported since that is most closely 
correlated with hormonal influence on the vaginal tissue) 
• 
Visual analog scale (VAS) score for dyspareunia, itching, dryness 
o 
Definition: visual scale attempting to capture the intensity of a symptom 
o 
Ratio variable ranging from 0 to 10 
o 
Single endpoint 
• 
Vaginal rugal folds 
o 
Definition: visualization of the presence of vaginal rugal folds on pelvic exam 
o 
Continous variable  
o 
Single endpoint 
10.4.3 Safety Analyses 
• 
Safety endpoints will be analyzed as summary statistics during treatment 
• 
Adverse events will be coded using the Medical Dictionary for Regulatory Activities 
o 
Each AE will be counted only once for a given participant  
o 
Each AE will be presented by System Organ Class 
o 
The duration, relationship, severity, and outcome of each AE will be reported 
o 
AE’s will be ascertained from adherence and PI-reported 
o 
AE’s leading to premature discontinuation from the study and serious treatment-emergent 
AE’s will be presented in a table 
10.4.4 Adherence and Retention Analyses 
Due to the nature of this study, study agent usage will be assessed solely by patient self-report. 
Participation and study retention will be assessed by a ratio of those who participated divided by 
the total starting cohort for that study arm. Those that discontinue and provide a reason for 
discontinuation will be categorized and the information will be presented in a table. 
10.4.5 Planned Interim Analysis 
 
No interim analyses are planned. 
10.4.5.1 Safety Review 
There are no anticipated side-effects to the investigational agent. The control agent is FDA 
approved for the condition being studied in this trial. Thus, study enrollment will only be stopped 
if unforeseeable, significant side effects or life-threatening adverse events occur in either study 
cohort. No statistical rules will be used to halt enrollment due to the short duration of the study 
and lack of interim analysis.  
 
Patients will be counseled at the start of the study to call Dr. Shavy Nagpal or Dr. Lila Nachtigall 
for any side-effect or AE they believe is related to study medication usage. Otherwise, after the 
baseline visit, the next formal visit will be the final visit at week 12 when medication safety 
questions will be asked.  
10.4.6 Additional Sub-Group Analyses 
Due to the small cohort size of this pilot study, there will be no sub-group analysis.  
10.4.7 Exploratory Analyses 
N/A 


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10.5 Sample Size 
This study would be the first US-based randomized trial investigating HLA’s usage for GSM 
treatment, to the authors’ best knowledge. Thus, the sample size of 60 has been chosen to pilot 
the presented protocol, to assess feasibility and acceptability in quality of life for HLAs and to 
gather preliminary effectiveness for planning a larger effectiveness trial. The authors 
acknowledge the limitations of having enrolling 60 individuals, including generalizability. 
However in this initial stage of study implementation and design, expect this number to provide 
sufficient information.   
 
No study to date has used the VSQ to assess the impact of treatment modalities for GSM, so 
there is no historical data to provide an assumed mean score. However, with 30 individuals 
randomized to each study treatment, we expect to have at least 80% probability of achieving a 
95% confidence interval (CI) width of 1.7, assuming a standard deviation in the VLM of 2.  With 
fewer individuals at any timepoint, the width of the CI will increase.  
 
The assumed drop-out, withdrawal, cross-over and missing data rate is assumed to be 33%, 
which explains the enrollment goal of 60 to allow for 40 evaluable patients. This is a 
conservative estimate because the missing data rates in RCT’s from four major journals has 
shown to be 20% or greater in about 18% of trials, which was also seen in quality-of-life studies 
(26, 27). We will monitor reasons for drop out and withdrawal of treatment to improve study 
adherence and follow up.  
 
All participants will be included in the intent to treat analyses, and those participants who use the 
study intervention for at least 12 weeks will be included in the per-protocol analysis.  
10.6 Measures to Minimize Bias 
10.6.1 Enrollment/Randomization/Masking Procedures 
While blinding would be desired in this study, it is not feasible due to the study drugs having 
different formulations. Therefore, once randomization is performed, investigators and patients 
will know which study arm patients are assigned to. The implication of lack of blinding is that 
there could be potential bias regarding patient report of symptomatic improvement and provider 
record of measurements, such as VAS scores. However, the goal of this study is to be a pilot 
study to allow for a larger RCT in the future that could potentially be blinded and allow for 
minimization of biases.  
 
To reduce bias, randomization will be used with allocation 1:1 to each treatment group. Block 
randomization will be used due to the small sample size of each study arm using Trialmaster. 
Replacement of patients who discontinue will not be allowed since the enrollment goal of 60 is 
conservative to account for drop-outs, early discontinuation, and lost to follow up patients.  
11 Source Documents and Access to Source Data/Documents 
Source data is all information, original records of clinical findings, observations, or other 
activities in a clinical trial necessary for the reconstruction and evaluation of the trial.  Source 
data are contained in source documents.  Examples of these original documents, and data records 
include: hospital records, clinical and office charts, laboratory notes, memoranda, subjects’ 


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diaries or evaluation checklists, pharmacy dispensing records, recorded data from automated 
instruments, copies or transcriptions certified after verification as being accurate and complete, 
microfiches, photographic negatives, microfilm or magnetic media, x-rays, subject files, and 
records kept at the pharmacy, at the laboratories, and at medico-technical departments involved 
in the clinical trial. It is acceptable to use CRFs as source documents. If this is the case, it should 
be stated in this section what data will be collected on CRFs and what data will be collected from 
other sources. 
 
The study case report form (CRF) is the primary data collection instrument for the study.  All 
data requested on the CRF must be recorded.  All missing data must be explained.  If a space on 
the CRF is left blank because the procedure was not done or the question was not asked, write 
“N/D”.  If the item is not applicable to the individual case, write “N/A”.  All entries should be 
printed legibly in black ink.  If any entry error has been made, to correct such an error, draw a 
single straight line through the incorrect entry and enter the correct data above it.  All such 
changes must be initialed and dated.  DO NOT ERASE OR WHITE OUT ERRORS.  For 
clarification of illegible or uncertain entries, print the clarification above the item, then initial and 
date it. 
 
Access to study records will be limited to IRB-approved members of the study team. The 
investigator will permit study-related monitoring, audits, and inspections by the IRB/EC, the 
sponsor, government regulatory bodies, and University compliance and quality assurance groups 
of all study related documents (e.g. source documents, regulatory documents, data collection 
instruments, study data etc.).  The investigator will ensure the capability for inspections of 
applicable study-related facilities (e.g. pharmacy, diagnostic laboratory, etc.). 
 
Participation as an investigator in this study implies acceptance of potential inspection by 
government regulatory authorities and applicable University compliance and quality assurance 
offices. 
12 Quality Assurance and Quality Control 
QC procedures will be implemented beginning with the data entry system and data QC checks 
that will be run on the database will be generated. Any missing data or data anomalies will be 
communicated to the site(s) for clarification/resolution. 
 
Following written SOPs, the monitors will verify that the clinical trial is conducted and data are 
generated, documented (recorded), and reported in compliance with the protocol, GCP, and the 
applicable regulatory requirements (e.g., Good Laboratory Practices (GLP), Good Manufacturing 
Practices (GMP)). 
 
The investigational site will provide direct access to all trial related sites, source data/documents, 
and reports for the purpose of monitoring and auditing by the sponsor, and inspection by local 
and regulatory authorities. 


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13 Ethics/Protection of Human Subjects 
13.1 Ethical Standard 
The investigator will ensure that this study is conducted in full conformity with Regulations for 
the Protection of Human Subjects of Research codified in 45 CFR Part 46, 21 CFR Part 50, 21 
CFR Part 56, and/or the ICH E6. 
13.2 Institutional Review Board 
The protocol, informed consent form(s), recruitment materials, and all participant materials will 
be submitted to the IRB for review and approval. Approval of both the protocol and the consent 
form must be obtained before any participant is enrolled. Any amendment to the protocol will 
require review and approval by the IRB before the changes are implemented to the study. All 
changes to the consent form will be IRB approved; a determination will be made regarding 
whether previously consented participants need to be re-consented. 
13.3 Informed Consent Process 
13.3.1 Consent/Assent and Other Informational Documents Provided to Participants 
Consent forms describing in detail the study agent, study procedures, and risks are given to the 
participant and written documentation of informed consent is required prior to starting 
intervention/administering study product. The following consent materials are submitted with 
this protocol: patient consent form, key study information. 
13.3.2 Consent Procedures and Documentation 
Informed consent is a process that is initiated prior to the individual’s agreeing to participate in 
the study and continues throughout the individual’s study participation. Extensive discussion of 
risks and possible benefits of participation will be provided to the participants and their families. 
Consent forms will be IRB-approved and the participant will be asked to read and review the 
document. The investigator will explain the research study to the participant and answer any 
questions that may arise. All participants will receive a verbal explanation in terms suited to their 
comprehension of the purposes, procedures, and potential risks of the study and of their rights as 
research participants. Participants will have the opportunity to carefully review the written 
consent form and ask questions prior to signing. The participants should have the opportunity to 
discuss the study with their surrogates or think about it prior to agreeing to participate. The 
participant will sign the informed consent document prior to any procedures being done 
specifically for the study. The participants may withdraw consent at any time throughout the 
course of the trial. A copy of the signed informed consent document will be given to the 
participants for their records. The rights and welfare of the participants will be protected by 
emphasizing to them that the quality of their medical care will not be adversely affected if they 
decline to participate in this study. 
 
A copy of the signed informed consent document will be stored in the subject’s research record. 
The consent process, including the name of the individual obtaining consent, will be thoroughly 
documented in the subject’s research record. Any alteration to the standard consent process (e.g. 
use of a translator, consent from a legally authorized representative, consent document presented 
orally, etc.) and the justification for such alteration will likewise be documented.  


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13.4 Posting of Clinical Trial Consent Form 
N/A 
13.5 Participant and Data Confidentiality 
Information about study subjects will be kept confidential and managed according to the 
requirements of the Health Insurance Portability and Accountability Act of 1996 (HIPAA).  
Those regulations require a signed subject authorization informing the subject of the following:  
• What protected health information (PHI) will be collected from subjects in this study 
• Who will have access to that information and why 
• Who will use or disclose that information  
• The rights of a research subject to revoke their authorization for use of their PHI.  
 
In the event that a subject revokes authorization to collect or use PHI, the investigator, by 
regulation, retains the ability to use all information collected prior to the revocation of subject 
authorization.  For subjects that have revoked authorization to collect or use PHI, attempts 
should be made to obtain permission to collect at least vital status (i.e. that the subject is alive) at 
the end of their scheduled study period. 
 
Participant confidentiality is strictly held in trust by the participating investigators, their staff, 
and the sponsor(s) and their agents. This confidentiality is extended to cover testing of biological 
samples and genetic tests in addition to the clinical information relating to participants. 
Therefore, the study protocol, documentation, data, and all other information generated will be 
held in strict confidence. No information concerning the study or the data will be released to any 
unauthorized third party without prior written approval of the sponsor. 
 
The study monitor, other authorized representatives of the sponsor, representatives of the IRB or 
pharmaceutical company supplying study product may inspect all documents and records 
required to be maintained by the investigator, including but not limited to, medical records 
(office, clinic, or hospital) and pharmacy records for the participants in this study. The clinical 
study site will permit access to such records. 
 
The study participant’s contact information will be securely stored at each clinical site for 
internal use during the study. At the end of the study, all records will continue to be kept in a 
secure location for as long a period as dictated by local IRB and Institutional regulations. 
 
Study participant research data, which is for purposes of statistical analysis and scientific 
reporting, will be transmitted to and stored at NYU Langone Medical Center. This will not 
include the participant’s contact or identifying information. Rather, individual participants and 
their research data will be identified by a unique study identification number. The study data 
entry and study management systems used by clinical sites and by NYU Langone Medical 
Center research staff will be secured and password protected. At the end of the study, all study 
databases will be de-identified and archived at the NYU Langone Medical Center. 
13.5.1 Research Use of Stored Human Samples, Specimens, or Data 
• Intended Use: Samples and data collected under this protocol may be used to study GSM. No 
genetic testing will be performed. 


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• Storage: Access to stored samples will be limited using locked cabinets. Samples and data will be 
stored using codes assigned by the investigators. Data will be kept in password-protected 
computers. Only investigators will have access to the samples and data. 
• Tracking: Data will be tracked using Trialmaster. 
Data collected for this study will be analyzed and stored using TrialMaster. After the study is 
completed, the de-identified, archived data will be transmitted to and stored on the NYUMC 
computer network, under the supervision of Dr. Shavy Nagpal, for use by other researchers 
including those outside of the study without patient identifiers. Permission to transmit data to 
NYUMC computer network will be included in the informed consent. 
 
There will be no biological samples stored. 
 
When the study is completed, access to study data will be provided through the password 
protected NYUMC computer network.  
14 Data Handling and Record Keeping 
14.1 Data Collection and Management Responsibilities 
Data collection is the responsibility of the clinical trial staff at the site under the supervision of 
the site PI. The investigator is responsible for ensuring the accuracy, completeness, legibility, 
and timeliness of the data reported. 
 
All source documents should be completed in a neat, legible manner to ensure accurate 
interpretation of data. Black ink is required to ensure clarity of reproduced copies. When making 
changes or corrections, cross out the original entry with a single line, and initial and date the 
change. DO NOT ERASE, OVERWRITE, OR USE CORRECTION FLUID OR TAPE ON 
THE ORIGINAL. 
 
Copies of the electronic CRF (eCRF) will be provided for use as source documents and 
maintained for recording data for each participant enrolled in the study. Data reported in the 
eCRF derived from source documents should be consistent with the source documents or the 
discrepancies should be explained and captured in a progress note and maintained in the 
participant’s official electronic study record. 
 
Clinical data (including AEs, concomitant medications, and expected adverse reactions data) and 
clinical laboratory data will be entered into TrialMaster. The data system includes password 
protection and internal quality checks, such as automatic range checks, to identify data that 
appear inconsistent, incomplete, or inaccurate. Clinical data will be entered directly from the 
source documents. 
14.2 Study Records Retention 
Study documents will be retained for the longer of 3 years after close-out, 5 years after final 
reporting/publication, or 2 years after the last approval of a marketing application is approved for 
the drug for the indication for which it is being investigated or 2 years after the investigation is 
discontinued and FDA is notified if no application is to be filed or if the application has not been 
approved for such indication. No records will be destroyed without the written consent of the 


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sponsor, if applicable. It is the responsibility of the sponsor to inform the investigator when these 
documents no longer need to be retained. 
14.3 Protocol Deviations 
A protocol deviation is any noncompliance with the clinical trial protocol, GCP, or Manual of 
Procedures (MOP) requirements. The noncompliance may be either on the part of the participant, 
the investigator, or the study site staff. As a result of deviations, corrective actions are to be 
developed by the site and implemented promptly. 
 
These practices are consistent with ICH E6: 
• 4.5 Compliance with Protocol, sections 4.5.1, 4.5.2, and 4.5.3 
• 5.1 Quality Assurance and Quality Control, section 5.1.1 
• 5.20 Noncompliance, sections 5.20.1, and 5.20.2. 
 
It is the responsibility of the site PI/study staff to use continuous vigilance to identify and report 
deviations within 7 working days of identification of the protocol deviation, or within 7 working 
days of the scheduled protocol-required activity. 
 
 
Protocol deviations must be reported to the local IRB per their guidelines. The site PI/study staff 
is responsible for knowing and adhering to their IRB requirements. Further details about the 
handling of protocol deviations will be included in the MOP. 
14.4 Publication and Data Sharing Policy 
This study will comply with the NIH Public Access Policy, which ensures that the public has 
access to the published results of NIH funded research. It requires scientists to submit final peer-
reviewed journal manuscripts that arise from NIH funds to the digital archive PubMed Central 
upon acceptance for publication. 
 
The International Committee of Medical Journal Editors (ICMJE) member journals have adopted 
a clinical trials registration policy as a condition for publication. The ICMJE defines a clinical 
trial as any research project that prospectively assigns human subjects to intervention or 
concurrent comparison or control groups to study the cause-and-effect relationship between a 
medical intervention and a health outcome. Medical interventions include drugs, surgical 
procedures, devices, behavioral treatments, process-of-care changes, and the like. Health 
outcomes include any biomedical or health-related measures obtained in patients or participants, 
including pharmacokinetic measures and AE. The ICMJE policy, and the Section 801 of the 
Food and Drug Administration Amendments Act of 2007, requires that all clinical trials be 
registered in a public trials registry such as ClinicalTrials.gov, which is sponsored by the 
National Library of Medicine. Other biomedical journals are considering adopting similar 
policies. For interventional clinical trials performed under NIH IC grants and cooperative 
agreements, it is the grantee’s responsibility to register the trial in an acceptable registry, so the 
research results may be considered for publication in ICMJE member journals. The ICMJE does 
not review specific studies to determine whether registration is necessary; instead, the committee 
recommends that researchers who have questions about the need to register err on the side of 
registration or consult the editorial office of the journal in which they wish to publish. 


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FDAAA mandates that a "responsible party" (i.e., the sponsor or designated principal 
investigator) register and report results of certain "applicable clinical trials": 
 
• Trials of Drugs and Biologics: Controlled, clinical investigations, other than Phase I investigations 
of a product subject to FDA regulation; 
• Trials of Devices: Controlled trials with health outcomes of a product subject to FDA regulation 
(other than small feasibility studies) and pediatric postmarket surveillance studies. 
• NIH grantees must take specific steps to ensure compliance with NIH implementation of FDAAA. 
15 Study Finances 
15.1 Funding Source 
This study is financed by JDS therapeutics.  
15.2 Costs to the Participant 
All office visits, tests and treatment drugs for the trial will be provided to the patient free of cost. 
However, the patient will not be compensated for participating in the study, nor will 
reimbursement be provided for travel costs to the office.  
16 Study Administration 
16.1 Study Leadership 
The Steering Committee will govern the conduct of the study. The Steering Committee will be 
composed of the Study Chairman, the PI of the Coordinating Center, the PI of the clinical sites, 
chairperson of the Study Coordinators subcommittee, and the PI of the Central Biochemistry 
Laboratory. The Steering Committee will meet in person at least annually. 
17 Conflict of Interest Policy 
The independence of this study from any actual or perceived influence, such as by the 
pharmaceutical industry, is critical. Therefore any actual conflict of interest of persons who have 
a role in the design, conduct, analysis, publication, or any aspect of this trial will be disclosed 
and managed. Furthermore, persons who have a perceived conflict of interest will be required to 
have such conflicts managed in a way that is appropriate to their participation in the trial. The 
study leadership has established policies and procedures for all study group members to disclose 
all conflicts of interest and will establish a mechanism for the management of all reported 
dualities of interest.  
 
Any investigator who has a conflict of interest with this study (patent ownership, royalties, or 
financial gain greater than the minimum allowable by their institution, etc.) must have the 
conflict reviewed by the NYU Langone Conflict of Interest Management Unit (CIMU) with a 
Committee-sanctioned conflict management plan that has been reviewed and approved by the 
study sponsor prior to participation in this study. All NYULMC investigators will follow the 
applicable conflict of interest policies. 
 


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18 References 
1. Portman, David J., Margery LS Gass, and Vulvovaginal Atrophy Terminology Consensus 
Conference Panel. "Genitourinary syndrome of menopause: new terminology for vulvovaginal 
atrophy from the International Society for the Study of Women's Sexual Health and the North 
American Menopause Society." Climacteric 17.5 (2014): 557-563. 
2. Gandhi, Jason, et al. "Genitourinary syndrome of menopause: an overview of clinical 
manifestations, pathophysiology, etiology, evaluation, and management." American journal of 
obstetrics and gynecology 215.6 (2016): 704-711. 
3. Krychman, Michael, et al. "The women's EMPOWER survey: women's knowledge and awareness 
of treatment options for vulvar and vaginal atrophy remains inadequate." The journal of sexual 
medicine 14.3 (2017): 425-433. 
4. Nappi, Rossella E., and Marta Kokot-Kierepa. "Women's voices in the menopause: results from 
an international survey on vaginal atrophy." Maturitas 67.3 (2010): 233-238. 
5. North American Menopause Society. "Management of symptomatic vulvovaginal atrophy: 2013 
position statement of The North American Menopause Society." Menopause 20.9 (2013): 888-
902. 
6. Papakonstantinou, Eleni, Michael Roth, and George Karakiulakis. "Hyaluronic acid: A key 
molecule in skin aging." Dermato-endocrinology 4.3 (2012): 253-258. 
7. Liu, Shuai-Bin, et al. "The effects of hyaluronic acid vaginal gel on the vaginal epithelium of 
ovariectomized rats." Gynecological Endocrinology 31.3 (2015): 208-213. 
8. Morali, Giancarlo, et al. "Open, non-controlled clinical studies to assess the efficacy and safety of 
a medical device in form of gel topically and intravaginally used in postmenopausal women with 
genital atrophy." Arzneimittelforschung 56.03 (2006): 230-238. 
9. Costantino, D., and C. Guaraldi. "Effectiveness and safety of vaginal suppositories for the 
treatment of the vaginal atrophy in postmenopausal women: an open, non-controlled clinical trial." 
Eur Rev Med Pharmacol Sci 12.6 (2008): 411-416. 
10. Chen, Junya, et al. "Evaluation of the efficacy and safety of hyaluronic acid vaginal gel to ease 
vaginal dryness: A multicenter, randomized, controlled, open‐label, parallel‐group, clinical trial." 
The journal of sexual medicine 10.6 (2013): 1575-1584. 
11. Jokar, Azam, et al. "Comparison of the hyaluronic acid vaginal cream and conjugated estrogen 
used in treatment of vaginal atrophy of menopause women: a randomized controlled clinical trial." 
International journal of community based nursing and midwifery 4.1 (2016): 69. 
12. Ekin, Murat, et al. "The comparison of hyaluronic acid vaginal tablets with estradiol vaginal tablets 
in the treatment of atrophic vaginitis: a randomized controlled trial." Archives of gynecology and 
obstetrics 283.3 (2011): 539-543. 
13. Origoni, M., et al. "Postmenopausal vulvovaginal atrophy (VVA) is positively improved by topical 
hyaluronic acid application. A prospective, observational study." Eur Rev Med Pharmacol Sci 
20.20 (2016): 4190-4195. 
14. McEndree, Barbara. "Clinical application of the vaginal maturation index." Nurse Practitioner 24.9 
(1999): 48. 
15. Erekson, Elisabeth A., et al. "The VSQ: a questionnaire to measure vulvovaginal symptoms in 
postmenopausal women." Menopause (New York, NY) 20.9 (2013): 973. 
16. Sturdee, D. W., and N. and Panay. "Recommendations for the management of postmenopausal 
vaginal atrophy." Climacteric 13.6 (2010): 509-522. 
17. Diem, Susan J., et al. "Effects of vaginal estradiol tablets and moisturizer on menopause-specific 
quality of life and mood in healthy postmenopausal women with vaginal symptoms: a randomized 
clinical trial." Menopause 25.10 (2018): 1086-1093. 
18. Caillouette, James C., et al. "Vaginal pH as a marker for bacterial pathogens and menopausal 
status." American journal of obstetrics and gynecology 176.6 (1997): 1270-1277. 
19. Estrace (estradiol vaginal cream) [prescribing information]. Madison, NJ: Allergan; June 2018. 


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20. Simon, James, et al. "Endometrial safety of ultra-low-dose estradiol vaginal tablets." Obstetrics & 
Gynecology 116.4 (2010): 876-883. 
21. Weisberg, E., et al. "Endometrial and vaginal effects of low-dose estradiol delivered by vaginal 
ring or vaginal tablet." Climacteric 8.1 (2005): 83-93.  
22. Bachmann, Gloria, et al. "Efficacy and safety of low-dose regimens of conjugated estrogens 
cream administered vaginally." Menopause 16.4 (2009): 719-727. 
23. North American Menopause Society. "The 2012 hormone therapy position statement of the North 
American Menopause Society." Menopause (New York, NY) 19.3 (2012): 257. 
24. Ayton, Rosemary A., et al. "A comparative study of safety and efficacy of continuous low dose 
oestradiol released from a vaginal ring compared with conjugated equine oestrogen vaginal 
cream in the treatment of postmenopausal urogenital atrophy." BJOG: An International Journal of 
Obstetrics & Gynaecology 103.4 (1996): 351-358. 
25. Ellerington, M. C., S. I. J. Whitcroft, and M. I. Whitehead. "HRT: Developments in therapy." Br 
Med Bull 48.2 (1992): 401-25. 
26. Fielding, Shona, et al. "A review of RCTs in four medical journals to assess the use of imputation 
to overcome missing data in quality of life outcomes." Trials 9.1 (2008): 51. 
27. National Research Council. The prevention and treatment of missing data in clinical trials. 
National Academies Press, 2010. 
 
 


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19 Attachments 
 
19a The Vulvovaginal Symptom Questionnaire 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 


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19b Revaree Package Insert 
 
 
19c Estrace Package Insert 
https://www.allergan.com/assets/pdf/estrace_pi 
 
19d Data Tracking Sheet Sample 
 
 
19e Patient Consent Form 
Attached separately 


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19f Patient Key Information 
Attached separately 
 
19g Female Sexual Function Index 
 


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19h Vaginal Symptom Index 
 
 
19i Patient Global Impression of Improvement 
 
Check the number that best describes how your post-intervention condition is now, 
compared with how it was before the intervention: 
 
Very much better = 1 
Much better = 2 
A little better =  3 
No change = 4 
A little worse = 5 
Much worse = 6 
Very much worse = 7 
 


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20 Schedule of Events 
 
Activity 
Visit 1 (Day 0) 
Visit 2 (12 weeks 
+/- 1 week) 
Study team procedures 
  
  
Routine history of present illness, 
medical, obstetrical, 
gynecological, surgical, 
medication, HRT usage history 
x 
 
Vitals and routine physical exam 
including pelvic 
x 
x 
GSM Diagnosis  
x 
 
Consent 
x 
 
VAS score for dyspareunia, 
itching, and dryness 
x 
x 
Rugal fold presence 
x 
x 
VSQ, FSFI, VSI  
x 
x 
Randomization 
x 
 
Study drug/device dispensation 
x 
 
Participant study drug/device 
compliance check 
 
x 
Check for side-effects and/or AE 
due to study agent  
 
x 
Laboratory Assessments 
 
 
Urine pregnancy test 
x 
 
Urine analysis 
x 
 
Vaginal pH 
x 
x 
VMI  
x 
x