Comparison of Vaginal Laser Therapy to Vaginal Estrogen Therapy

This is a multi-centered, randomized prospective single blinded clinical trial comparing CO2
fractionated vaginal laser therapy and vaginal estrogen cream therapy in the treatment of
vulvovaginal atrophy/GSM.

Subject Recruitment and Screening Study subjects will be recruited from patients who present
to the clinical sites at the Women's Health Institute at the Cleveland Clinic, Christ
Hospital, Stanford University Hospital, MedStar Washington Hospital Center, Women's and
Infants' Hospital of Rhode Island and Wake Forest Baptist Medical Center for treatment of
GSM. Cleveland Clinic will serve as the central Data Coordinating Center

Study Identification and Recruitment Potential subjects will be identified by members of the
sections of Urogynecology and Reconstructive Pelvic Surgery and Benign Gynecology at the
respective institutions. Eligible patients who agree to participate will be provided written
informed consent administered by the collaborators listed on this IRB.

Randomization The participants will then be randomized to either fractional CO2 vaginal laser
therapy or vaginal estrogen cream according to a computer-generated randomization schedule
with random block sizes with the use of the SAS statistical software package (SAS Institute,
Cary, NC). All patients will be unblinded to their assignment.

Diagnostic and Therapeutic Interventions In addition to a standardized evaluation including
the history and physical examination, patients will be asked to complete the Female Sexual
Function Inventory (FSFI) questionnaire, the Day-to-day Impact of Vaginal Aging (DIVA)
questionnaire, and the Urogenital Distress Inventory (UDI-6), at baseline, 3 months, and 6
months after baseline and visual analog scales (VAS) for GSM symptoms. The Patient Global
Index (PGI) will also be administered at 6 months. Completion of these questionnaires should
take no more than 15-20 minutes. A vaginal maturation index will be obtained at the baseline
visit on a regular Pap Smear side and fixed with cytofixative and air dried. This will be
repeated during the last follow up visit at 6 months.

Vaginal Laser Protocol Postmenopausal women will undergo treatment intravaginally with the
fractional microablative CO 2 laser system (SmartXide 2 V 2 LR, MonaLisa Touch, DEKA,
Florence, Italy), using the following setting: dot power 30 watt, dwell time 1000 μ s, dot
spacing 1000 μ m and the smart stack parameter from 1 to 3. Stack 1 is used at baseline and
stack 3 at 6 weeks and 3 months. The laser beam will be applied using a 90° vaginal probe
gently inserted up to the top of the vaginal canal and subsequently withdrawn at centimeter
intervals and rotated to 6 positions in an alternating clockwise and counterclockwise pattern
in order to provide a complete treatment of the vaginal wall. At the investigators discretion
a flat probe (vulvar probe) may be utilized to more efficiently treat the introital area and
vestibule. At the level of the vaginal introitus, the dot power will be decreased to 26
watts. A treatment cycle includes three laser applications (every 40-50 days, approximately 6
weeks). The procedure will be performed in the outpatient clinic and does not require any
specific preparation (e.g. analgesia/anesthesia). At the clinician's discretion, EMLA cream
may be applied to introitus for thirty minutes and wiped clean and dried prior to vulvar
laser therapy. Patients will be recommended to avoid coital sexual activity for at least 3
days after each laser application because a mild inflammatory reaction may last up to 48
hours after laser therapy. Topical lidocaine 5% ointment may be used for any vulvar pain
post-procedure.

Post Treatment Instructions

- Each subject shall be evaluated immediately post-treatment for complications and side
effects, excessive bleeding, symptomatic vaginal discharge, pain, etc.

- Each study subject will be asked to assess discomfort of treatment using a 5-point
Likert scale.

- The patient will be instructed on the specific activity limitations following the
procedure, sedentary activities are recommended for a least a few days.

- The subject will not engage in vigorous exercise or contact sports for at least 72
hours, or until approved by the physician.

- The subject will refrain from douching for at least 72 hours after the procedures.

- Subjects will not engage in intercourse for at least 72 hours post procedure.

- The subject may shower but may not bathe the day following the procedure. They will use
regular shower gel or soap.

Vaginal Estrogen Protocol The women in the vaginal estrogen group will be prescribed and
asked to administer the conjugated estrogen cream 0.5 g of cream (equivalent to 0.625 mg of
conjugated estrogen) intravaginally daily for two weeks (fourteen days) then twice weekly for
24 ± 2 additional weeks.

Vaginal examinations Vaginal Health Index (VHI) score including vaginal pH will be obtained
using litmus paper during baseline and each follow-up examination and recorded. This will be
obtained during baseline, 6 week, 3 month, and 6 month follow-up by a blinded examiner prior
to assessment of vaginal wall elasticity with silastic dilators. A limited vaginal exam will
be performed to assess the condition of the vaginal area. This exam will include a vaginal
calibration, performed with a standard vaginal dilator (Syracuse Medical). The investigator
will determine the largest dilator of the five sizes available (XS, S, M, L, XL), that the
subject can comfortably have placed in her vagina. The subject then assesses how much pain
she is experiencing when the dilator is placed in her vagina, using a 5-point Likert scale.

- GSM symptom (vaginal dryness, vaginal burning, vaginal itching, dysuria) will be
assessed using the VAS.

- Patient evaluation of the overall treatment (PGI) using a 5-point Likert scale will be
conducted at 6 week, 3 month and 6 month follow-up visits.

- After each treatment, the PI or co-investigator will be asked to evaluate the ease of
treatment using a 5-point Likert scale.

- After each treatment, the subject will be asked the degree of discomfort experienced as
a result of treatment using a 5-point Likert scale.

- Events will be evaluated and recorded.

Questionnaires and evaluations Questionnaires will be administered by a research nurse
coordinator who is blinded to the patient's therapy. Sexual function, GSM, and urinary
function will be evaluated with the 10- cm VAS, Female Sexual Function Index (FSFI),
Day-to-day Impact of Vaginal Aging (DIVA), and Urogenital Distress Inventory (UDI-6), both at
baseline prior to 1st laser treatment or commencing with vaginal estrogen (depending on
treatment group), and at 12 weeks from baseline (+/- 1week) but prior to 3rd laser treatment
(if applicable), and at 3 months follow-up after 3rd laser treatment (if applicable). Note
that all patients will follow up 6 months from baseline visit for final assessment.

The DIVA questionnaire will be administered at baseline, 3 month, and 6 month follow-up visit
period, in addition to the FSFI, UDI-6, VHI, and PGI during final assessment.

Data Collection & Management:

Baseline data will include the following:

- Patient age, race, vaginal parity, menopausal state, BMI, history of previous use of
vaginal estrogen

- FSFI, DIVA, and UDI-6 questionnaires

- VAS for GSM symptoms and VHI for objective GSM findings

Data points recorded during the procedure will include:

- Likert Scales for physician assessment of patient comfort during the procedure.

- Adverse events including inability to complete the procedure due to discomfort or
constricted vagina

Post-procedure data will include the following:

- The rate of satisfaction of patients with treatment by mean of the Patient Global
Impression of Improvement (PGI), using a 5-point Likert scale.

- The degree of difficulty encountered by the physician in performing the treatment, by
mean of a 5-point Likert scale.

- Additionally, untoward side effects of treatment such as new bothersome vaginal
irritation and significant vaginal bleeding will be recorded.

Protection of each subject's personal health information will be a priority in this study.
One master Excel file containing subject personal information including name and medical
record number will be kept in a password-protected file, on a designated protected research
drive on a password-protected computer in a locked office at each respective institution. In
that file, each subject will be assigned a subject identification number that will be used
for the purposes of data collection in order to de-identify subjects.

All paper forms used for data collection will be kept in a research cabinet dedicated to this
project, which will be locked at all times, in a locked office at the Cleveland Clinic (or
other institution name). All forms will contain de-identified information. Identification
numbers will correspond to the subjects listed in the master excel file.

All study data will be transferred and managed electronically using REDCap (Research
Electronic Data Capture). Each subject will be entered into REDCap using the assigned
identification number from the master excel file.

Inclusion Criteria:

- Menopausal with absence of menstruation for at least 12 months

- Presence of vaginal atrophy symptoms [subjective assessment of vaginal dryness >7cm on
VAS)

- Prolapse stage < II, according to the pelvic organ prolapse quantification (POP-Q)
system[31]

- No pelvic surgery within 6 months prior to treatment (vulva biopsy may be included
after 2 weeks)

- Understanding and acceptance of the obligation to return for all scheduled follow-up
visits

Exclusion Criteria:

- Personal history of vulvovaginal condyloma,,vaginal intraepithelial neoplasia (VAIN),
vaginal carcinoma, lichen sclerosis, lichen planus, history of vaginal radiation,
history of cervical cancer, other gynecologic cancer, or pelvic radiation

- Acute or recurrent urinary tract infection (UTI), or genital infection (e.g.
bacterial; vaginosis, herpes genitalis, candida).

- Personal history of Scleroderma

- Any serious disease, or chronic condition, that could interfere with the study
compliance

- Previously undergone reconstructive pelvic surgery within the past 6 months

- Previously undergone reconstructive pelvic surgery with transvaginal mesh kits and
sacrocolpopexy with synthetic mesh for prolapse, excluding synthetic slings (unless
current untreated exposure or extrusion)

- Have used vaginal estrogen cream, ring or tablet within 1 month prior to entering the
study

- Vaginal moisturizers, lubricants or homeopathic preparations within 2 weeks of therapy

- Personal history of thrombophlebitis

- Personal history of heart failure or myocardial infarction within 12 months of
procedure

- Use or anticipated use of antiplatelet therapy, anticoagulants, thrombolytics, vitamin
E or nonsteroidal anti-inflammatory drugs within 2 weeks pre-treatment

- Taking medications that are photosensitive

- Contraindication to Vaginal Estrogen Therapy

- Unwilling to Take Vaginal Estrogen

- Inability to give informed consent