Comparison of Vaginal Laser Therapy to Vaginal Estrogen Therapy
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.
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