Clinical trial NCT02691936
Conditions: Atrophic Vaginitis Menopause
Keywords: Genitourinary symptoms of menopause Menopause Atrophic vaginitis
Sponsor: The Cleveland Clinic
Start date: 2016-03-01; Completion date: 2018-12-01
Enrollment: 69 participants; Allocation: RANDOMIZED; Intervention model: PARALLEL

Brief summary:
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.

Detailed description:
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.

Arms: arm 1: Postmenopausal women will undergo treatment intravaginally with the fractional microablative CO2 laser system MonaLisa Touch vaginal laser protocol x 3 time points at baseline, 6 weeks and 3 months. arm 2: 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.
Interventions: intervention 1: CO2 fractionated vaginal laser intervention 2: Estrogens, Conjugated (USP)
Intervention descriptions: intervention 1: Intravaginal treatment with fractional microablative CO2 laser at baseline, 6 weeks and 3 months intervention 2: Conjugated estrogen cream 0.5g (equivalent of 0.625 mg of conjugated estrogen) daily for two weeks then twice weekly for 24 weeks

Protocol documents:
Prot_SAP_000.pdf: 
Protocol Version: 6.0 
 
1 
Dated:   16MAR2017 
 
 
 
 
 
 
OB/GYN & WOMEN’S HEALTH INSTITUTE 
CLEVELAND CLINIC  
 
 
 
A Randomized Clinical Trial Comparing  
Vaginal Laser Therapy to Vaginal Estrogen Therapy (VeLVET) 
in Women with Genitourinary Syndrome of Menopause (GSM) 
 
 
 
Principal Investigator:  Marie Fidela R. Paraiso, M.D. 
Cleveland Clinic, Cleveland, Ohio 
 
 
Co-Investigators: 
 
Cecile Unger, M.D., Cleveland Clinic, Cleveland, OH 
 
Mickey Karram, M.D., The Christ Hospital, Cincinnati, OH 
 
Eric Sokol, M.D., Stanford University, Palo Alto, CA 
 
Charley Rardin, M.D., Brown University and Women and Infants Hospital, Providence, RI 
 
Cheryl B.  Iglesia, M.D., MedStar Washington Hospital Center/Georgetown University, 
Washington, DC 
 
Catherine Matthews, M.D., Wake Forest School of Medicine, Winston-Salem, NC 
  
 


Protocol Version: 6.0 
 
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Dated:   16MAR2017 
INVESTIGATOR’S SIGNATURE PAGE  
 
 
Protocol Number or Version: 
______________________ 
 
Protocol Date: 
 
 
______________________ 
 
 
A Randomized Clinical Trial Comparing  
Vaginal Laser Therapy to Vaginal Estrogen Therapy 
in Women with Genitourinary Syndrome of Menopause 
 
The signature below constitutes the approval of this protocol and the attachments, and provides 
the necessary assurances that this trial will be conducted according to all stipulations of the 
protocol, including all statements regarding confidentiality, and according to local legal and 
regulatory requirements and applicable US federal regulations and ICH guidelines. 
 
 
Investigator:  ________________________________________________Date:       
________________ 
                         Printed Name and Title 
 
 
Signed: 
 
Date: 
 
 
Name and Title 
 
 
 
 
 
[PAGE TO BE PRINTED AND SIGNED WITH EACH FINAL PROTOCOL VERSION] 
 
 
Name and Address of Institution:  __________________________________________ 
 
 
 
 
                   __________________________________________ 
 
 
 
 
                   __________________________________________ 
 
 
 
 
                   __________________________________________ 
 
 
 
 
 
 
 
 


Protocol Version: 6.0 
 
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Dated:   16MAR2017 
 
 
 
Background and Significance 
Vulvovaginal atrophy,  referred to more recently as genitourinary syndrome of menopause 
(GSM), results from the involution of the vaginal epithelium and tissues of the vulva and vagina 
due to declining  levels of systemic estrogen during menopause [1]. The vagina may decrease in 
caliber, and the vaginal opening may become more narrow and constricted. These changes in the 
vulvovaginal environment can have a significant negative impact on a woman’s sexual health 
and quality of life. [9-13]. Other common changes include: progressive loss of elasticity and 
rugae, decreased glandular secretions leading to decreased lubrication, vaginal dryness and 
dyspareunia, as well as vaginal burning, discharge, itching, irritation, and dysuria [2-5]. 
Moreover, the weakened tissues are prone to developing traumatic tears, bleeding, petechiae, 
infection, and pain [2]. The prevalence of vulvovaginal symptoms has been consistently reported 
in approximately 50% of menopausal women.  [3, 6-10].  
 
Choice of therapy for GSM depends on symptom severity and treatment efficacy and safety. 
First-line treatment for symptomatic women with GSM, recommended by the North American 
Menopause Society, includes vaginal moisturizers, vaginal lubricants, and continued sexual 
activity. If these therapies fail, estrogen treatment should be considered in patients without 
contraindications. Topical estrogen therapy is designed to temporarily alleviate symptoms and 
reverse atrophic anatomical changes [14]. Despite proven effectiveness with symptom relief [14, 
15], compliance rates for estrogen are variable, ranging between 52-74% [16]. Furthermore, 
long-term data (> 1 year) of these topical estrogen therapies are lacking. [15]. Additionally, no 
information is available in high-risk patients [14], e.g. those with known breast or uterine cancer  
in whom estrogen therapy is relatively contraindicated and where the management depends on a 
woman’s preference, potential benefits,  understanding of potential risks, and recommendations 
from oncology specialists [14]. 
 
Fractional CO2 lasers have demonstrated safety and remodeling tissue properties in many body 
regions, such as the skin of the face, neck and chest, with the effect of producing new collagen 
and elastic fibers [17-20]. Moreover reports on the use of Er:YAG laser, similar to a CO2 laser 
for its superficial effect, showed improvement in two aspects of pelvic floor dysfunction (urinary 
incontinence and vaginal laxity) [21,22]. Recently, the regenerative effects of intravaginal 
fractional CO2 laser on the vaginal epithelium and lamina propria in postmenopausal women 
with GSM has been reported by Salvatore et al [23]. The same investigators found that  
microablative fractional CO2 laser was feasible, efficacious, and safe in improving GSM 
symptoms in postmenopausal women at 12-week follow-up [24]. Additionally, intravaginal 
fractional CO2 laser therapy caused a significant decrease in the severity of dyspareunia related 
to vaginal dryness in these patients, and was subsequently associated with a consistent 
improvement in sexual function and sexual satisfaction of menopausal women with GSM [25, 
26]. 
 
Hypothesis: The CO2 fractional vaginal laser therapy is non-inferior to vaginal estrogen therapy 
in the treatment of GSM. 
 


Protocol Version: 6.0 
 
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Dated:   16MAR2017 
 
 
Study Design and Aim: 
This is a multi-centered, randomized prospective single blinded clinical trial comparing CO2 
fractionated vaginal laser therapy and vaginal estrogen therapy in the treatment of vulvovaginal 
atrophy/GSM 
 
 
 
Study Outcomes: 
The primary outcome is subjective improvement of vaginal dryness using a 10 cm Visual analog 
scale. 
 
The secondary outcomes that will be assessed include 
1. 
An objective evaluation of vaginal atrophy/estrogenization measured by the globally 
validated “Vaginal Health Index” (VHI) score [reference Bachmann Maturitas 1995 
attached]  
2. 
The effect of GSM symptoms on QoL using the DIVA questionnaire  [28] 
3. 
The effect of treatment on the vaginal maturation index, at baseline and 6 month follow 
up   
4. 
The effect of treatment on vaginal wall elasticity, using standard vaginal dilators to 
determine vaginal caliber  
5. 
The effect of treatment on the female sexual function, by means of the Female Sexual 
Function Index (FSFI)[29]  
6. 
Calculation of the percentage of patients who are sexually active or resume intercourse 
after therapy.  A sexual function question not included in FSFI has been added to 
evaluate this. 
7. 
The effect of the treatment on urinary symptoms by means of the Urogenital Distress 
Inventory (UDI-6) [30] 
8. 
The degree of difficulty encountered by the physician in performing the MonaLisa laser 
treatment assessed via a 5-point Likert scale, 
9. 
The rate of satisfaction of patients with treatment assessed by the Patient Global 
Impression of Improvement (PGI), using a 5-point Likert scale. 
 
Subject Selection 
 
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 


Protocol Version: 6.0 
 
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Dated:   16MAR2017 
 English speaking and able to give informed consent 
 
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 
 Contraindication to vaginal estrogen therapy 
 Unwilling to Take vaginal estrogen therapy 
 Inability to give informed consent 
 
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 
School of Medicine 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 therapy 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.    
 
 
 


Protocol Version: 6.0 
 
6 
Dated:   16MAR2017 
 
 
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. 
 
 


Protocol Version: 6.0 
 
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Dated:   16MAR2017 
 
 
 
Vaginal Estrogen Protocol 
The women in the vaginal estrogen group will be prescribed and asked to administer one of three 
common choices of vaginal estrogen therapy based on patient’s formulary and preference of 
cream or tablet form:  
1) Conjugated estrogen cream (Premarin®):  0.5 g of cream intravaginally daily (using 
applicator or fingertip) for two weeks (fourteen days) then 0.5 g twice weekly  for 24 ± 2 
additional weeks, or   
2) Estradiol cream (ESTRACE®): 1.0 g of cream intravaginally daily (using applicator or 
fingertip) for two weeks (fourteen days) then 1.0 g twice weekly for 24 + 2 additional 
weeks, or 
3) Estradiol vaginal tablet (Vagifem®): one tablet (10 microgram) inserted daily into the 
vagina for two weeks (fourteen days) then 1 tablet inserted intravaginally 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 


Protocol Version: 6.0 
 
8 
Dated:   16MAR2017 
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.  All questionnaires 
are supplied in the appendix. 
 
Calendar of Study Procedures 
 
Baseline 
6 
weeks 
3 
months 
6 
months 
Informed Consent 
X 
 
 
 
H & P 
X 
 
 
 
MonaLisa Touch 
vaginal laser1  
X 
X 
X 
 
Vaginal estrogen 
therapy2, 3, 4 
X 
X 
X 
 
Vaginal symptom 
VAS 
X 
X 
X 
X 
Vaginal health 
index  VHI 
X 
X 
X 
X 
Vaginal 
maturation index  
X 
 
 
X 
DIVA 
questionnaire 
X 
 
X 
X 
Vagina dilator 
calibration 
X 
X 
X 
X 
FSFI 
X 
 
X 
X 
UDI-6 
X 
 
X 
X 
Likert scale (laser 
patient ) 
X 
X 
X 
 
PGI 
 
X 
X 
X 
Likert scale (laser 
provider  ease) 
X 
X 
X 
 
Adverse events 
X 
X 
X 
X 
Sexual activity 
X 
X 
X 
X 
 
 
 
1A treatment cycle includes three laser applications (every 5-7 weeks). 
2Conjugated estrogen cream (Premarin®): 0.5g of cream intravaginally daily (using applicator or 
fingertip) for two weeks (fourteen days) then 0.5 g twice weekly  for 24 ± 2 additional weeks, or 
3Estradiol cream (ESTRACE®): 1.0 g of cream intravaginally daily (using applicator or fingertip) 
for two weeks (fourteen days) then 1.0 g twice weekly for 24 + 2 additional weeks, or 
4Estradiol vaginal tablet (Vagifem®): one tablet (10 microgram) inserted daily into the vagina for 
two weeks (fourteen days) then 1 tablet inserted intravaginally twice weekly for 24 + 2 
additional weeks. 
 
 


Protocol Version: 6.0 
 
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Dated:   16MAR2017 
 
  
 
 
 
 
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). 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. REDCap is a secure, web-based application 
designed to support data capture for research studies, providing user-friendly web-based case 
report forms, real-time data entry validation, audit trials, and a de-identified data export 
mechanism to common statistical packages. The system was developed by a multi-institutional 
consortium which was initiated at Vanderbilt University and includes the Cleveland Clinic. The 


Protocol Version: 6.0 
 
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Dated:   16MAR2017 
database is hosted at the Cleveland Clinic Research Datacenter in the JJN basement and is 
managed by the Quantitative Health Sciences Department. The system is protected by a login 
and Secure Sockets Layers (SSL) encryption. Data collection is customized for each study as 
based on a study-specific data dictionary defined by the research team with guidance from the 
REDCap administrator in Quantitative Health Sciences at the Cleveland Clinic.  
 
Statistical Analysis Plan 
Sample Size Rationale 
We plan to enroll and randomize 196 patients in this non-inferiority trial comparing vaginal 
estrogen therapy to laser treatment of vaginal atrophy. The primary outcome will be subjective 
assessment of vaginal dryness as assessed by 10 cm visual analog scale at 6 months after 
initiating treatment. Assuming an alpha of 0.025 and a standard deviation of 2.0 [24], 85 subjects 
in each group will provide a 90% power to reject the null hypothesis (H0) that the true difference 
in vaginal dryness VAS score (Vaginal Estrogen – Vaginal Laser) is less than or equal to 1.0 cm 
on the VAS (effect size 0.5) in favor of the alternative hypothesis (H1): the true difference is 
greater than 1.0 cm using a one sided two sample t-test. Anticipating a 15% loss to follow-up 
and/or drop-rate over the period of the study, the total enrollment goal is 196 participants.  
 
Analysis Plan 
This study is a non-inferiority study design. The predefined non-inferiority margin is a difference 
of 1.0cm on a 10cm VAS. To minimize bias towards a finding of non-inferiority, data from 
women who were eligible and received the assigned treatment (per protocol) will be used for the 
analysis of the primary outcome. The primary outcome will be presented as the difference in 
VAS scores between treatments (Vaginal Estrogen – Vaginal Laser).  The hypothesis of non-
inferiority of the two treatment groups will be tested by comparing the lower limit of the two-
sided 95% confidence interval (equivalent of a one-sided significance level of 0.025%) of the 
absolute difference with the margin set at -1.0cm. A secondary analysis of the primary outcome 
according to original treatment assignment (intent to treat) will also be performed as well as 
standard superiority testing using Student’s t-test. If differences in baseline patient characteristics 
are noted, linear regression analysis adjusting for these differences will also be performed.  
Secondary outcomes will be analyzed using the intent to treat population using Pearson’s Chi-
square test for categorical data, Student’s t-test for parametric continuous data, or Wilcoxon rank 
sum test for ordinal or nonparametric continuous data. Changes in patient reported outcome 
questionnaires (FSFI, DIVA, UDI-6, etc.) will be compared between treatments using repeated 
measures ANCOVA.  
 
 
 
SAFETY AND ADVERSE EVENTS 
Definitions 
Adverse events include prolonged vaginal bleeding beyond 48 hours, heavy vaginal bleeding, 
bothersome vaginal irritation, bacterial vaginosis, vaginal yeast infection, post-procedural fever, 
and skin burn. 
 
 
 


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Recording of Adverse Events 
At each contact with the subject, the investigator will seek information on adverse events by specific 
questioning and, as appropriate, by examination. Information on all adverse events will be recorded 
immediately in the source document, and also in the appropriate adverse event section of the case 
report form (CRF).  All clearly related signs, symptoms, and abnormal diagnostic procedures results 
will also be recorded in the source document.  
 
The clinical course of each event will be followed until resolution, stabilization, or until it has been 
determined that the study treatment or participation is not the cause. Serious adverse events that are 
still ongoing at the end of the study period will be followed up to determine the final outcome. Any 
serious adverse event that occurs up to 30 days after the subjects final study visit, and is considered 
to be related to or possibly related to the study treatment or study participation, will be recorded and 
reported immediately. 
 
Reporting of Serious Adverse Events 
 
Notification to Data Coordinating Center 
 A Serious Adverse Event (SAE) form must be completed by the investigator and emailed to the 
DCC within 24 hours. The investigator will keep a copy of this SAE form on file at the study site.  
Report serious adverse events by email to:  
 
 
 
 
Dr. Paraiso – paraism@ccf.org  
  
 
 
Lynn Borzi – borzil@ccf.org 
 
 
 
At the time of the initial report, the following information should be provided: 
 
Study identifier 
 
Study Center 
 
Subject number 
 
A description of the
event 
 
Date of onset 
 
Current status 
 Whether study treatment was 
discontinued 
 The reason why the event is 
classified as serious 
 Investigator assessment of the 
association between the event and
study treatment 
 
 
Within the following 48 hours, the investigator must provide further information on the serious 
adverse event in the form of a written narrative.  This should include a copy of the completed Serious 
Adverse Event form, and any other diagnostic information that will assist the understanding of the 
event.  Significant new information on ongoing serious adverse events should be provided promptly 
to the DCC. 
 
 
 
 
 


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DATA SAFETY MONITORING  
 
The Data Safety Monitoring Board (DSMB) is the primary data and safety advisory group for 
the Female Foundation for Health Awareness (FFHA) trial entitled "A Randomized 
Clinical Trial Comparing Vaginal Laser Therapy to Vaginal Estrogen Therapy 
(VeLVET) in Women with Genitourinary Syndrome of Menopause (GSM)”.  The 
DSMB reviews study data, evaluates the treatments for excess adverse experiences according 
to treatment group, judges whether the overall integrity and conduct of the study remain 
acceptable and makes recommendations to the FFHA and the Cleveland Clinic Data 
Coordinating Center.  
 
 The DSMB will consist of 3members that are not participating in this trial.  All 
members have experience and expertise in their field of practice and in the conduct of 
clinical trials.  Members were selected by the Cleveland Clinic Data Coordinating 
Center in conjunction with Marie Fidela Paraiso, M.D., Principal Investigator, Co-
Investigators of the study and the FFHA.   
 
 The DSMB will meet via teleconferences after 5 subjects from each site is enrolled, 
or sooner if warranted. 
 During the initial portion of the conference call, members of the operational team will 
give an overview of the status of the trial and be available to answer questions from 
DSMB members.  The Cleveland Clinic DCC will provide a general study status 
update and enrollment update at the beginning of the call.  On conference calls, the 
Cleveland Clinic DCC will describe the reports to members.  The Cleveland Clinic 
DCC will be present for the presentation of results and entire discussion portion of all 
calls to answer questions.  He/she will not be present for the DSMB discussion and 
vote.  Only voting members of the DSMB and the Cleveland Clinic DCC recorder 
may be present during the presentation of results and actual vote. 
 After each conference call, the Cleveland Clinic DCC recorder, Lynn Borzi, reviewed 
by Dr. Paraiso, and distributed to the DSMB, will prepare minutes.   The Chairperson 
will send a letter to the Cleveland Clinic DCC recommending changes and 
continuation/discontinuation of the trial. At the end of the study, a copy of the 
minutes will be forwarded to the Cleveland Clinic DCC for archive. 
 


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References: 
1. van der Laak JA, de Bie LM, de Leeuw H, de Wilde PC, Hanselaar AG. The effect of Replens 
on vaginal cytology in the treatment of postmenopausal atrophy: cytomorphology versus 
computerised cytometry. J Clin Pathol. 2002;55:446-51. 
2. Bachmann GA, Cheng RJ, Rovner E. Vulvovaginal complaints. In: Lobo RA, ed. Treatment 
of the Postmenopausal Woman: Basic and Clinical Aspects, 3rd ed. Burlington, MA: Academic 
Press, 2007:263-270. 
3. Santoro N, Komi J. Prevalence and impact of vaginal symptoms among postmenopausal 
women. J Sex Med 2009;6:2133-2142. 
4. Pastore LM, Carter RA, Hulka BS, Wells E. Self-reported urogenital symptoms in 
postmenopausal women: Women_s Health Initiative. Maturitas 2004;49:292-303. 
5. Barnabei VM, Cochrane BB, Aragaki AK, et al. Women_s Health Initiative Investigators. 
Menopausal symptoms and treatment-related effects of estrogen and progestin in the Women_s 
Health Initiative. Obstet Gynecol 2005;105:1063-1073. 
6. Nappi RE, Kokot-Kierepa M. Women’s voices in the menopause: results from an international 
survey on vaginal atrophy. Maturitas. 2010;67(3):233–238. 
7. Nappi RE, Kokot-Kierepa M. Vaginal Health: Insights, Views and Attitudes (VIVA) – results 
from an international survey. Climacteric. 2012;15:36–44. 
8. Cumming GP, Currie HD, Moncur R, Lee AJ. Web-based survey on the effect of menopause 
on women’s libido in a computer-literate population. Menopause Int. 2009;15(1):8–12. 
9. Cumming GP, Herald J, Moncur R, Currie H, Lee AJ. Women’s attitudes to hormone 
replacement therapy, alternative therapy and sexual health: a web-based survey. Menopause Int. 
2007;13(2):79–83. 
10. Levine KB, Williams RE, Hartmann KE. Vulvovaginal atrophy is strongly associated with 
female sexual dysfunction among sexually active postmenopausal women. Menopause. 
2008;15(4 Pt 1):661–666. 
11. Nappi RE, Kingsberg S, Maamari R, Simon J. The CLOSER (Clarifying Vaginal Atrophy's 
Impact On Sex and Relationships) Survey: Implications of Vaginal Discomfort in 
Postmenopausal Women and in Male Partners. J Sex Med. 2013 [Epub ahead of print]. 
12. Lindau ST, Schumm LP. Laumann EO, Levinson W, O_Muircheartaigh CA, Waite LJ. A 
study of sexuality and health among older adults in the United States. N Engl J Med 
2007;357:762-774. 
13. Parish SJ, Nappi RE, Krychman ML, Kellogg-Spadt S, Simon JA, Goldstein JA, Kingsberg 
SA. Impact of vulvovaginal health on postmenopausal women: a review of surveys on symptoms 
of vulvovaginal atrophy. Int J Womens Health. 2013;5:437-47. 
14. The North American Menopause Society. Management of symptomatic vulvovaginal 
atrophy: 2013 position statement of The North American Menopause Society. Menopause. 
2013;20:888-902. 
15. Suckling J, Lethaby A, Kennedy R. Local oestrogen for vaginal atrophy in postmenopausal 
women. Cochrane Database Syst Rev. 2006 Oct 18;(4):CD001500. 
16. Shulman LP, Portman DJ, Lee WC, et al. A retrospective managed care claims data analysis 
of medication adherence to vaginal estrogen therapy: implications or clinical practice. Journal of 
Women’s Health (Larchmt) 2008;17:569–78. 
17. Ong MW, Bashir SJ. Fractional laser resurfacing for acne scars: a review. Br J Dermatol. 
2012;166:1160-9. 


Protocol Version: 6.0 
 
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18. Tierney EP, Hanke CW. Fractionated carbon dioxide laser treatment of photoaging: 
prospective study in 45 patients and review of the literature. Dermatol Surg. 2011;37:1279-90. 
19. Tierney EP, Hanke CW. Ablative fractionated CO2, laser resurfacing for the neck: 
prospective study and review of the literature. J Drugs Dermatol. 2009;8:723-31.  
20. Peterson JD, Goldman MP. Rejuvenation of the aging chest: a review and our experience. 
Dermatol Surg. 2011;37:555-71. 
21. Fistonić I, Findri-Guštek Š, Fistonić N. Minimally invasive laser procedure for early stages 
of stress urinary incontinence (SUI). J Laser Health Acad, 2012; 1: 67-74.  
22. Vizintin Z, Rivera M, Fistonić I, Saraçoğlu F, Guimares P, Gaviria J, Garcia V, Lukac M, 
Perhavec T, Marini L. Novel Minimally Invasive VSP Er:YAG Laser Treatments in 
Gynecology. J Laser Health Acad, 2012; 1: 46-58. 
23. Salvatore S, Leone Roberti Maggiore U, Athanasiou S, Origoni M, Candiani M, Alberto 
Calligaro A, Zerbinati N (2014) Histological study on the effects of microablative fractional CO2 
laser on atrophic vaginal tissue: an ex-vivo study. Menopause doi: 10.1097/GME. 
0000000000000401 
24. Salvatore S, Nappi RE, Zerbinati N, Calligaro A, Ferrero S, Origoni M, Candiani M, Leone 
Roberti Maggiore U (2014) A 12-week treatment with fractional CO2 laser for vulvovaginal 
atrophy: a pilot study. Climacteric 17:363–369 
25. Salvatore S, Leone Roberti Maggiore U, Origoni M, Parma M, Quaranta L, Sileo F, Cola A, 
Baini I, Ferrero S, Candiani M, Zerbinati N (2014) Microablative fractional CO2 laser improves 
dyspareunia related to vulvovaginal atrophy: a pilot study. J Endometr 6:150–156 
26. Salvatore S, Nappi RE, Parma M, Chionna R, Lagona F, Zerbinati N, Ferrero S, OrigoniM, 
Candiani M, Leone Roberti Maggiore U (2014) Sexual function after fractional microablative 
CO2 laser in women with vulvovaginal atrophy. Climacteric doi: 10.3109/13697137.2014. 
27. Bachmann G.  Urogenital aging: an old problem newly recognized.  Maturitas 1995;22:S1-5. 
28. Huang AJ, Gregorich SE, Kuppermann M, Nakagawa S, Van Den Eeden SK, Brown JS, 
Richter HE, Walter LC, Thom D, Stewart  AL. Day-to-day impact of vaginal aging 
questionnaire: a multidimensional measure of the impact of vaginal wymptoms on functioning 
and well-being in postmenopausal women.  Menopause 2014; 22(2): 144-154. 
29. Rosen R, Brown C, Heiman J, Leiblum S, Meston CM, Shabsigh R, Ferguson D, D’Agostino 
R Jr. A multidimensional self-report instrument for the assessment of  female sexual function. J 
of Sex and Marital Therapy 2000; 26:191-208. [Pubmed 10782451] 
30. Uebersax JS, Wyman JF, Shumaker SA, McClish DK, Fantl AJ.  Short forms to assess life 
quality and symptom distress for urinary incontinence in women: the incontinence impact 
questionnaire and the urogenital distress inventory.  Neurourol and Urodynam 1995;14:131-139.  
31. Bump RC, Mattiason A, Bo K, et al.  The standardization of terminology of female pelvic 
organ prolapse and pelvic floor dysfunction.  Am J Obstet Gynecol 1996;175-10. 
 
 
 
 
 
 
 
 
 


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Appendix 
Baseline Examination Data 
Pt. ID # 
Treatment Group 
□Vaginal Laser 
 
□Vaginal Estrogen 
Age 
_____  
 
BMI  ______ 
Race 
□Caucasian 
 
□African-American 
 
□Hispanic 
 
□Asian 
□Other, specify 
_______________________ 
Marital status 
□Single 
 
□Married 
 
□Divorced 
 
□Widowed 
Menopausal Status 
□Premenopausal 
□Perimenopausal 
□Postmenopausal (no menses for 6 months) 
Current use of oral or transdermal hormonal therapy 
□Yes  
□No 
History of vaginal estrogen use 
□Yes  
□No 
Sexually active 
□Yes  
□No 
Exam: 
Vaginal pH 
_______ 
Vaginal caliber 
□XS 
 
□S 
 
□M 
 
□L 
 
□XL 
Maturation Index Results: 
________________________________________ 
Data prior to and after Vaginal Laser  or Vaginal Estrogen therapy (6 wk, 3 mos, 6 mos): 
Exam 
Vaginal pH 
_______ 
Vaginal caliber 
□XS 
 
□S 
 
□M 
 
□L 
 
□XL 
Local anesthetic used? 
□Yes  
□No 
 
□N/A (Estrogen arm) 
Vulvovestibular laser therapy? 
□Yes  
□No 
 
□N/A (Estrogen arm) 
Adverse event laser arm: 
Inability to complete the procedure due to discomfort or constricted vagina 
□Yes  
□No 
Other:  Specify__________________ 
 
 
 
 
 
 
 
 
 
 
 
 


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5-Point Likert Scales (laser arm):  
Discomfort experienced by the patient during vaginal laser (please circle) 
Very Uncomfortable   Moderately Uncomfortable    Slightly Uncomfortable 
No Discomfort 
Comfortable 
 
1 
 
 
2 
 
 
3 
 
 
4 
 
5 
The degree of difficulty encountered by the physician in performing the treatment (circle) 
Very Difficult    Moderately Difficult 
Slightly Difficult  
No Difficulty 
Easily Performed
 
1 
 
2 
 
 
3 
 
 
4 
 
5 
 
 
 
 
6 week , 3 month, 6 month Post-procedure/treatment visit prior to laser treatment  
 
Data will include the following and PGI-I below: 
Did you experience bothersome vaginal irritation after vaginal therapy? 
□Yes  
□No 
Did you experience bothersome vaginal bleeding after your vaginal therapy? 
□Yes  
□No 
Did you experience a vaginal infection that required medical therapy after your vaginal therapy? 
□Yes  
□No 
Note that the PGI-I and questions above will be administered at the 6 month visit in both groups. 
 
 
 
 
 
 
 
 
 
 
 


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10 cm VISUAL ANALOG SCALE (VAS) 
0 indicating absent symptoms (no bother) and 10 indicating the worst the symptoms 
could be (bothers as much as you can imagine).  Please indicate your degree of bother 
with an X marked on the 10 cm line below next to each symptom. 
 
 
 
 
 
 
 
 
No Bother 
 Mild Bother 
 Moderate Bother    Most Bother 
 
 
 
              
Vaginal dryness 
 
 
 0________________________________________________10 
 
Vaginal itching   
 
 
0________________________________________________10 
 
Vaginal irritation 
 
       
0________________________________________________10 
 
Painful urination  
 
 
0________________________________________________10 
 
 
Additional question regarding sexual function not included in the FSFI.   
This question will be asked at baseline, 6 weeks, 3 months, and 6 months. 
Over the past 4 weeks have you been sexually active? (yes/no) 
The reason if your answer no 
a. no partner 
b. no interest 
c. due to pain 
d. due to other reason, please specify_____________________ 
 
 


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VAGINAL HEALTH INDEX SCALE 
 
 
 
Overall 
elasticity* 
Fluid secretion type  
& consistency 
pH 
Epithelial mucosa 
Moisture 
1 
None 
None 
6.1 
Petechiae noted  
before contact 
None, mucosa 
inflamed 
2 
Poor 
Scant, thin yellow 
5.6 – 6.0 
Bleeds with light contact 
None, mucosa 
not inflamed 
3 
Fair 
Superficial, thin white 
5.1 – 5.5 
Bleeds with scraping 
Minimal 
4 
Good 
Moderate, thin white 
4.7 – 5.0 
Not friable, thin mucosa 
Moderate 
5 
Excellent 
Normal              
(white flocculent) 
 ≤ 4.6 
Not friable, normal 
mucosa 
Normal 
*Lower score corresponds to greater urogenital atrophy  
Bachmann G. Maturitas 1995; 22:Suppl S1-5. 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 


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Medicine Compliance Log: 
Weeks 1 and 2, please place an X in the box for each day you inserted vaginal cream or tablet 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Weeks 3-6 
 
 
 
 
 
 
 
 
 
Weeks 7-12 
 
 
 
 
 
 
 
 
 
 
 
 
 
Weeks 13-18 
 
 
 
 
 
 
 
 
 
 
 
 
 
Weeks 19-24 
 
 
 
 
 
 
 
 
 
 
 
 
 


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DIVA questionnaire 


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