A Randomized Controlled Trial of Ultrasonic Aspiration Versus CO2 Laser Ablation for the Treatment of Vulvar Intraepithelial Neoplasia
Phase: NA
Conditions: Vulvar Intraepithelial Neoplasia (VIN)
Sponsor: University of Colorado, Denver

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Study Protocol 
 
 
Official Title of Study: A Randomized Controlled Trial of Ultrasonic Aspiration 
versus CO2 Laser Ablation for the Treatment of Vulvar Intraepithelial Neoplasia 
 
 
NCT Number: 02875561 
 
Approval Date of Document: April 12, 2021 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 

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A Randomized Controlled Trial of Ultrasonic Aspiration versus CO2 Laser 
Ablation for the Treatment of Vulvar Intraepithelial Neoplasia 
 
 
 
COMIRB Protocol: 16-0701 
 
Principal Investigator:    
Saketh R Guntupalli, MD 
University of Colorado; Department of Ob-Gyn 
12361 E. 17th Ave MS B198-4 
Aurora, Colorado 80045 USA 
303-724-2024(ph); 303-724-2053 (fax) 
saketh.guntupalli@ucdenver.edu 
 
 
Statistician:  
 
Colorado Biostatistics Consortium 
University of Colorado Cancer Center Biostatistics and Bioinformatics 
Aurora, CO 80045 
303-724-4472 (ph) 
debashis.ghosh@ucdenver.edu 
 
 
 
 
Protocol Version: April 12, 2021 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 

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A Randomized Controlled Trial of Ultrasonic Aspiration versus CO2 Laser 
Ablation for the Treatment of Vulvar Intraepithelial Neoplasia 
 
1. Introduction 
Vulvar intraepithelial neoplasia (VIN) is a chronic precancerous medical condition 
causing vulvar dysplasia affecting nearly 50,000 women in the United States each 
year. [1]The causes of pre-cancer of the vulva are multi-factorial but common risk 
factors including multiple sexual partners, early age at first coitus, smoking, and a 
history of vulvar irritation. Common to all of these causes is the association with 
the infection by the HPV virus. While the HPV vaccine has been used extensively 
to control the development of pre-cancer of the cervix, the effectiveness of this 
treatment has not been shown in pre-cancer of the vulva. Additionally, pre-cancers 
of the vulvar generally affect women in the 4th and 5th decade of life and therefore, 
many women have not received the HPV vaccine. If untreated, pre-cancers of the 
vulva can further develop into invasive cancers. The treatment of an actual vulvar 
cancer can include radical surgery for removal of the vulva, extensive dissection 
of the groins to obtain lymph nodes, as well as chemotherapy and radiation. These 
treatments can be incredible disfiguring, painful, and can have significant side 
effects for women. 
 
Incidence of VIN is increasing among women and there still lacks a standard of 
care for optimal treatment.  Current treatment options aim to treat the symptoms 
associated with VIN and result in a high recurrence rate.  Repeated treatment 
leads to psychosocial and sexual distress and decreased quality of life for the 
affected women.[1]  Treatment for vulvar dysplasia usually occurs in 3 categories: 
surgical excision, laser ablation and topical treatment with immune modulators. 
While the efficacy of all three modalities has been shown, each one has the 
potential for side effects. Surgical excision is difficult in multimodal disease states 
as this can leave the vulvar significantly disfigured. CO2 laser ablation, while 
effective, has been documented to scar and cause significant pain in the 1-2 weeks 
following surgery. [2] Topical treatments with imiquimod (an immune modulator) 
take up to 16 weeks to work, are difficult to apply and can cause local site irritation. 
Due to the high reoccurrence rate and the nature of the current treatments, a more 
effective treatment option is warranted.  An effective treatment that targets only the 
diseased areas could potentially decrease recurrence rates.  Additionally, a more 
conservative treatment modality could contribute to reduced risks of scarring, 
discomfort, and psychosocial and sexual distraught. 
 
Currently there are no recent studies that have compared ultrasonic laser 
aspiration with conventional treatment methods. Von Greunigen et al compared 
CO2 laser ablation in women with VIN with ultrasonic aspiration in a randomized 
trial from 2000-2005. This study found no difference in recurrence rates between 
the two techniques (HR=.96, 95% CI .64-1.50) and suggested that women who 
underwent ultrasonic aspiration had less pain and less disfigurement as compared 
to women who underwent CO2 laser ablation. While this study is compelling, due 

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to its age and statistical flaws, ultrasonic aspiration has yet to be accepted as a 
major modality by which to treat VIN. [3] 
 
1.1   
Significance 
Vulva preserving treatments are necessary women with dysplasia in order to 
maintain function and decrease discomfort typical with a vulvectomy. [4]  However, 
these less invasive techniques have a high recurrence rate. Recurrence is 
particularly greater for those with HPV and multifocal disease. [5, 6] Women must 
follow these treatments with long-term surveillance, which often leads to repeat 
treatment and eventually dysfunction and psychological morbidity.  [5] Studies 
have found that recurrence rates with CO2 laser ablation can range from 25-50% 
recurrence, while rates for ultrasonic aspiration have been found to range from 22-
35% recurrence.  [5, 7-13]  [2, 14]  
 
Von Greugenigen’s study failed to limit the study to women with high-grade 
dysplasia only.  As a result, the final analysis failed to meet statistical power. No 
RCT has been conducted since looking at reoccurrence difference and QOL 
outcomes associated with ultrasonic aspiration vs. CO2 laser.[3] 
 
We propose a similar study by which to randomize women to either CO2 laser 
ablation or ultrasonic aspiration for the treatment of vulvar dysplasia. We estimate 
that we need 150 patients to achieve statistical power.  We will similarly evaluate 
patients at 3, 6 and 12 months to assess for recurrence and pain. We will also 
have patients complete quality of life (QOL) surveys to assess which differences 
in wellness and function following treatment at baseline, 6, and 12 months. 
 
2. Study Objectives  
The primary objective of this study is to evaluate the incidence of vulva dysplasia 
recurrence within 12 months of treatment with CO2 laser ablation or ultrasonic 
aspiration.  Women referred for treatment following diagnosis of VIN II/III will be 
randomized to receive CO2 laser ablation (typical treatment for these cases) or 
ultrasonic aspiration (approved treatment providing a more targeted technique).   
 
Secondary objectives will examine incidences of pain, scarring, and sexual and 
psychosocial distraught following treatment for high-grade dysplasia.  
 
 
2.1  
Hypothesis 
Hypothesis 1: Treatment for VIN II/III with ultrasonic aspiration will have a 60% 
reduction in recurrence rates over 12 months as compared to CO2 
laser aspiration. 
 
Hypothesis 2: Treatment for VIN II/III with ultrasonic aspiration will demonstrate 
decreased incidence of pain and scarring up to 6 weeks following 
treatment as compared to CO2 laser aspiration. 
 

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Hypothesis 3: Treatment for VIN II/III with ultrasonic aspiration will demonstrate a 
decrease in change of sexual and psychosocial function (as 
demonstrated with validated instruments) in the 12 months 
following treatment as compared to CO2 laser aspiration. 
 
 
3. Preliminary Studies and Research Centers 
 
3.1 
Principal Investigator and Research Center 
Dr. Saketh Guntupalli is a trained gynecologic oncologist and surgeon at the 
University of Colorado Denver (UCD) whose research interests includes 
decreasing surgical morbidities for gynecologic cancer patients.  The University of 
Colorado Denver is a clinical research institution and one of the nation’s 40 
Comprehensive Cancer Centers.  UCD is the only National Cancer Institute-
designated cancer center serving Colorado and its surrounding states.  The goal 
of the University of Colorado Cancer Center is to provide cutting edge and 
nationally recognized clinical and translational research, to discover and shape 
tomorrow’s treatments, and improve survivorship. The Gynecologic Oncology 
clinic is made up of three board-certified Oncologists and a general gynecologist.  
The gynecologic oncology providers see approximately 350 new patients and 
perform over 600 surgeries per year. [15]  In addition the cancer center, Dr. 
Guntupalli and his partners oversee medical residency training in our general 
gynecologic colposcopy clinic.   
 
Additional sites will be identified and the protocol will be edited to reflect all 
participating sites upon receipt of each site’s local IRB approval. 
 
4.  Outcome Measures 
Primary Outcome: The primary outcome of this study is recurrence rates of 
dysplasia within 12 months of treatment. Rates of recurrence will be compared for 
CO2 laser ablation and ultrasonic aspiration, stratifying groups based on HPV and 
multifocal disease status.  Recurrence will be assessed at 3, 6, and 12 months 
following treatment.    Recurrence will be determined by repeat visual exam and 
colposcopy (followed by biopsy as warranted) at each of the follow-up visits.  
Those with recurrence will be discontinued from the study and receive appropriate 
treatment for their recurring dysplasia, per standard of care (SOC).  
 
Secondary outcomes:  
Secondary outcomes will compare:  
1) Incidence of pain in the initial 7-10 days following treatment. Pain will be 
assessed using a patient pain scale.  Participants will be asked to assess their own 
pain and report to the research team. 
 
2) Incidence of scarring due to treatment regimen.  Participants will be 
examined during regular post-procedure visit approximately 4-6 weeks following 
treatment.  A visual exam of the vulva will be conducted to assess scaring.   

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3) Sexual function will be measured at baseline and at the 6 and 12 month 
follow-up visits.  Changes in sexual function will be compared to baseline within 
each treatment arm.  Overall sexual dysfunction rates will be compared between 
treatment arms for each study time interval.  The Female Sexual Function (FSFI) 
and the Female Sexual Distraught Survey will be used to examine sexual function 
at each time point.  
 
4) Wellness and Function will be measured using a validated instrument 
FACT-V health survey, designed specifically for women with vulva disease. The 
FACT-V provides metrics for functional, emotional, physical, and social well-being. 
Wellness and function scores will be compared between treatment arms for each 
study time interval and compared to baseline within each treatment arm.  
 
Demographic and clinical data will also be collected in order to describe the study 
population and determine differences among the randomized groups. 
Demographic and clinical data will be verified against the participant medical 
records to assure data completion and minimize missing data in our analysis. 
 
Demographic data will include: name, medical record number, contact information, 
date of birth, age, race/ethnicity, relationship status, and smoking status.  
Identifying information (name, medical record number, and contact information) 
will not be entered into the database by ancillary sites, and will only be used by 
research site to verify data, access medical records, and contact the patient for 
study visits.  At these sites, a log will be kept with their identifiable data and 
participants will be linked to their study chart by study ID.   
 
Clinical Data will include: menopause status, colposcopy results, treatment history, 
history of STDs, pre-existing medical conditions, concomitant medications, 
allergies, and vitals (blood pressure, pulse, temperature, respiratory rate, height, 
weight, BMI).  
 
4.1.   Study Endpoints 
Patients will be enrolled at participating centers prior to receiving treatment for their 
VIN II/III.  Baseline assessments will include all study surveys and collection of 
demographic and clinical data.   
 
Pain and scarring will be assessed within the first 6 weeks following treatment.  
Participants will be followed at 3, 6, and 12 months for recurrence. Participants will 
be discontinued from the study at time of recurrence, or at the completion of 12 
months follow-up. Total participation is 12 months duration.  
 
5.  Ethical Considerations 
 
5.1 
Good Clinical Practice 

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This study will be conducted in accordance with Good Clinical Practice (GCP), as 
defined by the International Conference on Harmonisation (ICH) and in 
accordance with the ethical principles underlying European Union Directive 
2001/20/EC and the United States Code of Federal Regulations, Title 21, Part 50 
(21CFR50). 
The study will be conducted in compliance with the protocol. The protocol, any 
amendments, and the subject informed consent will receive Institutional Review 
Board (IRB) approval before initiation of the study. 
All potential serious breaches must be reported to The University of Colorado IRB 
immediately. A serious breach is a breach of the conditions and principles of GCP 
in connection with the study or the protocol, which is likely to affect, to a significant 
degree, the safety or physical or mental integrity of the subjects of the study or the 
scientific value of the study. 
Study personnel involved in conducting this study will be qualified by education, 
training, and experience to perform their respective tasks.  
This study will not use the services of study personnel where sanctions have been 
invoked or where there has been scientific misconduct or fraud (e.g., loss of 
medical licensure; debarment).  
 
5.2 
Institutional Review Board 
Before study initiation, the investigator will have written and dated approval from 
COMIRB for the protocol, consent form, subject recruitment process, and any other 
written information to be provided to subjects.  
The investigator will provide COMIRB with continuing review reports annually.  In 
addition, any revised study materials or amendments will be submitted for approval 
prior to use/implementation. 
Each additional site will obtain local IRB approval prior to any procedures being 
conducted. The University of Colorado Denver study team will provide study 
monitoring and will audit study sites, requiring direct access to source data and 
documents.    The study will remain open with each site’s local IRB until receipt of 
notification from coordinating site to close the study.  All correspondence with the 
local IRB will be maintained in the study regulatory files. The sponsor may request 
additional audit of study sites. 
 
5.3 
Informed Consent 
Potential Participants will be approached for participation at their initial visit in our 
gynecologic clinics.  Investigators will ensure that subjects are clearly and fully 
informed about the purpose, potential risks, and other critical issues regarding 
clinical studies in which they volunteer to participate. 
Investigators will: 
1) Provide a copy of the consent form and written information about the study prior 
to clinical study participation. The language will be non-technical and easily 
understood. 

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2) Allow time necessary for subject to inquire about the details of the study. 
3) Obtain an informed consent signed and personally dated by the participant and 
by the person who conducted the informed consent discussion.  
4) Obtain IRB approval of the written informed consent form and any other 
information to be provided to the subjects, prior to the beginning of the study, 
and after any revisions are completed for new information. 
5) Revise the informed consent whenever important new information becomes 
available that is relevant to the participant’s consent. The investigator, or a 
person designated by the investigator, will fully inform the subject of all 
pertinent aspects of the study and of any new information relevant to the 
participant’s willingness to continue participation in the study. This 
communication will be documented.  
The rights, safety, and well-being of the study participants are the most important 
considerations and will prevail over interests of science and society. 
 
6. Investigational Plan 
 
6.1  
Description of Population to be Enrolled 
Women diagnosed with high-grade vulvar intraepithelial neoplasia (VIN II/III) will 
be eligible to participate.  Women with prior treatment for dysplasia will be 
considered eligible for the study.  Prior treatment for dysplasia includes all 
treatments such as surgery, laser ablation, and/or aldara (a topical agent).   
 
6.1.1. 
Inclusion Criteria:  
• Women 18-89 years old 
• Diagnosed with VIN II/III (diagnosed by pathology) 
• Referred for vulva sparing treatment for dysplasia 
• Available for follow-up of treatment for 12 months 
 
6.1.2 Exclusion Criteria:  
• Women who are pregnant 
• Women with VIN I dysplasia (diagnosed by pathology) 
• Women with vaginal intraepithelial neoplasia (VAIN) 
• Women requiring vulvectomy for treatment 
• Women unable to provide informed consent 
 
Women with suspected dysplasia will undergo routine biopsy for diagnosis of vulva 
dysplasia.  Pathology will categorize disease as either “low-grade” or “high-grade” 
or using the grading I, II, and III.  Women with high-grade dysplasia, VIN II/III, will 
be referred for further treatment. Women meeting the inclusion criteria will be 
eligible for inclusion. Women with low-grade dysplasia, VIN I, will not be included 
in the study.  
 
6.2  
Sample Size 

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Based on previous studies, approximately 37.5% of patients will reoccur within 12 
months with traditional treatment (CO2 laser). [5, 7-13]  We can detect a 60% 
reduction of recurrence to a rate of 15% at 80% power and an alpha of 0.05 with 
62 patients per arm. [3] We will enroll an additional 13 patients per arm (n=75 per 
arm, 150 total) to account for noncompliance, lost to follow-up or misclassification 
diagnosis. 
 
Approximately 75% of participants will be recruited at the coordinating site, 
University of Colorado Denver.  The other 25% of participants will be recruited at 
the secondary sites Regional West Medical Center, and The University of 
Oklahoma are the secondary sites recruiting participants.   
 
6.3 
Research Design and Duration 
 
This study will employ a randomized controlled trial (RCT) design. This is a phase 
III study to determine the effectiveness of a more targeted treatment therapy for 
VIN II/III (comparing ultrasonic aspiration versus CO2 laser ablation). Potential 
participants will be identified through the gynecological clinical practices following 
diagnosis of VIN II/III and will be randomized (1:1) to one of the treatment therapies.  
Randomization will be stratified for multi-focal disease and HPV status.  
 
Participants will be followed for 1 year following initial treatment for recurrence of 
vulva dysplasia. Study events will be documented on the study clinical research 
forms for each visit. The study will continue until 150 participants have completed 
procedures, which is expected to take approximately 3 years. 
 
7. Treatments 
Both the Sonopet Ultrasonic Aspirator and the CO2 laser ablation devices are FDA 
approved devices for the treatment of vulvar dysplasia.   
 
7.1 
Treatment Assignment 
Participants will be randomized 1:1 to either treatment with Ultrasonic Aspiration 
or CO2 laser ablation after consent of study. Prior to treatment, participants will 
receive a local anesthesia (lidocaine) to numb the affected area. 
 
• Ultrasonic Aspiration: The Sonopet Ultrasonic Aspirator (manufactured by 
the Sponsor of this study) provides precise control of soft tissue while 
simultaneously allowing fine bone dissection in close proximity to delicate 
structures. The Sonopet Ultrasonic Aspirator is precise in its technique and 
allows users to independently control power, suction, and irrigation with one 
hand piece to maximize user control and efficiency. [1] The standard use of 
the Sonopet aspirator is to obtain a power density of 1,000 watts/cm2 in 
order to desiccate the tissue.  The tissue will change color to a yellow color 
indicating the epidermal layer had been ablated.   
 
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excision, coagulation, or vaporization of pelvic abnormalities. The carbon 
dioxide laser has been considered an effective modality for multiple tasks 
related to the treatment of intraepithelial neoplasia of the lower genital tract, 
most commonly for large lesions and for multifocal manifestations of human 
papilloma virus (HPV). The use of this technology is limited in some areas 
because of healthcare provider training and experience and because of a 
lack of availability of equipment. CO2 laser also leaves destruction of the 
skin at treatment site, and therefore no tissue remains for further histology. 
However it still remains a preferred treatment modality for VIN among 
women. [1] The treatment area will be identified by a 3-4 mm region beyond 
the affected area of the cervix. The entire circumference of the anticipated 
ablation area is outlined as if outlining a circle with dots. These dots are 
then connected, and the entire area is ablated with a consistent continuous 
movement of the laser beam at a pulse of 10 W. The area is measured 
periodically with a graduated probe used through the colposcope, and the 
ablation continues to a depth of 7-10 mm 
Following treatment participants will be prescribed NSAIDs for pain relief and a 
topical salve will be placed on the affected area to reduce the risk of scarring.  
Participants will be asked to refrain from exercise and sexual intercourse for two 
weeks following treatment.  
 
All study treatment will be conducted by study-trained investigators only.  The 
investigators chosen to participate in the study will all be board-certified 
gynecologists and will not include providers in-training.  Gynecologists are trained 
to perform vulva sparing treatment in the clinical setting.  All investigators elected 
for this study have a minimum of 3 years of clinical practice following fellowship.  
The coordinating site will host an in-service for all participating investigators prior 
to initiation of the study.  The in-service will review the standard operating protocols 
of both devices.  Ongoing monitoring and site visits by the PI will also be conducted 
to insure investigator compliance. In addition, secondary analysis will examine 
treatment differences per investigator.  
 
Block randomization will be conducted using randomization statistical software.  
Research personnel will login into the study database and enter information for 
block randomization on the day of surgery.  The randomization software 
associated with the REDCap data tool will provide the research team with the 
treatment assignment.  Stratification variables will include multifocal disease and 
HPV status. The statistician responsible for statistical analysis will be blinded to 
the treatment received.  
 
8. Study Procedures 
Participants will conduct the following study visits over 12 months. All costs 
associated with routine standard of care procedures for diagnosing and treating 
vulva dysplasia will be the responsibility of the patient and/or their insurance 
provider.   
 

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V0: Screening: All screening will be conducted during routine standard of care 
(SOC) visits to our gynecologic oncology clinic or colposcopy clinic after review of 
colposcopy results. Baseline assessment and quality of life assessments will be 
conducted at this visit, and informed consent will be obtained prior to any study 
procedures being conducted.  
 
V1: Enrollment Visit: All enrollments will be conducted at the time of treatment visit.  
Prescribed treatment will be covered by insurance, per SOC.  
 
V2. Pain will be assed at 7-10 days following treatment.  Participants will self-
evaluate pain by responding to a <5-minute survey (administered electronically or 
via phone) asking them to rate their pain using a standard patient pain scale.   
 
V3.  
Visit 3: Approximately 4-6 weeks following treatment you will be 
asked to come in for a follow-up visit. A study doctor will assess 
your scarring at this visit. This is part of routine care. This visit is 
expected to take approximately 20 minutes. 
 
 
 
V4: A SOC 6 month (± 30 days)  follow-up will be conducted following treatment.  
Assessments include physical exam with colposcopy (biopsies performed at the 
provider’s discretion).  Assessments at 6 months are to be conducted per standard 
of care. This visit will take approximately 30 minutes. Quality of life assessments 
will be conducted at this time. This visit can take place at Colorado, Oklahoma, or 
Nebraska site, depending on where subject was screened.  
 
V5: End of Treatment: A SOC 12 month (± 30 days) follow-up will be conducted 
following treatment.  Assessments include physical exam with colposcopy 
(biopsies performed at the provider’s discretion).  Assessments at 12 months are 
per standard of care. This visit will take approximately 30 minutes. Quality of life 
assessments will be conducted at this time. This visit can take place at Colorado, 
Oklahoma, or Nebraska site, depending on where subject was screened. 
 
 
Study Calendar 
 

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V0: Screening
V1: Enrollment
V2: Pain Assessment
V3: Scarring Assessment V4: 6 month follow up 
(±30 days)
V5: 12 month follow 
up (±30 days)
Unanticipated Visit
Baseline visit
0-30 days following V0
7-10 days after 
treatment (survey only)
4-6 weeks after 
treatment
6 months following 
treatment
12 months following 
treatment
Procedures
Informed Consent
X
Confirm eligibility 
(Inclusion/Exclusion 
criteria)
X
Randomization
X
Medical History
X
Concomitant
Medications and
Procedures
X
X
X
X
X
X
Adverse Events
X
X
X
X
X
X
Lesion 
assessment/colposcopy 
(biopsy if needed)
X
X
X
X
X
X
Physical Exam
X
X
X
X
Vitals (inc. 
height/weight)
X
X
X
X
X
X
Scar Assessment
X
Pain Assessment
X
X
X
X
X
Surveys
X
X
X

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9. Study Assessments 
Investigators will be expected to use the treatment assignment provided and will 
not have the option to elect a preferred treatment.  Data will be analyzed per 
protocol so only participants receiving the correct treatment assignment will be 
included in the final analysis.  Training of all study investigators will be conducted 
prior to initiation and regular monitoring and site visits will be conducted throughout 
the study to ensure continued compliance.  Secondary analysis will look at 
differences in treatment performance and scarring assessment among the 
investigators.  Any differences will be noted in any publication of the data.  
 
Women with gynecologic disease are afflicted with a number of psychological and 
social issues disrupting quality of life. Patients report changes to their social and 
functional well-being as well as changes to their sexual health. Quality of life 
assessments will be conducted at baseline, 6, and 12-month follow-ups.  Patients 
struggling with psychosocial aspects will be referred for clinical consult as needed. 
The University of Colorado Hospital staffs a group of social workers who are 
available to meet with patients in a private clinical office if the patient expresses a 
psychosocial issue that requires attention.  
 
9.1  
Social and Functional Well Being 
Perceived health status can be an important factor in the functional assessment 
for women with gynecologic disease.  We plan to study overall wellness and social 
support as it relates to treatment in women diagnosed with VIN II/III using the 
following validated survey instruments:  
• FACT-V: In order to assess functional health status we will use the 
Health Status the Functional Assessment of Cancer Therapy (FACIT) 
instrument specific for vulva disease called FACT-V (appendix 1.2). [16]  
 
9.2 
Sexual Function 
Sexual function is often affected following treatment for dysplasia due to the high 
occurrence of scarring and discomfort associated with these procedures.  We will 
evaluate sexual function as it relates to treatment women diagnosed with VIN II/III 
using the following validated survey instruments: 
• Female Sexual Function Index (FSFI) validated survey instrument, 
(appendix 1.3) for overall sexual function. [17]    
 
• Female Sexual Distress Survey (FSDS), a validated instrument for 
measuring sexual distraught (appendix 1.4) [18]. 
 
10. 
Protection Against Risks 
Study staff will obtain all necessary Good Clinical Practice (GCP) and human 
protection HIPAA training to oblige to such standards for maintaining participant’s 
privacy.  REDCap, a secure data collection system, will be used to capture 
data.[19] REDCap tools provide the highest possible degree of assurance that data 

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will be secure. The University IT department also provides encrypted email 
services to internal and external recipients. Any study information communicated 
among the research staff will be done using the encrypted University email service.  
 
There is a risk that subjects may feel uncomfortable answering the survey 
questions, particularly those regarding their sexual function. Participants will be 
informed that they may skip any question they feel uncomfortable answering. 
 
11. Event reporting 
11.1 Adverse Events 
An Adverse Event [AE] is defined as any unfavorable and unintended sign 
(including abnormal laboratory finding), symptom, or disease temporally 
associated with the use of a medical treatment or procedure, regardless of whether 
it is considered related to the medical treatment or procedure (attribution of 
unrelated, unlikely, possible, probable or definite).  An unanticipated event is 
defined as any adverse experience where the nature, severity or frequency is not 
described in the application form or detailed in the consent form. This can also 
include non-compliance issues such as over enrollment of subjects without prior 
COMIRB approval. 
 
The causal relationship to study treatment will be determined by the PI and used 
to assess all AEs and unanticipated problems. The causal relationship can be one 
of the following: 
Possibly related: In the opinion of the PI, the adverse event is unlikely to be 
related to the study intervention, drug or device. 
Probably related: In the opinion of the PI, it is more likely than not that the 
adverse event is related to the study intervention, drug or device. 
Related to the research: An event is “related to the research procedures” if in 
the opinion of the principal investigator, it was more likely than not [probably] to 
be caused by the research procedures or if it is more likely that not [probably] 
that the event affects the rights and welfare of current participants. 
 
The PI will report any unexpected event that is deemed to be probably related 
or related to the research within 5 days, per COMIRB’s policy.  
 
The risks associated with the ultrasonic aspirator and the CO2 laser ablation 
devices are similar with the exception that early studies suggest scarring may be 
significantly decreased with the use of the ultrasonic aspirator. [1]  Previous studies 
have also suggested that the ultrasonic aspirator will have less recurrence of 
dysplasia following treatment.  [3]Since these early studies have failed to provide 
significant power, this is only hypothesized at this time and is the primary outcome 
for this phase III study.   
 
Adverse events that are deemed not related will be documented in the study AE 
log, subject study charts, and reported to COMIRB at the time of annual review, 

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per their policy. The coordinating site will review AEs at interim analysis. 
Anticipated clinical adverse events may include: 
• Pain and/or discomfort (~25% of women) 
• Presence of scarring (~30% of women receiving CO2 laser, less than 5% 
in women receiving ultrasonic aspirator) 
• Dysureia or burning (~25% of women) 
• Adhesions (less than 5%) 
• Infection: yeast, UTI, or other (~10% of women) 
• Abnormal discharge (less than 10% of women) 
• Eschar (~10% of women).  [1] 
 
11.2 Serious Adverse Event  
A Serious Adverse Event (SAE) is any untoward medical occurrence at any dose 
that:  
• Results in death 
• Is life-threatening (defined as an event in which the subject was at risk of 
death at the time of the event; it does not refer to an event which 
hypothetically might have caused death if it were more severe) 
• Requires inpatient hospitalization or causes prolongation of existing 
hospitalization (see NOTE*: below for exceptions) 
• Results in persistent or significant disability/incapacity 
• Is a congenital anomaly/birth defect 
• Is an important medical event, defined as a medical event that may not be 
immediately life-threatening or result in death or hospitalization but, based 
on appropriate medical and scientific judgment, may jeopardize the subject 
or may require intervention (e.g., medical, surgical) to prevent one of the 
other serious outcomes listed above  
Suspected transmission of an infectious agent (e.g., pathogenic or non-
pathogenic) via the study treatment is an SAE.  
 
*NOTE: The following hospitalizations are not considered SAEs:  
• A visit to the emergency room or other hospital department lasting less than 
24 hours that does not result in admission (unless considered an “important 
medical event” or a life-threatening event) 
• Elective surgery planned before signing consent 
• Admissions as per protocol for a planned medical/surgical procedure 
• Routine health assessment requiring admission for baseline/trending of 
health status (e.g., routine colonoscopy) 
• Medical/surgical admission other than remedying ill health state that was 
planned before study entry. Appropriate documentation is required in these 
cases 
• Admission encountered for another life circumstance that carries no bearing 
on health status and requires no medical/surgical intervention (e.g., lack of 
housing, economic inadequacy, caregiver respite, family circumstances, 
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Participants experiencing a SAE should be discontinued from the study and 
followed per clinical standard of care.  SAEs should be documented on the AE 
CRF and reported to local IRB and the coordinating site within 48 hours of 
notification of event.   
 
There are no known reports of serious adverse events following CO2 laser and 
ultrasonic aspiration for vulva dysplasia.  
 
11.2.1 
SAE Reporting 
Following the subject’s written consent to participate in the study, all SAEs, 
whether related or not related to study procedures, must be collected, including 
those thought to be associated with protocol-specified procedures. If 
applicable, SAEs must be collected that relate to any later protocol-specific 
procedure (such as follow-up skin biopsy). 
 
The investigator should report any SAE occurring after these time periods that 
is believed to be related to study drug or protocol-specified procedure. An SAE 
report should be completed for any event where doubt exists regarding its 
status of seriousness.  
 
If the investigator believes that an SAE is not related to study treatment, but is 
potentially related to the conditions of the study (such as withdrawal of previous 
therapy, or a complication of a study procedure), the relationship should be 
specified in the narrative section of the SAE Report Form. 
 
SAEs, whether related or unrelated to the study intervention must be reported 
to the sponsor agent within 24 hours. SAEs must be recorded on the SAE 
Report Form;  
 
If only limited information is initially available, follow-up reports are required. 
(Note: Follow-up SAE reports should include the same investigator term(s) 
initially reported.) If an ongoing SAE changes in its intensity or relationship to 
study intervention or if new information becomes available, a follow-up SAE 
report should be sent within 24 hours to the sponsor (or designee) using the 
same procedure used for transmitting the initial SAE report. All SAEs should 
be followed to resolution or stabilization. 
 
11.3  Non-Serious Events 
A non-serious adverse event is an AE not classified as serious. 
 
11.3.1 
Non-Serious Adverse Events (NSAEs) Collecting and Reporting 
The collection of non-serious adverse event (NSAE) information will begin at 
initiation of study treatment.  
 

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Non-serious AEs will be followed to resolution or stabilization, or reported as 
SAEs if they become serious. Follow-up is also required for non-serious AEs 
that cause interruption or discontinuation of study treatment, or those that are 
present at the end of study treatment as appropriate.  
 
Non-serious Adverse Events are provided to local IRB and the sponsoring 
agent via annual safety reports (if applicable), and interim or final study reports. 
 
11.3.1.1 Anticipated Risks 
While the study anticipates minimal risks, the following outlines any potential 
minimum risk to subjects: 
i. Breach of Confidentiality:  Data obtained using information from medical 
records, poses minimum risk.  All procedures in which information is being 
obtained will be conducted per standard of care.  There is a risk that a patient’s 
privacy may not be protected. This risk is uncommon.  
 
ii. Discomforts:  Persons receiving treatment for Vulvar Intraepithelial 
Neoplasia can anticipate the following risks: infection, dysuria, burning, 
adhesions, light bleeding, and discharge.  Participants could expect to 
experience pain and discomfort following surgery for approximately 1 week. 
Participants should refrain from exercise and sexual intercourse in the two 
weeks following surgery in order to avoid addition discomfort.   
 
iii. Recurrence: Current treatment for vulva-sparing has a recurrence rate of 
25-50% of return disease.  Recurrence, left unmanaged, could lead to cancer 
of the vulva, vagina, or the cervix.   
 
Participation in this study will not have any influence on the patient’s current 
treatment. The study may include risks that are unknown at this time. 
 
12.  Data Collection and Confidentiality 
This study will obtain approval for conduct through the Colorado Multiple 
Institutional Review Board (COMIRB) for research involving human subjects.  All 
patients within the Gynecologic Oncology clinic at the University of Colorado 
Cancer Center who meet the study criteria will be considered eligible for the study.  
We will not enroll any vulnerable populations as defined by ethical guidelines, but 
will follow participants that may become pregnant during the 12 month participation 
duration. Potential participants will be screened by the PI/Co-I and the research 
team and approached for consent.  Consent will occur prior to the initiation of any 
study procedures at a scheduled clinic visit in the Gynecologic Oncology clinics of 
participating sites. Potential participants will be provided a private setting for in-
person consent and will be adequately informed of the study intent, requirements, 
and potential risks and benefits.  Patients will also be informed that any 
participation is voluntary and will not affect any clinical care they are to receive. 
Research staff providing consent will be certified in Collaborative Institutional 
Training Initiative (CITI) and Human Insurance Portability and Accountability Act 

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(HIPAA) trainings for ethics and human protection.  Patients will have time to 
review the consent and ask any questions prior to signing consent.  
 
For secondary sites, additional approval will be obtained by the institution’s local 
IRB.   
 
12.1  Data Collection Tools 
Data will be collected using clinical research forms (CRFs) followed by entry into 
the Research Electronic Data Capture (REDCap) database. For data collected via 
iPad tablet or secured web link, data will be entered directly into a Research 
Electronic Data Capture (REDCap) database.   Research coordinators should 
verify all demographic and health history to the participant’s medical records prior 
to entry into REDCap. REDCap is a secure, web-based application designed to 
support data capture for research studies.[19] REDCap provides: 1) secured 
interface for validated data entry, 2) audit trails for tracking data manipulations and 
data storage and export procedures, 3) automated export procedures for seamless 
data downloads to common statistical packages, and 4) procedures for importing 
data from external sources. The University of Colorado Denver Informational 
Technology (IT) department will provide the host services for the REDCap secure 
application. Data extracted from the database for analysis will de-identified and 
linked to the original source using only a coded study number.  All analysis will be 
conducted using SPSS statistical software program.  UCD will serve as the 
coordinating site for all participating research sites. Data intake at all locations will 
be inputted directly into the lead REDCap database and all data analysis will be 
conducted by research personnel at UCD. REDCap survey privileges will be 
restricted to the non-affiliated locations for data entry only.   
 
Study documents include study consent, CRFs, and study surveys. A study file 
should be constructed for each participant for maintaining these documents.  All 
paper records will be securely stored in the locked research offices with limited 
access.  
 
Data sources will not be shared with outside institutions. Non-affiliated institutions 
participating in this study will only have access to the study resources for data 
entry.  Any final study results presented to the non-affiliated sites will be de-
identified.  Data shared among the researchers will be sent in encrypted email 
messages.  All data will be maintained until completion of study and properly stored 
per federal regulations after completion of study analysis.   
 
All research sites will be responsible for maintaining a subject log with the subjects 
name and study ID number so that the patient’s name is not entered into the 
database maintained at the host site. The study ID will serve as a link for participant 
and study data and will be used for data verification. This will be done to maintain 
patient confidentiality.  
 
12.2   Data Integrity and Protection of Confidentiality 

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Data will be collected at the University of Colorado Denver by the research team. 
All data will be collected on source documents and entered in a Research 
Electronic Data Capture (REDCap) database. Data can also be entered directly 
into the database using a secure internet link accessed on study iPads tablets or 
via email. REDCap is a secure, web-based application designed to support data 
capture for research studies. The University of Colorado Denver Informational 
Technology (IT) department will provide the host services for the REDCap secure 
application. Data imported into the REDCap database will be de-identified and 
linked to the original source documents using a coded study number.  Study 
databases will be stored on secure computers of the research team and backed 
by the secured server of the University of Colorado Denver.  Any paper charts, 
including consent forms and intake data, will be maintained in locked offices within 
the academic offices of the research team. Data sources will not be shared with 
outside institutions. Any data shared among the research team will be sent in 
encrypted email messages or shared using the encrypted REDCap electronic 
database. Any electronic communication with study subjects will also be sent via 
encrypted email messages. All data will be maintained till completion of study and 
properly stored per federal regulations after completion of study analysis 
 
13.  Study Monitoring 
There are no investigational treatments associated with consent into the study, as 
both treatments are currently approved for the treatment of VIN in women 18-89 
years old.  Each study site will obtain local IRB approval. The Primary Investigator 
will be responsible for monitoring the study for unanticipated problems and SAEs 
and report them to lead and local IRBs as appropriate. No interim analysis will be 
conducted.   
 
13.1  Medical Monitoring 
Medical monitoring and monitoring of SAEs across all sites will be monitored by 
Dr. Saketh Guntupalli on a continuous basis. All SAEs must be reported to Dr. 
Guntupalli at the University of Colorado within 48 hours of event.  The sponsoring 
site will be responsible for reporting such events to the overseeing IRB within 5 
days of event.  Interim analysis will be done with data from all sites after 4 months 
of enrollment to examine any increased risk of SAEs as expected from standard 
of care. 
 
13.2 Safety Monitoring Plan 
The Principal Investigator (PI) will be responsible for executing the safety 
monitoring plan, and complying with all reporting requirements to local and federal 
authorities. This safety monitoring plan will be conducted via the use of a safety 
officer.  The safety officer will be a 3rd party reviewer, affiliated with the University 
of Colorado Denver but with no direct affiliation to the research study or the 
sponsor.  The safety officer will be identified by the PI prior to initiation of the study.  
This study does not require a full data safety monitoring board since there are no 
investigational devices or treatment interventions in this study.  
 

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The safety officer is responsible for providing an independent safety review and 
trial guidance during the course of the study.  A summary of the safety officer’s 
activities is as follows: 
• Review the initial protocol and make recommendations towards safety 
concerns 
• Review study recruitments and enrollments over course of the study 
• Review procedures for data quality control over the course of the study 
• Set the parameters for monitoring review, and interim safety analysis 
• Ongoing review of all serious adverse events (SAEs), unanticipated 
problems (UAPs) and reportable adverse events (AEs)  
• Has the authority to close and/or suspend trials for safety conduct issues 
• May submit recommendations for corrective actions to the PI to address 
safety concerns  
 
Per the Safety Monitoring Plan, SAEs, UAPs and reportable AEs are reported to 
the safety monitor, IRB and the sponsor per study protocol.  All SAEs, UAPs and 
reportable AEs are to be reported to the safety monitor within 5 business days of 
receiving notification of the occurrence. Non-reportable AEs will be reported in the 
safety monitoring report provided to the safety officer every 12 months.  
 
Each subject’s treatment outcomes will be discussed by the Investigators and 
Clinical Research Coordinators (CRCs) at regularly scheduled disease-oriented 
working group meetings.  Data regarding number of subjects, significant toxicities, 
dose modifications, and treatment responses will be discussed and documented 
in the meeting’s minutes. 
 
The PI will provide a safety report to the safety monitor on a 12-month basis. The 
report will include a protocol summary, current enrollment numbers, summary of 
data to include specific SAEs, UAPs and AEs, all protocol deviations, and protocol 
amendments. The safety report will also include, if applicable, the results of any 
efficacy data analysis conducted, as well as any sponsor-related safety reports. 
Results and recommendations from the review of this annual report by the safety 
monitor will then be submitted by the site to the IRB of record at the time of 
continuing review. 
 
The coordinating site (UCD) is responsible for organizing and conducting monthly 
teleconferences with all participating sites.  The PI will also be responsible for 
including data from all of the participating sites within the overall trial’s annual 
safety report to the safety officer to include minutes from monthly PI 
teleconferences. Research staff at the University of Colorado Denver Department 
of Obstetrics and Gynecology will conduct monitoring internally of the coordinating 
site internally and for all secondary sites outside the institution. Each participating 
site will be responsible for submitting the results and recommendations from the 
annual safety review to their IRB of record at the time of continuing review. 
 
14. Statistical Analysis 

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A per protocol analysis will be conducted.  Participants receiving treatment per 
protocol will be included in the final analysis.  Investigators will not have the option 
to change treatment assignment.  
   
Descriptive statistics using means, frequencies, and percentages will be computed 
to describe the study population.  Participant data will be analyzed employing the 
per protocol approach.    Student’s t-test (for continuous variables) and chi-square 
tests (for categorical variables) will be used to compare the two groups for 
demographic, and secondary outcome variables: pain, scarring, QOL scores.  For 
the primary outcome measure rate of recurrence for each of the study endpoints, 
3 months, 6 months and 12 months will be calculated per treatment arm and 
compared with initial bivariate analysis using chi—square analysis.  Additional 
predictors for recurrence (pain, scarring, sexual function, and general wellness) 
will be compared similarly with chi-square for categorical variables and t-tests for 
continuous variables. Potential covariates (age, race, previous disease, etc.) will 
also be analyzed using bi-variate analysis. Variables found to be significant in the 
bivariate analysis will be included in multivariable analysis using logistic 
regression. Logistic regression models will be used to identify significant 
independent predictors associated with recurrence for each treatment arm. The 
logistic model will allow for control of study covariates. A p-value of <0.05 will be 
used to demonstrate statistical significance.  IBM SPSS version 22 will be used for 
all statistical analyses.  
 
Incidence of AEs and SAEs will be compared between treatment arms using chi-
square analysis.  A p-value of <0.05 will be used to demonstrate statistical 
significance.   
 
14.1  Primary Endpoint 
The primary endpoint for the study is recurrence of vulvar dysplasia. Recurrence 
will be assessed by physical exam and colposcopy. Further exam by biopsy will 
used to assess recurrence when appropriate, per provider’s discretion.  All clinical 
guidelines for referring to colposcopy should be followed, per standard of care.   
 
14.2  Secondary Endpoints 
The secondary endpoints for this study are as follows: 
 
Pain: Pain in the initial 7-10 days following treatment will be self-assessed using 
a pain scale.  Average pain scores and incidence of high-level of pain will be 
determined for each treatment arm.   
 
Scarring: Scarring in the 6 weeks following treatment will be assessed via visual 
exam by a study investigator. Incidence rates of scarring   will be determined 
for each treatment arm.   
 
 
Sexual function and sexual distraught: Sexual function and distraught will be 
assessed at baseline, 6, and 12 months following treatment. Mean scores for 

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function and distraught will be determined for each treatment arm per study 
time-point. Sexual function and distraught will be measured with validated 
instruments, The Female Sexual Function Index, and the Female Sexual 
Distress survey (Appendix 1.3 and 1.4).  
 
Wellness and Function: General wellness and function will be assessed at 
baseline, 6, and 12 months following treatment. Mean scores for general 
function will be determined for each treatment arm per study time-point. 
Wellness will be measured using the validated instrument FACTS survey for 
vulvar malignancies (Appendix 1.2). 
 
15.  Study Management 
 
15.1 Compliance with the Protocol 
The study shall be conducted as described in this approved protocol. All revisions 
to the protocol must be reviewed by the study investigators and appropriate 
collaborators. The investigator will not implement any deviation or change to the 
protocol without prior review and documented approval from the IRB of an 
amendment, except where necessary to eliminate an immediate hazard(s) to study 
subjects. 
 
15.1.1 
Protocol Amendments 
Any amendments to the protocol will be first reviewed by the study team and 
then submitted to the IRB of the lead site for approval.  Sub-sites will then be 
required to submit the protocol amendment to their local IRB and maintain all 
submission and approvals in their regulatory files.  Sites will not initiate any 
changes to study procedures until after approval of the protocol amendment by 
their local IRB.  Insignificant changes (i.e. personnel changes) may not have to 
be submitted to the sponsor and/or lead site first.   
 
15.1.2 
Subject Withdrawals 
All participant documentation up until study withdrawal will be maintained and 
used for data analysis.  In the event a participant is lost to follow-up, 3 
documented attempts will be made to contact the participant to conduct an end 
of treatment visit.  If after 3 attempts, the participant still does not return, a 
certified letter noting withdraw from study should be sent to the participant.  The 
study coordinator will maintain a return receipt for such.  Additionally, the study 
coordinator should send a self-addressed package to the participant for return 
of any study medications and/or study documents.   
 
15.1.3 
Participant Confidentiality 
Data obtained during conduct of this study is to remain confidential and private.  
Participant confidentiality must be obtained in accordance to regulations set 
forth by Good Clinical Practice and HIPAA.  Release of study data should only 
be done through the publication/presentation of results, lead by the Principal 
Investigator (PI).  Study sites should not release any confidential data or 

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findings of this study without the consent of the PI and the study sponsor.  
 
15.1.4 
Clinical Monitoring 
Clinical monitoring of the study will be conducted by research personnel (data 
manager) from the University of Colorado Denver for all additional sites.  The 
University of Colorado will conduct their own audit and validation of study entry 
with internal research personnel through the Clinical Research Support Center.  
In order to conduct monitoring, study sites should make staff and resources 
available for the following: 
• Initial in-service of the study site, including investigator training and site tour 
• Regular attendance of progress meetings 
• Research staff available for interim monitoring visits 
• All study documents (consents, CRFs, et) available for site visits in which 
the monitor will verify accuracy of data as entered into the electronic database 
• Response to data requests via fax/email if site visit is not necessitated 
• Maintenance of all regulatory documents and accessible for monitor review 
(UCD may request these be sent to the lead site for regulatory maintenance) 
• Research staff available to response to data queries and resolve 
inconsistencies in study records 
• Close out of the study at the study site 
 
The study monitor will provide each site with a report of the monitoring visit to 
be submitted to their local IRB.  In addition to monitoring visits, a monthly 
conference call will take place among all sites to discuss treatment outcomes, 
enrollment, significant toxicities, dose modifications, and responses. These 
meetings will be documents and the minutes shared with all sites.  
 
Additionally, the University of Colorado DSMC may request a site audit to 
evaluate conduct and compliance of the investigational protocol as a study site.  
All study documents and regulatory documents must be available to audit.  The 
audit reviewer will also require direct access to study source (participant 
medical records relating to study) and time with the site investigator and/or 
regulatory personnel during their visit. 
 
 
15.2 Records Retention 
Study documents will be retained for 7 years after the IRB acknowledgement of 
study closure, per HIPAA regulations. 
 
All study documentation should remain on study site in a secured area with limited 
access. 
 
The investigator must retain all study records and source documents for the 
maximum period required by applicable regulations and guidelines, or institution 
procedures, or for the period specified by UCD, whichever is longer.  
 

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If the investigator withdraws from the study (e.g. relocation, retirement), the 
records shall be transferred to a mutually agreed upon designee (e.g. another 
investigator, IRB). Notice of such transfer will be given in writing to the study 
sponsor.  
 
15.2.1 
Research Electronic Data Capture 
All study data should be entered in the electronic data capture.  For this study 
the electronic data capture will be supported by REDCap.  Prior to the start of 
trial, site investigators and research staff must complete REDCap in-service 
provided by the University of Colorado Denver.  The study site will maintain 
documentation of REDCap training for each person approved for accessing 
REDCap.  Access will then be granted by the University of Colorado.  Site 
personnel with REDCap access will be able to maintain study records with 
review and edit permission. 
 
15.2.2. 
Data Management 
All data entered into the REDCap database will be maintained by the host site 
for the REDCap database, the University of Colorado Denver.  The University 
of Colorado research staff will review the database for completion of data and 
data inconsistencies and request resolution by the appropriate site.  The 
University of Colorado will be responsible for all export and analysis of study 
data.  Any requests for data sharing will be considered after completion of study 
analysis. 
 
15.2.3 
Confidentiality and Reporting of Results 
The information on individual subjects arising from this study is to be 
considered confidential and transmitted to the sponsor only in a form that will 
not permit identification of the individual. The information obtained from the 
subjects that can be identified with the subject will remain confidential within 
the research team. Research teams will maintain all records in a secure area 
with limited access. Regulatory and sponsoring agencies may request access 
to the study records and related medical records of each participating subject.  
If requested, the subject’s identity will remain confidential to the extent 
permitted by the applicable laws and regulations. The results of the research 
will be released to public agencies including regulatory agencies, clinical 
investigators, and research organizations without reference to items identifiable 
to a particular subject. The results will be published such that the identity of the 
subjects will not be disclosed and cannot be ascertained. 
 
15.3 Publication Policy 
Data on the use of the study interventions and results of all clinical study are 
considered confidential. UCD will lead any publication of the results of the study. 
Any publications or presentations that result from this study will maintain 
confidentiality of study participants.  
 
15.4 Conflict of Interest 

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Investigators will be affiliated with their study sites and have no affiliation with the 
sponsoring agency. They will receive support for this clinical trial from the study 
sponsor but will not profit from results, either positive or negative, with regard to 
the product being evaluated. The sponsoring agent could profit from the successful 
development of this product. 
 
 
 
 
 
16. References 
 
1. 
Kaushik, S., et al., Surgical interventions for high-grade vulval intraepithelial 
neoplasia. Cochrane Database Syst Rev, 2014. 3: p. CD007928. 
2. 
Miller, B.E., Vulvar intraepithelial neoplasia treated with cavitational ultrasonic 
surgical aspiration. Gynecol Oncol, 2002. 85(1): p. 114-8. 
3. 
von Gruenigen, V.E., et al., Surgical treatments for vulvar and vaginal dysplasia: 
a randomized controlled trial. Obstet Gynecol, 2007. 109(4): p. 942-7. 
4. 
Reitano, M., Counseling patients with genital warts. Am J Med, 1997. 102(5A): 
p. 38-43. 
5. 
Hillemanns, P., et al., Evaluation of different treatment modalities for vulvar 
intraepithelial neoplasia (VIN): CO(2) laser vaporization, photodynamic 
therapy, excision and vulvectomy. Gynecol Oncol, 2006. 100(2): p. 271-5. 
6. 
Rodolakis, A., et al., Vulvar intraepithelial neoplasia (VIN)--diagnostic and 
therapeutic challenges. Eur J Gynaecol Oncol, 2003. 24(3-4): p. 317-22. 
7. 
Hoffman, M.S., et al., Laser vaporization for vulvar intraepithelial neoplasia III. 
J Reprod Med, 1992. 37(2): p. 135-7. 
8. 
Hoffman, M.S., et al., Laser vaporization of grade 3 vaginal intraepithelial 
neoplasia. Am J Obstet Gynecol, 1991. 165(5 Pt 1): p. 1342-4. 
9. 
Sideri, M., et al., Evaluation of CO(2) laser excision or vaporization for the 
treatment of vulvar intraepithelial neoplasia. Gynecol Oncol, 1999. 75(2): p. 
277-81. 
10. 
Yalcin, O.T., et al., Vaginal intraepithelial neoplasia: treatment by carbon dioxide 
laser and risk factors for failure. Eur J Obstet Gynecol Reprod Biol, 2003. 
106(1): p. 64-8. 
11. 
Campagnutta, E., et al., Treatment of vaginal intraepithelial neoplasia (VAIN) 
with the carbon dioxide laser. Clin Exp Obstet Gynecol, 1999. 26(2): p. 127-30. 
12. 
Julian, T.M., B.J. O'Connell, and J.A. Gosewehr, Indications, techniques, and 
advantages of partial laser vaginectomy. Obstet Gynecol, 1992. 80(1): p. 140-
3. 
13. 
Wright, V.C. and E. Davies, Laser surgery for vulvar intraepithelial neoplasia: 
principles and results. Am J Obstet Gynecol, 1987. 156(2): p. 374-8. 
14. 
Robinson, J.B., et al., Cavitational ultrasonic surgical aspiration for the 
treatment of vaginal intraepithelial neoplasia. Gynecol Oncol, 2000. 78(2): p. 
235-41. 

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15. 
Facts and Figures 2013, U.o.C.C. Center, Editor 2013, University of Colorado: 
Aurora, CO. 
16. 
Webster, K., D. Cella, and K. Yost, The Functional Assessment of Chronic Illness 
Therapy (FACIT) Measurement System: properties, applications, and 
interpretation. Health Qual Life Outcomes, 2003. 1: p. 79. 
17. 
Rosen, R., et al., The Female Sexual Function Index (FSFI): a multidimensional 
self-report instrument for the assessment of female sexual function. J Sex Marital 
Ther, 2000. 26(2): p. 191-208. 
18. 
Derogatis, L., et al., Validation of the female sexual distress scale-revised for 
assessing distress in women with hypoactive sexual desire disorder. J Sex Med, 
2008. 5(2): p. 357-64. 
19. 
Harris, P.A., et al., Research electronic data capture (REDCap)--a metadata-
driven methodology and workflow process for providing translational research 
informatics support. J Biomed Inform, 2009. 42(2): p. 377-81. 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Appendix 1: Survey Instruments 
 
 
 
 
 
 
 
 
 
 
 
 
 

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Appendix 1.1 Pain Assessment Scale 

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Appendix 1.2  FACT-V (Version 4)   
 

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For Vulva Cancer diagnosis only  
Below is a list of statements that other people with your illness have said are 
important. Please circle or mark one number per line to indicate your 
response as it applies to the past 7 days. 
 
PHYSICAL WELL-BEING 
 
Not 
at all 
A little 
bit 
Some
-what 
Quite
a bit 
Very 
much 
GP1 
I have a lack of energy
 ........................................................................................................... 
0 
1 
2 
3 
4 
GP2 
I have nausea
 ........................................................................................................... 
0 
1 
2 
3 
4 
GP3 
Because of my physical condition, I have trouble 
meeting the needs of my family
 ........................................................................................................... 
 
0 
 
1 
 
2 
 
3 
 
4 
GP4 
I have pain
 ........................................................................................................... 
0 
1 
2 
3 
4 
GP5 
I am bothered by side effects of treatment
 ........................................................................................................... 
0 
1 
2 
3 
4 
GP6 
I feel ill
 ........................................................................................................... 
0 
1 
2 
3 
4 
GP7 
I am forced to spend time in bed
0 
1 
2 
3 
4 
 
 
SOCIAL/FAMILY WELL-BEING 
 
Not 
at all 
A little 
bit 
Some
-what 
Quite
a bit 
Very 
much 
GS1 
I feel close to my friends
 ........................................................................................................... 
0 
1 
2 
3 
4 
GS2 
I get emotional support from my family
 ........................................................................................................... 
0 
1 
2 
3 
4 
GS3 
I get support from my friends
 ........................................................................................................... 
0 
1 
2 
3 
4 
GS4 
My family has accepted my illness
 ........................................................................................................... 
0 
1 
2 
3 
4 

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Ultrasonic Aspiration vs. CO2 Laser Ablation  Version  04/12/2021 
COMIRB # 16-0701 
 
Please circle or mark one number per line to indicate your response as 
it applies to the past 7 days. 
 
 
 
EMOTIONAL WELL-BEING 
Not 
at all 
A little 
bit 
Some
-what 
Quite
a bit 
Very 
much 
GE1 
I feel sad
 ............................................................................................................ 
0 
1 
2 
3 
4 
GE2 
I am satisfied with how I am coping with my illness
 ............................................................................................................ 
0 
1 
2 
3 
4 
GE3 
I am losing hope in the fight against my illness
 ............................................................................................................ 
0 
1 
2 
3 
4 
GE4 
I feel nervous
 ............................................................................................................ 
0 
1 
2 
3 
4 
GE5 
I worry about dying
 ............................................................................................................ 
0 
1 
2 
3 
4 
GE6 
I worry that my condition will get worse
0 
1 
2 
3 
4 
 
 
 
 
FUNCTIONAL WELL-BEING 
 
Not 
at all 
A little 
bit 
Some
-what 
Quite
a bit 
Very 
much 
 
GS5 
I am satisfied with family communication about my 
illness
 ........................................................................................................... 
 
0 
 
1 
 
2 
 
3 
 
4 
GS6 
I feel close to my partner (or the person who is my 
main support)
 ........................................................................................................... 
 
0 
 
1 
 
2 
 
3 
 
4 
Q1 
Regardless of your current level of sexual activity, please 
answer the following question. If you prefer not to answer 
it, please mark this box           and go to the next section. 
 
 
 
 
 
GS7 
I am satisfied with my sex life
0 
1 
2 
3 
4 

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GF1 
I am able to work (include work at home)
 ............................................................................................................ 
0 
1 
2 
3 
4 
GF2 
My work (include work at home) is fulfilling
 ............................................................................................................ 
0 
1 
2 
3 
4 
GF3 
I am able to enjoy life
 ............................................................................................................ 
0 
1 
2 
3 
4 
GF4 
I have accepted my illness
 ............................................................................................................ 
0 
1 
2 
3 
4 
GF5 
I am sleeping well
 ............................................................................................................ 
0 
1 
2 
3 
4 
GF6 
I am enjoying the things I usually do for fun
 ............................................................................................................ 
0 
1 
2 
3 
4 
GF7 
I am content with the quality of my life right now
0 
1 
2 
3 
4 
 
 
 

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Please circle or mark one number per line to indicate your response as 
it applies to the past 7 days. 
 
 
 
ADDITIONAL CONCERNS 
 
Not 
at all 
A little 
bit 
Some
-what 
Quite 
a bit 
Very 
much 
V1 
I am bothered by discharge or bleeding from my 
vulva
 ............................................................................................................ 
0 
1 
2 
3 
4 
V2 
I am bothered by odor coming from my vulva
 ............................................................................................................ 
0 
1 
2 
3 
4 
Cx3 
I am afraid to have sex
 ............................................................................................................ 
0 
1 
2 
3 
4 
V3 
I am bothered by swelling/fluid in my legs
 ............................................................................................................ 
0 
1 
2 
3 
4 
Cx4 
My vagina feels too narrow or short
 ............................................................................................................ 
0 
1 
2 
3 
4 
V4 
I am bothered by discomfort in my groin or legs
 ............................................................................................................ 
0 
1 
2 
3 
4 
Cx5 
I am afraid the treatment may harm my body
 ............................................................................................................ 
0 
1 
2 
3 
4 
Bl4 
I am interested in sex
 ............................................................................................................ 
0 
1 
2 
3 
4 
C7 
I like the appearance of my body
 ............................................................................................................ 
0 
1 
2 
3 
4 
Cx6 
I am bothered by constipation
 ............................................................................................................ 
0 
1 
2 
3 
4 
C6 
I have a good appetite
 ............................................................................................................ 
0 
1 
2 
3 
4 
Bl1 
I have trouble controlling my urine
 ............................................................................................................ 
0 
1 
2 
3 
4 

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V5 
I am bothered by itching/burning in my vulva area
 ............................................................................................................ 
0 
1 
2 
3 
4 
Cx7 
I have discomfort when I urinate
 ............................................................................................................ 
0 
1 
2 
3 
4 
V6 
I am bothered by pain or numbness in my vulva area
 ............................................................................................................ 
0 
1 
2 
3 
4 
V7 
I have trouble bending
 ............................................................................................................ 
0 
1 
2 
3 
4 
V8 
I have discomfort when I am sitting
 ............................................................................................................ 
0 
1 
2 
3 
4 
V9 
I am bothered by wearing compression stockings
 ............................................................................................................ 
0 
1 
2 
3 
4 
H&N1 
I am able to eat the foods that I like
 ............................................................................................................ 
0 
1 
2 
3 
4 
 
Appendix 1.3  Female Sexual Function Index (FSFI)  
 
These questions ask about your sexual feelings and responses during the past 4 weeks. 
Please answer the following questions as honestly and clearly as possible.  
 
Sexual activity can include caressing, foreplay, masturbation and vaginal intercourse. 
Sexual intercourse is defined as penile penetration (entry) of the vagina. 
Sexual stimulation includes situations like foreplay with a partner, self-stimulation 
(masturbation), or sexual fantasy. 
Sexual desire or interest is a feeling that includes wanting to have a sexual experience, 
feeling receptive to a partner's sexual initiation, and thinking or fantasizing about having 
sex. 
Sexual arousal is a feeling that includes both physical and mental aspects of sexual 
excitement. It may include feelings of warmth or tingling in the genitals, lubrication 
(wetness), or muscle contractions. 
 
 
1. Over the past 4 weeks, how often did you feel sexual desire or interest? 
o Almost always or always 
o Most times (more than half the time) 
o Sometimes (about half the time) 
o A few times (less than half the time) 
o Almost never or never 
 
2. Over the past 4 weeks, how would you rate your level (degree) of sexual desire 

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or interest? 
o Very high 
o High 
o Moderate 
o Low 
o Very low or none at all 
 
3. Over the past 4 weeks, how often did you feel sexually aroused ("turned on") 
during sexual activity or intercourse? 
o No sexual activity 
o Almost always or always 
o Most times (more than half the time) 
o Sometimes (about half the time) 
o A few times (less than half the time) 
o Almost never or never 
 
4. Over the past 4 weeks, how would you rate your level of sexual arousal ("turn 
on") during sexual activity or intercourse? 
o No sexual activity 
o Very high 
o High 
o Moderate 
o Low 
o Very low or none at all 
 
5. Over the past 4 weeks, how confident were you about becoming sexually 
aroused during sexual activity or intercourse? 
o No sexual activity 
o Very high confidence 
o High confidence 
o Moderate confidence 
o Low confidence 
o Very low or no confidence 
 
6. Over the past 4 weeks, how often have you been satisfied with your arousal 
(excitement) during sexual activity or intercourse? 
o No sexual activity 
o Almost always or always 
o Most times (more than half the time) 
o Sometimes (about half the time) 
o A few times (less than half the time) 
o Almost never or never 
 
7. Over the past 4 weeks, how often did you become lubricated ("wet") during 
sexual activity or intercourse? 
o No sexual activity 

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o Almost always or always 
o Most times (more than half the time) 
o Sometimes (about half the time) 
o A few times (less than half the time) 
o Almost never or never 
 
8. Over the past 4 weeks, how difficult was it to become lubricated ("wet") during 
sexual activity or intercourse? 
o No sexual activity 
o Extremely difficult or impossible 
o Very difficult 
o Difficult 
o Slightly difficult 
o Not difficult 
 
9. Over the past 4 weeks, how often did you maintain your lubrication ("wetness") 
until completion of sexual activity or intercourse? 
o No sexual activity 
o Almost always or always 
o Most times (more than half the time) 
o Sometimes (about half the time) 
o A few times (less than half the time) 
o Almost never or never 
 
10. Over the past 4 weeks, how difficult was it to maintain your lubrication 
("wetness") until completion of sexual activity or intercourse? 
o No sexual activity 
o Extremely difficult or impossible 
o Very difficult 
o Difficult 
o Slightly difficult 
o Not difficult 
 
11. Over the past 4 weeks, when you had sexual stimulation or intercourse, how 
often did you reach orgasm (climax)? 
o No sexual activity 
o Almost always or always 
o Most times (more than half the time) 
o Sometimes (about half the time) 
o A few times (less than half the time) 
o Almost never or never 
 
12. Over the past 4 weeks, when you had sexual stimulation or intercourse, how 
difficult was it for you to reach orgasm (climax)? 
o No sexual activity 
o Extremely difficult or impossible 

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o Very difficult 
o Difficult 
o Slightly difficult 
o Not difficult 
 
13. Over the past 4 weeks, how satisfied were you with your ability to reach orgasm 
(climax) during sexual activity or intercourse? 
o No sexual activity 
o Very satisfied 
o Moderately satisfied 
o About equally satisfied and dissatisfied 
o Moderately dissatisfied 
o Very dissatisfied 
 
14. Over the past 4 weeks, how satisfied have you been with the amount of 
emotional closeness during sexual activity between you and your partner? 
o No sexual activity 
o Very satisfied 
o Moderately satisfied 
o About equally satisfied and dissatisfied 
o Moderately dissatisfied 
o Very dissatisfied 
 
15. Over the past 4 weeks, how satisfied have you been with your sexual 
relationship with your partner? 
o Very satisfied 
o Moderately satisfied 
o About equally satisfied and dissatisfied 
o Moderately dissatisfied 
o Very dissatisfied 
 
16. Over the past 4 weeks, how satisfied have you been with your overall sexual life? 
o Very satisfied 
o Moderately satisfied 
o About equally satisfied and dissatisfied 
o Moderately dissatisfied 
o Very dissatisfied 
 
17. Over the past 4 weeks, how often did you experience discomfort or pain during 
vaginal penetration? 
o Did not attempt intercourse 
o Almost always or always 
o Most times (more than half the time) 
o Sometimes (about half the time) 
o A few times (less than half the time) 
o Almost never or never 

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18. Over the past 4 weeks, how often did you experience discomfort or pain following 
vaginal penetration? 
o Did not attempt intercourse 
o Almost always or always 
o Most times (more than half the time) 
o Sometimes (about half the time) 
o A few times (less than half the time) 
o Almost never or never 
 
19. Over the past 4 weeks, how would you rate your level (degree) of discomfort or 
pain during or following vaginal penetration? 
o Did not attempt intercourse 
o Very high 
o High 
o Moderate 
o Low 
o Very low or none at all 
 
 
 
1.4 Female Sexual Distress Scale (FSDS-R)  
 
Below is a list of feelings and problems that women sometimes have concerning their 
sexuality. Please read each item carefully, and circle the number that best describes how 
often that problem has bothered you or causes you distress during the past 30 days 
including today. Circle only one number for each item, and take care not to 
skip any items.  
 
 
How often do you 
feel... 
 
Never 
Rarely 
Occasionally Frequently 
Always 
1. Distressed about your 
sex life 
0 
1 
2 
3 
4 
2. Unhappy about your 
sexual relationship 
0 
1 
2 
3 
4 
3. Guilty about sexual 
difficulties 
0 
1 
2 
3 
4 
4. Frustrated by your 
sexual problems 
0 
1 
2 
3 
4 
5. Stressed about sex 
0 
1 
2 
3 
4 
6. Inferior because of 
sexual problems 
0 
1 
2 
3 
4 
7. Worried about sex 
0 
1 
2 
3 
4 
8. Sexually inadequate 
0 
1 
2 
3 
4 
9. Regrets about your 
sexuality 
0 
1 
2 
3 
4 
10. Embarrassed about 
sexual problems 
0 
1 
2 
3 
4 

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COMIRB # 16-0701 
11. Dissatisfied with your 
sex life 
0 
1 
2 
3 
4 
12. Angry about your sex 
life 
0 
1 
2 
3 
4 
13. Bothered by low 
sexual desire 
0 
1 
2 
3 
4