Clinical trial NCT03578965
Conditions: Premalignant Vulvar Lesion Benign Vulvar Lesion
Sponsor: Washington University School of Medicine
Start date: 2018-07-13; Completion date: 2021-11-23
Enrollment: 50 participants; Allocation: RANDOMIZED; Intervention model: PARALLEL

Brief summary:
A randomized control trial will provide the most reliable data to determine the role of prophylactic antibiotics to decrease the wound complication rate. The investigators plan to perform a pilot study to evaluate actual rates of wound complications and how long it takes to recruit 50 patients.

Detailed description:

Arms: arm 1: -Women randomized to no antibiotic prophylaxis will not receive any antibiotics prior to skin incision. arm 2: -Women randomized to prophylactic antibiotics will receive a cefazolin as per ACOG guidelines.
Interventions: intervention 1: Cefazolin
Intervention descriptions: intervention 1: -If patient has a penicillin allergy then clindamycin will be used. Prophylactic antibiotics should be administered prior to skin incision

Protocol documents:
Prot_SAP_000.pdf: 
Protocol Version: 09/10//2020 
 
Page 1 of 25 
 
 
Does antibiotic prophylaxis reduce wound complications after vulvar excision of 
premalignant lesions: A Double-Blinded Randomized Controlled Trial 
 
Washington University School of Medicine 
Division of Gynecologic Oncology 
4911 Barnes Jewish Plaza 
Campus Box 8064 
St. Louis, MO  63110 
 
Protocol#:  201804136 
Version Date: September 10, 2020 
 
Principal Investigator:**  
Mary M. Mullen, M.D. 
 
 
 
 
4911 Barnes Jewish Plaza 
 
 
 
 
Campus Box 8064 
 
 
 
 
St. Louis, MO  63110 
 
 
 
 
Phone: (314) 655-8750  
 
 
 
 
Fax:  (314) 362-2893 
 
 
 
 
E-mail: marymullen@wustl.edu 
 
Sub-Investigators* 
 
Lindsay M. Kuroki, M.D. 
Gynecologic Oncology 
Katherine C. Fuh, M.D.  
Gynecologic Oncology 
Andrea R. Hagemann, M.D. 
Gynecologic Oncology 
 
 
 
 
L. Stewart Massad, M.D.  
Gynecologic Oncology 
Carolyn K. McCourt, M.D. 
Gynecologic Oncology 
David G. Mutch, M.D. 
 
Gynecologic Oncology 
 
 
 
 
Matthew A. Powell, M.D. 
Gynecologic Oncology 
 
 
 
 
Premal H. Thaker, M.D., M.S. 
Gynecologic Oncology  
 
 
 
 
David Eisenberg, M.D., MPH 
Gynecologic Oncology 
 
 
 
 
Dineo Khabele, M.D. 
 
Gynecologic Oncology 
 
 
 
 
Jerry Lowder, M.D. 
 
Gynecologic Oncology 
 
 
 
 
Tessa Madden, M.D., MPH 
Gynecologic Oncology 
 
 
 
 
 
Gillian Schivone, M.D., MS 
Gynecologic Oncology 
 
 
 
 
 
Tammy Sonn, MD 
 
Gynecologic Oncology 
 
 
 
 
 
Eric Strand, MD 
 
Gynecologic Oncology 
 
 
 
 
 
Denise Willers, MD 
 
Gynecologic Oncology 
 
 
 
 
 
 
 
 
 
 
 
 
Clinical Trials.gov# 
NCT03578965 
 
 
CONFIDENTIAL 
The information contained in this document is regarded as confidential and, except to the extent necessary to 
obtain informed consent, may not be disclosed to another party unless law or regulations require such 
disclosure.  Persons to whom the information is disclosed must be informed that the information is 
confidential and may not be further disclosed by them 


Protocol Version: 09/10//2020 
 
Page 2 of 25 
Protocol Revision History 
Initial Approval Version Date 
 04/25/2018 
Amendment #1 Version Date 
 06/11/2018 
Amendment #2 Version Date 
 08/08/2018 
Amendment #3 Version Date 
 12/19/2018 
Amendment #4 Version Date           04/02/2020 
Amendment #5 Version Date           09/10/2020 
 
 
 
 


Protocol Version: 09/10//2020 
 
Page 3 of 25 
Does antibiotic prophylaxis reduce wound complications after vulvar excision of 
premalignant lesions:  
A Double-Blinded Randomized Controlled Trial 
 
 
SCHEMA 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Treatment Plan (n=50) 
All patients will be 
randomized on the day of 
surgery 
Eligible Patients 
All women, >=18 years of age, undergoing vulvar surgery for a 
benign or premalignant indication under the supervision of a faculty 
member within the Division of OBGYN at Washington University 
School of Medicine will be eligible. 
Arm I (n=25) 
Antibiotic prophylaxis 
prior to skin incision 
Arm II (n=25) 
No antibiotic prophylaxis 
prior to skin incision  
Arm I (n=25) 
7-30 day follow-up  
exam and patient survey 
Arm II (n=25) 
7-30 day follow-up  
exam and patient survey 
Arm I (n=25) 
30(+/- 10) day follow-up 
from electronic medical 
record 
Arm II (n=25) 
30(+/- 10) day follow-up 
from electronic medical 
record 


Protocol Version: 09/10//2020 
 
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Glossary of Abbreviations  
 
AE 
ACOG 
Adverse event 
American Congress of Obstetrics and Gynecology 
CRF 
Case report form 
CTCAE 
Common Terminology Criteria for Adverse Events 
CTEP 
Cancer Therapy Evaluation Program 
DSM 
Data and Safety Monitoring  
DSMC 
Data Safety Monitoring Committee 
EC 
EMR 
Ethics Committee 
Electronic Medical Record 
HCG 
HRPO 
Human chorionic gonadotropin 
Human Research Protection Office (IRB) 
IRB 
Institutional Review Board 
ITT 
Intent-to-treat 
OHRP 
Office of Human Research Protections  
PI 
Principal investigator 
QASMC 
Quality Assurance and Safety Monitoring Committee 
 
 
 
 


Protocol Version: 09/10//2020 
 
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Does antibiotic prophylaxis reduce wound complications after vulvar excision of 
premalignant lesions:  
A Double-Blinded Randomized Controlled Trial 
 
Table of Contents 
 
1.0 
BACKGROUND AND RATIONALE 
 
2.0 
OBJECTIVES 
 
3.0 
PATIENT SELCTION/ELIGIBILITY CRITERIA 
 
4.0 
REGISTRATION AND RANDOMIZATION PROCEDURES 
 
5.0 
RESEARCH/TREATMENT PLAN 
 
6.0 
REGULATORY AND REPORTING REQUIREMENTS 
 
7.0 
STUDY CALENDAR 
 
8.0 
DATA SUBMISSION SCHEDULE 
 
9.0 
MEASUREMENT OF EFFECT 
 
10.0 
DATA AND SAFETY MONITORING 
 
11.0 
STATISTICAL CONSIDERATIONS 
 
12.0 
REFERENCES 
13.0 
ACKNOWLEDGMENTS 
 


Protocol Version: 09/10//2020 
 
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1.0 
BACKGROUND AND RATIONALE 
 
1.1 
Study Disease 
 
Premalignant vulvar lesions are extremely common with the incidence increasing over 
400% in the past 30 years, totaling up to 7,500 cases in the United States annually.1 Surgical 
excision is recommended when invasive carcinoma cannot be excluded. Depending on 
lesion(s) size and location, in order to achieve a 1 cm disease-free margin, some excisions 
can be extensive and at high-risk for wound separation and/or surgical site infection (SSI).2 
Vulvar wound complications are recognized as a major cause of postoperative morbidity 
but have predominantly been studied in the context of radical vulvectomies performed for 
cancer staging. Despite the finding that the majority of invasive and in situ vulvar 
carcinoma lesions are premalignant (57%), there is a lack of data regarding the risk of 
infection following conservative vulvar excisions.1 As such, there are no evidence-based 
guidelines regarding antibiotic prophylaxis for this patient population.   
 
To address this gap in the literature, we performed a retrospective cohort study at our 
institution which included all vulvar surgeries performed for premalignant lesions from 
January 2007 to 2017. Of 534 patients included, the overall wound complication rate was 
30%. The American Congress of Obstetricians and Gynecologists (ACOG) recommends 
prophylactic antibiotics for procedures such as anterior colporrhaphy which likely confer 
a similar infection risk to simple vulvectomies, but makes no recommendations about 
vulvar excision. If baseline wound complication rates approach 30% as demonstrated in 
our preliminary data, clinical practice of antibiotic administration should be addressed. 
Before clinical practice recommendations change we propose to test the central 
hypothesis that antibiotic prophylaxis will reduce the incidence of a composite wound 
complication (wound breakdown, SSI, seroma, and/or hematoma) within 30 days 
postoperatively. We propose a pilot study designed as a double-blinded randomized 
controlled clinical trial of women who undergo a vulvar excision for a premalignant 
lesions. 
 
1.2 
Study Rationale 
 
The use of antibiotics in common gynecologic procedures such as hysterectomy, 
laparoscopy, and surgical abortion is well established and has been described in many 
randomized control trials and meta-analyses.3-5 The rate of wound infection after vulvar 
excision for premalignant lesions (7.5%) is equal to or greater than that of vaginal 
hysterectomy (7-14%), abdominal hysterectomy (1-6%) for which antibiotic prophylaxis 
is routinely used. With the use of antibiotic prophylaxis, postoperative infection rates 
decrease greater than 20% for vaginal hysterectomy and 15% for abdominal 
hysterectomy.5 The relative risk for developing infection after an elective abortion in 
women who received antibiotic prophylaxis versus those who did not is 0.58.6 As a 
result, antibiotic use is strongly encouraged in these situations. Conversely, to our 
knowledge, there is no research evaluating the rate of vulvar wound complications after 
excision of premalignant or benign vulvar lesions and no formal recommendations exist 
regarding antibiotic prophylaxis.  


Protocol Version: 09/10//2020 
 
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Previous studies evaluating vulvar surgery are largely focus on wound complications after 
the treatment of vulvar cancer specifically with radical vulvectomy and inguinal 
lymphadenectomy.7-9 In cancer populations wound complications including infection and 
breakdown are one of the most common causes of postoperative morbidity resulting in 
increased healthcare costs and decreased quality of life.7-9 Extrapolation of this data to 
premalignant lesions is not valid given the differences in aggressiveness of surgical 
technique including both depth and width of the excision. More importantly, the majority 
of vulvar carcinomas are in fact in situ and not invasive and therefore it is important to 
study premalignant disease.1 Antibiotic prophylaxis has been suggested to improve the rate 
of wound complications, but no formalized randomized control trials have verified this 
practice.8     
Given the clean-contaminated nature and endogenous flora of the vulva, patients 
undergoing vulvar excision are at high risk for wound complications. This increased risk 
would suggest the benefit of antibiotic prophylaxis, however, indiscriminate antibiotic 
without demonstrated benefit on clinical outcomes is inefficient and potentially 
detrimental. Haphazard antibiotic administration is associated with antibiotic-resistant 
bacteria, and over 15% of patients will have adverse reactions to antibiotics ranging from 
skin rashes and diarrhea to anaphylaxis.10 Given the growing prevalence of premalignant 
vulvar lesions, having evidence-based guidelines for or against the use of antibiotic 
prophylaxis for these excisions would improve evidence-based practice standards for 
women’s health.  
 
We conducted a single-center, retrospective cohort study evaluating all vulvar excisions 
performed for a benign indication at our institution from 1/2007-1/2017. 534 patients 
were included, 227 patients who received preoperative antibiotics and 310 who did not. 
The overall wound complication rate was 28.8% with an infection rate of 6.9%. There 
was no difference in wound complication rates between patients who received 
preoperative antibiotics and those who did not (30.4% vs 27.4%, p=0.45). However, 
because this was a retrospective study it is possible that confounders such as inherent 
differences in the patient populations, clinical practice of the surgeons, or confounding by 
indication in who was given antibiotics and who was note may have influenced these 
findings. Current tobacco use (aOR 1.90, 95% CI 1.26-2.87), and concomitant 
reconstructive flap or graft (OR 1.67, 95% CI 1.02-2.73) were associated with increased 
wound complications. In short, the wound complication rate following vulvar surgery for 
nonmalignant lesions is substantial. It is well established that patients with wound 
complications require increased hospital stay, increased hospital cost, and decreased 
quality of life.3 Given the many confounding variables of this retrospective study, a 
randomized control trial will provide the most reliable data to determine the role of 
prophylactic antibiotics to decrease the wound complication rate. We plan to perform a 
pilot study to evaluate actual rates of wound complications and how long it takes to 
recruit 50 patients. Relying on retrospective data is difficult given documentation of 
wound complications and we only had <50% of patients who received antibiotics.  
 
 
 


Protocol Version: 09/10//2020 
 
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2.0 
OBJECTIVES 
 
2.1 
Primary Objective 
Evaluate for the difference in wound complications between women who receive 
antibiotic prophylaxis and those who do not:  
 
a) Wound complication will be defined as a composite outcome that includes wound 
breakdown, sterile site infection, hematoma, seroma diagnosed within 30 days 
after excision. 
• Sterile Site Infection (SSI) – defined as purulent drainage, cellulitis, 
abscess, or a wound that requires drainage, debridement or antibiotics 
associated with a clinical diagnosis of infection. 
2.2 
Secondary Objectives 
Determine the clinical risk factors that correlate with vulvar wound complications. 
b) Demographic variables that predispose patients to infection including medical 
history of diabetes, liver disease, human immunodeficiency virus, chronic kidney 
disease, congestive heart failure, chronic obstructive pulmonary disease, 
peripheral vasculature disease, dementia, connective tissues disease, leukemia, 
lymphoma, peptic ulcer disease, or hypertension. We will also record steroid use 
or the use of other immunosuppressive medications.  
c) Evaluation of vulvar hygiene through physician and patient survey  
d) Incidence of adverse events to antibiotic use 
 
2.3 
Tertiary Objectives 
Evaluate for differences in the following outcomes between women who receive 
antibiotic prophylaxis and those who do not: 
 
a) Inpatient re-admission for postoperative wound care within 30 days of surgery 
b) Antibiotic safety measures including allergic reaction type and severity 
3.0 
PATIENT SELECTION 
 
3.1 
Inclusion Criteria  
3.1.1 All women, >=18 undergoing vulvar surgery. 
 
3.1.2 Biopsy proven benign or premalignant lesion requiring surgical 
management.  
 
3.1.3 Women of childbearing age will be required to have a negative human 
chorionic gonadotropin (HCG) test within seven days of surgery.  
 
3.1.4 Scheduled to undergo surgical management for their vulvar disease 
supervised by a faculty member within the Division of OBGYN at 
Washington University School of Medicine  
 


Protocol Version: 09/10//2020 
 
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3.1.5 Ability to understand and willingness to sign an IRB approved written 
informed consent document (or that of legally authorized representative, if 
applicable). 
 
3.2 
Exclusion Criteria 
3.2.1 Women who are pregnant  
 
3.2.2 Women scheduled to undergo a radical vulvectomy 
 
3.2.3 Women scheduled to undergo a concomitant graft, flap or plastic surgery 
 
3.2.4 Women <18 years of age 
 
3.2.5 History of prior vulvar radiation 
 
3.2.6 Inability to sign an informed consent form prior to registration on study 
 
3.2.7 Inability to understand spoken or written English  
 
3.2.8 Prisoner  
 
 
3.3 
Inclusion of Minorities 
 
3.3.1 Members of all races and ethnic groups are eligible for this trial. As our patient 
population is solely female, only women will be eligible for this study.  
 
4.0 
REGISTRATION AND RANDOMIZATION PROCEDURES 
The following steps must be taken before registering patients to this study: 
 
1. Confirmation of patient eligibility as indicated in section 4.1. 
2. Assignment of unique patient number (UPN) as indicated in section 4.2. 
 
4.1 
Confirmation of Patient Eligibility 
 
Confirm patient eligibility by collecting the information listed below  
1. The registering MD’s name 
2. Patient’s race and DOB 
3. Three letters (or two letters and a dash) for the patient’s initials 
4. Copy of signed consent form  
5. Completed eligibility checklist, signed and dated by the PI or designated sub-
investigator 
6. Completed source document verifying negative pregnancy test (within 7 days of 
surgery).  
7. Copy of appropriate source documentation confirming patient eligibility 
 


Protocol Version: 09/10//2020 
 
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4.2 
Assignment of UPN 
 
Each patient will be identified with a unique patient number (UPN) for this study.  Patients 
will also be identified by first, middle, and last initials.  If the patient has no middle initial, 
a dash will be used. 
 
4.3 
Patient Registration and Randomization 
Prior to recruitment all Gynecology attending physicians of Washington University will 
receive an email from the principal investigator asking for permission to screen their 
patients for recruitment and to consent them for involvement in the study. Physicians will 
have the opportunity to opt out of the study over the next two weeks in which case their 
patients will not be screened for eligibility. If they agree to participation their patients 
will be included in the recruitment process noted below.  
 
All potential women who are scheduled with OBGYN faculty or fellows for vulvar 
surgery will be identified and screened for eligibility prior to their preoperative 
appointment. The principal investigator and members of the research team will identify 
patients who meet the inclusion criteria and who do not meet one of the exclusion criteria 
(eligibility checklist). PHI is obtained from the electronic medical record and if not 
available from the electronic medical record than physician operating room schedules 
will be used to determine eligibility. The attending physician will be emailed by a 
research assistant regarding the patient’s eligibility for the study. Attending physician 
emails will be obtained from a Washington University ListServs. During their 
preoperative or anesthesia appointment, the patient will receive a pre-surgical packet 
which is given to all patients undergoing gynecologic surgery at Washington University. 
This packet will include a brief description (Appendix A) of the study and contact 
information to reach a member of the research team who will be available if the patient 
should have any questions about the study. At either of these appointments, or otherwise 
on the day of surgery, a member of the research and surgical team will discuss the study 
with the patient and assess their willingness to be enrolled in the study. It will be 
emphasized to the patients that other than receiving antibiotics or not there will be no 
differences in their medical care regardless of whether they choose to participate in this 
study. All potential participants will be given the opportunity to have all of their 
questions regarding the research study answered prior to making a decision to participate.  
 
If the patient consents to the study an informed consent form will be signed with the 
patient at any of these encounters and she will be given a copy of the signed, dated 
consent. The PI and designated members of the research team will complete informed 
consent with participants.  
 
We are not offering any incentives or financial remuneration for participation in the 
study.  Patients who decline participation will receive prophylactic antibiotics as deemed 
appropriate by their attending surgeons. 
 
A 1:1 randomization will be done by computerized random number generation by 
Department of Biostatistics at Washington University in St. Louis using REDCap. 


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Randomization will occur on the day of surgery following confirmation of eligibility as 
outlined in Section 4.1. The Principal Investigator or designated sub-investigators will 
review, sign, and date the eligibility checklist. On the day of surgery the research 
assistant or designated team member will verify the remaining eligibility, negative urine 
HCG test within 7 days of surgery. 
 
The research team members working on this study have experience reviewing laboratory 
results in the electronic medical record and will confirm the negative urine HCG test 
when required. The research assistant will then document the results in a source 
document that will remain in the patient's research record. Once a participant consents to 
be enrolled in the study and is deemed eligible, the research assistant will randomize the 
patient using REDCap.   
 
The principal investigator along with all members of the study team involved in data 
analysis as well as the patients will be blinded to the randomization group. The patients 
will not be aware if they receive antibiotics given the antibiotics are flushed through the 
patient’s IV line which they will have regardless of their assigned study arm. The 
research assistant will disclose the randomization group to the anesthesiologist who will 
screen the patient for allergies and then obtain the appropriate antibiotics from the 
pharmacy and administer the antibiotics as appropriate. These will be administered prior 
to the procedure and so the surgeon will remain blinded to the administration. Standard 
practice regarding antibiotic prophylaxis is not clear, and therefore some surgeons use 
antibiotics preoperative and some do not. Thus, this study will not result in increased cost 
to the patient.  
 
5.0 
RESEARCH/TREATMENT PLAN 
 
5.1 
Intervention 
 
The administration of preoperative prophylactic antibiotics will be as per the 
randomization protocol. Women randomized to prophylactic antibiotics will receive a 
cefazolin as per ACOG guidelines. If she has a penicillin allergy then clindamycin will be 
used. Prophylactic antibiotics should be administered prior to skin incision. A traditional 
surgical timeout will be performed. During the timeout it will be announced that the 
patient is on study. The surgeon will then turn to anesthesia and ask “whichever arm we 
are randomized to are we okay to proceed?”. Once the anesthesia team answers yes 
indicating the antibiotics have been infused if appropriate, the surgical procedure will 
then be performed in the normal fashion. The skin and subcutaneous tissues will be 
opened either with a scalpel or with Bovie electrocautery on cutting current. Closure of 
subcutaneous tissue and skin will be performed at the discretion of the attending surgeon. 
Suturing will be performed under the supervision of the attending, fellow, or a member of 
the surgical team considered to have received appropriate training. At the time of surgery 
an operative data collection sheet (Appendix B) will be filled out by the surgeon 
collecting information on number of incision(s), method of incision and skin closure, 
suture used, if the subcutaneous tissue is closed,if local anesthesia was used, and if so, the 
type and when injection was placed (before incision or after closure).  


Protocol Version: 09/10//2020 
 
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5.2 
Patient Follow-up 
 
The patient will be discharged the day of surgery per standard practice.  
 
 
A standardized physical examination of the wound will be performed by a healthcare 
provider at the postoperative visit 7-30 days postoperatively. Data from the patient’s 
physical exam assessment (Appendix C) and administered patient survey (Appendix D) 
will be collected at this postoperative visit. If a patient is admitted to the hospital at the 
time of her scheduled clinic follow-up, the physical exam, assessment and surveys will be 
administered as an inpatient as per the protocol. The required follow-up data will be 
collected in telephone calls and/or at clinic visits until 30(+/- 10) days postoperatively. If 
patients present greater than 40 days postoperatively they will be considered lost to 
follow-up. All data from admissions to outpatient facilities prior to 30(+/- 10) days 
postoperatively will be included in our analysis. 
 
5.3 
Women of Childbearing Potential 
 
Women of childbearing potential (defined as women with regular menses, women with 
amenorrhea, women with irregular cycles, women using a contraceptive method that 
precludes withdrawal bleeding and women who have had a tubal ligation) are required to 
have a negative serum/urine pregnancy test within seven days of surgery.  
 
5.4 
Duration of Therapy 
 
If at any time the constraints of this protocol are considered to be detrimental to the 
patient’s health and/or the patient no longer wishes to continue the study, involvement in 
the study should be discontinued and the reason(s) for discontinuation documented 
appropriately.  
 
Follow-up assessment may continue for 30 days (+/- 10) after surgery or until one of the 
following criteria applies: 
 
• Death 
• Loss to follow-up 
• Patient withdraws consent 
• Investigator removes the patient from study 
• The Siteman Cancer Center decides to close the study 
 
Patients who prematurely discontinue treatment for any reason will be followed as per 
standard of care for a postoperative patient. 
 
6.0 
REGULATORY AND REPORTING REQUIREMENTS 
 
6.1 
Definitions 
 
6.1.1 Adverse Events (AEs) 


Protocol Version: 09/10//2020 
 
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Definition: any unfavorable medical occurrence in a human subject including any 
abnormal sign, symptom, or disease. 
 
Grading: the descriptions and grading scales found in the revised NCI Common 
Terminology Criteria for Adverse Events (CTCAE) version 4.0 will be utilized for 
all toxicity reporting.  A copy of the CTCAE version 4.0 can be downloaded from 
the CTEP website. 
 
Attribution (relatedness), Expectedness, and Seriousness: the definitions for the 
terms listed that should be used are those provided by the Department of Health 
and Human Services’ Office for Human Research Protections (OHRP).  A copy of 
this guidance can be found on OHRP’s website: 
http://www.hhs.gov/ohrp/policy/advevntguid.html 
 
6.1.2 Serious Adverse Event (SAE) 
 
Definition:  any adverse drug experience occurring at any dose that results in any 
of the following outcomes: 
o Death 
o A life-threatening adverse drug experience 
o Inpatient hospitalization or prolongation of existing hospitalization 
o A persistent or significant disability/incapacity (i.e., a substantial disruption 
of a person’s ability to conduct normal life functions) 
o A congenital anomaly/birth defect 
o Any other experience which, based upon appropriate medical judgment, 
may jeopardize the subject and may require medical or surgical intervention 
to prevent one of the outcomes listed above 
 
All unexpected SAEs must be reported to the FDA. 
 
6.1.3 Unexpected Adverse Experience 
 
Definition: any adverse drug experience, the specificity or severity of which is not 
consistent with the current investigator brochure (or risk information, if an IB is not 
required or available). 
 
Events that are both serious AND unexpected must be reported to the FDA.  
 
6.1.4 Life-Threatening Adverse Experience  
 
Definition: any adverse drug experience that places the subject (in the view of the 
investigator) at immediate risk of death from the reaction as it occurred, i.e., it does 
not include a reaction that, had it occurred in a more severe form, might have caused 
death. 
 


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Life-threatening adverse experiences must be reported to the FDA. 
 
6.1.5 Unanticipated Problems 
 
Definition: 
 
• unexpected (in terms of nature, severity, or frequency) given (a) the research 
procedures that are described in the protocol-related documents, such as the 
IRB-approved research protocol and informed consent document; and (b) 
the characteristics of the subject population being studied; 
• related or possibly related to participation in the research (“possibly related” 
means there is a reasonable possibility that the incident, experience, or 
outcome may have been caused by the procedures involved in the research); 
and 
• suggests that the research places subjects or others at a greater risk of harm 
(including physical, psychological, economic, or social harm) than was 
previously known or recognized. 
 
6.1.6 Noncompliance 
 
Definition: failure to follow any applicable regulation or institutional policies that 
govern human subjects research or failure to follow the determinations of the 
IRB.  Noncompliance may occur due to lack of knowledge or due to deliberate 
choice to ignore regulations, institutional policies, or determinations of the IRB. 
 
6.1.7 Serious Noncompliance 
 
Definition: noncompliance that materially increases risks, that results in substantial 
harm to subjects or others, or that materially compromises the rights or welfare of 
participants. 
 
6.1.8 Protocol Exceptions 
 
Definition: A planned deviation from the approved protocol that are under the 
research team’s control. Exceptions apply only to a single participant or a singular 
situation. 
 
IRB Pre-approval of all protocol exceptions must be obtained prior to the event.   
 
6.2 
Reporting to the Human Research Protection Office (HRPO) at Washington 
University 
 
The PI is required to promptly notify the IRB of the following events: 
 


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• Any unanticipated problems involving risks to participants or others which occur 
at WU, any BJH or SLCH institution, or that impacts participants or the conduct of 
the study. 
• Noncompliance with federal regulations or the requirements or determinations of 
the IRB. 
• Receipt of new information that may impact the willingness of participants to 
participate or continue participation in the research study. 
 
These events must be reported to the IRB within 10 working days of the occurrence of the 
event or notification to the PI of the event.  The death of a research participant that qualifies 
as a reportable event should be reported within 1 working day of the occurrence of the 
event or notification to the PI of the event. 
 
6.3 
Reporting to the Quality Assurance and Safety Monitoring Committee 
(QASMC) at Washington University 
 
The PI is required to notify the QASMC of any unanticipated problem occurring at WU or 
any BJH or SLCH institution that has been reported to and acknowledged by HRPO as 
reportable.  (Unanticipated problems reported to HRPO and withdrawn during the review 
process need not be reported to QASMC.) 
 
QASMC must be notified within 10 days of receipt of IRB acknowledgment via email to 
a QASMC auditor. 
 
6.4 
Reporting to [DRUG MANUFACTURER] 
 
Not applicable. 
 
6.5 
Reporting to the Institutional Biosafety Committee 
 
Not applicable. 
 
6.6 
Reporting to the FDA 
 
The conduct of the study will comply with all FDA safety reporting requirements.  
PLEASE NOTE THAT REPORTING REQUIREMENTS FOR THE FDA DIFFER 
FROM REPORTING REQUIREMENTS FOR HRPO/QASMC.  It is the 
responsibility of the principal investigator to report any unanticipated problem to the FDA 
as follows: 
 
• Report any unexpected fatal or life-threatening adverse experiences (Section 7.1.4) 
associated with use of the drug (i.e., there is a reasonable possibility that the 
experience may have been caused by the drug) by telephone or fax no later than 7 
calendar days after initial receipt of the information.   


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• Report any serious, unexpected adverse experiences (Section 7.1.2), as well as 
results from animal studies that suggest significant clinical risk within 15 calendar 
days after initial receipt of this information.  
All MedWatch forms will be sent by the investigator or investigator’s team to the FDA at 
the following address or by fax: 
 
Food and Drug Administration 
Center for Drug Evaluation and Research 
Division of Oncology Drug Products 
5901-B Ammendale Rd. 
Beltsville, MD 20705-1266 
FAX: 1-800-FDA-0178 
 
6.7 
Timeframe for Reporting Required Events  
 
Adverse events will be tracked for 30 days following the last day of study treatment.  For 
the purposes of this protocol, reportable adverse events are allergic reaction to either 
cefazolin or clindamycin.    
 
Deaths 
Any reportable death while on study or within 30 days of 
study 
Immediately, within 24 
hours, to PI and the IRB  
Any reportable death while off study  
Immediately, within 24 
hours, to PI and the IRB  
Adverse Events/Unanticipated Problems 
Any reportable adverse events as described in Sections 
6.1 and 6.2 (other than death)  
Immediately, within 24 
hours to PI and within 10 
working days to the IRB  
All adverse events regardless of grade and attribution 
should be submitted cumulatively  
Include in DSM report 
Noncompliance and Serious Noncompliance 
All noncompliance and serious noncompliance as 
described in Sections 6.3 and 6.4 
Immediately, within 24 
hours, to PI and within 10 
working days to the IRB  
 
 
 
 
 
 


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7.0 
STUDY CALENDAR 
 
Within 7 
days prior to 
enrollment 
Preoperative surgery 
holding area or 
preoperative/anesthesia 
appointment 
Day of Surgery 
7-30 days after 
surgery 
30(+/- 10) days 
after surgery 
Negative 
urine/ blood 
HCG test (for 
WOCBP) 
Consent form signed 
Randomization/Antibiotic 
Administration 
Evaluation in clinic 
Follow-up in EMR 
for wound 
complications and 
adverse events 
 
 
Data collection sheet 
Assessment of 
wound for infection 
or separation 
 
 
 
Collection of adverse 
events at time of 
antibiotic administration 
Completion of 
patient survey 
 
 
 
 
Evaluation for 
adverse events 
 
 
8.0 
DATA SUBMISSION SCHEDULE 
 
Case report forms with appropriate source documentation will be completed according to the 
schedule listed in this section. 
 
Forms 
Submission Schedule 
Original Consent Form 
Prior to registration 
Registration Form 
Eligibility Form 
On-Study Form 
Prior to starting treatment 
Day of Surgery Data Collection Form 
(Appendix B) 
After surgery 
2-week follow-up data collection form 
(Appendix C) 
Postoperative appointment (7-30 days 
postop) 
Vulvar Hygiene Survey (Appendix D) 
Postoperative appointment (7-30 days 
postop) 
30 day postoperative follow-up form  
30(+/- 10) days postoperative follow-up 
Adverse Event Forms 
Entire Study Period 
 
9.0 
MEASUREMENT OF EFFECT 
 
The purpose of this study is to assess for differences in wound outcomes between women receive 
prophylactic antibiotics and those who do not. The primary outcome will be a composite of wound 
complications, which will include wound infection or disruption within 30(+/- 10) days following 
surgery. This rate will be calculated as a composite from the postoperative follow-up forms as well 
as from chart review of the electronic medical record including up to 30 (+/- 10) days 


Protocol Version: 09/10//2020 
 
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postoperatively.  We will assess to see the wound complication rate is lower in either of these 
groups and as such should become the standard of care.   
 
Secondary outcomes will include determining clinical risk factors that correlate with vulvar wound 
complications as well as evaluating patient understanding of vulvar hygiene and its effect on 
wound complications. Lastly, we attempt to secondarily describe adverse events occurred in 
response to prophylactic antibiotic use. 
 
10.0 
DATA AND SAFETY MONITORING 
 
In compliance with the Washington University Institutional Data and Safety Monitoring Plan, the 
Principal Investigator will provide a Data and Safety Monitoring (DSM) report to the Washington 
University Quality Assurance and Safety Monitoring Committee (QASMC) semi-annually 
beginning six months after accrual has opened (if at least five patients have been enrolled) or one 
year after accrual has opened (if fewer than five patients have been enrolled at the six-month mark). 
 
The Principal Investigator will review all patient data at least every six months, and provide a 
semi-annual report to the QASMC. This report will include: 
• HRPO protocol number, protocol title, Principal Investigator name, data coordinator 
name, regulatory coordinator name, and statistician 
• Date of initial HRPO approval, date of most recent consent HRPO approval/revision, 
date of HRPO expiration, date of most recent QA audit, study status, and phase of study 
• History of study including summary of substantive amendments; summary of accrual 
suspensions including start/stop dates and reason; and summary of protocol exceptions, 
error, or breach of confidentiality including start/stop dates and reason 
• Study-wide target accrual and study-wide actual accrual 
• Protocol activation date 
• Average rate of accrual observed in year 1, year 2, and subsequent years 
• Expected accrual end date  
• Objectives of protocol with supporting data and list the number of participants who 
have met each objective 
• Measures of efficacy 
• Early stopping rules with supporting data and list the number of participants who have 
met the early stopping rules 
• Summary of toxicities  
• Abstract submissions/publications 
• Summary of any recent literature that may affect the safety or ethics of the study  
 
The study principal investigator will monitor for serious toxicities on an ongoing basis. Once the 
principal investigator or Research Patient Coordinator becomes aware of an adverse event, the AE 
will be reported to the HRPO and QASMC according to institutional guidelines. 
 
 
 
 
 


Protocol Version: 09/10//2020 
 
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11.0 
STATISTICAL CONSIDERATIONS 
 
11.1 
Study design overview: This study is designed as a randomized phase II clinical 
trial. This design will provide a direct assessment of the null hypothesis that there 
is no improvement in vulvar wound complication rates associated with antibiotic 
prophylaxis. All patients on this study will be randomized by the clinical research 
staff of the Division of Gynecologic Oncology.  The sequence of treatment 
assignments will be concealed from the patients, the surgeons, the Principal 
Investigator, and the research staff performing the analysis. Blocked 
Randomization with equal probabilities to the two treatment regimens will be 
carried out following study registration.   
 
Randomization will not be stratified by any factors.   
 
12.0 
Data collection: The principal parameters to be collected, analyzed and reported to 
determine the relative efficacy of the two treatment regimens are: 
12.1.1 Outcome measure: Wound disruption or infection occurring within 30(+/- 10) 
days of the primary surgery.  Incidence of wound infection (defined as purulent 
drainage, cellulitis, abscess or a wound that requires drainage, debridement or 
antibiotics associated with a clinical diagnosis of infection). Demographic factors 
as well as secondary outcomes such as hospital readmission, antibiotic safety 
measures will be collected. Data regarding vulvar hygiene will be obtained from 
patient surveys.   
 
12.2 
Accrual rate, sample size and duration: According to institutional data about 60 
patients undergo simple vulvectomy or wide local excision for benign or 
premalignant indications annually. We anticipate it will take approximately one 
year to accrue the 50 evaluable patients necessary for this pilot trial. This accounts 
for the possibly number of refusals and screen failures.   
 
12.3 
Hypotheses, planning parameters, and sample size justification:  
 
Primary hypothesis: This study will determine the effectiveness of antibiotic 
prophylaxis in reducing the rate of SSI after a vulvar excision for a premalignant 
lesion. We hypothesize that women who receive antibiotic prophylaxis will have 
lower rates of composite wound complications than their counterparts who do not 
receive antibiotics. The design of this study will provide evidence of benefit with 
regard to wound complication rate.   
 
Planning parameters: The patient population selected for this study is all women 
undergoing vulvar surgery for benign or premalignant lesions.  
 
Sample size justification: The total sample size of the pilot study is 50 evaluable 
women (prophylactic antibiotics, n=25 vs. no antibiotics, n=25) to provide 
preliminary data for grant funding for a large adequately powered RCT. This 
study will be a pilot study to evaluate actual rates of wound complications and 


Protocol Version: 09/10//2020 
 
Page 20 of 25 
how long it takes to recruit 50 patients. Based on our prior analysis, we see an 
average of 53-55 patients per year who meet our study criteria. Ultimately we 
estimate a sample size of 293 women per group will be needed for 80% power to 
detect a clinically meaningful 33% difference in wound complication rates 
between study groups. See trial design in section 11.5. 
 
12.4 
Trial design and Statistical analyses:  
 
The null hypothesis is that there is no improvement in wound complication rate 
associated with antibiotic prophylaxis (H0: p_antibiotic-p_noantibiotic=0), where 
p stands for wound complication rate. The one-sided alternative hypothesis is that 
there is improvement (Ha: p_antbiotic-p_noantibiotic < 0). Anecdotal evidence 
suggest up to a 35% decrease in wound complication rate association with 
prophylactic antibiotics. The power analysis is based on detecting a 33% 
reduction in wound complication rate from 30% (no antibiotic) to 20% 
(antibiotic) at a significance level of 0.05. 
 
In order to conduct the larger multicenter trial we propose a pilot study consisting 
of 50 evaluable women in order to establish the feasibility of our study.  
 
Statistical analysis:  
Statistical analysis will be performed by intention to treat analysis. However, if 
there are a large number of patients who are treated with prophylactic antibiotics 
off protocol or if patients follow-up greater than 30 days postoperatively we will 
perform a sensitivity analysis and will analyze per protocol.  
 
Descriptive statistics will characterize and investigate baseline clinical and surgical 
characteristics between groups as well as evaluate the difference in adverse events. 
Categorical factors will be compared between groups by using the Chi-squared or 
Fisher’s exact test as appropriate. Independent t-test and Mann-Whitney U-test will 
be used to compare normally and non-normally distributed continuous variables, 
respectively. The primary outcome will be compared between groups by using a 
Chi-squared test. We will calculate common relative risks and 95% confidence 
intervals associated with the primary outcome. All analyses will be performed using 
SAS version 9.4 (SAS Institute, Cary, NC). 
 
13.0 
REFERENCES 
 
1. 
Judson PL, Habermann EB, Baxter NN, Durham SB, Virnig BA. Trends in the incidence 
of invasive and in situ vulvar carcinoma. Obstetrics and gynecology. 2006;107(5):1018-22. 
2. 
ACOG Committee Opinion No. 509: Management of vulvar intraepithelial neoplasia. 
Obstetrics and gynecology. 2011;118(5):1192-4. 
3. 
ACOG Practice Bulletin No. 74. Antibiotic prophylaxis for gynecologic procedures. 
Obstetrics and gynecology. 2006;108(1):225-34. 


Protocol Version: 09/10//2020 
 
Page 21 of 25 
4. 
Mittendorf R, Aronson MP, Berry RE, Williams MA, Kupelnick B, Klickstein A, et al. 
Avoiding serious infections associated with abdominal hysterectomy: a meta-analysis of 
antibiotic prophylaxis. American journal of obstetrics and gynecology. 1993;169(5):1119-24. 
5. 
Ayeleke RO, Mourad S, Marjoribanks J, Calis KA, Jordan V. Antibiotic prophylaxis for 
elective hysterectomy. The Cochrane database of systematic reviews. 2017;6:Cd004637. 
6. 
Sawaya GF, Grady D, Kerlikowske K, Grimes DA. Antibiotics at the time of induced 
abortion: the case for universal prophylaxis based on a meta-analysis. Obstetrics and gynecology. 
1996;87(5 Pt 2):884-90. 
7. 
Gaarenstroom KN, Kenter GG, Trimbos JB, Agous I, Amant F, Peters AA, et al. 
Postoperative complications after vulvectomy and inguinofemoral lymphadenectomy using 
separate groin incisions. International journal of gynecological cancer : official journal of the 
International Gynecological Cancer Society. 2003;13(4):522-7. 
8. 
Wills A, Obermair A. A review of complications associated with the surgical treatment of 
vulvar cancer. Gynecologic oncology. 2013;131(2):467-79. 
9. 
Janda M, Obermair A, Cella D, Perrin LC, Nicklin JL, Ward BG, et al. The functional 
assessment of cancer-vulvar: reliability and validity. Gynecologic oncology. 2005;97(2):568-75. 
10. 
Idsoe O, Guthe T, Willcox RR, de Weck AL. Nature and extent of penicillin side-
reactions, with particular reference to fatalities from anaphylactic shock. Bulletin of the World 
Health Organization. 1968;38(2):159-88. 
 
14.0 
Acknowledgements 
 
We would like to thank the Alvin J. Siteman Cancer Center at Washington University School of 
Medicine and Barnes-Jewish Hospital in St. Louis, Missouri, for the use of the Clinical Trials 
Core which provided statistical services. The Siteman Cancer Center is supported in part by an 
NCI Cancer Center Support Grant #P30 CA91842. 
 
 


Protocol Version: 09/10//2020 
 
Page 22 of 25 
Appendix A 
Washington University School of Medicine 
Division of Gynecologic Oncology  
 
Does antibiotic prophylaxis reduce wound complications after vulvar excision of 
premalignant lesions:  
A Double-Blinded Randomized Controlled Trial 
 
We are currently studying the use of antibiotics to decrease wound complication rates in women 
undergoing vulvar surgery for noncancerous indications. Given the location of this surgery we 
know women who undergo vulvar surgery are at a high risk for wound complications after 
surgery including wound infections and skin separations which can require special care for 
closure, including special dressings, nursing care and sometimes antibiotics.  This represents a 
burden for patients, and family members who assist with wound care. Receiving antibiotics prior 
to your surgery may lead to a decreased complication rates. As such, we are performing a study 
to determine if our patients would benefit from the use of preoperative, preventative antibiotics. 
 
All women, age 18 and older, undergoing vulvar surgery for a noncancerous indication are 
eligible for this study.  If you choose to participate in this study you will be randomly assigned to 
receive antibiotics or not.  Prior to skin closure we will measure the length and depth of your 
incision.  Other than these two interventions there will be no other changes from the routine 
management. 
 
If you choose not to participate in this study you will receive antibiotics at the discretion of your 
surgeon and you will receive routine operative and postoperative care. 
 
There is no financial charge to participate in this study nor is there financial compensation for 
participation.  
 
If you have any questions please contact one of the members of our research staff:  Zuhra 
Korkutovic at (314) 273-1580. 
 
Thank you very much, 
 
 
Mary Mullen, M.D. 
 


Protocol Version: 09/10//2020 
 
Page 23 of 25 
Appendix B – Day of Surgery Data Collection Sheet  
 
Date of surgery: ____/_____/____ 
Patient ID _________ 
Did the attending surgeon know whether the patient received antibiotics? Yes 
No 
Number of Incision(s): ____________ 
What did you use to make the skin incision (circle one only)? 
A) Scapel 
B) Bovie electrocautery 
C) Other _______________________ 
Subcutaneous Tissue Closed Yes 
No 
Was the skin closed with single interrupted stitches? Yes  No 
 
If no, how did you close the incision(s)?_______________________________ 
Skin incision closed with what kind of suture ______________ 
Local anesthesia used? 
Yes 
No 
 
If yes, type of local anesthesia used _______________________ 
 
If yes, injection placed (circle appropriate) Before incision 
After Closure 
 
 
 
 
 
 
 
 
 
 
 
 
 
 


Protocol Version: 09/10//2020 
 
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Appendix C – 2-week Follow-up Data Collection Sheet  
Patient ID _________ 
Date of Follow-up visit ____________ 
Wound Separation 
Yes 
No 
Length of Separation ____________ 
Width of Separation _____________ 
Depth of Separation _____________ 
WTD Dressing 
Yes 
No 
Wound Vac 
Yes 
No 
Infection 
Yes 
No 
Erythema 
Yes 
No 
Seroma 
Yes 
No 
Hematoma 
Yes 
No 
Purulent Drainage 
Yes 
No 
Postoperative Antibiotics 
Yes 
No 
If antibiotics, which one _______________  
PO 
IV 
Hospital Admission for Wound 
Yes 
No 
Wound Culture Sent Yes 
No 
Need for Debridement 
Yes 
No 
Postoperative Fever  
Yes 
No 
 
 
 


Protocol Version: 09/10//2020 
 
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Appendix D. Vulvar Hygiene Survey (Patient) 
Subject ID: 
                                           
Date: 
Vulvar Hygiene Survey 
Have you heard of vulvar hygiene or vulvar wound care prior to today? 
 YES     
NO 
PRIOR TO SURGERY…  Date of surgery: ____/____/______ 
Did your doctor instruct you about vulvar wound care?      
 
 YES     
NO 
Did your doctor talk about sitz baths? 
 
 
 
     
 YES     
NO 
How many times a day should you do sitz baths or cleanse with a showerhead after surgery? 
 1 
       2            3            4 
Did your doctor talk about keeping your vulva dry?  
     
 
 YES     
NO 
Did your doctor talk about cleaning your vulva after urination or bowel movement?   
YES     
NO 
Did you make it a point not to regularly sit and to lie/stand when possible?  
    
 YES     
NO 
AFTER SURGERY…  Date of post-op survey ____/____/_____ 
Did you regularly perform vulvar wound care? 
 
 
 
 YES    
NO 
Did you perform sitz baths or cleanse with a showerhead two-three times a day?  
 
     
 
 
 
 
 
 
 
 
 
 
 YES    
NO 
 
If yes, how many days did you do this?  
____________________________ 
Did you actively keep your vulva dry? 
 
 
 
 
 YES    
NO 
If yes, how many days did you do this?  
____________________________ 
Did you clean your vulva after urinating or having a bowel movement? 
 YES    
NO 
If yes, how many days did you do this?  
____________________________ 
If yes, how many days did you do this?  
____________________________