A Feasibility Trial of Alternating Intravaginal Application of 5-Fluorouracil and Imiquimod for Treatment of High-Grade Cervical Squamous Intraepithelial Lesions
Phase: EARLY_PHASE1
Conditions: Cervical Intraepithelial Neoplasia Grade 2/3, Cervical Squamous Cell Carcinoma In Situ, Cervical Squamous Intraepithelial Neoplasia 2, High Grade Cervical Intraepithelial Neoplasia
Sponsor: National Cancer Institute (NCI)

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COVER PAGE 
 
 
 
 
 
DCP Protocol #: 
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A feasibility trial of alternating intravaginal application of 5-fluorouracil and imiquimod for treatment of 
high-grade cervical squamous intraepithelial lesions 
 
Consortium Name: 
 
 
The University of Arizona Early Phase Cancer Prevention Consortium  
Name of Consortium Principal  
H-H Sherry Chow, PhD 
Investigator:  
 
 
University of Arizona Cancer Center 
 
 
 
 
 
1515 N. Campbell Ave. 
 
 
 
 
 
Tucson, AZ 85724 
 
 
 
 
 
Telephone: (520) 626-3358:  
 
 
 
 
 
Fax: (520) 626-5348 
 
 
 
 
 
schow@azcc.arizona.edu  
 
 
 
 
 
*No participant accrual occurs at this site  
 
Organization Name:  
 
University of North Carolina School of Medicine  
Protocol Principal Investigator: Lisa Rahangdale, MD, MPH 
 
 
 
 
 
Obstetrics & Gynecology 
 
 
 
 
 
3031 Old Clinic Bldg 
 
 
 
 
 
CB #7570 
 
 
 
 
 
Chapel Hill, NC 27599 
 
 
 
 
 
Telephone: 919-843-7851  
 
 
 
 
 
Fax: 919-966-6001 
 
 
 
 
 
lisa_rahangdale@med.unc.edu 
 
Organization:  
 
 
University of North Carolina School of Medicine 
Investigator:  
 
 
Siobhan O’Connor, MD 
 
 
 
 
 
Pathology and Laboratory Medicine 
 
 
 
 
 
101 Manning Dr, CB # 7525 
 
 
 
 
 
Chapel Hill, NC 27599 
 
 
 
 
 
Telephone:  984-974-9154 
 
 
 
 
 
Fax: 984-974-9177 
 
 
 
 
 
Siobhan.O’Connor@unchealth.unc.edu 
 
Organization:   
 
 
University of California-Los Angeles  
Investigator:  
 
 
Anna Barbara Moscicki, MD 
 
 
 
 
 
Professor of Pediatrics 
 
 
 
 
 
10833 Le Conte Avenue, 22-432 MDCC 
 
 
 
 
 
Los Angeles, CA 90095 
 
 
 
 
 
Telephone: (310) 206-6345 
 
 
 
 
 
Fax: (310) 206-4855 
 
 
 
 
 
amoscicki@mednet.ucla.edu 
 
 
 
 
     *No participant accrual occurs at this site 
 
Organization:  
 
 
University of Arizona 
Statistician: 
 
 
 
Paul Hsu, PhD 
 
 
 
 
 
The University of Arizona Cancer Center 
 
1515 N. Campbell Ave. 
 
Tucson, AZ 85724 
 
Telephone: (520) 626-5054 

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 Fax: (525) 626-2767 
 
pchhsu@email.arizona.edu 
 
Organization: 
 
Division of Cancer Prevention 
Scientific Monitor: 
 
Vikrant Sahasrabuddhe, MBBS, MPH, DrPH 
 
 
Program Director 
 
 
Breast and Gynecologic Cancer Research Group 
 
 
9609 Medical Center Dr.  
 
 
Rockville, MD 20850 
Tel: (240) 276-7332 
Email: sahasrabuddhevv@mail.nih.gov    
 
Medical Monitor: 
Edward Sauter, MD, PhD 
Breast and Gynecologic Cancer Research Group 
Division of Cancer Prevention 
9609 Medical Center Dr., Rm 5E326 
Bethesda, MD 20892-9783 
Phone: (240)276-7657 
Email: edward.sauter@nih.gov 
 
IND Sponsor:  
 
 
DCP 
 
IND#  
 
 
 
 
  
Agent(s)/Supplier: 
 
 
5-fluorouracil and imiquimod/commercial sources 
 
NCI Contract # 
 
 
HHSN2612012000311 
 
Protocol Version Date: 
 
04/9/2020 
 
Protocol Revision or   
Amendment #  
 
Version 3, Amendment 11 
 
 
 
 
 
 
 
 
 
 
 

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 SCHEMA  
 
A feasibility trial of alternating intravaginal application of 5-fluorouracil and imiquimod for treatment of 
high-grade cervical squamous intraepithelial lesions 
 
Women with biopsy-confirmed high grade cervical squamous intraepithelial lesions (i.e., CIN3 lesions, and p16-
immunohistochemistry-positive CIN2 lesions) 
 
Screening/Consenting Visit 
Informed consent, medical history, conmeds, baseline signs and symptoms, Karnofsky performance status, height, weight, vital signs, 
blood and urine collection for clinical laboratory tests, urine pregnancy test 
 
Baseline Visit  
Colposcopy with digital imaging of the cervix 
Cervical specimen, blood, and urine collection for research endpoints 
Weight, vital signs, urine pregnancy test, conmeds, adverse event (AE) evaluation, tobacco and alcohol assessment 
 dispense 5-fluorouracil for 4 applications 
 
Agent Intervention*  
•  Applications of intravaginal 5-fluorouracil (5%) self-administered once every other week (Initiation phase: weeks 1, 3, 5, 7; If 
optional extension phase: weeks 9, 11, 13, 15**) 
• Applications of intravaginal imiquimod cream 5% provider-administered once every other week (Initiation phase: weeks 2, 4, 
6, 8; If optional extension phase: weeks 10, 12, 14, 16**) 
 
Regular contact  
Alternating weekly reminder of 5-flurouracil application and  
for AE and compliance evaluation 
 
 
Clinic visits for imiquimod application  
(Initiation phase: weeks 2, 4, 6, 8; Optional extension phase: weeks 10, 12, 14, 16**)   
Colposcopy with digital imaging of the cervix (and further management if evidence of disease progression) 
Application of imiquimod by provider, collect unused agents 
Weight, vital signs, urine pregnancy test, concomitant medications, AE evaluation 
 
Additional procedures at week 8 visit only if continuing into optional extension phase**:  
Blood for clinical labs, cervical specimen, blood, and urine collection for research endpoints 
 
 
End of Study Visit  
(4-6 weeks after last agent application) 
Weight, vital signs, urine pregnancy test, conmeds and AE evaluation, collect unused agents 
Blood for clinical labs, urine for urinalysis, cervical specimen, blood, and urine collection for research endpoints  
Tobacco and alcohol assessment 
Colposcopy with digital imaging of the cervix 
LEEP or cone biopsy or colposcopy directed biopsy, HPV testing, cytology, optional participant survey 
 
Follow-up 
Collect results from the follow-up cervical exams/procedures/tests (LEEP, biopsies, cytology, HPV) performed within 14 months after 
the End of Study Visit from the medical records. 
 
Endpoints 
• 
Primary: Feasibility  
• 
Secondary: histological regression, type-specific high risk HPV clearance, biomarkers of local immune activation  
 
*Agent application may be delayed until the end of menstrual cycle if application date occurs during menses. No dose will be applied any sooner 
than 7 days apart even in the setting of dose delay. **Participants will be offered option to participate in an optional extension phase for an additional 
8 weeks for a total intervention period of 16 weeks.  
 

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TABLE OF CONTENTS 
 
COVER PAGE .......................................................................................................................... 1 
SCHEMA ................................................................................................................................. 3 
1. 
OBJECTIVES................................................................................................................... 6 
1.1 
Primary Objectives..............................................................................................................................................6 
1.2 
Secondary Objectives..........................................................................................................................................6 
2. 
BACKGROUND............................................................................................................... 6 
2.1 
Cervical Cancer ...................................................................................................................................................6 
2.2 
5-Fluorouracil and Imiquimod ...........................................................................................................................7 
2.3  
Summary of Justification/Rationale...................................................................................................................8 
3. 
SUMMARY OF STUDY PLAN.......................................................................................... 9 
4. 
PARTICIPANT SELECTION ............................................................................................11 
4.1 
Inclusion Criteria...............................................................................................................................................11 
4.2 
Exclusion Criteria..............................................................................................................................................12 
4.3 
Inclusion of Women and Minorities ................................................................................................................13 
4.4 
Recruitment and Retention Plan.......................................................................................................................13 
5. 
AGENT ADMINISTRATION............................................................................................13 
5.1 
Dose Regimen and Dose Groups .....................................................................................................................13 
5.2 
5-Fluorouracil and Imiquimod Administration ...............................................................................................13 
5.3 
Run-in Procedures .............................................................................................................................................14 
5.4 
Contraindications ..............................................................................................................................................14 
5.5 
Concomitant Medications .................................................................................................................................14 
5.6 
Dose Modification.............................................................................................................................................15 
5.7 
Adherence/Compliance.....................................................................................................................................15 
6. 
PHARMACEUTICAL INFORMATION .............................................................................15 
6.1 
5-Fluoruracil and Imiquimod ...........................................................................................................................15 
6.2 
Reported Adverse Events and Potential Risks ................................................................................................15 
6.3  
Availability ........................................................................................................................................................16 
6.4 
Agent Distribution.............................................................................................................................................16 
6.5  
Agent Accountability ........................................................................................................................................16 
6.6 
Packaging and Labeling....................................................................................................................................17 
6.8 
Registration/Randomization .............................................................................................................................17 
6.9 
Blinding and Unblinding Methods...................................................................................................................17 
6.10 Agent Destruction/Disposal..............................................................................................................................17 
7. 
CLINICAL EVALUATIONS AND PROCEDURES .............................................................18 
7.1 
Schedule of Events............................................................................................................................................18 
7.2 
Baseline Testing/Prestudy Evaluation .............................................................................................................20 
7.3 
Evaluation During Study Intervention .............................................................................................................20 
7.4 
Evaluation at Completion of Study Intervention ............................................................................................21 
7.5 
Post-intervention Follow-up Period .................................................................................................................21 
7.6 
Methods for Clinical Procedures......................................................................................................................22 
8.  
CRITERIA FOR EVALUATION AND ENDPOINT DEFINITION.........................................22 
8.1 
Primary Endpoint ..............................................................................................................................................22 
8.2 
Secondary Endpoints ........................................................................................................................................22 
8.3 
Off-Agent Criteria .............................................................................................................................................22 
8.4 
Off-Study Criteria .............................................................................................................................................22 
8.5 
Study Termination.............................................................................................................................................23 
9. 
CORRELATIVE/SPECIAL STUDIES ................................................................................23 
9.1 
Rationale for Methodology Selection ..............................................................................................................23 
9.2 
Comparable Methods ........................................................................................................................................23 
10. 
SPECIMEN MANAGEMENT ...........................................................................................23 
10.1 Laboratories .......................................................................................................................................................23 
10.2 Collection and Handling Procedures ...............................................................................................................23 
10.3 Shipping Instructions ........................................................................................................................................25 
10.4 Tissue Banking ..................................................................................................................................................25 

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11. 
REPORTING ADVERSE EVENTS ....................................................................................25 
11.1 Adverse Events..................................................................................................................................................26 
11.2 Serious Adverse Events ....................................................................................................................................27 
12. 
STUDY MONITORING ...................................................................................................28 
12.1 Data Management .............................................................................................................................................28 
12.2 Case Report Forms............................................................................................................................................28 
12.3 Source Documents ............................................................................................................................................29 
12.4 Data and Safety Monitoring Plan .....................................................................................................................29 
12.5 Sponsor or FDA Monitoring ............................................................................................................................29 
12.6 Record Retention...............................................................................................................................................29 
12.7 Cooperative Research and Development Agreement (CRADA)/Clinical Trials Agreement (CTA) ..........29 
13. 
STATISTICAL CONSIDERATIONS .................................................................................29 
13.1 Study Design/Description.................................................................................................................................29 
13.2 Randomization/Stratification............................................................................................................................30 
13.3 Accrual and Feasibility .....................................................................................................................................30 
13.4 Primary Objective, Endpoint(s), Analysis Plan ..............................................................................................30 
13.5 Secondary Objectives, Endpoints, Analysis Plans ..........................................................................................31 
13.6 Reporting and Exclusions .................................................................................................................................31 
13.7 Evaluation of Toxicity ......................................................................................................................................31 
13.8 Evaluation of Response ....................................................................................................................................31 
13.9 Interim Analysis ................................................................................................................................................31 
13.10 Ancillary Studies ...............................................................................................................................................31 
14. 
ETHICAL AND REGULATORY CONSIDERATIONS ........................................................32 
14.1 Form FDA 1572 ................................................................................................................................................32 
14.2 Other Required Documents ..............................................................................................................................32 
14.3 Institutional Review Board Approval ..............................................................................................................32 
14.4 Informed Consent..............................................................................................................................................32 
14.5 Submission of Regulatory Documents ............................................................................................................33 
14.6 Other...................................................................................................................................................................33 
15. 
FINANCING, EXPENSES, AND/OR INSURANCE .............................................................33 
REFERENCES .........................................................................................................................33 
CONSENT FORM ....................................................................................................................36 
APPENDIX A ..........................................................................................................................49 
APPENDIX B ..........................................................................................................................50 
APPENDIX C ..........................................................................................................................62 
APPENDIX D ..........................................................................................................................71 
 
 
 
 
 
 
 

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1. 
OBJECTIVES 
 
1.1 
Primary Objectives  
Assess feasibility, evaluated based on safety and tolerability, of a combination agent intervention (once-weekly 
self-administered intravaginal application of 5-fluorouracil alternating with once-weekly provider-applied 
imiquimod) for treatment of high-grade cervical squamous intraepithelial lesions 
1.2 
Secondary Objectives  
1.2.1 
Assess efficacy of the combination agent intervention on cervical disease regression (endpoint based on histologic 
regression from high-grade lesions to low-grade or no lesions and clearance of high risk-HPV detection) between 
baseline and study exit visits. 
1.2.2 
Assess efficacy of the combination agent intervention on genotype-specific HPV clearance between baseline and 
study exit visits. 
1.2.3 
Assess efficacy of the combination agent intervention on biomarkers of local immune activation (measurement of 
changes in expression of Toll-like receptors (TLR) and T-regulatory cells and the levels of innate, immune 
mediating and proinflammatory cytokines with intravaginal 5-FU and imiquimod) between baseline and study exit 
visits.  
 
The study will also collect specimens for exploratory studies of vaginal microbiome, proteomics, and metabolomics to 
identify factors affecting histologic regression, HPV clearance, and immune activation. 
  
2. 
BACKGROUND 
 
2.1 
Cervical Cancer 
 
High-risk human papillomavirus (HR-HPV) infection is a precursor to cervical cancer, the leading cause of 
gynecologic cancer worldwide.1 HR-HPV genotypes 16 and 18 are associated with approximately 70% of cervical 
cancers.2 Roughly 25 million women in the U.S. are actively infected with HPV, and an estimated 80% of sexually active 
women will contract genital HPV by age 50.3 While most HR-HPV infections are transient, persistent HR-HPV infections 
are considered the most significant risk factor for the development of high-grade cervical intraepithelial lesions (CIN 2-3) 
and cancer.4 Long standing clinical practice has been to treat all high grade CIN similarly by recommending immediate 
treatment for all women regardless of age or risk factors. Current clinical guidelines recognize that the prevalence of HPV 
is high in young women (particularly in the 3rd decade of life) and that disease can be transient. 5 Therefore, intervals of 
follow up have been lengthened and options for observation of high grade CIN 2 lesions have been encouraged. 5 This 
approach has been implemented to decrease the over-treatment of women of childbearing age, which can put them at a 
higher risk for preterm delivery, pain, and bleeding.6-8  
 
Current screening for and management of cervical precancer is based on surveillance and destructive surgical 
therapy. Pap smear surveillance has significantly reduced the incidence of and mortality from cervical cancer by early 
identification of high-grade cervical intraepithelial lesions and preventative treatment through excisional or ablative 
surgical procedures.9 A large majority of women with low-grade CIN  (also known as CIN 1) regress to normal within 12-
36 months (Figure 1).10 Approximately 40-58% of CIN 2 lesions regress spontaneously, 30-35% persist, and 10-22% 
progress to CIN 3.10-13 More than 12% of women with CIN 3 will advance to invasive cancer over 5-10 years.14 A key 
variable in risk is age; young women are more likely to experience regression of cervical dysplasia. Therefore, current 
clinical guidelines suggest observation with Pap smears and colposcopies at 6 month intervals for “young women” with 
high-grade CIN.9 The term “young woman” is loosely defined as women planning future pregnancies.15  
 
Surgical therapy for high-grade cervical intraepithelial lesions includes cryotherapy, laser therapy, and excisional 
procedures within the cervical transformation zone.9 Excisional options consist of Loop Electrosurgical Excision 
Procedures (LEEP) or cold-knife-cone (CKC), which remove large biopsies (1-3 cm) from the cervical transformation 
zone. Although surgical therapy is highly successful in 90-95% of women, 5-16% of women with high-grade CIN will 
have a recurrence of disease within 5 years of an excisional procedure, with most recurring within 2 years of 
treatment.15,16 The exact reasoning for recurrence is unclear, although it may be because of residual disease,17 re-infection 

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Topical 5-FU induces regression of CIN 2 and has the potential to be an effective medical therapy. Our group 
hypothesized that low-frequency dosing of self-administered intravaginal  5-FU could serve as primary treatment of CIN 
2 in healthy women and avoid the side effects of prior dosing regimens. Our randomized controlled trial in 60 healthy 
women, aged 18-29 years, with CIN 2 demonstrated that women treated with a 16-week course of biweekly 5-FU (2 g 5% 
5-FU per application once every 2 weeks) were more likely to show disease regression (to CIN 1 or normal) than 
observation alone (84% 5-FU versus 52% control under the intent-to-treat analysis).34 A relative risk for disease 
regression of 1.62 [95% confidence interval (CI) 1.10, 2.56, (p ≤ 0.01)] was found between the 5-FU and observation 
arms. When histology, Pap smear, and HR-HPV results were combined, women in the 5-FU group were more likely to 
have all categories normal [RR = 2.25 (95% CI = 1.05, 5.09, p < 0.05)] compared with the observation group post-
treatment. Using a validated scale,35 48% of women in the intervention group reported a side effect (e.g. pain, bleeding, 
discharge, burning/itching/irritation, urinary concerns, other). No participants reported that symptoms caused interference 
with usual activities, and there were no moderate or severe side effects in the intervention group. Most (86%) participants 
reported feeling satisfied with the use of the 5-FU cream. This preliminary work provides valuable data for acceptability, 
feasibility, and efficacy regarding the use of 5-FU in young women with CIN 2. However, to test efficacy on cervical 
precancers overall, we propose we need to test this treatment in women with CIN 3 as well since they have no other 
alternatives to surgical therapy.  
 
Imiquimod 
Imiquimod functions at the TLR7 receptor to stimulate the innate immune system and lead to cytokine production, 
particularly interferon α, IL-6, and TNF-α. It is a treatment for genital warts and vulvar/vaginal dysplasia. It has also been 
studied as a medical therapy for high-grade squamous intraepithelial lesions.36-39 Imiquimod is typically used as a topical 
cream applied 3-7 times per week for 8 to 16 weeks. Local reactions can include erythema, pruritus, excoriation, erosion, 
edema, scabbing or crusting. Though used topically with minimal systemic absorption, imiquimod therapy can produce 
systemic reactions such as myalgia, headache, fatigue and nausea. A Cochrane Review of its use for treatment of external 
genital warts showed a higher rate of local reactions compared to placebo (RR 1.71, 95% CI 1.18 to 2.53; 5 trials, 1225 
participants) but no significant difference on systemic reactions compared to placebo (RR 0.91, 95% CI 0.63 to 1.32, 2 
trials, 313 participants).40 A review of its use in cervical, vulvar and vaginal dysplasia also described mild to moderate 
local and systemic side effects but overall a well-tolerated treatment by patients.41 
 
We wish to improve overall treatment success by adding imiquimod to the therapeutic regimen. Though there was a 
high rate of histologic regression in the 5-FU treated patients in our prior study, only 56% of women were HPV-negative 
after treatment.34 A randomized controlled trial conducted by Grimm et al. 36 showed that a 16-week course of dose 
escalating intravaginal imiquimod treatment in women with high-grade squamous intraepithelial lesions led to histologic 
regression and HPV clearance (73% versus 39%, p < 0.05 for histologic regression and 60% versus 14%, p < 0.05 for 
HPV clearance) similar to that observed in our 5-FU trial. The treatment regimen was more intensive than our 5-FU trial 
as it required increased dosing over time (one dose (6.25 mg imiquimod) per week for 2 weeks followed by 2 doses per 
week for 2 weeks and 3 doses per week for 12 weeks). More than 90% of participants in the imiquimod arm reported both 
local and systemic (flu-like symptoms and fatigue). 36 
 
Successful medical therapy for high-grade cervical intraepithelial lesions must suppress cellular proliferation within the 
cervical epithelium and promote a sufficient local immune response to suppress HR-HPV infection. Both 5-FU and 
imiquimod have similar efficacy as mono-therapies; however, ideal therapy is needed to achieve higher HR-HPV 
clearance. We propose that dual therapy with 5-FU and imiquimod is biologically rational: 5-FU’s mechanism of action is 
based on local cellular death; imiquimod’s mechanism of action is based on modulation of the host immune response. We 
propose that dual therapy with 5-FU and imiquimod allows for lower dose, less intensive treatment that will result in 
superior efficacy but fewer side effects for treatment of high-grade cervical intraepithelial lesions. 
 
2.3  
Summary of Justification/Rationale 
• 
Many young women need treatment for cervical disease and no conservative medical options are available. Based 
on the burden of disease, high likelihood of exposure to HPV, costs, and long-term consequences described 
above, alternatives to surgery are necessary.  

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• 
Successful medical therapy for high-grade cervical intraepithelial lesions must suppress cellular proliferation 
within the cervical epithelium and promote a sufficient local immune response to clear HR-HPV infection. Both 
5-FU and imiquimod have similar efficacy as mono-therapies. We propose that dual therapy with 5-FU and 
imiquimod would lead to improved efficacy because 5-FU’s mechanism of action is based on local cellular death 
whereas imiquimod’s mechanism of action is based on modulation of the host immune response. Successful 
medical therapy may also serve as (i) adjunct to excisional methods, or (ii) allow women to delay excisional 
therapy.    
• 
Due to lack of safety data of combining therapeutic agents on the cervix, we propose to conduct a Phase 1 study 
to evaluate the safety and tolerability of dual intravaginal therapy of 5-FU and imiquimod prior to conducting an 
efficacy trial. Both 5-FU and imiquimod are approved by the Federal Drug Administration (FDA) for other 
topical indications. 42,43 We hypothesize that dual therapy will not lead to significant increase side effects of either 
treatment individually. The anticipated improved side effect profile is primarily due to the lower dosing of both 
medications compared to usual treatment dosing for vaginal/vulvar dysplasia and genital warts. 
• 
We are limiting the study population to women younger than 45 years of age since less women are interested in 
childbearing after 45 years old and risks of cervical cancer increase in older age groups. 44 Additionally, as 
women become post-menopausal, vaginal dryness and atrophy may be associated with less tolerance of 
intravaginal therapies.45 
 
Increasing evidence suggests that tobacco and alcohol use are risk factors in the development of intraepithelial neoplasia 
and cancer. In addition, tobacco and alcohol use may adversely affect agent intervention, for example by altering the 
safety profile or metabolism of a drug. Standardized assessments of tobacco and alcohol use during clinical trials will aid 
in understanding the potential relationship between the use of these products and clinical endpoints or cancer prevention 
biomarkers. Therefore, NCI, DCP is including assessment of tobacco and alcohol use at baseline and follow-up, to 
determine the potential impact of tobacco and alcohol use on 1) treatment toxicity and symptom burden, and 2) the 
efficacy of treatment intervention.  
 
3. 
SUMMARY OF STUDY PLAN 
 
This is a pilot study in women aged 18-45 years with biopsy confirmed high-grade cervical intraepithelial lesions to assess 
the feasibility of once-weekly intravaginal application of 5-FU and imiquimod used on alternating weeks for 8 to 16 
weeks.  
 
The study will have two phases:  
1. Initiation phase, which will include 12 to 14 participants and applications of 5-FU and imiquimod on alternating 
weeks for 8 applications. Participants will self-administer intravaginal 5-FU (2 g of 5% 5-fluorouracil, Effudex) once 
every other week for a total of 4 applications (wks 1, 3, 5, 7)*. Participants will receive provider-applied 
commercially available imiquimod cream 5% (12.5 mg imiquimod in 250 mg cream) directly to the cervix once every 
other week for a total of 4 applications (wks 2, 4, 6, 8)*.  
2. Extension phase, which will include no more than the original 12 to 14 participants and continue their participation 
for applications of 5-FU and imiquimod on alternating weeks for 8 additional applications as described in the 
initiation phase. Participants will self-administer intravaginal 5-FU (2 g of 5% 5-fluorouracil, Effudex) once every 
other week for a total of 4 applications (wks 9, 11, 13, 15)*. Participants will receive provider-applied commercially 
available imiquimod cream 5% (12.5 mg imiquimod in 250 mg cream) directly to the cervix once every other week 
for a total of 4 applications (wks 10, 12, 14, 16)*.  
 
*Agent application may be delayed until the end of menstrual cycle if application date occurs during menses. No dose will 
be applied any sooner than 7 days apart even in the setting of dose delay.   
The projected accrual rate is 4/month.  
At the Screening/consenting Visit, participants will sign informed consent, sign medical records and tissue release form, 
undergo evaluation of medical history and concomitant medications, have a blood sample collected for complete blood 
count with differential (CBC with diff), comprehensive metabolic panel (CMP) and HIV test, and have a urine sample 
collected for urinalysis as well as tests on pregnancy, Chlamydia trachomatis, and Neiserria  Gonorrhea. Participants will 

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undergo a brief physical exam including weight, height, vital signs including temperature, blood pressure, and heart rate. 
Performance status will be collected. Participants will be given a symptom diary to record adverse events (AEs) during 
study participation. 
 
Participants who meet the eligibility assessment will return to the clinic for a Baseline Visit.  Vital signs will be collected 
including weight, temperature, blood pressure and heart rate. Urine will be collected for pregnancy test. Participants will 
complete tobacco and alcohol assessment forms. Adverse events and concomitant medications will be reviewed. 
Participants will undergo a colposcopic examination with digital imaging of the cervix and cervical specimen collection 
(cericovaginal lavage, swab of the cervix, swab of the vagina, and cervical brushing for research endpoints and banking). 
Blood and urine will be collected and banked for future research. Participants will receive education regarding 
intravaginal 5-FU self-application, condoms and contraception use, and scheduling information about study visits for 
imiquimod application. They will receive an initial supply of the following: intravaginal 5-FU preparation, condoms, and 
pregnancy test kits and instructions on agent application. The 5-FU will be supplied to participants in a commercially 
available tube with vaginal applicators for 4 applications. Participants will be taught how to remove the 5-FU cream from 
the tube to fill the applicator with 2 grams of the cream prior to each self-application. This method of application has been 
chosen in order to preserve the shelf-life of the commercially available 5-FU cream. Once the study agent has been 
applied, if needed, participants may apply lidocaine jelly or a topical protective barrier cream to the vulva or take oral 
ibuprofen to minimize vulvar irritation or pain. If a participant experiences an allergic reaction (swelling, rash, hives), she 
may use diphenhydramine and should notify the study physician. Use of these products will be recorded on the study 
calendar. 
 
Participants will self-apply 5-FU intravaginally on weeks 1, 3, 5, and 7. Study staff will contact participants via phone 
call, text, or email to remind them to use the 5-FU, to answer questions participants may have and to review AEs and 
concomitant medications. Participants will also be reminded to perform pregnancy testing prior to using the study 
medication with each dose, to avoid sexual activity for at least 48 hours after each application of study medication, and to 
use two forms of birth control including condoms and one other form of contraception when participating in sexual 
activity. Agent application will be delayed until the end of menstrual cycle if application date occurs during menses. No 
dose will be applied any sooner than 7 days apart even in the setting of dose delay. Participants will record study agent 
applications on a study calendar. If a safety concern is identified during the regular contact, participants will be asked to 
come in for an interim clinic exam.  
 
Participants will return to the clinic every other week (weeks 2, 4, 6, and 8) to assess safety and compliance and for 
provider application of imiquimod. Prior to study visits, participants will be reminded to bring unused applicators, tube of 
5-FU, symptom diary and study calendar to the study visits. Visits may be delayed due to menstrual cycle. The following 
tests/assessments will be performed at each of these clinic visits: weight, vital signs, concomitant medications, review of 
symptom diary and study calendar, and a urine pregnancy test. The tube of 5-FU cream will be weighed at each visit to 
check compliance. At these visits, participants will also undergo a colposcopic examination with digital imaging of the 
cervix and examination of genital tissues for any adverse outcomes.  Imiquimod will be applied by the provider directly 
on the cervix. If there is any evidence of disease progression, they will undergo biopsy confirmation. Participants will be 
taken off study for biopsy confirmed invasive cervical cancer or cervical adenocarcinoma. Similarly, participants will be 
reminded to avoid sexual activity for at least 48 hours after each application of study medication, and to use two forms of 
birth control including condoms and one other form of contraception when participating in sexual activity. 
 
At the Week 8 Visit, participants will also undergo blood collection for CBC with diff and CMP. Participants will return 
unused agents. At this point, they will be offered the option to continue study participation for applications of 5-FU and 
imiquimod on alternating weeks for 8 additional applications (extension phase).  
Participants who opt into the extension phase will be provided with 5-FU for 4 additional applications. The timeline and 
visits for the extension phase will be the same as for the 8 applications of the initiation phase. Cervical and vaginal 
specimens, blood, and urine collection for research endpoints and for future research will be collected at this visit only for 
participants who choose to continue participation for an additional 8 weeks. Participants will self-administer intravaginal 
5-FU once every other week for a total of 4 applications (wks 9, 11, 13, 15), and will receive provider-applied imiquimod 
cream 5% directly to the cervix once every other week for a total of 4 applications (wks 10, 12, 14, 16). 

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Four to six weeks after 8 (or 16) applications of agent (or 4-6 weeks after the last agent application, if off agent before 
completing the 8 or 16 week cycle), participants will return for an End of Study Visit. They will be assessed for weight, 
vital signs, concomitant medications, review symptom diary and study calendar with study staff. Paricipants will complete 
tobacco and alcohol assessment forms and will be given the option to complete a survey about their experiences while 
participating in the study. Participants who completed participation in the study and were not given the opportunity to 
complete the survey at that time may do so by telephone, mail or email once verbal consent has been obtained. They will 
undergo blood and urine collection for future research. In addition, a blood sample will be collected for CBC with diff and 
CMP and urine will be collected for a urinalysis and urine pregnancy test. They will undergo a colposcopic examination 
with digital imaging of the cervix. Cervical specimens will be collected for research endpoints and future research. 
Additional cervical cells will be collected and sent to the institutional pathology lab for Pap smear and HR-HPV testing. 
Participants will undergo a LEEP or Cold Knife Cone procedure at this time. If participants decline LEEP or are young 
women with CIN 2 whose standard of care recommendation had been to observe disease for 6 months, then participants 
will be given the option to first undergo colposcopy-directed biopsy to assess for residual disease. If subjects opt to have 
colposcopy-directed biopsy first, then subjects will undergo a minimum of 2 cervical biopsies (one will be at the site of 
previously noted disease, second will be an endocervical curettage) for histopathological confirmation to verify no 
microscopic disease.  If there is histologic confirmation of residual high-grade squamous intraepithelial lesions or 
cytologic evidence of ASC-H/HSIL, participants will undergo a LEEP or cone biopsy at future clinical visit according to 
current clinical care recommendations. If they have evidence of regression (i.e., < CIN2 on histology or cytologic 
evidence of LSIL/ASC-US/NILM), participants will be recommended to return 6 months later to repeat colposcopic 
examination with Pap smear and HR-HPV testing (to be performed as the standard of care).   
 
Digital photos will be evaluated for repeat assessment and lesion measurement by a board-certified Gynecologist or 
Gynecologic Oncologist.  
 
Study staff will contact the participant within 2 weeks of receiving pathology reports of the colposcopically-directed 
biopsies Women with CIN 1-3 disease or adenocarcinoma-in-situ will be offered current clinical management. Any 
participant with cancer will be referred for management by gynecologic oncology.  
 
The study team will collect results from the follow-up cervical exams/procedures/tests performed within 14 months after 
the End of Study Visit from the medical records of all participants. 
 
4. 
PARTICIPANT SELECTION 
 
4.1 Inclusion Criteria 
 
4.1.1 
Women with biopsy confirmed high grade cervical squamous intraepithelial lesions (i.e., CIN3 lesions, and CIN2 
lesions with diagnosis confirmed by positive p16 immunohistochemistry staining) within 12 weeks of Baseline 
Visit 
 
4.1.2 
Age 18-45 years 
 
4.1.3 
Karnofsky ≥70% 
 
4.1.4 
Participants must have normal organ and marrow function as defined below: 
Leukocytes 
 
≥3,000/microliter 
Absolute neutrophil count 
≥1,500/microliter 
Platelets 
 
≥100,000/microliter 
Serum creatinine 
≤ the upper institutional limits 
 
4.1.5 
Participants must have a negative HIV antibody/antigen test and negative C. trachomatis/N. gonorrhea NAAT.  
 

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4.1.6 
Agree to use an effective form of contraception. The effects of intravaginal 5-fluorocuracil and imiquimod on the 
developing human fetus at the recommended therapeutic dose are unknown. For this reason and because 5-
fluorouracil is known to be teratogenic, women of child-bearing potential must agree to use adequate dual 
methods of contraception (hormonal method of birth control, intrauterine device, or tubal ligation - plus condoms) 
or abstinence prior to study entry and for the duration of study participation. Should a woman become pregnant or 
suspect she is pregnant while participating in this study, she should inform her study physician immediately. 
 
 
4.1.7  Ability to understand and the willingness to sign a written informed consent document. 
 
4.2 
Exclusion Criteria 
 
4.2.1 
Women treated previously with 5-fluorouracil or imiquimod or other medications for high-grade squamous 
intraepithelial lesions will be excluded from the study. 
 
4.2.2 
Concurrent vaginal, vulvar, anal lesions or symptomatic infections. 
 
4.2.3 
Pregnant or planning pregnancy within the next 6 months, or breastfeeding. Pregnant women are excluded from 
this study because 5-fluorouracil is an antimetabolite with the potential for teratogenic effects. Because there is an 
unknown but potential risk for AEs in nursing infants secondary to treatment of the mother with 5-fluorouracil, 
breastfeeding should be discontinued if the mother is treated with 5-fluorouracil. 
 
4.2.4 
Inability to speak or read English or Spanish 
 
4.2.5  Prior hysterectomy 
 
4.2.6 
Use of anticoagulant medications 
 
4.2.7 
Subjects who have a known immunocompromised condition (HIV+, use of immunosuppressive medications or 
systemic steroids, organ transplant recipients) or autoimmune conditions (e.g. psoriasis, rheumatoid arthritis or 
other known autoimmune condition). 
 
4.2.8 
Evidence of invasive anal, vulva, vaginal, or cervical carcinoma; prior LEEP or ablative treatment within 6 
 
months prior to study entry; other invasive malignancies, with the exception of non-melanoma skin cancer, within 
 
the last 5 years;  
 
4.2.9 
Pathologic findings consistent with 
• atypical endometrial cells or serious glandular-cell atypia (atypical glandular cells, favor neoplasia cytology 
diagnosis) 
• evidence of cervical carcinoma on Pap smear or biopsy 
• more than two cervical quadrants of CIN 3 as visualized by colposcopy 
• nonvisual squamous columnar junction on colposcopy with no concurrent endocervical sampling performed 
 
4.2.10 Use of other investigational agents within 6 months prior to enrollment. 
 
4.2.11 History of allergic reactions attributed to compounds of similar chemical or biologic composition to  
 
5-fluorouracil or imiquimod. 
 
4.2.12 Uncontrolled intercurrent illness including, but not limited to, ongoing or active infection (other than HPV), 
symptomatic congestive heart failure, unstable angina pectoris, cardiac arrhythmia, or psychiatric illness/social 
situations that would limit compliance with study requirements. 
 
4.2.13 Subjects with known partial or complete dihydropyrimidine dehydrogenase (DPD) enzyme deficiency. 

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4.3 
Inclusion of Women and Minorities 
 
 
Women and members of all races and ethnic groups are eligible for this trial. Men are not included because 
they do not have a cervix or vagina. 
 
4.4 
Recruitment and Retention Plan 
 
Study participants will be recruited from patients seen at the Protocol PI’s UNC OBGYN outpatient clinics, and from 
outside referring physicians. The Protocol PI is the Medical Director of the UNC Cervical Dysplasia Clinic and Senior 
Medical Director of all the UNC Obstetrics & Gynecology clinics and will have access to all patients seen in them. These 
include UNC OBGYN at Hillsborough, UNC OBGYN Weaver Crossing, and UNC GYN Oncology at Rex Hospital in 
Raleigh. Potentially eligible patients will be identified and contacted about the study. If they express interest in 
participation, they will present for an in person consent and screening visit. Patients contacted for the study will be listed 
on the AQUIP enrollment log as required by DCP. Reasons for refusal of study participation will be recorded by the study 
coordinator and evaluated regularly by the Protocol PI. 
 
Retention will be centered upon follow-up telephone or other contacts (e.g., email or in person). The study team will 
provide a friendly and comfortable study setting for participants from initial contact through the completion of their study 
activities. Demands upon the subjects will be minimized to foster comfort while preserving the research goals. Wherever 
possible, flexibility will be built into the study schedule to promote compliance. 
 
5. 
AGENT ADMINISTRATION 
 
Intervention will be administered on an out-patient basis. Reported AEs and potential risks are described in Section 6.2.  
 
5.1 
Dose Regimen and Dose Groups 
 
The study will have two phases:  
1. Initiation phase, which will include a total of 12 to 14 participants and applications of 5-FU and imiquimod on 
alternating weeks for 8 applications. Participants will self-administer intravaginal 5-FU (2 g of 5% 5-fluorouracil, 
Effudex) once every other week for a total of 4 applications (wks 1, 3, 5, 7). Participants will receive provider-applied 
commercially available imiquimod cream 5% (12.5 mg imiquimod in 250 mg cream) directly to the cervix once every 
other week for a total of 4 applications (wks 2, 4, 6, 8).  
2. Extension phase, which will include no more than the original 12 to 14 participants and continue their participation 
for applications of 5-FU and imiquimod on alternating weeks for 8 additional applications as described in the 
initiation phase.  
 
Weekly treatment regimen*  
WEEKS (Initiation 
phase) 
1 
2 
3 
4 
5 
6 
7 
8 
WEEKS (if continuing to 
Extension phase)  
9 
10 
11 
12 
13 
14 
15 
16 
5-FU (self-applied) 
X 
 
X 
 
X 
 
X  
5-FU (self-applied) 
X  
X 
 
X 
 
X 
 
Imiquimod (provider-
applied) 
 
X  
X  
X 
 
X 
Imiquimod (provider-applied)  
X 
 
X 
 
X 
 
X 
*Agent application may be delayed until the end of menstrual cycle if application date occurs during menses. No dose will 
be applied any sooner than 7 days apart even in the setting of dose delay.  
 
 
5.2 
5-Fluorouracil and Imiquimod Administration 
 

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5-FU Administration 
• 
The 5-FU will be supplied to participants in a commercially available multi-dose tube with vaginal applicators for 
individual use. Participants will be taught how to remove the 5-FU cream from the tube to fill the applicator with 2 
grams of the cream prior to each self-application. This method of application has been chosen in order to preserve 
the shelf-life of the commercially available 5-FU cream.  
• 
Participants will receive phone call, text or email reminders to use the 5-FU cream every other week.  
• 
Participants will self-administer 5-FU on alternating weeks via vaginal applicators. They will perform home 
pregnancy testing prior to each application.  
• 
5-FU will be self-applied prior to bedtime. After agent application, the participant will place a tampon in the 
vagina overnight and remove it in the morning. She will wash the agent preparations off externally and wear panty 
liners that will be replaced every 2-3 hours or as needed throughout the next day.  
• 
Agent application will be delayed until the end of menstrual cycle if application date occurs during menses.  
• 
Participants will be advised to avoid agent application in circumstances where pregnancy is suspected for any 
reason by the participant. If this is the case, she will notify study staff. 
• 
Participants will be instructed to dispose the used applicators in trash, away from the reach of other household 
individuals. 
• 
The participant will enter date and time of drug administration into the study calendar to document adherence to 
regimen. 
 
Imiquimod Administration 
• 
Commercially available imiquimod cream 5% will be applied by the provider directly to the cervix in the 
clinic on alternating weeks. Urine pregnancy test will be performed prior to each application. 
• 
Visits may be delayed until the end of menstrual cycle if application date occurs during menses. No dose will be 
applied any sooner than 7 days apart even in the setting of dose delay. 
• 
Date and time of imiquimod application will be documented in the study calendar by the provider.  
• 
After the application, the participant will lay in the supine position for at least 30 min. The participant will then 
place a tampon in the vagina. Before going to bed, she will remove the tampon and shower to wash any agent 
preparations off externally and wear a pad during the night. The pad will be replaced every 2-3 hours or as needed 
throughout the next day. 
 
 
5.3 
Run-in Procedures  
 
Not Applicable. 
 
5.4 
Contraindications 
 
Participants will be informed to avoid intercourse for 48 hours after each agent application. Dual contraception with 
condoms and another hormonal or long-acting method will be required. Condoms will be recommended for additional 
contraception, for the prevention of sexually transmitted infections, and to potentially protect male partners from any 
residual medication.   
 
5.5 
Concomitant Medications 
 
Women will be excluded if they are using anticoagulants or immunosuppressive medications. 
 
All medications (prescription and over-the-counter), vitamin and mineral supplements, and/or herbs taken by the 
participant will be documented on the concomitant medication CRF and will include: 1) start and stop date, dose and route 
of administration, and indication. Medications taken for a procedure (e.g., biopsy) and those used to minimize vulvular 
irritation or pain should also be included. 
 

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5.6 
Dose Modification  
 
Participants will be asked to contact the study team when experiencing a possibly related adverse event. Section 11.1.3.1 
describes the assessment of the severity of an adverse event.  Briefly, adverse events (except female genital AEs) will be 
assessed according to the grade associated with the CTCAE term. Female genital AEs will be assessed according to the 
NIAID DAIDS Female Genital Grading Table (FGGT) (Appendix B), rather than using CTCAE.    
 
For a Grade 1 toxicity of any genital lesion(s) (blisters, ulcerations, or pustules), that is possibly, probably, or definitely 
related to the study medication, the participant will not receive applications of the study drug until the toxicity has 
resolved. No dose modification will be made for other Grade 1 adverse events.  
For Grade 2 adverse events definitely, probably or possibly related to study agent persisting until the next scheduled agent 
application, the next application(s) will be omitted until toxicity is resolved to Grade 1 or less. 
Participants with Grade 3 or 4 events that are definitely, probably or possibly related to the study agent will receive no 
further doses and be followed for resolution of adverse events. If appropriate, they should remain on-study and undergo 
the post-intervention biopsy. 
 
For adverse events not considered related to study agent persisting until the next agent application, the scheduled agent 
application may be continued or omitted at the discretion of the study physician.   
 
5.7 
Adherence/Compliance 
 
5.7.1 
Participants will be considered compliant if they have applied/received ≥ 80% of the assigned number of 
applications.  
 
5.7.2 
The compliance will be assessed by the number of applications based on the study calendar and provider 
applications. The information will be further confirmed by remaining weight of the returned 5-FU cream.  
 
 
6. 
PHARMACEUTICAL INFORMATION 
 
6.1 
5-Fluoruracil and Imiquimod  
 
5% 5-FU cream will be acquired from Valeant Pharmaceuticals or Spear Dermatology and will be ordered by the UNC 
Outpatient Pharmacy and distributed by Investigational Drug Services (IDS). Every effort will be made to acquire the 
agent from the same supplier throughout the study. The 5-FU will be supplied to participants in the commercially 
available tube with vaginal applicators. Participants will be taught how to remove the 5-FU cream from the tube to fill the 
applicator to the 2 gram mark with the cream prior to each self-application. This method of application has been chosen in 
order to preserve the shelf-life of the commercially available 5-FU cream.  
Commercially available imiquimod cream 5% (trade name Aldara) will be acquired from a commercial source (e.g., 
Fougera, Glenmark, Perrigo) and will be ordered by the UNC Outpatient Pharmacy and distributed by Investigational 
Drug Services (IDS). Every effort will be made to acquire the agent from the same supplier throughout the study.  
 
6.2 
Reported Adverse Events and Potential Risks 
 
5-FU: Participants may have side effects from the 5-FU medication. Mild side effects include symptoms, such as burning, 
redness, or vaginal discharge. Serious side effects include pain, bleeding or vaginal ulcers. This treatment (5% 5-FU once 
every 2 weeks) has been previously studied in other women and 2% of women (1 out 50) reported mild side effects related 
to the cream.31 Our research team assessed women undergoing the same treatment regimen and 48% reported some genital 
side effect (e.g. burning, irritation, spotting). However, none reported that these side effects interfered with usual 

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activities, and 83% reported that they had a good experience using the cream. No women reported serious side effects.34 
 
Because systemic 5-FU is listed as Federal Drug Administration (FDA) Category X, participants should not be pregnant, 
and should not become pregnant or breast-feed while using the 5-FU cream because the drug in this study could be 
teratogenic.42 To minimize this risk, women will be required to use 2 forms of birth control while consuming the study 
drug if they are using a short acting form of birth control, such as hormonal oral, transdermal, intravaginal or injectable 
contraception. Condoms will still be recommended for women who are using long acting forms of contraception or have 
had a tubal ligation to prevent acquisition of a sexually transmitted infection. Use of condoms will also minimize risk of 
irritation to a sexual partner. We completed a randomized-controlled trial in women ages 18-29 years and reported no 
pregnancies during use of the 5-FU study drug using these parameters. Participants will be advised to wash hand 
thoroughly after use of the cream and bring any unused medications back to study team at the subsequent study visit.  
 
Imiquimod: Imiquimod is FDA approved for treatment of external genitalia and perineal warts, condyloma acuminate as 
well as actinic keratosis and primary superficial basal cell carcinoma in immunocompetent adults. 43 Imiquimod may 
induce both local and systemic side effects as has been noted in prior studies. A previous trial of women with high-grade 
squamous intraepithelial lesions reported women having both local and systemic side effects using self-administered 
imiquimod therapy intravaginally once a week for 2 weeks, twice a week for 2 weeks and then 3 times a week for 12 
weeks (total 16 week therapy, total 42 doses). Mild local side effects (vulvar pain or pruritus) were reported in 92% of 
participants. Flu-like symptoms and fatigue were reported in 97% of imiquimod participants and 34% of placebo 
participants. Investigators reported findings, such as erythema, edema, erosion, and ulceration during treatment. Severe 
findings were improved by holding one dose of therapy.36 Another trial of self-administered imiquimod (twice a week or 
every other day dosing for up to 12 doses) for women with CIN 1-3 reported the most common side effect as vaginal 
discharge. Other reported events included vulvar pain, pruritus, erythema, erosion, myalgia and flu-like symptoms; 
however, no participant discontinued the study due to these side effects.38   
 
Our dosing in this trial (one dose every 2 weeks, up to a total of 8 doses) will be much lower than the above noted studies. 
Therefore, we expect an improved safety profile. Participants will be advised to use nonsteroidal anti-inflammatory drugs 
(NSAIDs) (or acetaminophen, if not tolerable to NSAIDs) in the event of systemic symptoms which has been shown to be 
beneficial and not interfere with efficacy of imiquimod.46 
 
6.3  
Availability 
 
5% 5-FU (trade name Efudex,Valeant Pharmaceuticals) and vaginal applicators will be ordered by the UNC Outpatient 
Pharmacy and distributed by Investigational Drug Services (IDS).  
Commercially available imiquimod cream 5% (trade name Aldara) will be acquired from a commercial source (e.g., 
Fougera, Glenmark, Perrigo) by the UNC IDS. Every effort will be made to acquire the agent from the same supplier 
throughout the study.  
 
6.4 
Agent Distribution 
 
The 5-FU cream and imiquimod cream will be sent directly to the UNC IDS from UNC outpatient pharmacy. 
 
UNC IDS will distribute the study agents to the study staff. 5-FU cream will be distributed to the study participants. 
Imiquimod cream will be applied by the study physician. 
 
6.5  
Agent Accountability 
 
The Investigator, or a responsible party designated by the Investigator, must maintain a careful record of the inventory and 
disposition of all agents received from DCP using the NCI Drug Accountability Record Form (DARF). The Investigator is 
required to maintain adequate records of receipt, dispensing and final disposition of study agent. This responsibility has 
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whom the agent was received and to whom study agent was shipped, date, quantity and batch or lot number. On 
dispensing record, note quantities and dates study agent was dispensed to and returned by each participant.  
 
6.6 
Packaging and Labeling 
 
5-FU will be packaged by Valeant Pharmaceuticals or Spear Dermatology. It will be ordered by the UNC Outpatient 
Pharmacy and stored at the UNC Investigational Drug Service.  
 
Commercially available imiquimod cream 5%  will be packaged by the supplier (e.g., Fougera, Glenmark, Perrigo), 
ordered by the UNC Outpatient Pharmacy and stored at the UNC Investigational Drug Service. Every effort will be made 
to acquire the agent from the same supplier throughout the study.  
 
6.7 
Storage 
 
Medications will be stored at room temperature (between 59°F and 86°F) at the UNC IDS. Participants will be instructed 
to store the agent at room temperature away from the reach of other individuals. 
 
6.8 
Registration/Randomization 
 
Participants will be considered registered on the date they sign the approved informed consent document with a member 
of the study staff. A participant identification number (PID) will be assigned by the coordinator from a predetermined list 
once the subject has been consented. This study does not involve randomization. 
 
6.9 
Blinding and Unblinding Methods 
 
Not applicable 
 
6.10 
Agent Destruction/Disposal 
 
The UNC IDS will receive all unused study agents for disposal according to the institutional standards. 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 

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1 Height required at Visit 1 only. 
2 CMP includes serum glucose, urea nitrogen, creatinine, sodium, potassium, chloride, bicarbonate, total protein, albumin, calcium, alkaline phosphatase, 
ALT, AST, total bilirubin. 
3 Biopsy confirmed high grade cervical squamous intraepithelial lesions (i.e., CIN3 lesions and CIN2 lesions diagnosis confirmed by positive p16 
immunohistochemistry staining) within 12 weeks prior to Baseline Visit. 
4 Urine pregnancy test will be done at each visit. Participants will be provided with home pregnancy tests and will be instructed to use them prior to each 
self-application. 
5 Self-administered 5-FU and provider-administered imiquimod visits will be scheduled on alternating weeks. Agent applications will be delayed during 
menstrual cycles or omitted for occurrence of study related ≥ grade 2 adverse events. No dose will be applied any sooner than 7 days apart even in the 
setting of dose delay. 
6 Following the first 8 applications of study agent, participant will be offered option to continue agent intervention for extension phase for an additional 8 
weeks. 
7  End of Study Visit to occur 4-6 weeks after the last agent application unless encountering scheduling difficulty9.  
8 Contact via phone call, text or email will be used to remind participants to use the study medication, to answer questions participants may have and to 
review AEs and concomitant medications.  Participants will also be reminded to perform pregnancy testing prior to using the study medication, to avoid 
sexual activity for at least 48 hours after each application of study medication, and to use two forms of birth control including condoms and one other 
form of contraception when participating in sexual activity. Prior to study visits, participants will be reminded to bring unused applicators/agents, 
symptom diary and study calendar to the study visits.  
 9 When encountering scheduling difficulties, all efforts will be made to ensure that the visit date does not deviate for more than 5 business days of the 
specified timeframe.  
10 If not done at the End of Study Visit, the procedure will be scheduled within 2 weeks of the End of Study Visit, when feasible. 
11 The study team will collect results from the follow-up cervical exams/procedures/tests performed within 14 months after the End of Study Visit from 
the medical records for all participants. 
12 Cericovaginal lavage for collection of specimens for research endpoints and blood and urine for exploratory endpoints will only be collected at Visit 8 
if participant opts to extend treatment for an additional 8 weeks. 
13 Participants who initiate study agent but terminate prior to study completion should return to the clinic for End of Study procedures. 
14 Participant Survey is optional. Participants who completed participation in the study and were not given the opportunity to complete the survey at that 
time may do so by telephone, mail or email once verbal consent has been obtained. 
 
 
Adverse Events 
 
X 
X 
X 
X 
X 
X 
X 
X 
Telephone/email 
Contact8 
 
 
X 
 
 
X 
 
 
 
Collection of results 
from additional 
tests/procedures11 
 
 
 
 
 
 
 
 
 

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7.2 
Baseline Testing/Prestudy Evaluation 
 
Participants will undergo a Screening Evaluation to be assessed for study eligibility. The informed consent form, medical 
records release and tissue release form will be signed. Participants must have biopsy confirmed high grade cervical 
squamous intraepithelial lesions (i.e., CIN3 lesions and CIN2 lesions diagnosis confirmed by positive p16 
immunohistochemistry staining) within 12 weeks prior to the Baseline Visit.   
 
Participants will be evaluated for concomitant medications, medical history and baseline symptoms and signs.  
 
Participants will undergo a brief physical exam including weight, height, vital signs including temperature, blood 
pressure, and heart rate. Performance status will be collected.  
 
Blood will be collected for complete blood count with differential (CBC-diff) and comprehensive metabolic panel (CMP) 
and HIV test. Urine will be collected for urinalysis, tests on pregnancy, Chlamydia, and Gonorrhea. 
 
A symptom diary for recording adverse events will be provided to participants at this visit. 
 
7.3 
Evaluation During Study Intervention 
 
Participants who meet the eligibility assessment will return to the clinic for a Baseline Visit. Vital signs will be collected 
including weight, temperature, blood pressure and heart rate. Participants will complete tobacco and alcohol assessment 
forms.  Urine will be collected for pregnancy test. Adverse events and concomitant medications will be reviewed. 
 
Participants will undergo colposcopic examination with digital imaging of the cervix and cervical specimen collection 
(cericovaginal lavage, swab of the cervix, swab of the vagina, and cervical brushing for research endpoints and banking; 
see section 10.2.2 for detailed information). Blood and urine will be collected and banked for future research. Participants 
will receive education regarding 5-FU self-application, condoms and contraception use, and scheduling information about 
study visits for imiquimod application. They will receive an initial supply of the following: intravaginal 5-FU, condoms, 
pregnancy test kits and instructions on agent application. The 5-FU will be supplied to participants in a commercially 
available tube with vaginal applicators for 4 applications. Participants will be shown how to remove the 5-FU cream from 
the tube to fill the applicator with 2 grams of the cream prior to each self-application. If needed, participants may use 
lidocaine jelly or a topical protective barrier cream to the vulva and/or take oral ibuprofen to minimize vulvar irritation or 
pain from the application of study agent. If the participant experiences an allergic reaction (swelling, rash, hives), she may 
use diphenhydramine and should notify the study physician. Use of these products will be recorded on the study calendar.  
 
Participants will self-apply 5-FU intravaginally on weeks 1, 3, 5 and 7. They will be contacted via phone call, text or 
email to remind them to use the 5-FU, to answer questions participants may have and to review AEs and concomitant 
medications. Participants will also be reminded to perform pregnancy testing prior to each time they use the study 
medication, to avoid sexual activity for at least 48 hours after each application of study medication, and to use two forms 
of birth control including condoms and one other form of contraception when participating in sexual activity. Agent 
application will be delayed until the end of menstrual cycle if application date occurs during menses. No dose will be 
applied any sooner than 7 days apart even in the setting of dose delay. Participants will record study agent applications on 
study calendar. If a safety concern is identified during the regular contact, participants will be asked to come in for an 
interim clinic exam.  
 
Participants will return to the clinic every other week (weeks 2, 4, 6 and 8) to assess safety and compliance and for 
provider applications of imiquimod. Prior to study visits, participants will be reminded to bring unused applicators, tube 
of 5-FU, symptom diary and study calendar to the study visits. Visits may be delayed due to menstrual cycle. No dose will 
be applied any sooner than 7 days apart even in the setting of dose delay. At each of these interim visits, participants will 
be assessed for weight, vital signs, concomitant medications, review of symptom diary and study calendar with study 
staff, and undergo a urine pregnancy test. The tube of 5-FU cream will be weighed at each visit to check compliance. 
Participants will undergo a colposcopic examination with digital imaging of the cervix and examination of genital tissues 

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for any adverse outcomes. They will undergo a urine pregnancy test prior to receiving application of study agent. 
Imiquimod will be applied by the provider directly onto the cervix.  If there is any evidence of disease progression, they 
will undergo biopsy confirmation. Participants will be taken off study for biopsy confirmed invasive squamous cervical 
cancer or cervical adenocarcinoma or adenocarcinoma-in-situ. Similarly, participants will be reminded to avoid sexual 
activity for at least 48 hours after each application of study medication, and to use two forms of birth control including 
condoms and one other form of contraception when participating in sexual activity.  
 
At the Week 8 Visit, participants will also undergo blood collection for CBC with diff and CMP. Participants will return 
unused agents. At this point, they will be offered the option to continue with study participation for applications of 5-FU 
and imiquimod on alternating weeks for an additional 8 applications (extension phase). Participants who opt into the 
extension phase will be provided with 5-FU for 4 additional applications. The timeline and visits for the extension phase 
will be the same as for the 8 applications of the initiation phase, however, cervical and vaginal specimens, blood, and 
urine collection for research endpoints and for future research will only be collected at this visit for participants who 
choose to continue participation for an additional 8 weeks.   
 
7.4 
Evaluation at Completion of Study Intervention 
 
The use of the study agents will be completed after 8 applications of agents or after 16 applications if the participant opts 
to continue participation for an additional 8 applications of treatment.  
Four to six weeks after 8 (or 16) applications of agent (or 4-6 weeks after the last agent application, if off agent before 
completing the 8 or 16 application cycle), participants will return for an End of Study Visit. Participants will be assessed 
for weight, vital signs, and concomitant medications; review symptom diary and study calendar with study staff.  
Participants will complete tobacco and alcohol assessment forms and will be given the option to complete a survey about 
their experiences while participating in the study. Participants who completed participation in the study and were not 
given the opportunity to complete the survey at that time may do so by telephone, mail or email once verbal consent has 
been obtained. They will undergo blood and urine collection for future research. In addition, a blood sample will be 
collected for CBC with diff and CMP and urine will be collected for a urinalysis and urine pregnancy test. Participants 
will undergo a colposcopic examination with digital imaging of the cervix. Cervical and vaginal specimens will be 
collected for research endpoints and future research. Additional cervical cells will be collected and sent to the institutional 
pathology lab for Pap smear and HR-HPV testing. Participants will be scheduled for LEEP or Cold Knife Cone procedure 
at this time. If participants decline LEEP or are young women with CIN 2 whose standard of care recommendation had 
been to observe disease for 6 months, then participants will be given the option to first undergo colposcopy-directed 
biopsy to assess for residual disease. If subjects opt to have colposcopy-directed biopsy first, then subjects will undergo a 
minimum of 2 cervical biopsies (one will be at the site of previously noted disease, second will be an endocervical 
curettage) for histopathological confirmation to verify no microscopic disease.  If there is histologic confirmation of 
residual high-grade squamous intraepithelial lesions or ASCH/HSIL pap, participants will undergo a LEEP or cone biopsy 
at future clinical visit according to current clinical care recommendations. If they have evidence of regression (LSIL or 
normal histology or LSIL, ASCUC, normal pap), participants will be recommended to return 6 months later to repeat 
colposcopic examination with Pap smear and HR-HPV (to be performed as the standard of care).   
 
Digital photos will be evaluated for repeat assessment and lesion measurement by a board-certified Gynecologist or 
Gynecologic Oncologist. 
 
7.5 
Post-intervention Follow-up Period 
 
Study staff will contact the participant within 2 weeks of receiving pathology reports of the colposcopically-directed 
biopsies. Women with CIN 1-3 disease will be offered current clinical management. Any participant with more severe 
lesions, such as adenocarcinoma-in-situ or cancer, will be referred for management by gynecologic oncology.  
 
The study team will collect results from the follow-up cervical exams/procedures/tests performed within 14 months after 
the End of Study Visit from the medical records for all participants. 
 

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7.6 
Methods for Clinical Procedures 
 
Colposcopy and biopsy will be carried out according to standard clinical procedures. Colposcopic images will be obtained 
at low magnification (10X/20X) with acetic acid according to standard clinical practice. Cervical biopsies will be taken 
after application of acetic acid.  
 
8.  
CRITERIA FOR EVALUATION AND ENDPOINT DEFINITION 
 
8.1 
Primary Endpoint 
 
 
The primary endpoint is feasibility of a combination agent intervention (once-weekly self-administered intravaginal 5-FU 
alternating with once-weekly provider-administered imiquimod) in women with biopsy confirmed high grade cervical 
squamous intraepithelial lesions (i.e., CIN3 lesions and CIN2 lesions diagnosis confirmed by positive p16 
immunohistochemistry staining).  
 
Feasiblity is evaluated based on safety and tolerability of the study intervention. For safety, we will assess the number of 
participants experiencing the dose limiting toxicity (DLT). DLT is defined as Grade 2 or greater toxicity (or Grade 1 
toxicity of any genital lesion (blisters, ulcerations, or pustules)) that is possibly, probably, or definitely related and lasts 
for more than 5 days. For tolerability, we will assess the number of participants who are not able to apply at least 50% of 
the treatment due to DLT.  
 
8.2 
Secondary Endpoints 
 
8.2.1 
Response to the combination of agent intervention on cervical disease regression (endpoint based on histologic 
regression from high-grade lesions to low-grade- or no lesions and clearance of high risk-HPV detection) between 
baseline and study exit visits.  
8.2.2 
Effect of the combination agent intervention on genotype-specific HPV clearance between baseline and study exit 
visits.  
8.2.3 
Effect of the combination agent intervention on biomarkers of local immune activation (measurement of changes 
in  expression of Toll-like receptors (TLR2, TLR 3, TLR7, TLR8 and TLR9) and T-regulatory cells (Foxp3) and 
the levels of mRNA expression and the innate (IFN-α2), immune mediating (IFN-Υ, IL-10, IL-12), and pro-
inflammatory (IL-1α, -1β, -6, -8, MIP-1α, TNF) cytokine with intravaginal 5-FU and imiquimod between baseline 
and study exit visits.  
The study will also collect specimens for exploratory studies of vaginal microbiome, proteomics and metabolomics to 
identify factors affecting histologic regression, HPV clearance and immune activation. 
 
8.3 
Off-Agent Criteria  
 
Participants may stop taking study agent for the following reasons: completed the protocol-prescribed intervention, AE or 
serious adverse event (SAE), inadequate agent supply, noncompliance, concomitant medications, medical 
contraindication. Participants will continue to be followed, if possible, for safety reasons and in order to collect endpoint 
data according to the schedule of events.  
 
 
8.4 
Off-Study Criteria 
 
Participants may go ‘off-study’ for the following reasons: the protocol intervention and any protocol-required follow-up 
period is completed, AE/SAE, lost to follow-up, non-compliance, concomitant medication, medical contraindication, 
withdraw consent, death, determination of ineligibility (including screen failure), pregnancy.  

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8.5 
Study Termination 
 
NCI, DCP as the study sponsor has the right to discontinue the study at any time.  
 
 
9. 
CORRELATIVE/SPECIAL STUDIES 
9.1 
Rationale for Methodology Selection 
 
HR-HPV DNA testing and genotyping: The genomic DNA will be isolated using a QIAampMinElute Media Kit 
(QiagenInc, Valencia, CA). The purified genomic DNA will be amplified (PCR Cycler, AB 2720, Applied Biosystems, 
Grand Island, NY) and genotyped for HPV 6, 11, 16, 18, 26, 31, 33, 35, 39, 40, 42, 45, 51, 52, 53, 54, 55, 56, 58, 59, 61, 
62, 64, 66, 67, 68, 69, 70, 71, 72, 73, 81, 82, 83, 84, IS39, and CP6108 using a Roche Linear Array (RLA) assay (Roche, 
Pleasanton, CA). This is a quantitative test that detects 37 high-risk and low-risk HPV genotypes. 
  
Cytokine testing by Luminex. Cytokines (IFN-alpha2, IFN-gamma, IL-1alpha, IL-1beta, IL-6, IL-8, IL-10, IL-12 [p70 
heterodimer], MIP-1alpha, and TNF) in cervicovaginal lavage will be measured by Luminex technology using Milliplex 
Human Cytokine Magnetic-bead Kits (Millipore Corporation, Billerica MA).47,48 Luminex assays will allow us to 
simultaneously detect and quantify multiple cytokines of interest. They require small sample volumes, are cost-effective, 
and allow researchers to collect more data in less time than other assays.  
 
TLR and T-regulatory expression: RNA will be extracted using TRI Reagent (Molecular Research Center, Cincinnati, 
OH)49. DNase treatment (TURBO DNA-free, Ambion), reverse transcription (OmniScript RT, Qiagen, Germantown, 
Maryland), and quantitative PCR on TLR and Foxp3 (T-regulatory cells) mRNA expression will be performed as 
previously described.50,51 Using real time RT-PCR is a feasible option since the samples can be stored and processed in 
batches.  Other options such as flow cytometry are not feasible because of the small amount of sample from the cervix and 
the feasibility of collecting samples.  
 
9.2 
Comparable Methods 
 
Each of the proposed methods for the correlative studies has been used in previous research. We will be able to compare 
data generated from this study with prior research. 
 
10. 
SPECIMEN MANAGEMENT  
 
10.1 
Laboratories 
 
Clinical laboratory tests and histopathology will be performed at the UNC Clinical and Pathology Labs.  
 
Oncogenic HPV testing and genotyping, TLR, T-regulatory, and cytokine assays will be performed in the laboratory of 
Dr. Barbara Moscicki at UCLA. 
 
 
10.2 
Collection and Handling Procedures 
 
 
10.2.1 Clinical laboratory tests 
 
CBC with diff: One 3 ml EDTA vacutainer tube to be collected at Screening, Week 8 and End of Study Visits. Blood 
tubes will be prepped, labeled, and packaged according to the recommendations from the diagnostic laboratory.  
 

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CMP: One 7 ml SST or tiger top Vacutainer tubes at Screening, Week 8 and End of Study Visits. Blood tubes will be 
prepped, labeled, and packaged according to the recommendations from the diagnostic laboratory.  
 
HIV:  A minimum of 5 mL of blood will be collected at Screening in a blood/separator tube/gold top. Blood tubes will be 
prepped, labeled, and packaged according to the recommendations from the diagnostic laboratory.  
 
Urinalysis: A minimum of 4 mL of urine will be collected for point of care testing by the research team. 
 
Urine Chlamydia, and Gonorrhea: No more than 15 mL of urine will be obtained at Screening from the initial stream of 
urine. Sample will be prepped, labeled, and packaged according to the recommendations from the diagnostic laboratory.  
 
Urine pregnancy: A minimum of 4 mL of urine will be collected for point of care testing by the research team. 
 
10.2.2 Specimens for research endpoints 
 
The following cervical specimens will be collected in the sequence listed below. 
 
Cervicovaginal lavage (CVL) will be collected at Baseline, Week 8 (only for participants who choose to continue 
participation for an additional 8 weeks), and End of Study Visits. A continuous stream of 10 ml of normal saline will be 
aimed directly at and into the cervical opening to bathe the endocervix and ectocervix. The fluid will pool in the posterior 
fornix and then be aspirated. Repeat this procedure three times with the same fluid. The aspirate will be aliquoted into 5 x 
2 ml sterile cryovials (~1.5 ml volume each) and labeled with study ID, subject ID, and visit type/date.  The samples will 
be stored at -70 ºC or below for cytokines and HPV testing. 
 
Swab of the cervix will be collected at Baseline, Week 8 (for participants who choose to continue participation for an 
additional 8 weeks) and End of Study Visits. A Dacron swab will be inserted to swab the endo and exocervix. The swab 
will then be placed into sterile tube spiked with 2 ml normal saline. Rotate the swab against the side of the tube to remove 
as much fluid as possible. Vortex the tube, if possible. The fluid will be placed in a 2 ml cryovial and labeled with study 
ID, subject ID, and visit type/date.  The samples will be stored at -70ºC or below for future microbiome and metabolome 
analysis. 
 
Swab of the vagina will be collected at Baseline, Week 8 (for participants who choose to continue participation for an 
additional 8 weeks) and End of Study Visits.  A Dacron swab will be inserted to swab the walls of vagina. The swab will 
then be placed into sterile tube spiked with 2 ml normal saline. Rotate the swab against the side of the tube to remove as 
much fluid as possible. Vortex the tube, if possible. The fluid will be placed in a 2 ml cryovial and labeled with study ID, 
subject ID, and visit type/date.  The samples will be stored at -70ºC or below for future microbiome analysis. 
 
Cervical brushing will be collected at Baseline, Week 8 (for participants who choose to continue participation for an 
additional 8 weeks) and End of Study Visits. A cervical cytobrush will be placed into the endocervical os and rotated 
gently 2 times. The cytobrush will be placed into a 5 ml cryotube prespiked with RNA later. The end of the cytobrush will 
be snapped off so that the brush portion can fit into the cryotube. The tube will be labelled with study ID, subject ID, and 
visit type/date.  The samples will be stored at -70ºC or below for mRNA analysis. 
 
Cervical cells for Pap smear and HR-HPV will be obtained at End of Study Visit using ThinPrep collection devices and 
cytology medium. The specimen will be prepped, labeled, and packaged according to the recommendations from the UNC 
pathology laboratory. The sample will be submitted to UNC pathology for cytology analysis and HR-HPV testing. The 
remaining sample will be stored for any potential future study.  
 
Cervical biopsies will be collected at the End of Study Visit or at a subsequent clinical visit. The specimen will be 
prepped, labeled, and packaged according to the recommendations from the UNC pathology laboratory. The sample will 
be submitted to UNC pathology for histopathology and p16 staining. 
 

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One 7 ml SST or tiger top Vacutainer tubes at Baseline, Week 8 (for participants who choose to continue participation for 
an additional 8 weeks) and End of study Visits. The SST tube will be held at room temperature for 30 min and then 
centrifuged. Serum will be aliquoted evenly into 5 x 2 ml cryovials and stored at -70°C or below. The cryovials will be 
labeled with study ID, subject ID, and visit date. 
 
Urine will be collected at Baseline, Week 8 (for participants who choose to continue participation for an additional 8 
weeks) and End of study Visits and aliquoted 5 x 2 ml cryovials (~1.5 ml volume each) and stored at -70°C or below. The 
cryovials will be labeled with study ID, subject ID, and visit type/date. 
 
 
10.3 
Shipping Instructions 
 
All samples will be shipped in compliance with the International Air Transport Association (IATA) Dangerous Goods 
Regulations. Current shipper and institutional procedures must be followed.  Biologic specimens (Category B, UN3373) 
will be in leak-proof primary and secondary receptacles with puncture resistant packaging and absorbent material.   
 
Shipments are to be preceded with phone contact to the receiving lab to assure the shipment will be met and stored 
promptly.   
 
Cervical specimens for cytokines, HPV testing, and mRNA analysis will be shipped overnight in batches on dry ice to the 
laboratory of Dr. Barbara Moscicki at UCLA. 
 
Dr. Anna-Barbara Moscicki 
10833 Le Conte Ave # MDCC 22-452 
Los Angeles CA 90095 
Telephone: (310) 206-6345 
Fax: (310) 206-4855 
amoscicki@mednet.ucla.edu 
 
10.4 
Tissue Banking 
 
Biologic specimens collected during the conduct of each clinical trial that are not used during the course of the study will 
be considered deliverables under the contract and thus the property of the NCI. At study completion, NCI reserves the 
option to either retain or relinquish ownership of the unused biologic specimens. If NCI retains ownership of specimens, 
the Contractor shall collect, verify and transfer the requested biologic specimens from the site to a NCI-specified 
repository or laboratory at NCI’s expense.  
 
In concordance with the NCI Genomic Data Sharing Policy, genomic data generated in this study will be deposited in 
dbGaP and will be available in a controlled-access manner. 
 
11. 
REPORTING ADVERSE EVENTS  
 
DEFINITION: AE means any untoward medical occurrence associated with the use of a drug in humans, whether or not 
considered drug related. An AE can therefore be any unfavorable and unintended sign), symptom, or disease temporally 
associated with participation in a study, whether or not related to that participation. This includes all deaths that occur 
while a participant is on a study. 
 
Please note that all abnormal clinical laboratory values that are determined to be of clinical significance based on a 
physician’s assessment are to be reported as AEs. Those labs determined to be of no clinical significance or of unknown 
clinical significance (per the physician’s assessment) should not be reported as AEs. Any lab value of unknown clinical 
significance should continue to be investigated/followed-up further for a final determination, if possible. 

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A list of AEs that have occurred or might occur can be found in §6.2 Reported Adverse Events and Potential Risks, as 
well as the Investigator Brochure or package insert.  
 
11.1 
Adverse Events 
 
11.1.1 Reportable AEs 
 
All AEs that occur after the informed consent is signed and baseline assessments are completed (including run-in) must be 
recorded on the AE CRF (paper and/or electronic) whether or not related to study agent. 
 
11.1.2 AE Data Elements: 
 
The following data elements are required for AE reporting. 
• 
AE verbatim term 
• 
NCI Common Terminology Criteria for Adverse Events version 4.0 (CTCAE v4.0) AE term (MedDRA lowest 
level term) 
• 
CTCAE (MedDRA) System Organ Class (SOC) 
• 
Event onset date and event ended date 
• 
Treatment assignment code (TAC) at time of AE onset 
• 
Severity grade 
• 
Attribution to study agent (relatedness) 
• 
Whether or not the event was reported as a SAE 
• 
Whether or not the subject dropped due to the event 
• 
Outcome of the event 
 
11.1.3  Severity of AEs 
 
11.1.3.1 
Identify the AE using the CTCAE version 4.0. The CTCAE provides descriptive terminology (MedDRA 
lowest level term) and a grading scale for each AE listed. A copy of the CTCAE can be found at 
http://ctep.cancer.gov/protocolDevelopment/electronic_applications/ctc.htm 
 
AEs (except female genital AEs) will be assessed according to the grade associated with the CTCAE term. Female genital 
AEs will be assessed according to the NIAID DAIDS Female Genital Grading Table (FGGT) (weblinks below; Appendix 
B), rather than using CTCAE:  
http://www.mtnstopshiv.org/sites/default/files/attachments/Addendum 1 Female Genital Grading Table v1 Nov 2007.
pdf or https://rsc.tech-res.com/docs/default-source/safety/addendum_1_female_genital_grading_table_v1_nov_2007.pdf  
 
If an AE can be found in both CTCAE and FGGT, FGGT will be used for the assessment. 
  
Other AEs that do not have a corresponding CTCAE term will be assessed according to the general guidelines for grading 
used in the CTCAE v4.0. as stated below.  
 
CTCAE v4.0 general severity guidelines:  
 
Grade 
Severity 
Description  
1 
Mild 
Mild; asymptomatic or mild symptoms; clinical or diagnostic observations only; 
intervention not indicated. 
2 
Moderate 
Moderate; minimal, local or noninvasive intervention indicated; 
limiting age-appropriate instrumental activities of daily living (ADL)*. 
3 
Severe 
Severe or medically significant but not immediately life-threatening; 
hospitalization or prolongation of hospitalization indicated; disabling; limiting self-
care ADL**. 
4 
Life-threatening 
Life-threatening consequences; urgent intervention indicated. 

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Grade 
Severity 
Description  
5 
Fatal 
Death related to AE. 
   
ADL 
 
*Instrumental ADL refers to preparing meals, shopping for groceries or clothes, using the telephone, managing money, 
etc. 
 
**Self-care ADL refers to bathing, dressing and undressing, feeding self, using the toilet, taking medications, and not 
bedridden. 
 
11.1.4 Assessment of relationship of AE to treatment 
 
 
The possibility that the AE is related to study agent will be classified as one of the following: not related, unlikely, 
possible, probable, definite. 
  
11.1.5 Follow-up of AEs 
 
All AEs, including lab abnormalities that in the opinion of the investigator are clinically significant, will be followed 
according to good medical practices and documented as such.  
 
11.2 
Serious Adverse Events  
 
11.2.1 DEFINITION: Regulations at 21 CFR §312.32 (revised April 1, 2014) defines an SAE as any untoward medical 
occurrence that at any dose has one or more of the following outcomes: 
 
• 
Death 
• 
A life-threatening AE 
• 
Inpatient hospitalization or prolongation of existing hospitalization 
• 
A persistent or significant incapacity or substantial disruption of the ability to perform normal life functions 
• 
A congenital anomaly or birth defect 
• 
Important medical events that may not be immediately life-threatening or result in death or 
hospitalization should also be considered serious when, based upon appropriate medical judgment, they 
may jeopardize the participant and may require intervention to prevent one of the other outcomes. 
 
11.2.2 Reporting SAEs to DCP 
 
11.2.2.1 
The Lead Organization and all Participating Organizations will report SAEs on the DCP SAE Report Form 
found at http://prevention.cancer.gov/clinical-trials/clinical-trials-management/protocol-information-office/pio-
instructions-and-tools/2012-consortia. 
 
11.2.2.2 
Contact the DCP Medical Monitor by phone within 24 hours of knowledge of the event.  
 
DCP Medical Monitor: 
Edward Sauter, MD, PhD 
Breast and Gynecologic Cancer Research Group 
Division of Cancer Prevention 
9609 Medical Center Dr., Rm 5E326 
Bethesda, MD 20892-9783 
Phone: (240)276-7657 
Email: edward.sauter@nih.gov 
 

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Include the following information when calling the Medical Monitor: 
• 
Date and time of the SAE 
• 
Date and time of the SAE report 
• 
Name of reporter 
• 
Call back phone number 
• 
Affiliation/Institution conducting the study 
• 
DCP protocol number 
• 
Title of protocol 
• 
Description of the SAE, including attribution to drug 
 
11.2.2.3 
The Lead Organization and all Participating Organizations will email written SAE reports to DCP’s 
Regulatory Contractor CCS Associates, Inc. (CCSA; phone: 650-691-4400) at safety@ccsainc.com within 48 hours of 
learning of the event using the fillable PDF SAE Report Form.    
  
11.2.2.4 
The DCP Medical Monitor and CCSA regulatory and safety staff will determine which SAEs require 
FDA submission as IND safety reports. 
 
11.2.2.5 
The Lead Organization and all Participating Organizations will comply with applicable regulatory 
requirements related to reporting SAEs to the IRB/IEC.  
 
11.2.3 Follow-up of SAE 
 
Site staff should send follow-up reports as requested when additional information is available. Additional information 
should be entered on the DCP SAE Report Form in the appropriate format. Follow-up information should be sent to DCP 
as soon as available. SAE related to the study agent will be followed until resolved, or deemed unlikely to further resolved 
by the Protocol Chair, or until the subject withdraws consent for further follow-up. SAE unrelated or unlikely to be related 
to study agent will be followed for at least 30 days after the last dose of study agent.    
 
12. 
STUDY MONITORING 
 
12.1 
Data Management 
 
This study will report clinical data using the OnCore application from Forte Research Systems, Inc., as stated in the 
Master Data Management Plan.  All users of the database will have appropriate education, training and experience to 
perform assigned tasks.  The data collection and management will be done according to the Consortia 2012 DMP. 
 
12.2 
Case Report Forms 
 
Participant data will be collected using protocol-specific case report forms (CRF) developed from the standard set of DCP 
Chemoprevention CRF Templates and utilizing NCI-approved Common Data Elements (CDE). The approved CRFs will 
be used to create the electronic CRF (e-CRF) screens in the OnCore application. Consortia site staff will enter data into 
the e-CRF for transmission to DCP according to pre-established DCP standards and procedures. Amended CRF will be 
submitted to the DCP Protocol Information Office for review and approval.  Approved changes will be programmed into 
the OnCore database by the Consortium Data Management staff.  
 
CRF Submission Information: 
University of Arizona Early Phase Chemoprevention Consortium Office 
Attn: Bonita Weible 
1430 E. Fort Lowell, Suite 304 
Tucson, AZ 85719 
Phone: (520) 318-7178 
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Email: UACC-CPRE@UACC.arizona.edu 
 
 
12.3 
Source Documents 
 
Source documentation for this trial will consist of protocol-specific source documents as well as clinical and research 
laboratory reports.  In the event of a Serious Adverse Event, medical records related to the event will be sought for source 
documentation of the event and its treatment, if any. 
 
12.4 
Data and Safety Monitoring Plan 
 
The University of Arizona Cancer Center (UACC) Data and Safety Monitoring Board (DSMB) will provide oversight for 
subject safety for all UA Consortium clinical trials consistent with the National Institutes of Health Policy for Data and 
Safety Monitoring dated June 10, 1998; further guidance statement issued by the NIH on June 5, 2000, and the policy for 
Data and Safety Monitoring by Data and Safety Monitoring Boards.  The UACC DSMB meets quarterly. 
 
Regular monthly meetings of the UA Consortium, are used as a forum to review accrual rates, problematic issues relating 
to accrual and protocol implementation, adverse events occurrence, follow-up, and reporting; submission of all required 
study reports; and progress and outcomes of laboratory analyses.  
 
12.5 
Sponsor or FDA Monitoring 
 
The NCI, DCP (or their designee), pharmaceutical collaborator (or their designee), or FDA may monitor/audit various 
aspects of the study. These monitors will be given access to facilities, databases, supplies and records to review and verify 
data pertinent to the study.  
 
12.6 
Record Retention 
 
Clinical records for all participants, including CRFs, all source documentation (containing evidence to study eligibility, 
history and physical findings, laboratory data, results of consultations, etc.), as well as IRB records and other regulatory 
documentation will be retained by the Investigator in a secure storage facility in compliance with Health Insurance 
Portability and Accountability Act (HIPAA), Office of Human Research Protections (OHRP), Food and Drug 
Administration (FDA) regulations and guidances, and NCI/DCP requirements, unless the standard at the site is more 
stringent. The records for all studies performed under an IND will be maintained, at a minimum, for two years after the 
approval of a New Drug Application (NDA). For NCI/DCP, records will be retained for at least three years after the 
completion of the research. NCI will be notified prior to the planned destruction of any materials. The records should be 
accessible for inspection and copying by authorized persons of the Food and Drug Administration. If the study is done 
outside of the United States, applicable regulatory requirements for the specific country participating in the study also 
apply. 
 
12.7 
Cooperative Research and Development Agreement (CRADA)/Clinical Trials Agreement (CTA) 
 
Not applicable. 
 
 
13. 
STATISTICAL CONSIDERATIONS 
 
13.1 
Study Design/Description 
 
This is a pilot study aiming to assess the feasibility of a combination regimen of 5-FU and imiquimod. As mentioned in 
Section 3, the study will have two phases:  
1. Initiation phase, which will include a total of 12 to 14 participants  

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2. Extension phase, which will include no more than the original 12 to 14 participants. 
Study participants will be given the option to continue treatment during the extension phase.  Data collected 
during this phase will be used to further assess the safety, tolerability, and efficacy of the combination therapy. 
 
13.2 
Randomization/Stratification  
 
No randomization/stratification will be performed. 
 
13.3 
Accrual and Feasibility 
 
We plan to screen/consent 14 women, assuming a screen fail rate of 10%, to have at least 12 initiating agent intervention. 
The projected accrual rate is 4/month and it is anticipated that the accrual will take 3-4 months. In addition, it is expected 
that additional delays and deferrals would occur due to menstrual periods and/or other medically-indicated reasons. 
 
13.4 
Primary Objective, Endpoint(s), Analysis Plan 
 
The primary objective of the study is to assess the feasibility of intravaginal use 5-FU and imiquimod on alternating 
weeks in women with biopsy confirmed high grade cervical squamous intraepithelial lesions (i.e., CIN3 lesions and CIN2 
lesions diagnosis confirmed by positive p16 immunohistochemistry staining).  
 
Feasiblity is evaluated based on safety and tolerability of the study intervention. For safety, we will assess the number of 
participants experiencing the dose limiting toxicity (DLT). DLT is defined as Grade 2 or greater toxicity (or Grade 1 
toxicity of any genital lesion (blisters, ulcerations, or pustules)) that is possibly, probably, or definitely related and lasts 
for more than 5 days. For tolerability, we will assess the number of participants who are not able to apply at least 50% of 
the treatment due to DLT.  
 
The proportion of participants experiencing DLT and the proportion of tolerable participants will be reported along with 
their 95% confidence intervals. We plan to accrue at least 12 participants to evaluate the feasibility of the intervention to 
determine whether this intervention is worth exploring further in a subsequent trial. If  ≥ 33% experience DLT, we will 
not proceed with further exploration using the combined agent intervention. 
 
In the prior trial conducted by Dr Rahangdale, self-administration of 5FU once every two weeks for a total of 16 weeks 
did not result in adverse events that were Grade 2 or higher34. Addition of imiquimod in alternating weeks to the 5FU 
alone treatment may increase the type or severity of the adverse events than those observed with 5FU alone. Nevertheless, 
our proposed intervention is expected to have an improved safety profile than prior trials of intravaginal imiquimod36,38 
because of the less frequent dosing of imiquimod employed in our trial. Therefore, we do not expect to observe a toxicity 
rate of greater than 30% with our study intervention. 
 
The probabilities of observing DLT in 33% or more participants for toxicity rates no greater than 30% are listed below: 
Projected toxicity rate 
Probability of observing DLT in 
≥ 33% participants 
≤ 5% 
< 1% 
10% 
2.6% 
20% 
20.5% 
30% 
50.7% 
 
The probabilities of having less than 66% tolerable participants with projected tolerability rates of 50-80% are listed 
below: 
Projected tolerability rate 
Probability of < 66% tolerable 
participants 
80% 
7.3% 

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70% 
27.6% 
60% 
56.2% 
50% 
80.6% 
 
13.5 
Secondary Objectives, Endpoints, Analysis Plans 
 
The secondary objectives include describing the response (composite endpoint based on histologic regression and 
clearance of HR-HPV) to intravaginal 5-FU and imiquimod and type specific HR-HPV clearance and measuring changes 
in the expression of biomarkers of local immune activation (including IFN-α2, IFN-Υ, IL-10, IL-12, IL-1α, -1β, -6, -8, 
MIP-1α, TNF) after treatment with self-administered intravaginal use of 5-FU and imiquimod. The response and type-
specific HR-HPV clearance will be reported along with their 95% confidence intervals. For each biomarker, the mean 
change and the associated standard deviation will be reported. Analyses will be performed on all participants who provide 
post-intervention specimens for endpoint evaluation. Assume an attrition rate of 15% (for completing intervention and 
providing post-intervention specimens). There will be at least10 participants available for the secondary analyses. Based 
on a sample size of 10, it allows us to construct a 95% confidence interval for the overall response and clearance rate, 
respectively, with a width ≤0.72.  It also allows us to construct a 95% confidence interval for the overall change in 
expression of each biomarker with a distance from the mean change ≤ 0.72 standard deviations. With an anticipated 
attrition rate of 15%, we will try to reduce the fraction of participants with missing outcomes as much as possible. Also, 
multiple imputation techniques will be used to handle missing data. Similar to the primary endpoints, each of the 
secondary endpoints will be also reported by whether or not the participants continue to the expansion phase.  
 
13.6 
Reporting and Exclusions 
 
The study will report the primary and secondary study endpoints based on the intent-to-treat population. The study may 
also report the response rate in those who have applied ≥80% of the assigned dose. 
 
 
13.7 
Evaluation of Toxicity 
 
All participants will be evaluable for toxicity from the time of their first dose of self-administered intravaginal use  5-FU 
and imiquimod. Descriptive statistics of the type and frequency of all adverse events will be generated, including 95% 
confidence intervals. 
 
13.8 
Evaluation of Response 
 
As described in Section 13.5, the analysis the response rate will be based on the intent-to-treat population. All subjects 
with endpoint data will be assessed for response to intervention.  
 
Sub-analyses may be performed on the subsets of participants, excluding those who have applied < 80% of the assigned 
application or for whom major protocol deviations have been identified (e.g., early discontinuation of intervention, major 
protocol violations, etc.).  However, sub-analyses may not serve as the basis for drawing conclusions concerning efficacy, 
and the reasons for excluding participants from the analysis should be clearly reported. 
 
 
13.9 
Interim Analysis 
 
No formal interim statistical analyses are planned for this pilot/feasibility trial.  Accrual, data collection, and any adverse 
events will be monitored on a regular basis 
 
13.10 Ancillary Studies 
 
None.  

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14. 
ETHICAL AND REGULATORY CONSIDERATIONS 
 
14.1 
Form FDA 1572 
 
Prior to initiating this study, the Protocol Lead Investigator at the Lead or Participating Organization(s) will provide a 
signed Form FDA 1572 stating that the study will be conducted in compliance with regulations for clinical investigations 
and listing the investigators, at each site that will participate in the protocol. All personnel directly involved in the 
performance of procedures required by the protocol and the collection of data should be listed on Form FDA 1572. 
 
14.2 
Other Required Documents 
 
14.2.1 Current (within two years) CV or biosketch for all study personnel listed on the Form FDA 1572 and Delegation 
of Tasks form for the Lead Organization and all Participating Organizations.  
 
14.2.2 Current medical licenses (where applicable) for all study personnel listed on Form FDA 1572 and Delegation of 
Tasks form for the Lead Organization and all Participating Organizations. 
 
14.2.3 Lab certification (e.g., CLIA, CAP) and lab normal ranges for all labs listed on Form FDA 1572 for the Lead 
Organization and all Participating Organizations. 
 
14.2.4 Documentation of training in “Protection of Human Research Subjects” for all study personnel listed on the FDA 
Form 1572 and Delegation of Tasks form for the Lead Organization and all Participating Organizations. 
 
14.2.5 Documentation of Federalwide Assurance (FWA) number for the Lead Organization and all Participating 
Organizations. 
 
14.2.6 Signed Investigator’s Brochure/Package Insert acknowledgement form 
 
14.2.7 Delegation of Tasks form for the Lead Organization and all Participating Organizations signed by the Principal 
Investigator for each site and initialed by all study personnel listed on the form 
 
14.2.8 Signed and dated NCI, DCP Financial Disclosure Form for all study personnel listed on Form FDA 1572 for the 
Lead Organization and all Participating Organizations 
 
14.3 
Institutional Review Board Approval 
 
Prior to initiating the study and receiving agent, the Investigators at the Lead Organization and the Participating 
Organization(s) must obtain written approval to conduct the study from the appropriate IRB. Should changes to the study 
become necessary, protocol amendments will be submitted to the DCP PIO according to DCP Amendment Guidelines. 
The DCP-approved amended protocol must be approved by the IRB prior to implementation 
 
 
14.4 
Informed Consent 
 
All potential study participants will be given a copy of the IRB-approved Informed Consent to review. The investigator 
will explain all aspects of the study in lay language and answer all questions regarding the study. If the participant decides 
to participate in the study, he/she will be asked to sign and date the Informed Consent document. The study agent(s) will 
not be released to a participant who has not signed the Informed Consent document. Subjects who refuse to participate or 
who withdraw from the study will be treated without prejudice. 
 

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Participants must be provided the option to allow the use of blood samples, other body fluids, and tissues obtained during 
testing, operative procedures, or other standard medical practices for further research purposes. If applicable, statement of 
this option may be included within the informed consent document or may be provided as an addendum to the consent. A 
Model Consent Form for Use of Tissue for Research is available through a link in the DCP website. 
 
Prior to study initiation, the informed consent document must be reviewed and approved by NCI, DCP, the Consortium 
Lead Organization, and the Central IRB. Any subsequent changes to the informed consent must be approved by NCI, 
DCP, and the Central IRB. 
 
14.5 
Submission of Regulatory Documents 
 
All regulatory documents are collected by the Consortia Lead Organization and reviewed for completeness and accuracy. 
Once the Consortia Lead Organization has received complete and accurate documents from a participating organization, 
the Consortium Lead Organization will forward the regulatory documents to DCP’s Regulatory Contractor: 
 
 
Paper Document/CD-ROM Submissions: 
 
Regulatory Affairs Department 
 
CCS Associates, Inc. 
 
2001 Gateway Place 
 
Suite 350 West 
 
San Jose, CA 95110 
 
Phone: 650-691-4400 
 
Fax: 650-691-4410 
 
 
E-mail Submissions: 
 
regulatory@ccsainc.com 
 
Regulatory documents that do not require an original signature may be sent electronically to the Consortium Lead 
Organization for review, which will then be electronically forwarded to DCP’s Regulatory Contractor. 
 
14.6 
Other 
 
This trial will be conducted in compliance with the protocol, Good Clinical Practice (GCP), and the applicable regulatory 
requirements. 
 
 
15. 
FINANCING, EXPENSES, AND/OR INSURANCE 
 
Study procedures performed during study visits will be covered by the study budget.  Research tests will not be billed to 
the subject.  Subjects may incur minimal out-of-pocket expenses for transportation but will not be charged for study agent 
or any study-related activities.  Subjects will receive monetary compensation which they may use at their discretion for 
out of pocket cost such as transportation.  If injury occurs, medical care will be provided and charged to the subject’s 
insurer. 
 
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Saslow D, Solomon D, Lawson HW, et al. American Cancer Society, American Society for Colposcopy and 
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Chan JK, Monk BJ, Brewer C, et al. HPV infection and the number of lifetime sexual partners are strong predictor 
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Castle PE, Schiffman M, Wheeller CM, Solomon D. Evidence for frequent regression of Cervical Intraepithelial 
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Bleecker E, Koehler E, Smith J, Budwit D, Rahangdale L. Outcomes after management of young women wth 
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Padilla-Paz LA, Carlson J, Twiggs LB. Evidence supporting the current management guidelines for high-grade 
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American College of Obstetricians and Gyncologists. Management of abnormal cervical cancer screening test 
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Katki HA, Schiffman M, Castle PE, et al. Five-year risk of recurrence after treatment of CIN 2, CIN 3, or AIS: 
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Ghaem-Maghami S, Sagi S, Majeed G, Soutter WP. Incomplete excision of cervical intraepithelial neoplasia and 
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Trottier H, Ferreira S, Thomann P, et al. Human papillomavirus infection and reinfection in adult women: the role 
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Noehr B, Jensen A, Fredricksen K, Tabor A, Kjaar SK. Loop electrosurgical excision of the cervix and 
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Rogstad KE. The psychological impact of abnormal cytology and colposcopy. Br J Obstet Gynecol. 
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Insinga RP, Dasback EJ, Elbasha EH. Assessing the annual economic burden of preventing and treating 
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Shireman TI, Tsevat J, Goldie SJ. Time costs associated with cervical cancer screening. Int J Technol Assess 
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Henk HJ, Insinga RP, Singhal PK, Darkow T. Incidence and costs of cervical intraepithelial neoplasia in a US 
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Insinga RP, Glass AG, Rush BB. The health care costs of cervical human papillomavirus-related disease. Am J 
Obstet Gynecol. 2004;191:114-120. 
25. 
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13 through 17 years --- United States, 2010. MMWR. 2010;60:1117-1123. 
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van de Nieuwenhof HP, van der Avoort IA, de Hullu JA. Review of squamous premalignant vulvar lesions. Crit 
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31. 
Maiman M, Watts DH, Andersen J, Clax P, Merino M, Kendall MA. Vaginal 5-Fluorouracil for high-grade 
cervical dysplasia in Human Immunodeficiency Virus infection: A randomized trial. Obstet Gynecol. 
1999;94:954-961. 
32. 
Syed TA, Quereshi ZA, Ahmad SA, Ali SM. Management of intravaginal warts in women with 5-flourouracil 
(1%) in vaginal hydrophilic gel: a placebo-controlled double-blind study. Int J STD AIDS. 2000;11:371-374. 
33. 
Maiman M, Watts DH, Andersen J, Clax P, Merino M, Kendall MA. Vaginal 5-fluorouracil for high-grade 
cervical dysplasia in human immunodeficiency virus infection: a randomized trial. Obstet Gynecol. 
1999;94(6):954-961. 
34. 
Rahangdale L, Lippmann Q, Garcia K, Budwit D, Smith JS, Van le L. Topical 5-fluorouracil for treatment of 
Cerivcal Intraepithelial Neoplasia 2: a randomized controlled trial. Am J Obstet Gynecol. 2014;210:e1-8. 
35. 
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events. 2004; http://www.mtnstopshiv.org/sites/default/files/attachments/Addendum 1  
Female_Genital_Grading_Table_v1_Nov_2007.pdf. Accessed September 17, 2009. 
36. 
Grimm C, Polterauer S, Natter C, et al. Treatment of cervical intraepithelial neoplasia with topical imiquimod: a 
randomized controlled trial. Obstet. Gynecol. 2012;120(1):152-159. 
37. 
Pachman DR, Barton DL, Clayton AC, et al. Randomized clinical trial of imiquimod: an adjunct to treating 
cervical dysplasia. Am. J. Obstet. Gynecol. 2012;206(1):42 e41-47. 
38. 
Lin CT, Qiu JT, Wang CJ, et al. Topical imiquimod treatment for human papillomavirus infection in patients with 
and without cervical/vaginal intraepithelial neoplasia. Taiwanese journal of obstetrics & gynecology. 
2012;51(4):533-538. 
39. 
Chen FP. Efficacy of imiquimod 5% cream for persistent human papillomavirus in genital intraepithelial 
neoplasm. Taiwanese journal of obstetrics & gynecology. 2013;52(4):475-478. 
40. 
Grillo-Ardila CF, Angel-Muller E, Salazar-Diaz LC, Gaitan HG, Ruiz-Parra AI, Lethaby A. Imiquimod for 
anogenital warts in non-immunocompromised adults. Cochrane Database Syst Rev. 2014(11). 
41. 
de Witte CJ, van de Sande AJM, van Beekhuizen HJ, Koeneman MM, Kruse AJ, Gerestein CG. Imiquimod in 
cervical, vaginal and vulvar intraepithelial neoplasia: A review. Gynecol Oncol. 2015;139:377-384. 
42. 
Federal Drug Administration. Efudex topical solutions and cream. 2005; 
http://www.accessdata.fda.gov/drugsatfda docs/label/2005/016831s049lbl.pdf. 
43. 
Federal Drug Administration. Aldara (imiquimod) 5% cream.  
https://www.accessdata.fda.gov/drugsatfda docs/label/2010/020723s022lbl.pdf. Accessed June 30, 2016. 
44. 
National Cancer Insititute. SEER Stat Fact Sheets: Cervix Uteri Cancer. 2016; 
http://seer.cancer.gov/statfacts/html/cervix.html. Accessed July 13, 2016. 
45. 
Calleja-Agius J, Brincat MP. The urogenital system and the menopause. Climacteric. 2015;18(Suppl 1):18-22. 
46. 
Terlou A, Kleinjan A, Beckmann I, et al. Nonsteroidal anti-inflammatory drugs do not interfere with imiquimod 
treatment for usual type vulvar intraepithelial neoplasia. Int J Cancer. 2011;128:2463-2469. 
47. 
Scott ME, Wilson SS, Cosentino LA, et al. Interlaboratory reproducibility of female genital tract cytokine 
measurements by Luminex: implications for microbicide safety studies. Cytokine. 2011;56:430-434. 
48. 
Scott ME, Shvetsov YB, Thompson PJ, et al. Cervical cytokins and clearance of incident human papillomavirus 
infection: Hawaii HPV cohort study. Int J Cancer. 2013;133:1187-1196. 
49. 
Scott ME, Y. M, Farhat S, Shiboski S, Moscicki AB. Covariate of cervical cytokine mRNA expression by real-
time PCR in adolescents and young women: effects of Chlamydia trachomatis infection, hormonal contraception, 
and smoking. J Clin Immunol. 2006;26:222-232. 
50. 
Daud, II, Scott ME, Ma Y, Shiboski S, Farhat S, Moscicki AB. Association between toll-like receptors expression 
and human papillomavirus type 16 persistence. Int J Cancer. 2011;128(4):879-886. 
51. 
Scott ME, Ma Y, Kuzmich L, Moscicki AB. Diminished IFN-gamma and IL-10 and elevated Foxp3 mRNA 
expression in the cervix are associated with CIN 2 or 3. Int J Cancer. 2009;124(6):1379-1383. 
 
 
 

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CONSENT FORM 
 
Study Title for Study Participants: 
Intravaginal use of 5-FU and imiquimod for women with cervical precancer. 
 
Official Study Title for Internet Search on http://www.ClinicalTrials.gov: 
A feasibility trial of alternating intravaginal application of 5-fluorouracil and imiquimod for treatment of high-
grade cervical squamous intraepithelial lesions. 
  
Introduction  
 
This is a clinical trial, a type of research study. Your study doctor will explain the clinical trial to you. Clinical 
trials include only people who choose to take part in the research. Please take your time to make your decision 
about volunteering. You may discuss your decision with your friends and family. You can also discuss this 
study with your health care team. If you have any questions, you can ask your study doctor for more of an 
explanation. You should only agree to participate in this study when you are comfortable enough with the 
information so that you can make an informed decision about joining. 
What is the usual approach to my cervical intraepithelial lesions?  
You are being asked to take part in this study because you have cervical precancer (moderate/severe 
abnormality of the cervix tissue) which increases your risk for cervical cancer. People who are at increased risk 
for cervical cancer and choose not to participate in a study have other options for treatment, including 
cryotherapy (use of cold substance to freeze and remove lesions), laser therapy (use of light beam to remove 
lesions), or surgery for treatment or removal of their cervix. 
 
What are my other choices if I do not take part in this study?  
If you decide not to take part in this study, you have other choices. For example: 
• you may choose to have the usual approach described above, 
• you may choose to take part in a different study, if one is available,  
• or you may choose to do nothing. 
 
Why is this study being done? 
The purpose of this study is to test the safety of alternating weekly applications of two intravaginal products, 5-
fluorouracil (5-FU) cream and imiquimod cream in women with cervical precancer. The study will also find out 
what effects, if any, the two products have on cervical abnormality. The abnormal tissue will be removed from 
the cervix at the end of the study. 5-FU is a drug approved in the US which has been widely used to treat several 
types of cancers. Imiquimod has been used to stimulate the body’s immune response and is also approved for 
use in the US to treat genital warts. However, 5-FU and imiquimod have not been approved for treating cervical 
precancer and the use of this drug combination is not standard of care. There will be about 12-14 women taking 
part in this study.  
What are the study groups?  
Two study drugs, 5-FU cream and imiquimod cream, will be used in this study. There will be two phases in the 
study:  
 

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Initiation Phase:  In the first phase, participants will self-administer one dose of the 5-FU cream into the vagina 
every other week (weeks 1, 3, 5, and 7). On alternate weeks (weeks 2, 4, 6, and 8) the study physician will 
apply one dose of the imiquimod cream into the vagina.  This phase will last for 8 applications and 
approximately 8 weeks.  
 
Initial Phase - Weekly treatment schedule  
WEEK  
1 
2 
3 
4 
5 
6 
7 
8 
5-FU (self-applied) 
X  
X  
X  
X 
 
Imiquimod (study physician-applied) 
 
X 
 
X 
 
X 
 
X 
 
Extension Phase:  Participants who complete the first 8 weeks of treatment will be offered the option to 
continue treatment for 8 additional applications.  During this phase, participants will self-administer one dose of 
the 5-FU cream into the vagina every other week (weeks 9, 11, 13, and 15). On alternate weeks (weeks 10, 12, 
14, and 16) the study physician will apply one dose of the imiquimod cream into the vagina.  This phase will 
also last for 8 applications (in other words, for 8 additional weeks). 
 
Extension Phase - Weekly treatment schedule 
WEEK  
9 
10 
11 
12 
13 
14 
15 
16 
5-FU (self-applied) 
X  
X 
 
X 
 
X 
 
Imiquimod (study physician-applied) 
 
X 
 
X 
 
X 
 
X 
 
A final study visit will be conducted 4-6 weeks following the final application of study medication. 
 
How long will I be in this study?  
Participation in the study will last 12 weeks or longer for those who receive 8 applications of treatment and 20 
weeks or longer for those who receive 16 applications of treatment. You will apply the 5-FU cream once every 
other week at home and the study physician will apply the imiquimod cream on alternate weeks in the clinic. 
The periods for study participation and study medication could be longer due to delays caused by your 
menstrual cycle. If you stop the study medications at any time before the end of the study, you will be asked to 
return to the clinic for an additional visit for follow up safety procedures including blood and urine tests and 
other procedures which the doctor may feel are necessary for your safety. The study team will continue to 
collect results from your medical records on any follow-up cervical exams/procedures/tests performed within 14 
months after the End of Study Visit. 
 
What extra tests and procedures will I have if I take part in this study? 
You will need to have the following exams, tests or procedures if you take part in the study.  These exams, tests 
or procedures may be part of regular care for someone with cervical precancer. However, they may be done 
more often because you are in this study.  All exams, tests and biopsies will be performed in the clinic. 
 
Before you begin the study: 
You will need to have the following extra tests, and/or procedures in a Screening Visit to find out if you can be 
in the study.  
• The study staff will discuss this consent form with you and answer any questions you may have. Once 
you have signed it, the following procedures will be done. 
• A brief physical exam including height, weight, and vital signs (blood pressure, pulse, and temperature).  

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• A review of your medical history and current medications, including any symptoms you may be 
currently experiencing. 
• Collection of 2 teaspoons of blood for routine blood tests for clinical care (a complete blood count and a 
group of blood tests to check the condition of your kidney, liver, electrolytes and blood sugar level). 
• Collection of 1 teaspoon of blood for HIV testing. If the test is positive, you will be brought in to the 
clinic and your doctor will inform you the result and refer you to specialty care. 
• Urine test for urinalysis, pregnancy, Chlamydia and Gonorrhea. Your doctor will refer you to specialty 
care if any of the tests is positive. 
• You will be given a symptom diary to record any illness or injury (adverse events) during the study.  
 
Once you are determined to be eligible to participate in the study, you will return to the clinic for the following 
procedures in a Baseline Visit: 
• A review of your symptom diary and current medications. 
• A brief physical exam including weight, and vital signs (blood pressure, pulse, and temperature).  
• You will complete tobacco and alcohol assessment forms. 
• Pelvic exam will be performed and will include the following: 
o Colposcopy, a procedure using a special lighted microscope to visualize the cervix and vaginal 
walls 
o Digital photos of the cervix 
o Collection of cells from your cervix for Human Papillomavirus  (HPV) testing using a pap smear 
brush 
o Cervicovaginal lavage, or a washing of the tissues of the vagina and cervix, to collect research 
samples 
o Collection of cells from your cervix and vaginal walls using a swab for research testings 
• Collection of 1½ teaspoons of blood for research testings.  
• Collection of urine for research testings. 
• You will be given study medication for home use and instructions for using it.  
• You will be given a study calendar to mark each day you use the study medication. 
• You will be given urine pregnancy tests to use at home prior to using the study medication and 
directions for using them. 
  
 
Weeks 1, 3, 5 and 7 
• Each week, before using the study medication, you will use a home pregnancy test.  You should only 
use the study medication if your pregnancy test is negative. 
• Study staff will contact you by telephone, text or email on weeks 1, 3, 5, and 7 to remind you to apply 
the study medication, and to review any changes in your current medications, and any symptoms you 
may be experiencing.  Study staff will also answer questions you may have about the study medication. 
• Using a vaginal applicator, you will apply the 5-FU cream into the vagina on weeks 1, 3, 5, and 7.   
• If you are menstruating when it is time to use the 5-FU cream, you should not use the cream until your 
menstrual period has ended.  You should contact the study staff for any delay in applying study 
medication (including delay for your menstrual period) as there must be a  minimum of 7 days between 
study doses.  The staff will work with you to adjust the study medication calendar. 
 
Weeks 2, 4, 6, 8 
You will return to the clinic during weeks 2, 4, 6, and 8 for the procedures listed below.  If you are menstruating 
when it is time for your appointment, you should call the study staff to reschedule your appointment as the 
study medication cannot be applied during your menstrual period. 

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• A review of your study calendar, symptom diary, current medications. 
• A brief physical exam including weight, and vital signs (blood pressure, pulse, and temperature).  
• Urine test for pregnancy. 
• Pelvic exam including colposcopy and digital photos of the cervix. Biopsies may be taken from your 
cervix if there is any evidence of worsening disease based on viewing your cervix through the 
colposcope. You will come off study if the test on the biopsies confirms worsening of the disease.  
• The study physician will apply imiquimod cream to your cervix. You will be provided with  instructions 
for your care following the application of the medication. 
• You will return unused study medication at each visit and be given more study medication to take home. 
 
At Week 8 the following additional procedures will be performed: 
• Collection of 2 teaspoons of blood for routine blood tests for clinical care (a complete blood count and a 
group of blood tests to check the condition of your kidney, liver, electrolytes and blood sugar level). 
 
If you complete all eight applications of study medication, you may be offered the option to continue 
participation in the Extension Phase of the study for an additional 8 applications (that is, for an additional 8 
weeks). The procedures for the additional 8 applications during the Extension Phase will be same as for the first 
8 applications you did during the Initial Phase.  
 
If you choose to participate in the Extension Phase, you will also have the following procedures performed at 
Visit 8: 
• Collection of 1½ teaspoons of blood for research testings.  
• Collection of urine for research testings.  
• Collection of samples from the cervix and vagina for research testings. 
 
End of Study Visit - You will return to the clinic for the following procedures 4-6 weeks after the final 
application of study medication (either after 8 applications at the end of the Initial Phase, or if you opt to 
continue participation In the Extension Phase for an additional 8 applications, this visit will occur after the 16th 
application): 
• A review of your study calendar, symptom diary, current medications. 
• A brief physical exam including weight, and vital signs (blood pressure, pulse, and temperature).  
• Urine test for urinalysis and pregnancy. 
• Collection of 2 teaspoons of blood for routine blood tests for clinical care (a complete blood count and a 
group of blood tests to check the condition of your kidney, liver, electrolytes and blood sugar level). 
• You will complete tobacco and alcohol assessment forms. 
• Pelvic exam will be performed and will include the following: 
o Colposcopy 
o Digital photos of the cervix 
o Collection of samples from cervix and vagina as described for Baseline Visit 
o Collection of additional samples from cervix using a pap smear brush and spatula for cervical 
screening test to check for abnormal cells and HPV testing 
• Biopsies will be taken of your cervix. This may be done by loop electrosurgical excision procedure 
(LEEP) using a wire loop heated by electric current to remove cells and tissue in the cervix or vagina, or 
by cone biopsy where a cone shaped piece of tissue is removed, or by colposcopy-directed biopsy. The 
study physician will decide which procedure would be best for you and will discuss this with you. You 
will sign a separate consent from for that procedure. 
• Collection of 1½ teaspoons of blood for research testings. 

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• Collection of urine for research testings. 
• Any remaining study medication will be collected. 
• You will be asked to complete a survey about your experience while participating in the study. The 
survey will take about 10 minutes to complete. The survey is optional, you do not have to complete it if 
you don’t want to. 
• Once the results of the biopsy and Pap smear are available, you will be contacted by the study staff or 
the study physician to discuss additional tests/procedures with you.   
 
Follow-up – The study physician may recommend additional exams/procedures/tests for your cervix after you 
complete the End of Study Visit. These exams/procedures/tests will be part of your standard of care. The study 
team will review your medical records and collect the results from the additional exams/procedures/tests 
performed within 14 months after the End of Study Visit. 
 
Instructions for using the study medication 
The study medications may be irritating if they come in contact with normal skin. Therefore, please follow the 
instructions below closely. 
 
Home application of 5-FU cream: 
• Store study medication at room temperature away from the reach of other individuals. 
Remember to perform a urine pregnancy test prior to using each dose of the study medication. 
Record the date of the test and the test result on the study calendar. You should only use the study 
medication if your pregnancy test is negative. 
• Using the vaginal applicator, insert the 5-FU study medication into the vagina at night once every other 
week, or as directed by the study staff.  
• After inserting the study medication, place a tampon in the vagina to keep the study medication from 
spilling out.  Applying the study medication at night, just before bed, is best since you will be lying 
down. Wash your hands thoroughly after using the study medication to avoid spreading the cream to 
other areas of your body and causing skin irritation. 
• Discard the used applicators in trash, away from the reach of other household individuals. 
• In the morning remove the tampon and take a shower.  Let all of the study medication run out and make 
sure that you wash any skin that may have come into contact with the medication. 
• During the day wear a pad (not a tampon).  If there is a lot of discharge, remember to change pads often 
so that you are not sitting for a long period of time in any excess study medication. You may have 
vaginal discharge from the study medication for several days following the last application so remember 
to continue to wear a pad.  Also, remember to wash your hands. 
• Do not use the study medication if you are having your menstrual period. You will use the study 
medication once your menstrual period has finished. The dates of your menstrual period, and the date 
you used the study medication once your period finished should be noted on the study calendar. You 
should contact the study staff for any delay in applying study medication (including delay for your 
menstrual period) as there must be a  minimum of 7 days between study doses.  The staff will work with 
you to adjust the study medication calendar. 
• Return unused study medication at your next study visit. 
 
Following applications of imiquimod cream in the clinic: 
• After the application, you will remain lying on your back for at least 30 min.  
• You will then be asked to place a tampon in the vagina. Wash your hands thoroughly to avoid spreading 
the cream to other areas of your body and causing skin irritation. 

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• Remove the tampon before going to bed and take a shower.  Let all of the study medication run out and 
make sure that you wash any skin that may have come into contact with the medication. 
• During the night wear a pad (not a tampon). You may have vaginal discharge from the study medication 
for several days following the last application so remember to continue to wear a pad.  If there is a lot of 
discharge, remember to change pads often so that you are not sitting for a long period of time in any 
excess study medication. Also, remember to wash your hands. 
 
General instructions following application of study creams: 
• Remember to avoid sexual activity (including oral sex) for at least 48 hours after each application. After 
the 48 hour waiting period, you may resume sexual activity but remember to use condoms to help 
prevent skin irritation to your sexual partner. 
• Contact the study team if you experience any symptoms or negative effects you think may be associated 
with the use of the study medication. If you experience symptoms suggestive of infection in the urinary 
tract and genital region contact the study team for further evaluation.  
o Symptoms of urinary tract infects may include a strong urge to urinate often, burning pain during 
urination, cloudy urine, blood in urine, strong urine smell, pelvic pain especially above the pubic 
bone. 
o Symptoms of infections in the genital region may include ulcers, pain, soreness, itching, burning, 
tingling, redness, swelling of the vaginal area. 
o Symptoms of an allergic reaction may include swelling, rash or hives. You may use Benadryl 
(diphenhydramine) for the symptoms. This should be recorded on the study calendar. 
• Throughout your participation in the study, you must use 2 forms of birth control during sexual activity. 
For example, use birth control pills and condoms; intrauterine device (IUD) and condoms; tubal ligation 
and condoms.  
• Vaginal douching is not permitted during the study participation. 
• You may apply the over-the-counter lidocaine jelly or a topical protective barrier cream to the outer 
vaginal area and/or take oral ibuprofen, as necessary, to reduce irritation or discomfort that you may 
experience from the study agent.  
• Please call the study physician, _________ (insert name of study doctor), at __________ (insert phone 
number) or email at _____________ (insert email) if you have any questions or problems. 
 
As part of this study you will also be asked to answer questions about your tobacco and alcohol use, both before 
you begin the study and again at the End of Study visit. Researchers want to see if tobacco and alcohol use 
affects the side effects people might get while on this study, or if tobacco and alcohol use modifies the effects of 
the study agents. 
 
What possible risks can I expect from taking part in this study?  
 
 
If you choose to take part in this study, there is a risk that you may:  
• Lose time at work or home and spend more time in the hospital or doctor’s office than usual. 
• Be asked sensitive or private questions which you normally do not discuss, for example about your 
tobacco and alcohol use. There is a risk someone could get access to the personal information in your 
medical records or other information researchers have kept about you. Someone might be able to trace 
this information back to you. The researchers believe the chance that someone will identify you is very 
small, but the risk may change in the future as people come up with new ways of tracing information. 
The researchers believe the chance these things will happen is very small, but cannot promise that they 
will not occur.  

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The 5-FU and imiquimod products used in this study have not been approved for intravaginal use and may 
affect how different parts of your body work, such as your liver, kidneys, heart, and blood. The study doctor 
will be testing your blood and will let you know if changes occur that may affect your health.  
 
There is also a risk that you could have side effects.  
 
Here are important points about side effects: 
• The study doctors do not know who will or will not have side effects. 
• Some side effects may go away soon, some may last a long time, or some may never go away.  
• Some side effects may be serious and may even result in death.  
 
Here are important points about how you and the study doctor can make side effects less of a problem: 
• Tell the study doctor if you notice or feel anything different so they can see if you are having a side 
effect. 
• The study doctor may be able to treat some side effects. 
• The study doctor may adjust the schedule of study drugs application to try to reduce side effects. 
 
Intravaginal use of 5-FU cream has been previously studied in women with cervical precancer. Based on the 
previous studies, possible side effects for intravaginal use of 5-FU cream include: 
Common, some may be serious 
In 100 people receiving intravaginal 5-FU, more than 20 may have: 
• 
itching  
• 
burning 
• 
irritation in the vagina 
• 
redness in the vagina 
• 
vaginal discharge 
• 
vaginal bleeding  
 
If you notice ulceration in the vagina or on the outside surface of the genital area indicated by pain or unusual 
bleeding, do not administer the 5-FU cream.  
 
5-FU should not be used in people with partial or complete dihydropyrimidine dehydrogenase (DPD) enzyme 
deficiency. This is a metabolic disorder in which the body cannot break down certain substances and can cause 
neurological problems. This condition can also cause toxic reactions to some types of drugs such as 5-FU. It is 
possible to have this condition and not be aware of it.  
 
Stop using 5-FU and notify your study physician immediately if you experience severe abdominal pain, 
bloody diarrhea, vomiting, fever, chills. mouth sores, any abnormal bleeding, redness, swelling, numbness, 
peeling of the skin on the palms and soles (hand-foot syndrome); shortness of breath; or hair loss. If you are 
unable to contact the study physician, call <insert phone number> and ask for the gynecologist on call. 
 
Exposure to ultraviolet light (e.g., tanning beds, excessive unprotected sun exposure) should be avoided during 
treatment with 5-FU since it can increase the intensity of a drug reaction. 
 
Intravaginal application of imiquimod has also been studied in a previous study of women with cervical 
precancer. Based on the previous study, the possible side effects for intravaginal application of imiquimod 
include: 

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Common, some may be serious 
In 100 people receiving intravaginal imiquimod, more than 20 may have: 
• 
pain on the outside surface of the genital area  
• 
itching on the outside surface of the genital area 
• 
redness in the vagina and on the outside surface of the genital area 
• 
swelling in the vagina and on the outside surface of the genital area 
• 
erosion in the vagina and on the outside surface of the genital area 
• 
ulceration in the vagina and on the outside surface of the genital area (symptoms include pain, 
unusual bleeding) 
• 
flu-like symptoms 
• 
fatigue  
• 
chills 
• 
vaginal discharge 
• 
headache 
• 
muscle aches 
Occasional, some may be serious 
In 100 people receiving intravaginal imiquimod, from 4 to 20 may have 
• 
fever 
 
If you have an allergic reaction (swelling, rash, hives) to the study medication, call the study physician to report 
it. You may use Benadryl (diphenhydramine) for the symptoms. This should be recorded on the study calendar. 
 
In the previous study, the imiquimod product was applied to the vagina more often (total 42 applications over 
16 weeks) than the frequency to be used in this study (total 8 applications over 16 weeks). There is a possibility 
that a participant in this study may experience fewer side effects.   
 
The side effects from using 5-FU and imiquimod vaginal products in alternating weeks are not known. There is 
a risk that you may experience vaginal scarring as a result of this experimental treatment although this has not 
been reported in prior studies of intravaginal application of 5-FU or imiquimod.     
 
Careful hand washing after using the cream is important to avoid skin irritation to other parts of the body. 
 
Reproductive risks: You should not get pregnant or breastfeed while in this study. The drugs used in this study 
could be very damaging to an unborn baby. You must use two forms of contraception while participating in 
sexual activity throughout the study.  For example, use birth control pills and condoms, intrauterine device 
(IUD) and condoms, tubal ligation and condoms.  If you are pregnant, you will not be enrolled on this study. If 
you become pregnant or suspect that you are pregnant, you must tell your study doctor right away. Getting 
pregnant will result in your removal from this study. 
 
Risks from biopsy: You may have cramping during the biopsy. You may have a brownish discharge for one or 
two days. If LEEP is done, you may experience some mild pain, discomfort, or bleeding. Notify your doctor if 
you have heavy bleeding (heavier than your usual menstrual period) or significant pain. 
Risks related to blood tests: Blood tests can cause mild discomfort, bruising and/or bleeding at the blood draw 
site. Less likely is the possibility of significant bleeding or infection. 
 
What possible benefits can I expect from taking part in this study? 
This study may or may not help you because we do not know how the study drugs will compare to the usual 
approach for your condition. This study may help us learn things that could help people in the future. 
 

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Can I stop taking part in this study? 
Yes. You can decide to stop at any time. If you decide to stop for any reason, it is important to let the study 
doctor know as soon as possible so you can stop safely and get the treatment you need for your cervical disease. 
If you stop, you can decide whether or not to let the study doctor continue to provide your medical information 
to the organization running the study.  
For the tobacco and alcohol use questions, you can decide not to answer some or all of the questions. Your 
decision will not affect whether you can participate in the study, and it will not affect your relationship with 
your doctor or the study staff. 
 
The study doctor will tell you about any new information or changes in the study that could affect your 
health or your willingness to continue in the study. 
The study doctor may take you out of the study: 
• If your health changes.  
• If you become pregnant. 
• If your cervical disease worsens. 
• If the study is no longer in your best interest. 
• If new information becomes available. 
• If you do not follow the study rules. 
• If the study is stopped early for any reason by the sponsor, IRB or FDA. 
 
What are my rights in this study? 
Taking part in this study is your choice. No matter what decision you make, and even if your decision changes, 
there will be no penalty to you. You will not lose medical care or any legal rights. For questions about your 
rights while in this study, call the ______________________ (insert name of center) Institutional Review 
Board at __________________ (insert telephone number).  
 
What are the costs of taking part in this study? 
The 5-FU and imiquimod products will be supplied at no charge while you take part in this study. Condoms, 
pregnancy test kits, and instructions on agent application will also be supplied at no cost. The cost of study-
specific exams, tests, and any other procedures such as HIV testing and the colposcopies will be paid for by the 
study. 
 
Some costs associated with your care may be considered standard of care (such as biopsies, pap smear, LEEP), 
and will be billed to you or your insurance company. You will have to pay for any costs (including deductibles 
and co-payments) not covered by your health insurer. 
 
Before you decide to be in the study, you should check with your health plan or insurance company to find out 
exactly what they will pay for.  
 
You will receive $50 per visit for completing each of the following visits: Baseline Visit, Week 2, Week 4, 
Week 6 and Week 8 visits. You will receive $60 per visit for completing each of the following visits: Week 10, 
Week 12, Week 14 and Week 16 visits, if you decide to continue into the extension phase of the study. You will 
receive an additional $100 for the End of Study Visit, regardless of whether the end of study occurs at 8 weeks 
or 16 weeks. If extra visits to the clinic are required to find out if you can be in the study, you will receive $50 
for each extra visit. You will receive an additional $10 for completing the survey at the end of the study. This 

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money is to reimburse you for your time and help cover any costs you may have in being on the study.  
 
What happens if I am injured or hurt because I took part in this study? 
If you feel you have been injured or hurt as a result of taking part in the study, it is important that you tell the 
study doctor immediately. You will get medical treatment if you are injured or hurt as a result of taking part in 
this study.  
 
The study sponsors will not offer to pay for medical treatment for injury. Your insurance company may not be 
willing to pay for study-related injury. If you have no insurance coverage, you would be responsible for any 
costs. Even though you are in a study, you keep all of your legal rights to receive payment for injury caused by 
medical errors. 
 
Who will see my medical information?  
 
Your privacy is very important to us and we will make every effort to protect it. Your information may be given 
out if required by law. For example, certain states require doctors to report to health boards if they find a disease 
like tuberculosis. However, we will do our best to make sure that any information that is released will not be 
able to identify you. Some of your health information, and/or information about your specimen, from this study 
will be kept in a central database for research. Your name or contact information will not be put in the database. 
 
There are organizations that may inspect your records. These organizations are required to make sure your 
information is kept private. Some of these organizations are: 
• The study sponsor, the National Cancer Institute (NCI) and NCI agents and partners. 
• The authorized representatives of the study Coordinating Center, the University of Arizona Cancer 
Center. 
• The Institutional Review Board, IRB, is a group of people who review the research with the goal of 
protecting the people who take part in the study. 
• The Food and Drug Administration and the National Cancer Institute in the US. 
• The National Cancer Institute will obtain information for this clinical trial under data collection 
authority Title 42 U.S.C. 285. 
• Every health care personnel who provides services to you in connection with this study.  
• Any laboratories, other individuals/organizations that analyze your health information in 
 
connection with this study as defined by protocol. 
 
Where can I get more information? 
The National Cancer Institute will obtain information from this clinical trial under data collection authority Title 
42 U.S.C. 285. 
 
You may visit the NCI website at http://cancer.gov/ for more information about studies or general 
information about cancer. You may also call the NCI Cancer Information Service to get the same 
information at: 1-800-4-CANCER (1-800-422-6237).  
 
A description of this clinical trial will be available on http://www.ClinicalTrials.gov, as  required by US law. 
This website will not include information that can identify you. At most, the website will include a summary of 
the results. You can search this website at any time. 
 
 

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Who can answer my questions about this study? 
You can talk to the study doctor about any questions or concerns you have about this study or to report side 
effects or injuries. Contact the study doctor __________________ (insert name of study doctor[s]) at 
__________________ (insert telephone number). 
 
THIS SECTION IS ABOUT OPTIONAL STUDIES YOU CAN CHOOSE TO TAKE PART IN. 
There may be some specimens (cervical samples, blood, urine) remaining once the study is complete. The 
researchers would like to store and use your remaining samples for future medical research. The research that 
may be done is unknown at this time but your samples could help researchers to find new ways to prevent, 
detect, treat, or cure health problems, including cervical cancer. Some of these studies may be about genes. 
Genes carry information about features that are found in you and in people who are related to you. Researchers 
are interested in the way that genes affect how your body responds to treatment. You can take part in the main 
research study described above without giving your consent for your samples to be stored.  
 
WHAT IS INVOLVED?  
If you agree to take part, here is what will happen next: 
1) Your remaining samples will be stored at the study institution until the end of the study. 
2) After study completion, your remaining samples and some related information may be transferred to a 
central facility (Biobank) supported by the National Institutes of Health and stored in the Biobank along 
with samples and information from other people who take part.  
3) Qualified researchers can submit a request to use the materials stored. A research committee will review 
each request. There will also be an ethics review to ensure that the request is necessary and proper. 
Researchers will not be given your name or any other information that could directly identify you.  
4) Neither you nor your study doctor will be notified if/when research is conducted using your samples.  
5) Some of your genetic and health information may be placed in central databases that may be public, 
along with information from many other people. Information that could directly identify you will not be 
included.  
 
WHAT ARE THE POSSIBLE RISKS?  
1) There is a risk that someone could get access to the personal information in your medical records or 
other information we have stored about you.  
2) There is a risk that someone could trace the information in a central database back to you. Even without 
your name or other identifiers, your genetic information is unique to you. The researchers believe the 
chance that someone will identify you is very small, but the risk may change in the future as people 
come up with new ways of tracing information.  
 
There are laws against the misuse of genetic information, but they may not give full protection. New 
health information about inherited traits that might affect you or your blood relatives could be found 
during a study. The researchers believe the chance these things will happen is very small, but cannot 
promise that they will not occur.  
 
A new Federal law, called the Genetic Information Nondiscrimination Act (GINA), generally makes it 
illegal for health insurance companies, group health plans, and most employers to discriminate against 
you based on your genetic information. This law generally will protect you in the following ways: 
 
• Health insurance companies and group health plans may not request your genetic 
information that we get from this research.  

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• Health insurance companies and group health plans may not use your genetic information 
when making decisions regarding your eligibility or premiums. 
 
Employers with 15 or more employees may not use your genetic information that we get from this 
research when making a decision to hire, promote, or fire you or when setting the terms of your 
employment. All health insurance companies and group health plans must follow this law by May 21, 
2010. All employers with 15 or more employees must follow this law as of November 21, 2009. 
 
 
 
Be aware that this new Federal law does not protect you against genetic discrimination by companies 
that sell life insurance, disability insurance, or long-term care insurance.  
 
3) There are laws against the misuse of genetic information, but they may not give full protection. New 
health information about inherited traits that might affect you or your blood relatives could be found 
during a study. The researchers believe the chance these things will happen is very small, but cannot 
promise that they will not occur. 
 
 
HOW WILL INFORMATION ABOUT ME BE KEPT PRIVATE?  
Your privacy is very important to the researchers and they will make every effort to protect it. Here are just a 
few of the steps they will take: 
1) When your sample(s) is sent to the researchers, no information identifying you (such as your name or 
social security number) will be sent. Samples will be identified by a unique study code only.  
2) The list that links the unique code to your name will be kept separate from your sample and health 
information. Any Biobank and the study team with access to the list must sign an agreement to keep 
your identity confidential. 
3) Researchers to whom the study team sends your sample and information will not know who you are. 
They must also sign an agreement that they will not try to find out who you are. 
4) Information that identifies you will not be given to anyone, unless required by law. 
5) If research results are published, your name and other personal information will not be used. 
 
WHAT ARE THE POSSIBLE BENEFITS?  
You will not benefit from taking part in the optional studies. The researchers, using the samples from you and 
others, might make discoveries that could help people in the future. 
 
ARE THERE ANY COSTS OR PAYMENTS?  
There are no costs to you or your insurance. If any of the research leads to new tests, drugs, or other commercial 
products, you will not share in any profits. 
 
 
WHAT IF I CHANGE MY MIND?  
If you decide you no longer want your samples to be used, you can call the study doctor, _________________, 
(insert name of study doctor for main trial) at ________________________ (insert telephone number of study 
doctor for main trial) who will let the researchers know. Then, any sample that remains in the bank will no 
longer be used. Samples or related information that have already been given to or used by researchers will not 
be returned. 
 
WHAT IF I HAVE MORE QUESTIONS?  
If you have questions about the use of your samples for research, contact the study doctor, 
_________________, (insert name of study doctor for main trial) at ________________________ (insert 
telephone number of study doctor for main trial). 

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Please circle your answer to show whether or not you would like to take part in each option.  
 
SAMPLES AND INFORMATION FOR FUTURE RESEARCH STUDIES: 
 
 
Indicate your choice of “yes” or “no” for each of the following studies.  
 
1.  My remaining samples and related information may be kept in a Biobank for use in future health research.   
 
Yes     
No  
 
2. The information from my tobacco and alcohol use questionnaires may be used in future health research. 
        Yes         No 
 
3.  I agree that my study doctor, or their representative, may contact me or my physician to see if I wish to 
participate in other research in the future. 
 
Yes     
No  
 
4. My genetic data and health information can be released, with no direct identifiers, into scientific databases. 
 
  Yes     
No  
 
This is the end of the section about optional studies. 
 
My Signature Agreeing to Take Part in the Main Study 
I have read this consent form or had it read to me. I have discussed it with the study doctor and my questions 
have been answered. I will be given a signed copy of this form. I agree to take part in the main study and any 
additional studies where I circled ‘yes’.  
 
Participant’s signature ______________________________________________________ 
 
Date of signature _____________________________ 
 
Signature of person(s) conducting the informed consent discussion 
 
_____________________________________________________________________________ 
 
Date of signature _________________________  

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APPENDIX A 
Performance Status Criteria 
 
 
Karnofsky Performance Scale 
Percent 
Description 
100 
Normal, no complaints, no 
evidence of disease. 
90 
Able to carry on normal activity; 
minor signs or symptoms of 
disease. 
80 
Normal activity with effort; some 
signs or symptoms of disease. 
70 
Cares for self, unable to carry on 
normal activity or to do active 
work. 
60 
Requires occasional assistance, but 
is able to care for most of his/her 
needs. 
50 
Requires considerable assistance 
and frequent medical care. 
40 
Disabled, requires special care and 
assistance. 
30 
Severely disabled, hospitalization 
indicated. Death not imminent. 
20 
Very sick, hospitalization 
indicated. Death not imminent. 
10 
Moribund, fatal processes 
progressing rapidly. 
0 
Dead. 
 
 
 

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APPENDIX C 
TOBACCO ASSESSMENT – BASELINE 
 
REGISTERING INSTITUTION  
 
_________________________________ 
PARTICIPANT ID 
 
______________________ 
VISIT TYPE 
 
 BASELINE  
VISIT DATE 
(MM/DD/YYYY) 
___ ___ / ___ ___ / ___ ___ ___ ___ 
 
Instructions:  
When a number is requested in the response, please enter a whole number (i.e. “4”) and not a range or fraction of 
a number 
 
Section A. Basic Cigarette Use Information 
 
1. Have you smoked at least 100 cigarettes (5 packs = 100 cigarettes) in your entire life? 
 
Yes  
 
 No → Skip to Section B 
 Don’t know/Not sure → Skip to Section B 
 
2. How old were you when you first smoked a cigarette (even one or two puffs)? 
 
_______ Years old  
 
3. How old were you when you first began smoking cigarettes regularly?   
 
_______ Years old  
  Check here if you have never smoked cigarettes regularly. 
 
4. How many total years have you smoked (or did you smoke) cigarettes? Do not count any time you may have stayed off 
cigarettes. 
 
______ Years (If you smoked less than one year, write “1.”)  
 
5. On average when you have smoked, about how many cigarettes do you (or did you) smoke a day? (A pack usually has 
20 cigarettes in it).  
 
_____ Number of cigarettes per day 
 
6. Do you NOW smoke cigarettes?  
 
 Everyday 
 Some days 
 Not at all → Skip to question 8 
 
7.  How soon after you wake up do you smoke your first cigarette?  
 
  Within 30 minutes 
  After 30 minutes

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8. How long has it been since you last smoked a cigarette (even one or two puffs)? 
 
First check which one of the following choices applies to you. Then, if applicable, write a number on the line 
for how many days, weeks, months, or years it has been since your last cigarette. 
 
 I smoked a cigarette today (at least one puff) 
 1-7 days → Number of days since last cigarette  ________ 
 Less than 1 month → Number of weeks since last cigarette  _________ 
 Less than 1 year → Number of months since last cigarette  __________ 
 More than 1 year → Number of years since last cigarette  ___________ 
 Don’t know/Don’t remember 
 
Section B. Use of Other Forms of Tobacco 
 
9.  Have you ever used other forms of tobacco, not including cigarettes? 
  
 Yes  
 No → Skip to Section C 
 
10. How often do you/did you use other forms of tobacco?  
 
 Every day → Number of times per day  ________ 
 Some days → Number of days _______ per 
 Week 
 Month 
Year 
 
11. Which of the following products have you ever used regularly? 
 Check all that apply  
 
 Cigarettes 
 E-cigarettes or other electronic nicotine delivery system 
 Traditional cigars, cigarillos or filtered cigars 
 Pipes 
 Waterpipe 
 Hookah 
 Clove cigarettes or kreteks 
 Bidis  
 Smokeless tobacco, like dip, chew, or snuff 
 Snus 
 Paan with tobacco, gutka, zarda, khaini 
 Other, Please specify:___________________________

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12. If you do not currently use other forms of tobacco, but did in the past, how long has it been since you last used other 
forms of tobacco regularly?  
 
 Within the past month (0 to 1 month ago) 
 Between 1 and 3 months (1 to 3 months ago) 
 Between 3 and 6 months (3 to 6 months ago) 
 Between 6 and 12 months (6 to 12 months ago) 
 Between 1 and 5 years (1 to 5 years ago) 
 Between 5 and 15 years (5 to 15 years ago) 
 More than 15 years ago 
 Don’t know/Not sure 
 Never used other forms of tobacco regularly 
 
Section C. Second-Hand Smoke Exposure 
 
13. Are you currently living with a smoker?   
 
Yes 
 
 No  
 
14. In the past 30 days, have you lived in a place where other people smoked cigarettes indoors?  
 
Yes 
 
 No  
 
15. In the past 30 days, have you worked in a place where other people smoked cigarettes indoors? 
 
Yes 
 
 No  
 
16. Thinking of all your childhood and adult years, have you ever lived in a place where other people smoked cigarettes 
indoors? 
 
 Yes 
In total, for about how many years?_______ If less than 1, write “1.”   
 No  
 
17. Thinking of all the years you have worked, have you ever worked in a place where other people smoked cigarettes 
indoors?    
 
Yes 
→ In total, for about how many years?_______ If less than 1, write “1.”    
 No 
 
 
Investigator Signature  _______________________________   Date  __ __ / __ __ / __ __ __ __ 
 
(MM/DD/YYYY) 
Investigator Name (please print)  ___________________________________________________ 

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TOBACCO ASSESSMENT - FOLLOW-UP 
REGISTERING INSTITUTION 
 
_________________________________ 
PARTICIPANT ID 
 
______________________ 
VISIT TYPE 
 
__________________________ 
VISIT DATE 
(MM/DD/YYYY) 
___ ___ / ___ ___ / ___ ___ ___ ___ 
 
Instructions:  
When a number is requested in the response, please enter a whole number (i.e. “4”) and not a range or fraction of 
a number.  
 
1. Do you NOW smoke cigarettes?  
 
 Everyday 
 Some days 
 Not at all → Skip to Question 3. 
 Never smoked → Skip to Question 4 
 
2. On average, when you smoked, about how many cigarettes do you (or did you) smoke a day? (A pack usually has 20 
cigarettes in it).    
 
_____ Number of cigarettes per day 
 
3. How long has it been since you last smoked a cigarette (even one or two puffs)?    
 
First check which one of the following choices applies to you. Then, if applicable, write a whole number on the line for 
how many days, weeks, months, or years it has been since your last cigarette. 
 
 I smoked a cigarette today (at least one puff) 
 1-7 days → Number of days since last cigarette ________ 
 Less than 1 month → Number of weeks since last cigarette _________ 
 Less than 1 year → Number of months since last cigarette __________ 
 More than 1 year → Number of years since last cigarette ___________ 
 Don’t know/Don’t remember 
 
4. Since your last visit, have you used other forms of tobacco, not including cigarettes?  
 
 Yes 
  No (End) 
 
5. How often do you/did you use other forms of tobacco?  
 
 Every day → Number of times per day ________ 
 Some days → Number of days _______ per 
 Week 
 Month 
Year

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6. Since your last visit, which of the following products have you used?  Check all that apply 
 
 Cigarettes 
 E-cigarettes or other electronic nicotine delivery system 
 Traditional cigars, cigarillos or filtered cigars 
 Pipes 
 Waterpipe 
 Hookah 
 Clove cigarettes or kreteks 
 Bidis  
 Smokeless tobacco, like dip, chew, or snuff 
 Snus 
 Paan with tobacco, gutka, zarda, khaini 
 Other, Specify____________________________________________________________________ 
 
7. If you do not currently use other forms of tobacco, but did in the past, how long has it been since you last used other 
forms of tobacco regularly?  
 
 Within the past month (0 to 1 month ago) 
 Between 1 and 3 months (1 to 3 months ago) 
 Between 3 and 6 months (3 to 6 months ago) 
 Between 6 and 12 months (6 to 12 months ago) 
 Between 1 and 5 years (1 to 5 years ago) 
 Between 5 and 15 years (5 to 15 years ago) 
 More than 15 years ago 
 Don’t know/Not sure 
 Never used other forms of tobacco regularly 
 
The following instructions pertain to questions 8 - 10.  During each of the following time frames, please indicate 
whether you smoked cigarettes every day, some days, or not at all. 
 
8.  During study treatment 
 
 Smoked every day 
 Smoked some days 
 Did not smoke at all 
 Don’t know/not sure 
 Not applicable  
 
9.  After the end of study treatment 
 
 
 Smoked every day 
 Smoked some days 
 Did not smoke at all 
 Don’t know/not sure 
 Not applicable (I have not completed the study treatment)

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10.  Since your last visit to this clinic 
 
 
 Smoked every day 
 Smoked some days 
 Did not smoke at all 
 Don’t know/not sure 
 
 
 
Investigator Signature _______________________________       Date __ __ / __ __ / __ __ __ __ 
(MM/DD/YYYY) 
 
 
Investigator Name (please print) __________________________________________________ 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 

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ALCOHOL ASSESSMENT – BASELINE 
REGISTERING INSTITUTION  
 
_________________________________ 
PARTICIPANT ID 
 
______________________ 
VISIT TYPE 
 
__________________________ 
VISIT DATE 
(MM/DD/YYYY) 
___ ___ / ___ ___ / ___ ___ ___ ___ 
Instructions: 
For the following questions about drinking alcoholic beverages, a drink means a 12 oz. beer, a 5 oz. glass of wine, 
or one and a half ounces of liquor. 
When a number is requested in the response, please enter a whole number (i.e. “4”) and not a range or fraction of 
a number.  
 
1. In your entire life, have you had at least 12 drinks of any kind of alcoholic beverage?  
 
 Yes 
 No (End) 
 Refused (End) 
 Don’t know/Not sure 
 
2. In the past 12 months, on average, how often did you drink any type of alcoholic beverage?  
 
________ (Enter the number of days you drank based on the timeframe checked below.  Enter 0 if you never drank 
and skip to Question 6.)  
 Week  
 Month 
 Year 
 Refused 
 Don’t know/Not sure 
 
3. In the past 12 months, on those days that you drank alcoholic beverages, on average, how many drinks   
did you have per day?  
 
________ (Enter the average number of drinks per day) 
 
 Refused 
 Don’t know/Not sure 
 
4. In the past 12 months, on how many days did you have 5 or more drinks of any alcoholic beverage?  
 
_________ (Enter the number of days you had 5 or more drinks, or enter 0 if none.) 
 
 Refused 
 Don’t know/Not sure 
 
5. Was there ever a time or times in your life when you drank 5 or more drinks of any kind of alcoholic beverage almost 
every day?  
 
 Yes 
 No  
 Refused 
 Don’t know/Not sure 

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6. If you do not currently drink alcoholic beverages, but did in the past, how long has it been since 
you last drank regularly?  
 
 Within the past month (0 to 1 month ago) 
 Between 1 and 3 months (1 to 3 months ago) 
 Between 3 and 6 months (3 to 6 months ago) 
 Between 6 and 12 months (6 to 12 months ago) 
 Between 1 and 5 years (1 to 5 years ago) 
 Between 5 and 15 years (5 to 15 years ago) 
 More than 15 years ago  
 Don’t know/Not sure 
 Never drank regularly 
 
7. At the heaviest point, either now or in the past, on the days when you drank, about how many drinks did you drink a 
day on the average?  
 
__________ (Enter the number of drinks a day) 
  
 Refused 
 Don’t know/Not sure 
 
8. How many years have you been drinking (or did drink) regularly?  
 
______ years 
 
 Refused 
 Don’t know/Not sure  
 
9. At what age did you begin drinking regularly?  
 
______ years of age 
 
 Refused 
 Don’t know/Not sure  
 
10. What type(s) of alcohol do you drink? (Mark ALL that apply) 
 
 Wine 
 Liquor 
 Beer 
 Wine cooler 
 
Investigator Signature _______________________________   Date __ __ / __ __ / __ __ __ __ 
 
(MM/DD/YYYY) 
 
 
Investigator Name (please print) ___________________________________________

 
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ALCOHOL ASSESSMENT - FOLLOW-UP 
 
REGISTERING 
INSTITUTION  
 
_________________________________ 
PARTICIPANT ID 
 
______________________ 
VISIT TYPE 
 
__________________________ 
VISIT DATE 
(MM/DD/YYYY) 
___ ___ / ___ ___ / ___ ___ ___ ___ 
Instructions: 
For the following questions about drinking alcoholic beverages, a drink means a 12 oz. beer, a 5 oz. glass 
of wine, or one and a half ounces of liquor. 
When a number is requested in the response, please enter a whole number (i.e. “4”) and not a range or 
fraction of a number. 
 
1. During the past 30 days, did you drink any alcoholic beverages?  
 
 Yes 
 No (End) 
 Refused (End) 
 Don’t know/Not sure 
 
2. During the past 30 days, how many days per week or per month did you drink any alcoholic beverages, on 
the average?  
 
________ (Enter number of days you drank based on the timeframe checked below.  Enter 0 if you did not 
drink.)  
 
 Week  
 Month 
 Refused 
 Don’t know/Not sure 
 
3. On the days when you drank, on average, about how many drinks did you have?  
 
________ (Enter the average number of drinks you had per day.) 
 
 Refused 
 Don’t know/Not sure 
 
4. In the past 30 days, on how many days did you have 5 or more drinks per day?  
 
_____________ (Enter the number of days you had 5 or more drinks, or enter 0 if none.) 
 
 Refused  
 Do not know/Not sure 
 
 
Investigator Signature _______________________________   Date __ __ / __ __ / __ __ __ __ (MM/DD/YYYY) 
 
 
Investigator Name (please print) __________________________________

 
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APPENDIX D 
Telephone Consent for Participant Survey 
 
Hello, my name is ____________ (name of person calling) and I am from the _____________ (insert 
institution name). 
 
I am calling you because you recently participated in Dr. Rahangdale’s cervical study at our site and 
we would like to see if you would be interested in taking a survey about your experiences in that 
study. This call will take 10-15 minutes. Is this a good time to talk? 
 
If No: Is there a better time to speak to you about this survey? (Get time and best phone number to 
reach them). If they aren’t interested in being called again, thank them and disconnect phone contact.   
 
If Yes: Continue with the script 
We are interested in your thoughts and experiences while participating in the study. The survey will 
take about 10 minutes to complete. If you agree to take the survey, I can ask you the survey questions 
now while we’re on the phone, or I will mail or email it to you and you can return it to us either by 
return mail or email. You will receive $10 for completing the survey. Participation in taking this 
survey is voluntary. You can decide not to complete the survey without any consequences to any on-
going care. 
 
Do you have any questions?     ☐ Yes           ☐ No 
 
Note questions, if any: 
__________________________________________________________________________________
__________________________________________________________________________ 
 
Would you be interested in taking the survey? 
 
☐ No: If Patient DOES NOT agree: Thank her for the call and do not proceed further. 
 
☐ Yes: Would you like to take the survey now over the phone or have it mailed/emailed to you?  
 
☐ If participant would like to take the survey over the phone now you must obtain verbal consent prior 
to initiating survey: Please note that this will be documented as your verbal consent to continue with  
the survey. Document date and time of verbal consent given before continuing with the survey. Staff 
member calling must also sign and date this form and proceed with the survey. 
 
☐ If participant would rather receive survey in the mail/email:  
Please note that this will be documented as your verbal consent to provide you with the survey.  
 
Document date and time of verbal consent given.  Staff member calling must also sign and date this 
form. 
 
Verbal consent given at __________ am/pm on   _____________ (date). 
 
Participant’s Name: _____________________________________________________________ 

 
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Address/Email address (for mailing/emailing the survey): 
__________________________________________________________________________________
__________________________________________________________________________________
______________________________________________________________________ 
 
 
____________________________________ 
 
______________________________ 
Signature of staff member calling 
 
 
 
Date of call