Cervical Cancer, CIN2, CIN3, Human Immunodeficiency Virus, Human Papillomavirus
Conditions
Keywords
5-fluorouracil cream, Loop electrosurgical excision
Brief summary
The purpose of this study is to explore whether an anti-cancer medication (5-fluorouracil cream) placed in the vagina after a surgical excision procedure is an acceptable and useful form of treatment for cervical precancer among the woman with HIV infection.
Detailed description
There are currently no medical therapies recommended to promote the clearance of human papillomavirus (HPV) infection, regression of cervical dysplasia, or treatment of cervical intraepithelial neoplasia (CIN). Human immunodeficiency virus (HIV)-infected women are at higher risk of HPV infection, with rates as high as 45% - 90%. Despite being preventable, cytologic abnormalities, cervical precancer (high-grade cervical intraepithelial neoplasia \[CIN2/3\]), and invasive cervical cancer also occur more frequently in HIV infected women. This study is testing whether topical 5-fluorouracil (5FU) can be used as a patient-controlled adjuvant treatment for cervical precancer (CIN2/3) to be self-administered after surgical excision to reduce the risk of persistent/recurrent CIN2/3 and progression to cervical cancer among HIV-infected women.
Interventions
DRUG5 Fluorouracil (5 FU) Cream
Intravaginal topical chemotherapy, 5-fluorouracil cream
DRUGPlacebo
Intravaginal topical placebo cream
Sponsors
UNC Lineberger Comprehensive Cancer Center
National Cancer Institute (NCI)
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
PREVENTION
Masking
QUADRUPLE (Subject, Caregiver, Investigator, Outcomes Assessor)
Eligibility
Sex/Gender
FEMALE
Age
18 Years to No maximum
Healthy volunteers
No
Inclusion criteria
* Confirmed HIV-1 infection * On antiretroviral therapy (ART), for at least 90 days prior to enrollment * Cervical biopsy demonstrating CIN2/3 within the preceding 120 days.
Exclusion criteria
* pregnancy, * breastfeeding, * intend to become pregnant within 180 days of enrollment * have an active sexually transmitted infection (women may participate once treated) * have a surgically absent cervix * have a history of anogenital (cervical, vaginal, vulvar, or anal) cancer or a biopsy suspicious for cervical cancer * have a medical comorbidity that would interfere with study participation.
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Number of Participants Retained in the Study Through Week 24 | Baseline (Week 0) through Week 24 | Retention was defined as the number of participants who remained in follow-up and completed the Week 24 study visit. The number and percentage of participants retained at Week 24 were reported for each study arm. |
| Number of Participants With ≥80% Acceptability Summary Score at Week 10 | Week 10 | Acceptability was defined as a summary score ≥80% on a 7-item questionnaire administered at Week 10. Each item was rated on a 5-point Likert scale and coded from 0 (lowest acceptability) to 4 (highest acceptability), yielding a total possible score of 0 to 28. A summary acceptability score was calculated as a percentage (0% to 100%) of the total possible score. The number and percentage of participants meeting this definition were reported for each study arm. |
| Number of Participants With ≥80% Acceptability Summary Score by Week 24 | Week 24 | Acceptability was defined as a summary score ≥80% on the same 7-item questionnaire administered at Week 24. Each item was rated on a 5-point Likert scale and coded from 0 (lowest acceptability) to 4 (highest acceptability), yielding a total possible score of 0 to 28. A summary acceptability score was calculated as a percentage (0% to 100%) of the total possible score. The number and percentage of participants meeting this definition were reported for each study arm. |
| Number of Participants Experiencing a Treatment-Related Grade ≥2 Adverse Event or Grade 1 Genital Lesion | Week 4 (randomization) through Week 24 | A safety event was defined as any Grade 2 or higher adverse event (AE), or any Grade 1 AE involving a genital lesion (blister, ulceration, or pustule), that was assessed as possibly, probably, or definitely related to the study drug. Adverse events were assessed from Week 4 (randomization) through Week 24. The number and percentage of participants experiencing at least one such event were reported for each study arm. |
| Number of Participants Unable or Unwilling to Apply ≥50% of Study Cream Doses Due to Dose-Limiting Toxicity | Week 4 (randomization) through Week 18 | A tolerability event was defined as inability or unwillingness to apply ≥4 of 8 planned doses of the study treatment due to a dose-limiting toxicity (DLT). A DLT was defined as (1) any Grade 2 or higher AE, or (2) any Grade 1 AE involving a genital lesion (blister, ulceration, or pustule), that was assessed as possibly, probably, or definitely related to study drug and resulted in an investigator decision to reduce the number of doses or discontinue study treatment. Tolerability was assessed from randomization through the dosing period (Week 18), with follow-up censored at the last tolerability assessment for participants who exited early without experiencing an event. The number and percentage of participants experiencing a tolerability event were reported for each study arm. |
| Number of Participants Adherent to ≥75% of Study Cream Doses Based on Ultraviolet Inspection | Week 4 (randomization) through Week 24 | Adherence was defined as administration of at ≥6 of 8 planned doses of study treatment, as determined by ultraviolet inspection of returned applicators. Applicator collection occurred through Week 24, including for participants who completed dosing earlier, to allow complete ascertainment of dose use. Each applicator was independently assessed by ≥2 reviewers; in cases of disagreement, a third reviewer adjudicated the result. Participants were classified as adherent if ≥6 applicators showed evidence of use. Participants who did not meet this threshold, including those with missing or incomplete applicator data, were classified as non-adherent. The number and percentage of participants meeting this definition were reported for each study arm. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Percent of Participants With CIN2/3 at Baseline Who Regressed to CIN1 or Normal Histology at Week 24 | Baseline (Week 0) through Week 24 | The analysis population included all randomized participants, all of whom had CIN2 or CIN3 at baseline (Week 0) confirmed by loop electrosurgical excision procedure (LEEP) histology. The analysis population was restricted to participants who completed the Week 24 visit and had cervical biopsy results available. This included 89 participants in the placebo arm and 81 participants in the 5FU arm. Regression was defined as improvement from CIN2 or CIN3 at baseline to CIN1 or normal histology at Week 24, as assessed by cervical biopsy. Participants missing Week 24 data were not included and not considered to have experienced CIN2/3 regression. The number and percentage of participants meeting this definition were reported for each study arm. The Wilson score method was used to estimate 95% confidence intervals around percentages. |
| Percent of Participants With Baseline High-Risk HPV Who Achieved Genotype-Specific Clearance at Week 24 | Baseline (Week 0) through Week 24 | The analysis population was restricted to participants with at least one high-risk HPV (hrHPV) genotype detected at baseline and with hrHPV results available at Week 24. A total of 69 participants in the 5FU arm and 80 participants in the placebo arm met these criteria. High-risk HPV clearance was defined as absence at Week 24 of all hrHPV genotypes detected at baseline. Participants without baseline hrHPV infection or without Week 24 hrHPV results were excluded from this analysis. The number and percentage of participants meeting this definition were reported for each study arm. The Wilson score method was used to estimate 95% confidence intervals around percentages. |
Countries
South Africa
Contacts
PRINCIPAL_INVESTIGATORCarla Chibwesha, MD, MSc
University of North Carolina, Chapel Hill
Baseline characteristics
| Characteristic | — |
|---|---|
| Age, Continuous | 42 years |
| High-Risk HPV Positive | 77 Participants |
| HPV Vaccination | 0 Participants |
| Race (NIH/OMB) American Indian or Alaska Native | 0 Participants |
| Race (NIH/OMB) Asian | 0 Participants |
| Race (NIH/OMB) Black or African American | 90 Participants |
| Race (NIH/OMB) More than one race | 0 Participants |
| Race (NIH/OMB) Native Hawaiian or Other Pacific Islander | 0 Participants |
| Race (NIH/OMB) Unknown or Not Reported | 0 Participants |
| Race (NIH/OMB) White | 0 Participants |
| Region of Enrollment South Africa | 180 Participants |
| Sex: Female, Male Female | 90 Participants |
| Sex: Female, Male Male | 0 Participants |
| Years Since HIV Diagnosis | 9 years |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk | EG002 affected / at risk | EG003 affected / at risk |
|---|---|---|---|---|
| deaths Total, all-cause mortality | 0 / 90 | 0 / 90 | 0 / 90 | 0 / 90 |
| other Total, other adverse events | 79 / 90 | 74 / 90 | 2 / 90 | 3 / 90 |
| serious Total, serious adverse events | 2 / 90 | 1 / 90 | 1 / 90 | 0 / 90 |
Outcome results
None listed