Cervical Intraepithelial Neoplasia Grade 1, Cervical Intraepithelial Neoplasia Grade 2/3, Cervical Intraepithelial Neoplasia Grade 3, Cervix Cancer, CIN, CIN1, CIN2, CIN3, HIV Infections, HPV Infection
Conditions
Keywords
5-fluorouracil (5FU), thermal ablation (TA), placebo, intravaginal topical
Brief summary
This randomized, placebo-controlled trial will evaluate self-administered 5-fluorouracil (5FU) to improve human papillomavirus (HPV) clearance after thermal ablation (TA) in Women With Human Immunodeficiency Virus (HIV) (WWH) in Kenya. The trial will also assess the safety, adherence, and acceptability of 5FU. Starting four weeks after TA, participants will self-administer 5FU cream or matched placebo intravaginally once every other week for 12 applications, with clinic visits at weeks 2, 8, 16, 24, and 48 for evaluation. All participants will be followed up to 48 weeks. It is hypothesized that, compared to placebo, 5FU will increase HPV clearance at 24 weeks and that the proposed dosing schedule will be safe, well-tolerated, and acceptable in this population. Together with data from other studies, this trial will provide evidence on the use of self-administered intravaginal 5FU to improve HPV treatment outcomes in WWH in low- and middle-income countries, where the burden of cervical cancer is highest.
Detailed description
WWH face up to six times higher risk of cervical cancer, a leading cause of death in this population. Cervical cancer is caused by persistent HPV infection, which can lead to cervical intraepithelial neoplasia grade 2/3 (CIN2/3), also called cervical precancer. If untreated, CIN2/3 can progress to cervical cancer. Thermal ablation (TA) is the most commonly used treatment for HPV/precancer in low- and middle-income countries, including Kenya. However, among WWH, TA has suboptimal efficacy, with only 44-66% clearing HPV or CIN2/3 at 6-12 months, compared to 83-95% in women without HIV. This highlights the need for adjuvant therapies to improve outcomes. Studies in high-income countries suggest that off-label, self-administered intravaginal 5FU cream can improve HPV and CIN2/3 treatment outcomes in both HIV-negative and HIV-positive women. This trial will evaluate its potential as an adjuvant therapy following TA in WWH.
Interventions
DRUG5% 5-fluorouracil Topical Cream
Starting four weeks after thermal ablation, participants will self-administer 2 g of 5FU cream intravaginally once every two weeks for 12 doses.
DRUGPlacebo Cream
Starting four weeks after thermal ablation, participants will self-administer 2g of placebo cream intravaginally once every two weeks for 12 doses.
Sponsors
UNC Lineberger Comprehensive Cancer Center
National Cancer Institute (NCI)
UNC Department of Obstetrics and Gynecology
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
DOUBLE (Subject, Investigator)
Eligibility
Sex/Gender
FEMALE
Age
25 Years to No maximum
Healthy volunteers
No
Inclusion criteria
* Women aged 25 years or older * Known HIV-positive status * On antiretroviral therapy (ART) for at least 60 days prior to enrollment * Positive HPV screening test screening result * Able to provide informed consent in English, Swahili, or Dholuo * Agree to use dual contraception during dosing phase if of childbearing potential * Planning to remain in study locale for duration of study (48 weeks)
Exclusion criteria
* Current pregnancy or breastfeeding * History of anogenital cancer (cervical, vulvar, or anal) * Current use of immunosuppressive medications * History of total hysterectomy * Known allergy to 5FU * Medical comorbidity that would interfere with study participation * Unwilling or unable to use contraception during study participation
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| High-risk human papillomavirus (hrHPV) Clearance among WWH randomized to adjuvant self-administered 5FU cream versus placebo cream following Thermal ablation (TA) | Up to 24 weeks | Vaginal samples will be collected at baseline and approximately every four weeks. Clearance of hrHPV genotypes will be assessed using Polymerase Chain Reaction (PCR)-based human papillomavirus (HPV) Deoxyribonucleic Acid (DNA) testing on these follow-up samples. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Adverse Event per National Cancer Institute Common Terminology Criteria for Adverse Events (NCI CTCAE) v5.0 | 24 weeks | Type, frequency, severity and duration of adverse events (AEs) using NCI CTCAE v5.0 will be reported. The NCI Common Terminology Criteria for Adverse Events is a descriptive terminology which can be utilized for Adverse Event (AE) reporting. A grading (severity) scale is provided for each AE term. Grade 1 Mild; asymptomatic or mild symptoms; clinical or diagnostic observations only; intervention not indicated. Grade 2 Moderate; minimal, local or noninvasive intervention indicated; limiting age-appropriate instrumental Activities of Daily Living (ADL). Grade 3 Severe or medically significant but not immediately life-threatening; hospitalization or prolongation of hospitalization indicated; disabling; limiting self-care ADL. Grade 4 Life-threatening consequences; urgent intervention indicated. Grade 5 Death related to AE. |
| Adverse Event per National Institute of Health (NIH) Division of Acquired Immunodeficiency Syndrome (AIDS) Adverse Event Grading Criteria (DAIDS) | Up to 24 weeks | Type, frequency, severity and duration of adverse events (AEs) using per DAIDS standardized scales will be reported. The DAIDS grading table provides an AE severity grading scale ranging from grades 1 to 5 with descriptions for each AE based on the following general guidelines: Grade 1 indicates a mild event, Grade 2 indicates a moderate event, Grade 3 indicates a severe event, Grade 4 indicates a potentially life-threatening event, Grade 5 indicates death. |
| Number of successful self-administration of the intravaginal cream by participants | Up to 24 weeks | Number of confirmed successful self-administrations of intravaginal 5FU or placebo cream by participants. |
Countries
Kenya
Contacts
CONTACTSorgi Kate
PRINCIPAL_INVESTIGATORChemtai Mungo, MD, MPH
UNC Lineberger Comprehensive Cancer Center
Outcome results
None listed