Anal Intraepithelial Neoplasia, High-grade Squamous Intraepithelial Lesion, HIV Infection
Conditions
Brief summary
This randomized phase III trial studies imiquimod or fluorouracil to see how well they work compared to observation in treating patients with high-grade anal squamous skin lesions who are human immunodeficiency virus (HIV)-positive. Biological therapies, such as imiquimod, may stimulate the immune system in different ways and stop tumor cells from growing. Drugs used in chemotherapy, such as fluorouracil, work in different ways to stop the growth of tumor cells, either by killing the cells or by stopping them from dividing. It is not yet known whether imiquimod or fluorouracil is more effective than observation in treating high-grade anal squamous skin lesions.
Detailed description
PRIMARY OBJECTIVES: I. To assess the efficacy of intra-anal imiquimod 2.5% for treatment of anal high-grade squamous intraepithelial lesions (HSIL) compared to observation only. II. To assess the efficacy of intra-anal topical 5-fluorouracil (fluorouracil) 5% for treatment of anal HSIL compared to observation only. SECONDARY OBJECTIVES: I. To assess the safety and tolerability of intra-anal imiquimod 2.5% and topical 5-fluorouracil 5%. II. To compare the efficacy of intra-anal imiquimod 2.5% and topical 5-fluorouracil 5%. III. To assess for partial response of intra-anal imiquimod 2.5% or topical 5-fluorouracil 5% as compared to observation only. IV. To evaluate the effect of intra-anal imiquimod 2.5% and topical 5-fluorouracil 5% on human papilloma virus (HPV) persistence. V. To evaluate anal HSIL outcomes at week 44. VI. To evaluate the effect of behavioral patterns including tobacco smoking and sexual activity on treatment efficacy, tolerability and HPV. OUTLINE: Patients are randomized to 1 of 3 treatment arms. ARM A: Patients apply imiquimod intra-anally once daily (QD) for 16 weeks. (closed as of protocol version 5.0) ARM B: Patients apply fluorouracil intra-anally twice daily (BID) on days 1-5. Treatment repeats every 2 weeks for 8 courses in the absence of disease progression or unacceptable toxicity. ARM C: Patients receive no treatment. Patients who still have HSIL at week 20 and who agree to randomization may cross-over to Arm A or B. After completion of study treatment, patients are followed up at weeks 20, 24, 26, 32, 40, and 44.
Interventions
DRUGimiquimod
Given intra-anally
DRUGfluorouracil
Given intra-anally
OTHERquestionnaire administration
Ancillary studies
OTHERlaboratory biomarker analysis
Correlative studies
Sponsors
National Cancer Institute (NCI)
The Emmes Company, LLC
University of Arkansas
AIDS Malignancy Consortium
Study design
Allocation
RANDOMIZED
Intervention model
CROSSOVER
Primary purpose
TREATMENT
Masking
SINGLE (Outcomes Assessor)
Eligibility
Sex/Gender
ALL
Age
21 Years to No maximum
Healthy volunteers
No
Inclusion criteria
* HIV-positive; documentation of HIV infection must be based on a federally approved, licensed HIV test performed in conjunction with screening (enzyme linked immunosorbent assay \[ELISA\], western blot, or other test); alternatively, this documentation may include a record that another physician has documented that the patient has HIV based on prior ELISA and western blot; an approved antibody test will be used to confirm diagnosis; if the physician is treating a patient with combination antiretroviral therapy (cART) with a history of HIV positivity based on an approved antibody test then repeat antibody confirmation is not necessary * Biopsy-proven HSIL (anal intraepithelial neoplasia 2 (AIN2) and/or AIN3) of the anal canal at either the squamocolumnar junction or distal anus, documented within 60 days prior to enrollment, but not less than 1 week prior to enrollment * HSIL occupies at least 25% of the circumference of the anal canal at either the squamocolumnar junction or distal anus on high-resolution anoscopy (HRA) at screening or entry based on available biopsy results and visual appearance * Anal HSIL lesions are visible at study entry and no lesions are suspicious for invasive cancer * Ability to understand and willing to provide informed consent * Participants must, in the opinion of the Investigator, be capable of complying with the requirements of this protocol including self-administration of study treatment * Karnofsky performance status of \>= 70% * Cluster of differentiation (CD)4 count \>= 200 within 120 days prior to enrollment or plasma HIV-1 ribonucleic acid (RNA) \< 200 copies/mL within 120 days prior to enrollment * For females, cervical cytology (if having a cervix) and gynecologic evaluation within 12 months prior to enrollment * Absolute neutrophil count (ANC) \> 750 cells/mm\^3 within 90 days prior to enrollment * Hemoglobin \>= 9.0 g/dL within 90 days prior to enrollment * Platelet count \>= 75,000/mm\^3 within 90 days prior to enrollment
Exclusion criteria
* History of anal cancer * Prior intra-anal use of topical 5-fluorouracil 5% or imiquimod 2.5%, 3.75% or 5% at any point, or use of perianal imiquimod 2.5%, 3.75% or 5% or topical 5-fluorouracil 5% within 6 months prior to enrollment * Extensive concurrent perianal or lower vulvar HSIL or condyloma requiring a different treatment modality than the study treatment, or treatment that cannot be deferred in observation arm, per examining provider * Condyloma occupying more than 50% of the circumference of the anal canal or that obscures a satisfactory exam * Ongoing use of anticoagulant therapy other than aspirin or nonsteroidal anti-inflammatory drugs (NSAIDs) * Acute treatment for an infection (excluding fungal infection of the skin and sexually transmitted infections) or other serious medical illness within 14 days prior to study entry * Malignancy requiring systemic therapy; note: Kaposi's sarcoma limited to the skin is not exclusionary unless requiring systemic chemotherapy * Concurrent systemic corticosteroids, cytokines, and immunomodulatory therapy (e.g. interferons) * Prior history of HPV vaccination * Treatment for anal or perianal HSIL, low-grade squamous intraepithelial lesion (LSIL) or condyloma within 4 months of entry; please note that infrared coagulation (IRC) or electrocautery of a biopsy site to stop bleeding does not constitute treatment * Female participants who are pregnant or breastfeeding; women of childbearing potential must have a negative urine or serum pregnancy test within 72 hours prior to initiating study treatment; all women of childbearing potential must be willing to comply with an acceptable birth control regimen to prevent pregnancy while receiving treatment and for 3 months after treatment is discontinued as determined by the Investigator; post-menopausal women must be amenorrheic for at least 12 months to be considered of non-childbearing potential; (note: a woman of childbearing potential is one who is biologically capable of becoming pregnant; this includes women who are using contraceptives or whose sexual partners are either sterile or using contraceptives)
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Number of Participants With Intra-anal HSIL | At week 20 | Intra-anal HSIL lesions are those lesions that are detected in intra-anal region. It will be detected using visual inspection using HRA followed by positive identification of HSIL using biopsy or cytology. Presence of intra-anal HSIL lesions will be descriptively reported across the three arms |
| Percentage of Participants Achieving Complete Response in 5-FU Arm and Observation Arm Using ITT Population | At week 20 | Complete response is defined as the absence of HSIL histology for all biopsies and the absence of HSIL cytology. The percentage of participants achieving complete response in the 5-FU and observation arms will be reported and compared across sites, along with the corresponding p-value, using stratified Mantel-Haenszel-Cochran tests at a one-sided alpha level of 0.025. |
| Percentage of Participants Achieving Complete Response (5-FU vs Observation ) Using Per Protocol Population | At week 20 | Complete response is defined as the absence of HSIL histology for all biopsies and the absence of HSIL cytology. The percentage of participants achieving complete response in the 5-FU and observation arms will be reported, along with the corresponding p-value, using stratified Mantel-Haenszel-Cochran tests to compare results across sites at a one-sided alpha level of 0.025. |
| Percentage of Participants Achieving Complete Response in 5-FU vs. Imiquimod, Using the ITT Population Restricted to Those Randomized to Either Treatment Prior to the Closure of the Imiquimod Arm. | Week 20 | Complete response is defined as an absence of HSIL histology for all biopsies and the absence of HSIL cytology. Compare the percentage of complete response in 5-FU vs Imiquimod arms across sites using stratified CMH test at one-sided 0.05 alpha. |
| Percentage of Participants Achieving Complete Response in 5-FU vs. Imiquimod, Using the PP Population Restricted to Those Randomized to Either Treatment Prior to the Closure of the Imiquimod Arm. | Week 20 | Complete response is defined as the absence of HSIL histology for all biopsies and the absence of HSIL cytology. Compare the complete response by 5-FU vs Imiquimod across sites using stratified CMH test at one-sided 0.05 alpha using only the participants randomized to imiquimod and 5-FU prior to closure of the imiquimod arm. |
| Percentage of Participants Achieving Complete Response in Imiquimod vs Observation Arm, Using ITT Population Restricted to Those Randomized to Either Treatment Prior to the Closure of the Imiquimod Arm. | Week 20 | Complete response is defined as the absence of HSIL histology for all biopsies and the absence of HSIL cytology. Compare the complete response by Observation vs Imiquimod across sites using stratified CMH test at two-sided 0.05 alpha using only the participants randomized to imiquimod and observation prior to closure of the imiquimod arm. |
| Percentage of Participants Achieving Complete Response in Imiquimod vs Observation Arm, Using Per Protocol Population Restricted to Those Randomized to Either Treatment Prior to the Closure of the Imiquimod Arm. | Week 20 | Complete response is defined as the absence of HSIL histology for all biopsies and the absence of HSIL cytology. Compare the complete response by Observation vs Imiquimod across sites using stratified CMH test at two-sided 0.05 alpha using only the participants randomized to imiquimod and observation prior to closure of the imiquimod arm. |
| Number of Participants With Peri-anal HSIL Confirmed by Histology Across All Study Arms | At week 20 | Perianal HSIL are HSIL lesions detected in peri-anal region; These lesions will be detected by visual inspection using high resolution anoscopy and biopsy. Number of participants with presence of peri-anal HSIL on histology |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Number of Participants Who Experienced an Adverse Event of Grade 1 to 5 by Week 44, Irrespective of Relatedness to the Intervention. AEs Were Stratified According to Those Reported at or Before Week 20 and After Week 20. | Up to week 44 | Adverse events are graded on a scale from 1 (mild) to 5 (death) as per CTCAE v. 5.0, with higher grades indicating greater severity. The number of participants who experienced an adverse event of grade 1 to 5 by Week 44, regardless of its relatedness to the intervention, will be reported. AEs were stratified according to those reported at or before Week 20 and after Week 20. |
| Percentage of Participants Achieving Complete or Partial Response in 5-FU vs Observation Using ITT Population | Up to week 20 | Complete response is defined as the absence of HSIL histology for all biopsies and the absence of HSIL cytology. Partial response is defined as either 1) The regression of HSIL histology but HSIL cytology is present, or 2) Reduction in number of octants with HSIL. Percentages will be compared across sites using the stratified Mantel-Haenszel-Cochran test at the two-sided 0.05 alpha level. |
| Percentageof Patients Achieving Complete or Partial Response in Imiquimod vs Observation Arm, Using ITT Population Restricted to Those Randomized to Either Treatment Prior to the Closure of the Imiquimod Arm. | Up to week 20 | Complete response is defined as the absence of HSIL histology for all biopsies and the absence of HSIL cytology. Partial response is defined as 1) The regression of HSIL histology but HSIL cytology is present, or 2) Reduction in number of octants with HSIL. Percentage of patients achieving complete or partial responses with imiquimod will be compared to observation using participants randomized to imiquimod and observation prior to closure of the imiquimod arm. |
| Amount of Drug Consumed in 5-FU and Imiquimod Arm by Week 16 | Week 16 | Amount of study drug consumed by measuring the mass of study drug dispensed (weight of study drug container at baseline - weight of study drug at the end of treatment) by study arm (5FU vs imiquimod) by the time of receiving 8 cycle treatment |
| Percentage of Patients Achieving Complete or Partial Response in Imiquimod vs Observation Arm, Using ITT Population Restricted to Those Randomized to Either Treatment Prior to the Closure of the Imiquimod Arm. | Up to week 44 | The proportion of patients achieving complete or partial responses with imiquimod will be compared to observation using participants randomized to imiquimod and observation prior to closure of the imiquimod arm. Complete response is defined as the absence of HSIL based on central pathology review, if available; otherwise, local biopsy results will be used. Partial Response is defined as: 1) The regression of HSIL histology but HSIL cytology is present, or 2) Reduction in number of octants with HSIL. |
| Persistence and New Infections of HPV Type Specific Infections | At week 20 | The proportion of participants with persistent HPV infection, defined as the presence of the same HPV type detected at both baseline and Week 20. The proportion of participants who acquire a new HPV infection at Week 20 that was not detected at baseline is new infection. Persistence and new infection will be assessed separately for each HPV type. |
| Comparison of the Number of hrHPV Genotypes in Each Arm Observed at Baseline vs at Week 20 | week 20 | hrHPV genotypes will be detected in anal swabs specimens processed using polymerase chain reaction (PCR) and reverse line blot analysis. Comparison of mean number of hrHPV genotypes in each arm observed at baseline vs at week 20 |
| HPV Genotypes Present at Baseline But no Longer Detected at Week 20 | 20 weeks | Count of HPV genotypes present at baseline but no longer detected at week 20. |
Countries
Puerto Rico, United States
Participant flow
Recruitment details
Patients were screened between December 2015 to August 2022 at one of the 11 AMC sites certified by the HPV Working Group in HRA. Participants were selected from established HSIL-positive clinic patients or referrals from physicians, such as primary care physicians, HIV specialists, dermatologists, or colorectal surgeons.
Pre-assignment details
142 patients were screened using HRA, clinical examination and laboratory tests (within 90 days) to ensure they meet the eligibility criteria. 91 patients were considered eligible and assigned to one of the three study arms.
Participants by arm
| Arm | Count |
|---|---|
| Arm A (Imiquimod) Patients apply imiquimod intra-anally QD for 16 weeks.
imiquimod: Given intra-anally
questionnaire administration: Ancillary studies
laboratory biomarker analysis: Correlative studies | 18 |
| Arm B (Fluorouracil) Patients apply fluorouracil intra-anally BID on days 1-5. Treatment repeats every 2 weeks for 8 courses in the absence of disease progression or unacceptable toxicity.
fluorouracil: Given intra-anally
questionnaire administration: Ancillary studies
laboratory biomarker analysis: Correlative studies | 36 |
| Arm C (Observation) Patients receive no treatment. Patients who still have HSIL at week 20 and who agree to randomization may cross-over to Arm A or B. | 37 |
| Total | 91 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 | FG002 |
|---|---|---|---|---|
| Cross-over Post-week 20 (Re-randomized) | Lost to Follow-up | 0 | 3 | 0 |
| Post-week 20 | Lost to Follow-up | 0 | 2 | 0 |
| Post-week 20 | Treatment not as per protocol criteria | 3 | 4 | 9 |
| Post-week 20 | Withdrawal by Subject | 0 | 1 | 0 |
| Upto Week 20 | Lost to Follow-up | 2 | 6 | 0 |
| Upto Week 20 | No treatment per protocol criteria | 0 | 0 | 5 |
| Upto Week 20 | Treatment completed per protocol criteria | 0 | 2 | 0 |
| Upto Week 20 | Withdrawal by Subject | 1 | 1 | 0 |
Baseline characteristics
| Characteristic | Arm B (Fluorouracil) | Arm C (Observation) | Arm A (Imiquimod) | Total |
|---|---|---|---|---|
| Age, Continuous | 43.1 years STANDARD_DEVIATION 12.9 | 44.7 years STANDARD_DEVIATION 14 | 48.2 years STANDARD_DEVIATION 14.3 | 44.8 years STANDARD_DEVIATION 13.6 |
| Cytology at baseline Atypical Squamous Cells, cannot exclude High-grade Squamous Intraepithelial Lesion (ASC-H) or HSIL | 21 Participants | 19 Participants | 8 Participants | 48 Participants |
| Cytology at baseline Atypical Squamous Cells of Undetermined Significance (ASCUS) | 11 Participants | 12 Participants | 7 Participants | 30 Participants |
| Cytology at baseline Low-grade Squamous Intraepithelial Lesion (LSIL) | 3 Participants | 4 Participants | 2 Participants | 9 Participants |
| Cytology at baseline Normal | 1 Participants | 2 Participants | 1 Participants | 4 Participants |
| Ethnicity (NIH/OMB) Hispanic or Latino | 13 Participants | 13 Participants | 4 Participants | 30 Participants |
| Ethnicity (NIH/OMB) Not Hispanic or Latino | 21 Participants | 22 Participants | 14 Participants | 57 Participants |
| Ethnicity (NIH/OMB) Unknown or Not Reported | 2 Participants | 2 Participants | 0 Participants | 4 Participants |
| Number of octants involved as per visual appearance and biopsy performed through HRA | 4 octant | 4 octant | 4 octant | 4 octant |
| Race (NIH/OMB) American Indian or Alaska Native | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Asian | 1 Participants | 1 Participants | 1 Participants | 3 Participants |
| Race (NIH/OMB) Black or African American | 11 Participants | 14 Participants | 5 Participants | 30 Participants |
| Race (NIH/OMB) More than one race | 2 Participants | 3 Participants | 1 Participants | 6 Participants |
| Race (NIH/OMB) Native Hawaiian or Other Pacific Islander | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Unknown or Not Reported | 6 Participants | 3 Participants | 2 Participants | 11 Participants |
| Race (NIH/OMB) White | 16 Participants | 16 Participants | 9 Participants | 41 Participants |
| Sex: Female, Male Female | 6 Participants | 5 Participants | 2 Participants | 13 Participants |
| Sex: Female, Male Male | 30 Participants | 32 Participants | 16 Participants | 78 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk | EG002 affected / at risk | EG003 affected / at risk | EG004 affected / at risk | EG005 affected / at risk |
|---|---|---|---|---|---|---|
| deaths Total, all-cause mortality | 0 / 18 | 0 / 36 | 0 / 37 | 0 / 5 | 0 / 14 | 0 / 13 |
| other Total, other adverse events | 2 / 18 | 5 / 36 | 2 / 37 | 0 / 5 | 1 / 14 | 0 / 13 |
| serious Total, serious adverse events | 2 / 18 | 4 / 36 | 0 / 37 | 0 / 5 | 0 / 14 | 0 / 13 |
Outcome results
Primary
Number of Participants With Intra-anal HSIL
Intra-anal HSIL lesions are those lesions that are detected in intra-anal region. It will be detected using visual inspection using HRA followed by positive identification of HSIL using biopsy or cytology. Presence of intra-anal HSIL lesions will be descriptively reported across the three arms
Time frame: At week 20
Population: ITT
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Arm C (Observation) | Number of Participants With Intra-anal HSIL | 12 Participants |
| Arm B (Fluorouracil) | Number of Participants With Intra-anal HSIL | 27 Participants |
| Arm C (Observation) | Number of Participants With Intra-anal HSIL | 32 Participants |
Primary
Number of Participants With Peri-anal HSIL Confirmed by Histology Across All Study Arms
Perianal HSIL are HSIL lesions detected in peri-anal region; These lesions will be detected by visual inspection using high resolution anoscopy and biopsy. Number of participants with presence of peri-anal HSIL on histology
Time frame: At week 20
Population: Enrolled patients in each study arm
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Arm C (Observation) | Number of Participants With Peri-anal HSIL Confirmed by Histology Across All Study Arms | 1 Participants |
| Arm B (Fluorouracil) | Number of Participants With Peri-anal HSIL Confirmed by Histology Across All Study Arms | 0 Participants |
| Arm C (Observation) | Number of Participants With Peri-anal HSIL Confirmed by Histology Across All Study Arms | 0 Participants |
Primary
Percentage of Participants Achieving Complete Response (5-FU vs Observation ) Using Per Protocol Population
Complete response is defined as the absence of HSIL histology for all biopsies and the absence of HSIL cytology. The percentage of participants achieving complete response in the 5-FU and observation arms will be reported, along with the corresponding p-value, using stratified Mantel-Haenszel-Cochran tests to compare results across sites at a one-sided alpha level of 0.025.
Time frame: At week 20
Population: Per protocol population
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Arm C (Observation) | Percentage of Participants Achieving Complete Response (5-FU vs Observation ) Using Per Protocol Population | 9 Participants |
| Arm B (Fluorouracil) | Percentage of Participants Achieving Complete Response (5-FU vs Observation ) Using Per Protocol Population | 5 Participants |
p-value: 0.1068Cochran-Mantel-Haenszel
Primary
Percentage of Participants Achieving Complete Response in 5-FU Arm and Observation Arm Using ITT Population
Complete response is defined as the absence of HSIL histology for all biopsies and the absence of HSIL cytology. The percentage of participants achieving complete response in the 5-FU and observation arms will be reported and compared across sites, along with the corresponding p-value, using stratified Mantel-Haenszel-Cochran tests at a one-sided alpha level of 0.025.
Time frame: At week 20
Population: ITT population
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Arm C (Observation) | Percentage of Participants Achieving Complete Response in 5-FU Arm and Observation Arm Using ITT Population | 5 Participants |
| Arm B (Fluorouracil) | Percentage of Participants Achieving Complete Response in 5-FU Arm and Observation Arm Using ITT Population | 9 Participants |
p-value: 0.1877Cochran-Mantel-Haenszel
Primary
Percentage of Participants Achieving Complete Response in 5-FU vs. Imiquimod, Using the ITT Population Restricted to Those Randomized to Either Treatment Prior to the Closure of the Imiquimod Arm.
Complete response is defined as an absence of HSIL histology for all biopsies and the absence of HSIL cytology. Compare the percentage of complete response in 5-FU vs Imiquimod arms across sites using stratified CMH test at one-sided 0.05 alpha.
Time frame: Week 20
Population: ITT population. Since the imiquimod arm was stopped early, this comparison uses only the ITT subset with participants randomized to imiquimod and 5-FU prior to closure of the imiquimod arm.
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Arm C (Observation) | Percentage of Participants Achieving Complete Response in 5-FU vs. Imiquimod, Using the ITT Population Restricted to Those Randomized to Either Treatment Prior to the Closure of the Imiquimod Arm. | 5 Participants |
| Arm B (Fluorouracil) | Percentage of Participants Achieving Complete Response in 5-FU vs. Imiquimod, Using the ITT Population Restricted to Those Randomized to Either Treatment Prior to the Closure of the Imiquimod Arm. | 5 Participants |
p-value: 0.8071Cochran-Mantel-Haenszel
Primary
Percentage of Participants Achieving Complete Response in 5-FU vs. Imiquimod, Using the PP Population Restricted to Those Randomized to Either Treatment Prior to the Closure of the Imiquimod Arm.
Complete response is defined as the absence of HSIL histology for all biopsies and the absence of HSIL cytology. Compare the complete response by 5-FU vs Imiquimod across sites using stratified CMH test at one-sided 0.05 alpha using only the participants randomized to imiquimod and 5-FU prior to closure of the imiquimod arm.
Time frame: Week 20
Population: PP population restricted to those randomized to either treatment prior to the closure of the imiquimod
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Arm C (Observation) | Percentage of Participants Achieving Complete Response in 5-FU vs. Imiquimod, Using the PP Population Restricted to Those Randomized to Either Treatment Prior to the Closure of the Imiquimod Arm. | 5 Participants |
| Arm B (Fluorouracil) | Percentage of Participants Achieving Complete Response in 5-FU vs. Imiquimod, Using the PP Population Restricted to Those Randomized to Either Treatment Prior to the Closure of the Imiquimod Arm. | 5 Participants |
p-value: 0.6562Cochran-Mantel-Haenszel
Primary
Percentage of Participants Achieving Complete Response in Imiquimod vs Observation Arm, Using ITT Population Restricted to Those Randomized to Either Treatment Prior to the Closure of the Imiquimod Arm.
Complete response is defined as the absence of HSIL histology for all biopsies and the absence of HSIL cytology. Compare the complete response by Observation vs Imiquimod across sites using stratified CMH test at two-sided 0.05 alpha using only the participants randomized to imiquimod and observation prior to closure of the imiquimod arm.
Time frame: Week 20
Population: ITT population restricted to those randomized to either treatment prior to the closure of the imiquimod arm.
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Arm C (Observation) | Percentage of Participants Achieving Complete Response in Imiquimod vs Observation Arm, Using ITT Population Restricted to Those Randomized to Either Treatment Prior to the Closure of the Imiquimod Arm. | 5 Participants |
| Arm B (Fluorouracil) | Percentage of Participants Achieving Complete Response in Imiquimod vs Observation Arm, Using ITT Population Restricted to Those Randomized to Either Treatment Prior to the Closure of the Imiquimod Arm. | 0 Participants |
p-value: 0.0141Cochran-Mantel-Haenszel
Primary
Percentage of Participants Achieving Complete Response in Imiquimod vs Observation Arm, Using Per Protocol Population Restricted to Those Randomized to Either Treatment Prior to the Closure of the Imiquimod Arm.
Complete response is defined as the absence of HSIL histology for all biopsies and the absence of HSIL cytology. Compare the complete response by Observation vs Imiquimod across sites using stratified CMH test at two-sided 0.05 alpha using only the participants randomized to imiquimod and observation prior to closure of the imiquimod arm.
Time frame: Week 20
Population: PP population restricted to those randomized to either treatment prior to the closure of the imiquimod arm.
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Arm C (Observation) | Percentage of Participants Achieving Complete Response in Imiquimod vs Observation Arm, Using Per Protocol Population Restricted to Those Randomized to Either Treatment Prior to the Closure of the Imiquimod Arm. | 5 Participants |
| Arm B (Fluorouracil) | Percentage of Participants Achieving Complete Response in Imiquimod vs Observation Arm, Using Per Protocol Population Restricted to Those Randomized to Either Treatment Prior to the Closure of the Imiquimod Arm. | 0 Participants |
p-value: 0.0141Cochran-Mantel-Haenszel
Secondary
Amount of Drug Consumed in 5-FU and Imiquimod Arm by Week 16
Amount of study drug consumed by measuring the mass of study drug dispensed (weight of study drug container at baseline - weight of study drug at the end of treatment) by study arm (5FU vs imiquimod) by the time of receiving 8 cycle treatment
Time frame: Week 16
Population: ITT
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Arm C (Observation) | Amount of Drug Consumed in 5-FU and Imiquimod Arm by Week 16 | 39.5 grams | Standard Deviation 7.7 |
| Arm B (Fluorouracil) | Amount of Drug Consumed in 5-FU and Imiquimod Arm by Week 16 | 32.6 grams | Standard Deviation 17.2 |
Secondary
Comparison of the Number of hrHPV Genotypes in Each Arm Observed at Baseline vs at Week 20
hrHPV genotypes will be detected in anal swabs specimens processed using polymerase chain reaction (PCR) and reverse line blot analysis. Comparison of mean number of hrHPV genotypes in each arm observed at baseline vs at week 20
Time frame: week 20
Population: Per protocol
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Arm C (Observation) | Comparison of the Number of hrHPV Genotypes in Each Arm Observed at Baseline vs at Week 20 | Baseline | 3.75 hrHPV genotypes | Standard Deviation 1.81 |
| Arm C (Observation) | Comparison of the Number of hrHPV Genotypes in Each Arm Observed at Baseline vs at Week 20 | Week 20 | 3.67 hrHPV genotypes | Standard Deviation 2.06 |
| Arm B (Fluorouracil) | Comparison of the Number of hrHPV Genotypes in Each Arm Observed at Baseline vs at Week 20 | Baseline | 4.25 hrHPV genotypes | Standard Deviation 2.41 |
| Arm B (Fluorouracil) | Comparison of the Number of hrHPV Genotypes in Each Arm Observed at Baseline vs at Week 20 | Week 20 | 3.5 hrHPV genotypes | Standard Deviation 2.36 |
| Arm C (Observation) | Comparison of the Number of hrHPV Genotypes in Each Arm Observed at Baseline vs at Week 20 | Baseline | 3.32 hrHPV genotypes | Standard Deviation 2.01 |
| Arm C (Observation) | Comparison of the Number of hrHPV Genotypes in Each Arm Observed at Baseline vs at Week 20 | Week 20 | 2.62 hrHPV genotypes | Standard Deviation 1.65 |
Comparison: Comparison of number of hrHPV genotypes in each arm observed at baseline vs at week 20 in imiquimod armp-value: 0.3Wilcoxon (Mann-Whitney)
Comparison: Comparison of the count of hrHPV genotypes observed at baseline vs at week 20 in 5FU armp-value: 0.3Wilcoxon (Mann-Whitney)
Comparison: Comparison of the count of hrHPV genotypes observed at baseline vs at week 20 in observation armp-value: 0.26Wilcoxon (Mann-Whitney)
Secondary
HPV Genotypes Present at Baseline But no Longer Detected at Week 20
Count of HPV genotypes present at baseline but no longer detected at week 20.
Time frame: 20 weeks
Population: Per protocol
| Arm | Measure | Group | Value (COUNT_OF_UNITS) |
|---|---|---|---|
| Arm C (Observation) | HPV Genotypes Present at Baseline But no Longer Detected at Week 20 | Count and percentage of unique HPV genotypes undetected at week 20 | 2 Unique HPV genotypes |
| Arm C (Observation) | HPV Genotypes Present at Baseline But no Longer Detected at Week 20 | Count and percentage of unique HPV genotypes re-detected at week 20 | 12 Unique HPV genotypes |
| Arm B (Fluorouracil) | HPV Genotypes Present at Baseline But no Longer Detected at Week 20 | Count and percentage of unique HPV genotypes undetected at week 20 | 0 Unique HPV genotypes |
| Arm B (Fluorouracil) | HPV Genotypes Present at Baseline But no Longer Detected at Week 20 | Count and percentage of unique HPV genotypes re-detected at week 20 | 15 Unique HPV genotypes |
| Arm C (Observation) | HPV Genotypes Present at Baseline But no Longer Detected at Week 20 | Count and percentage of unique HPV genotypes undetected at week 20 | 1 Unique HPV genotypes |
| Arm C (Observation) | HPV Genotypes Present at Baseline But no Longer Detected at Week 20 | Count and percentage of unique HPV genotypes re-detected at week 20 | 14 Unique HPV genotypes |
Secondary
Number of Participants Who Experienced an Adverse Event of Grade 1 to 5 by Week 44, Irrespective of Relatedness to the Intervention. AEs Were Stratified According to Those Reported at or Before Week 20 and After Week 20.
Adverse events are graded on a scale from 1 (mild) to 5 (death) as per CTCAE v. 5.0, with higher grades indicating greater severity. The number of participants who experienced an adverse event of grade 1 to 5 by Week 44, regardless of its relatedness to the intervention, will be reported. AEs were stratified according to those reported at or before Week 20 and after Week 20.
Time frame: Up to week 44
Population: ITT population
| Arm | Measure | Group | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|---|
| Arm C (Observation) | Number of Participants Who Experienced an Adverse Event of Grade 1 to 5 by Week 44, Irrespective of Relatedness to the Intervention. AEs Were Stratified According to Those Reported at or Before Week 20 and After Week 20. | After Week 20: Grade 2 | 0 Participants |
| Arm C (Observation) | Number of Participants Who Experienced an Adverse Event of Grade 1 to 5 by Week 44, Irrespective of Relatedness to the Intervention. AEs Were Stratified According to Those Reported at or Before Week 20 and After Week 20. | After week 20: Grade 4 | 0 Participants |
| Arm C (Observation) | Number of Participants Who Experienced an Adverse Event of Grade 1 to 5 by Week 44, Irrespective of Relatedness to the Intervention. AEs Were Stratified According to Those Reported at or Before Week 20 and After Week 20. | After Week 20: Grade 3 | 0 Participants |
| Arm C (Observation) | Number of Participants Who Experienced an Adverse Event of Grade 1 to 5 by Week 44, Irrespective of Relatedness to the Intervention. AEs Were Stratified According to Those Reported at or Before Week 20 and After Week 20. | After week 20: Grade 1 | 0 Participants |
| Arm C (Observation) | Number of Participants Who Experienced an Adverse Event of Grade 1 to 5 by Week 44, Irrespective of Relatedness to the Intervention. AEs Were Stratified According to Those Reported at or Before Week 20 and After Week 20. | Up to week 20: Grade 2 | 3 Participants |
| Arm C (Observation) | Number of Participants Who Experienced an Adverse Event of Grade 1 to 5 by Week 44, Irrespective of Relatedness to the Intervention. AEs Were Stratified According to Those Reported at or Before Week 20 and After Week 20. | Up to Week 20: Grade 3 | 1 Participants |
| Arm C (Observation) | Number of Participants Who Experienced an Adverse Event of Grade 1 to 5 by Week 44, Irrespective of Relatedness to the Intervention. AEs Were Stratified According to Those Reported at or Before Week 20 and After Week 20. | After Week 20: Grade 5 | 0 Participants |
| Arm C (Observation) | Number of Participants Who Experienced an Adverse Event of Grade 1 to 5 by Week 44, Irrespective of Relatedness to the Intervention. AEs Were Stratified According to Those Reported at or Before Week 20 and After Week 20. | Up to Week 20: Grade 4 | 1 Participants |
| Arm C (Observation) | Number of Participants Who Experienced an Adverse Event of Grade 1 to 5 by Week 44, Irrespective of Relatedness to the Intervention. AEs Were Stratified According to Those Reported at or Before Week 20 and After Week 20. | Up to week 20: Grade 1 | 0 Participants |
| Arm C (Observation) | Number of Participants Who Experienced an Adverse Event of Grade 1 to 5 by Week 44, Irrespective of Relatedness to the Intervention. AEs Were Stratified According to Those Reported at or Before Week 20 and After Week 20. | Up to Week 20: Grade 5 | 0 Participants |
| Arm B (Fluorouracil) | Number of Participants Who Experienced an Adverse Event of Grade 1 to 5 by Week 44, Irrespective of Relatedness to the Intervention. AEs Were Stratified According to Those Reported at or Before Week 20 and After Week 20. | After Week 20: Grade 2 | 0 Participants |
| Arm B (Fluorouracil) | Number of Participants Who Experienced an Adverse Event of Grade 1 to 5 by Week 44, Irrespective of Relatedness to the Intervention. AEs Were Stratified According to Those Reported at or Before Week 20 and After Week 20. | Up to Week 20: Grade 5 | 0 Participants |
| Arm B (Fluorouracil) | Number of Participants Who Experienced an Adverse Event of Grade 1 to 5 by Week 44, Irrespective of Relatedness to the Intervention. AEs Were Stratified According to Those Reported at or Before Week 20 and After Week 20. | After Week 20: Grade 3 | 2 Participants |
| Arm B (Fluorouracil) | Number of Participants Who Experienced an Adverse Event of Grade 1 to 5 by Week 44, Irrespective of Relatedness to the Intervention. AEs Were Stratified According to Those Reported at or Before Week 20 and After Week 20. | Up to week 20: Grade 1 | 2 Participants |
| Arm B (Fluorouracil) | Number of Participants Who Experienced an Adverse Event of Grade 1 to 5 by Week 44, Irrespective of Relatedness to the Intervention. AEs Were Stratified According to Those Reported at or Before Week 20 and After Week 20. | After week 20: Grade 4 | 0 Participants |
| Arm B (Fluorouracil) | Number of Participants Who Experienced an Adverse Event of Grade 1 to 5 by Week 44, Irrespective of Relatedness to the Intervention. AEs Were Stratified According to Those Reported at or Before Week 20 and After Week 20. | Up to week 20: Grade 2 | 4 Participants |
| Arm B (Fluorouracil) | Number of Participants Who Experienced an Adverse Event of Grade 1 to 5 by Week 44, Irrespective of Relatedness to the Intervention. AEs Were Stratified According to Those Reported at or Before Week 20 and After Week 20. | Up to Week 20: Grade 3 | 2 Participants |
| Arm B (Fluorouracil) | Number of Participants Who Experienced an Adverse Event of Grade 1 to 5 by Week 44, Irrespective of Relatedness to the Intervention. AEs Were Stratified According to Those Reported at or Before Week 20 and After Week 20. | After Week 20: Grade 5 | 0 Participants |
| Arm B (Fluorouracil) | Number of Participants Who Experienced an Adverse Event of Grade 1 to 5 by Week 44, Irrespective of Relatedness to the Intervention. AEs Were Stratified According to Those Reported at or Before Week 20 and After Week 20. | After week 20: Grade 1 | 0 Participants |
| Arm B (Fluorouracil) | Number of Participants Who Experienced an Adverse Event of Grade 1 to 5 by Week 44, Irrespective of Relatedness to the Intervention. AEs Were Stratified According to Those Reported at or Before Week 20 and After Week 20. | Up to Week 20: Grade 4 | 1 Participants |
| Arm C (Observation) | Number of Participants Who Experienced an Adverse Event of Grade 1 to 5 by Week 44, Irrespective of Relatedness to the Intervention. AEs Were Stratified According to Those Reported at or Before Week 20 and After Week 20. | After Week 20: Grade 2 | 0 Participants |
| Arm C (Observation) | Number of Participants Who Experienced an Adverse Event of Grade 1 to 5 by Week 44, Irrespective of Relatedness to the Intervention. AEs Were Stratified According to Those Reported at or Before Week 20 and After Week 20. | After Week 20: Grade 3 | 0 Participants |
| Arm C (Observation) | Number of Participants Who Experienced an Adverse Event of Grade 1 to 5 by Week 44, Irrespective of Relatedness to the Intervention. AEs Were Stratified According to Those Reported at or Before Week 20 and After Week 20. | Up to Week 20: Grade 4 | 0 Participants |
| Arm C (Observation) | Number of Participants Who Experienced an Adverse Event of Grade 1 to 5 by Week 44, Irrespective of Relatedness to the Intervention. AEs Were Stratified According to Those Reported at or Before Week 20 and After Week 20. | Up to Week 20: Grade 3 | 0 Participants |
| Arm C (Observation) | Number of Participants Who Experienced an Adverse Event of Grade 1 to 5 by Week 44, Irrespective of Relatedness to the Intervention. AEs Were Stratified According to Those Reported at or Before Week 20 and After Week 20. | Up to Week 20: Grade 5 | 0 Participants |
| Arm C (Observation) | Number of Participants Who Experienced an Adverse Event of Grade 1 to 5 by Week 44, Irrespective of Relatedness to the Intervention. AEs Were Stratified According to Those Reported at or Before Week 20 and After Week 20. | After week 20: Grade 1 | 0 Participants |
| Arm C (Observation) | Number of Participants Who Experienced an Adverse Event of Grade 1 to 5 by Week 44, Irrespective of Relatedness to the Intervention. AEs Were Stratified According to Those Reported at or Before Week 20 and After Week 20. | Up to week 20: Grade 2 | 0 Participants |
| Arm C (Observation) | Number of Participants Who Experienced an Adverse Event of Grade 1 to 5 by Week 44, Irrespective of Relatedness to the Intervention. AEs Were Stratified According to Those Reported at or Before Week 20 and After Week 20. | After week 20: Grade 4 | 0 Participants |
| Arm C (Observation) | Number of Participants Who Experienced an Adverse Event of Grade 1 to 5 by Week 44, Irrespective of Relatedness to the Intervention. AEs Were Stratified According to Those Reported at or Before Week 20 and After Week 20. | After Week 20: Grade 5 | 0 Participants |
| Arm C (Observation) | Number of Participants Who Experienced an Adverse Event of Grade 1 to 5 by Week 44, Irrespective of Relatedness to the Intervention. AEs Were Stratified According to Those Reported at or Before Week 20 and After Week 20. | Up to week 20: Grade 1 | 2 Participants |
| Arm C (Observation) After Week 20-Imiquimod | Number of Participants Who Experienced an Adverse Event of Grade 1 to 5 by Week 44, Irrespective of Relatedness to the Intervention. AEs Were Stratified According to Those Reported at or Before Week 20 and After Week 20. | Up to Week 20: Grade 4 | 0 Participants |
| Arm C (Observation) After Week 20-Imiquimod | Number of Participants Who Experienced an Adverse Event of Grade 1 to 5 by Week 44, Irrespective of Relatedness to the Intervention. AEs Were Stratified According to Those Reported at or Before Week 20 and After Week 20. | After Week 20: Grade 2 | 0 Participants |
| Arm C (Observation) After Week 20-Imiquimod | Number of Participants Who Experienced an Adverse Event of Grade 1 to 5 by Week 44, Irrespective of Relatedness to the Intervention. AEs Were Stratified According to Those Reported at or Before Week 20 and After Week 20. | Up to week 20: Grade 1 | 0 Participants |
| Arm C (Observation) After Week 20-Imiquimod | Number of Participants Who Experienced an Adverse Event of Grade 1 to 5 by Week 44, Irrespective of Relatedness to the Intervention. AEs Were Stratified According to Those Reported at or Before Week 20 and After Week 20. | Up to week 20: Grade 2 | 0 Participants |
| Arm C (Observation) After Week 20-Imiquimod | Number of Participants Who Experienced an Adverse Event of Grade 1 to 5 by Week 44, Irrespective of Relatedness to the Intervention. AEs Were Stratified According to Those Reported at or Before Week 20 and After Week 20. | Up to Week 20: Grade 3 | 0 Participants |
| Arm C (Observation) After Week 20-Imiquimod | Number of Participants Who Experienced an Adverse Event of Grade 1 to 5 by Week 44, Irrespective of Relatedness to the Intervention. AEs Were Stratified According to Those Reported at or Before Week 20 and After Week 20. | Up to Week 20: Grade 5 | 0 Participants |
| Arm C (Observation) After Week 20-Imiquimod | Number of Participants Who Experienced an Adverse Event of Grade 1 to 5 by Week 44, Irrespective of Relatedness to the Intervention. AEs Were Stratified According to Those Reported at or Before Week 20 and After Week 20. | After week 20: Grade 1 | 0 Participants |
| Arm C (Observation) After Week 20-Imiquimod | Number of Participants Who Experienced an Adverse Event of Grade 1 to 5 by Week 44, Irrespective of Relatedness to the Intervention. AEs Were Stratified According to Those Reported at or Before Week 20 and After Week 20. | After Week 20: Grade 3 | 0 Participants |
| Arm C (Observation) After Week 20-Imiquimod | Number of Participants Who Experienced an Adverse Event of Grade 1 to 5 by Week 44, Irrespective of Relatedness to the Intervention. AEs Were Stratified According to Those Reported at or Before Week 20 and After Week 20. | After week 20: Grade 4 | 0 Participants |
| Arm C (Observation) After Week 20-Imiquimod | Number of Participants Who Experienced an Adverse Event of Grade 1 to 5 by Week 44, Irrespective of Relatedness to the Intervention. AEs Were Stratified According to Those Reported at or Before Week 20 and After Week 20. | After Week 20: Grade 5 | 0 Participants |
| Arm C (Observation) After Week 20- Fluorouracil | Number of Participants Who Experienced an Adverse Event of Grade 1 to 5 by Week 44, Irrespective of Relatedness to the Intervention. AEs Were Stratified According to Those Reported at or Before Week 20 and After Week 20. | Up to Week 20: Grade 4 | 0 Participants |
| Arm C (Observation) After Week 20- Fluorouracil | Number of Participants Who Experienced an Adverse Event of Grade 1 to 5 by Week 44, Irrespective of Relatedness to the Intervention. AEs Were Stratified According to Those Reported at or Before Week 20 and After Week 20. | Up to Week 20: Grade 3 | 0 Participants |
| Arm C (Observation) After Week 20- Fluorouracil | Number of Participants Who Experienced an Adverse Event of Grade 1 to 5 by Week 44, Irrespective of Relatedness to the Intervention. AEs Were Stratified According to Those Reported at or Before Week 20 and After Week 20. | After week 20: Grade 1 | 0 Participants |
| Arm C (Observation) After Week 20- Fluorouracil | Number of Participants Who Experienced an Adverse Event of Grade 1 to 5 by Week 44, Irrespective of Relatedness to the Intervention. AEs Were Stratified According to Those Reported at or Before Week 20 and After Week 20. | Up to week 20: Grade 2 | 0 Participants |
| Arm C (Observation) After Week 20- Fluorouracil | Number of Participants Who Experienced an Adverse Event of Grade 1 to 5 by Week 44, Irrespective of Relatedness to the Intervention. AEs Were Stratified According to Those Reported at or Before Week 20 and After Week 20. | Up to week 20: Grade 1 | 0 Participants |
| Arm C (Observation) After Week 20- Fluorouracil | Number of Participants Who Experienced an Adverse Event of Grade 1 to 5 by Week 44, Irrespective of Relatedness to the Intervention. AEs Were Stratified According to Those Reported at or Before Week 20 and After Week 20. | After Week 20: Grade 5 | 0 Participants |
| Arm C (Observation) After Week 20- Fluorouracil | Number of Participants Who Experienced an Adverse Event of Grade 1 to 5 by Week 44, Irrespective of Relatedness to the Intervention. AEs Were Stratified According to Those Reported at or Before Week 20 and After Week 20. | After Week 20: Grade 3 | 1 Participants |
| Arm C (Observation) After Week 20- Fluorouracil | Number of Participants Who Experienced an Adverse Event of Grade 1 to 5 by Week 44, Irrespective of Relatedness to the Intervention. AEs Were Stratified According to Those Reported at or Before Week 20 and After Week 20. | After week 20: Grade 4 | 0 Participants |
| Arm C (Observation) After Week 20- Fluorouracil | Number of Participants Who Experienced an Adverse Event of Grade 1 to 5 by Week 44, Irrespective of Relatedness to the Intervention. AEs Were Stratified According to Those Reported at or Before Week 20 and After Week 20. | After Week 20: Grade 2 | 0 Participants |
| Arm C (Observation) After Week 20- Fluorouracil | Number of Participants Who Experienced an Adverse Event of Grade 1 to 5 by Week 44, Irrespective of Relatedness to the Intervention. AEs Were Stratified According to Those Reported at or Before Week 20 and After Week 20. | Up to Week 20: Grade 5 | 0 Participants |
| Arm C (Observation) After Week 20-Not Crossed Over | Number of Participants Who Experienced an Adverse Event of Grade 1 to 5 by Week 44, Irrespective of Relatedness to the Intervention. AEs Were Stratified According to Those Reported at or Before Week 20 and After Week 20. | After Week 20: Grade 2 | 0 Participants |
| Arm C (Observation) After Week 20-Not Crossed Over | Number of Participants Who Experienced an Adverse Event of Grade 1 to 5 by Week 44, Irrespective of Relatedness to the Intervention. AEs Were Stratified According to Those Reported at or Before Week 20 and After Week 20. | After Week 20: Grade 5 | 0 Participants |
| Arm C (Observation) After Week 20-Not Crossed Over | Number of Participants Who Experienced an Adverse Event of Grade 1 to 5 by Week 44, Irrespective of Relatedness to the Intervention. AEs Were Stratified According to Those Reported at or Before Week 20 and After Week 20. | After Week 20: Grade 3 | 0 Participants |
| Arm C (Observation) After Week 20-Not Crossed Over | Number of Participants Who Experienced an Adverse Event of Grade 1 to 5 by Week 44, Irrespective of Relatedness to the Intervention. AEs Were Stratified According to Those Reported at or Before Week 20 and After Week 20. | Up to Week 20: Grade 3 | 0 Participants |
| Arm C (Observation) After Week 20-Not Crossed Over | Number of Participants Who Experienced an Adverse Event of Grade 1 to 5 by Week 44, Irrespective of Relatedness to the Intervention. AEs Were Stratified According to Those Reported at or Before Week 20 and After Week 20. | After week 20: Grade 1 | 0 Participants |
| Arm C (Observation) After Week 20-Not Crossed Over | Number of Participants Who Experienced an Adverse Event of Grade 1 to 5 by Week 44, Irrespective of Relatedness to the Intervention. AEs Were Stratified According to Those Reported at or Before Week 20 and After Week 20. | Up to week 20: Grade 2 | 0 Participants |
| Arm C (Observation) After Week 20-Not Crossed Over | Number of Participants Who Experienced an Adverse Event of Grade 1 to 5 by Week 44, Irrespective of Relatedness to the Intervention. AEs Were Stratified According to Those Reported at or Before Week 20 and After Week 20. | Up to Week 20: Grade 5 | 0 Participants |
| Arm C (Observation) After Week 20-Not Crossed Over | Number of Participants Who Experienced an Adverse Event of Grade 1 to 5 by Week 44, Irrespective of Relatedness to the Intervention. AEs Were Stratified According to Those Reported at or Before Week 20 and After Week 20. | Up to week 20: Grade 1 | 0 Participants |
| Arm C (Observation) After Week 20-Not Crossed Over | Number of Participants Who Experienced an Adverse Event of Grade 1 to 5 by Week 44, Irrespective of Relatedness to the Intervention. AEs Were Stratified According to Those Reported at or Before Week 20 and After Week 20. | After week 20: Grade 4 | 0 Participants |
| Arm C (Observation) After Week 20-Not Crossed Over | Number of Participants Who Experienced an Adverse Event of Grade 1 to 5 by Week 44, Irrespective of Relatedness to the Intervention. AEs Were Stratified According to Those Reported at or Before Week 20 and After Week 20. | Up to Week 20: Grade 4 | 0 Participants |
Secondary
Percentage of Participants Achieving Complete or Partial Response in 5-FU vs Observation Using ITT Population
Complete response is defined as the Complete response is defined as the absence of HSIL histology for all biopsies and the absence of HSIL cytology. Partial response is defined as 1) The regression of HSIL histology but HSIL cytology is present, or 2) Reduction in number of octants with HSIL. Percentage will be compared across sites using the stratified Mantel-Haenszel-Cochran test at the two-sided 0.05 alpha level.
Time frame: At 44 weeks
Population: ITT population
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Arm C (Observation) | Percentage of Participants Achieving Complete or Partial Response in 5-FU vs Observation Using ITT Population | 17 Participants |
| Arm B (Fluorouracil) | Percentage of Participants Achieving Complete or Partial Response in 5-FU vs Observation Using ITT Population | 19 Participants |
p-value: 0.5726Cochran-Mantel-Haenszel
Secondary
Percentage of Participants Achieving Complete or Partial Response in 5-FU vs Observation Using ITT Population
Complete response is defined as the absence of HSIL histology for all biopsies and the absence of HSIL cytology. Partial response is defined as either 1) The regression of HSIL histology but HSIL cytology is present, or 2) Reduction in number of octants with HSIL. Percentages will be compared across sites using the stratified Mantel-Haenszel-Cochran test at the two-sided 0.05 alpha level.
Time frame: Up to week 20
Population: ITT
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Arm C (Observation) | Percentage of Participants Achieving Complete or Partial Response in 5-FU vs Observation Using ITT Population | 21 Participants |
| Arm B (Fluorouracil) | Percentage of Participants Achieving Complete or Partial Response in 5-FU vs Observation Using ITT Population | 15 Participants |
p-value: 0.1409Cochran-Mantel-Haenszel
Secondary
Percentage of Patients Achieving Complete or Partial Response in Imiquimod vs Observation Arm, Using ITT Population Restricted to Those Randomized to Either Treatment Prior to the Closure of the Imiquimod Arm.
The proportion of patients achieving complete or partial responses with imiquimod will be compared to observation using participants randomized to imiquimod and observation prior to closure of the imiquimod arm. Complete response is defined as the absence of HSIL based on central pathology review, if available; otherwise, local biopsy results will be used. Partial Response is defined as: 1) The regression of HSIL histology but HSIL cytology is present, or 2) Reduction in number of octants with HSIL.
Time frame: Up to week 44
Population: ITT population restricted to those randomized to either treatment prior to the closure of the imiquimod arm.
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Arm C (Observation) | Percentage of Patients Achieving Complete or Partial Response in Imiquimod vs Observation Arm, Using ITT Population Restricted to Those Randomized to Either Treatment Prior to the Closure of the Imiquimod Arm. | 11 Participants |
| Arm B (Fluorouracil) | Percentage of Patients Achieving Complete or Partial Response in Imiquimod vs Observation Arm, Using ITT Population Restricted to Those Randomized to Either Treatment Prior to the Closure of the Imiquimod Arm. | 10 Participants |
p-value: 0.6184Cochran-Mantel-Haenszel
Secondary
Percentageof Patients Achieving Complete or Partial Response in Imiquimod vs Observation Arm, Using ITT Population Restricted to Those Randomized to Either Treatment Prior to the Closure of the Imiquimod Arm.
Complete response is defined as the absence of HSIL histology for all biopsies and the absence of HSIL cytology. Partial response is defined as 1) The regression of HSIL histology but HSIL cytology is present, or 2) Reduction in number of octants with HSIL. Percentage of patients achieving complete or partial responses with imiquimod will be compared to observation using participants randomized to imiquimod and observation prior to closure of the imiquimod arm.
Time frame: Up to week 20
Population: ITT population restricted to those randomized to either treatment prior to the closure of the imiquimod arm.
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Arm C (Observation) | Percentageof Patients Achieving Complete or Partial Response in Imiquimod vs Observation Arm, Using ITT Population Restricted to Those Randomized to Either Treatment Prior to the Closure of the Imiquimod Arm. | 11 Participants |
| Arm B (Fluorouracil) | Percentageof Patients Achieving Complete or Partial Response in Imiquimod vs Observation Arm, Using ITT Population Restricted to Those Randomized to Either Treatment Prior to the Closure of the Imiquimod Arm. | 6 Participants |
p-value: 0.0805Cochran-Mantel-Haenszel
Secondary
Persistence and New Infections of HPV Type Specific Infections
The proportion of participants with persistent HPV infection, defined as the presence of the same HPV type detected at both baseline and Week 20. The proportion of participants who acquire a new HPV infection at Week 20 that was not detected at baseline is new infection. Persistence and new infection will be assessed separately for each HPV type.
Time frame: At week 20
Population: ITT
| Arm | Measure | Group | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|---|
| Arm C (Observation) | Persistence and New Infections of HPV Type Specific Infections | Persistent : HPV 52 | 0 Participants |
| Arm C (Observation) | Persistence and New Infections of HPV Type Specific Infections | Persistent : HPV 39 | 0 Participants |
| Arm C (Observation) | Persistence and New Infections of HPV Type Specific Infections | Overall number of patients with hrHPV positivity at week 20 | 12 Participants |
| Arm C (Observation) | Persistence and New Infections of HPV Type Specific Infections | Persistent : HPV 45 | 0 Participants |
| Arm C (Observation) | Persistence and New Infections of HPV Type Specific Infections | New infections : HPV 33 | 3 Participants |
| Arm C (Observation) | Persistence and New Infections of HPV Type Specific Infections | Persistent : HPV 51 | 1 Participants |
| Arm C (Observation) | Persistence and New Infections of HPV Type Specific Infections | New infections : HPV 58 | 3 Participants |
| Arm C (Observation) | Persistence and New Infections of HPV Type Specific Infections | New infections : HPV 56 | 5 Participants |
| Arm C (Observation) | Persistence and New Infections of HPV Type Specific Infections | Persistent : HPV 53 | 1 Participants |
| Arm C (Observation) | Persistence and New Infections of HPV Type Specific Infections | Persistent : HPV 56 | 1 Participants |
| Arm C (Observation) | Persistence and New Infections of HPV Type Specific Infections | New infections : HPV 45 | 2 Participants |
| Arm C (Observation) | Persistence and New Infections of HPV Type Specific Infections | New infections : HPV 51 | 1 Participants |
| Arm C (Observation) | Persistence and New Infections of HPV Type Specific Infections | New infections : HPV 39 | 1 Participants |
| Arm C (Observation) | Persistence and New Infections of HPV Type Specific Infections | New infections : HPV 52 | 0 Participants |
| Arm C (Observation) | Persistence and New Infections of HPV Type Specific Infections | Persistent : HPV 58 | 2 Participants |
| Arm C (Observation) | Persistence and New Infections of HPV Type Specific Infections | New infections : HPV 53 | 2 Participants |
| Arm C (Observation) | Persistence and New Infections of HPV Type Specific Infections | New infections : HPV 59 | 3 Participants |
| Arm C (Observation) | Persistence and New Infections of HPV Type Specific Infections | Persistent : HPV 59 | 0 Participants |
| Arm C (Observation) | Persistence and New Infections of HPV Type Specific Infections | Persistent : HPV 66 | 0 Participants |
| Arm C (Observation) | Persistence and New Infections of HPV Type Specific Infections | Persistent : HPV 68 | 2 Participants |
| Arm C (Observation) | Persistence and New Infections of HPV Type Specific Infections | New infections : HPV 66 | 0 Participants |
| Arm C (Observation) | Persistence and New Infections of HPV Type Specific Infections | Persistent: any high-risk HPV infection | 12 Participants |
| Arm C (Observation) | Persistence and New Infections of HPV Type Specific Infections | New infections : HPV 16 | 5 Participants |
| Arm C (Observation) | Persistence and New Infections of HPV Type Specific Infections | New infections : HPV 68 | 3 Participants |
| Arm C (Observation) | Persistence and New Infections of HPV Type Specific Infections | New infections : HPV 18 | 3 Participants |
| Arm C (Observation) | Persistence and New Infections of HPV Type Specific Infections | Persistent : HPV 16 | 1 Participants |
| Arm C (Observation) | Persistence and New Infections of HPV Type Specific Infections | New infections : HPV 35 | 1 Participants |
| Arm C (Observation) | Persistence and New Infections of HPV Type Specific Infections | Persistent : HPV 18 | 1 Participants |
| Arm C (Observation) | Persistence and New Infections of HPV Type Specific Infections | Persistent : HPV 31 | 1 Participants |
| Arm C (Observation) | Persistence and New Infections of HPV Type Specific Infections | New infections: any high-risk HPV | 11 Participants |
| Arm C (Observation) | Persistence and New Infections of HPV Type Specific Infections | Persistent : HPV 33 | 0 Participants |
| Arm C (Observation) | Persistence and New Infections of HPV Type Specific Infections | New infections : HPV 31 | 2 Participants |
| Arm C (Observation) | Persistence and New Infections of HPV Type Specific Infections | Persistent : HPV 35 | 0 Participants |
| Arm B (Fluorouracil) | Persistence and New Infections of HPV Type Specific Infections | Persistent : HPV 58 | 1 Participants |
| Arm B (Fluorouracil) | Persistence and New Infections of HPV Type Specific Infections | New infections : HPV 56 | 5 Participants |
| Arm B (Fluorouracil) | Persistence and New Infections of HPV Type Specific Infections | Persistent : HPV 33 | 1 Participants |
| Arm B (Fluorouracil) | Persistence and New Infections of HPV Type Specific Infections | Persistent : HPV 39 | 3 Participants |
| Arm B (Fluorouracil) | Persistence and New Infections of HPV Type Specific Infections | Persistent : HPV 18 | 3 Participants |
| Arm B (Fluorouracil) | Persistence and New Infections of HPV Type Specific Infections | New infections : HPV 31 | 2 Participants |
| Arm B (Fluorouracil) | Persistence and New Infections of HPV Type Specific Infections | Overall number of patients with hrHPV positivity at week 20 | 22 Participants |
| Arm B (Fluorouracil) | Persistence and New Infections of HPV Type Specific Infections | Persistent : HPV 59 | 3 Participants |
| Arm B (Fluorouracil) | Persistence and New Infections of HPV Type Specific Infections | New infections : HPV 59 | 4 Participants |
| Arm B (Fluorouracil) | Persistence and New Infections of HPV Type Specific Infections | Persistent : HPV 45 | 1 Participants |
| Arm B (Fluorouracil) | Persistence and New Infections of HPV Type Specific Infections | New infections : HPV 35 | 3 Participants |
| Arm B (Fluorouracil) | Persistence and New Infections of HPV Type Specific Infections | New infections : HPV 33 | 4 Participants |
| Arm B (Fluorouracil) | Persistence and New Infections of HPV Type Specific Infections | New infections : HPV 53 | 3 Participants |
| Arm B (Fluorouracil) | Persistence and New Infections of HPV Type Specific Infections | New infections : HPV 18 | 1 Participants |
| Arm B (Fluorouracil) | Persistence and New Infections of HPV Type Specific Infections | Persistent : HPV 51 | 0 Participants |
| Arm B (Fluorouracil) | Persistence and New Infections of HPV Type Specific Infections | Persistent : HPV 66 | 1 Participants |
| Arm B (Fluorouracil) | Persistence and New Infections of HPV Type Specific Infections | Persistent : HPV 35 | 1 Participants |
| Arm B (Fluorouracil) | Persistence and New Infections of HPV Type Specific Infections | Persistent : HPV 52 | 2 Participants |
| Arm B (Fluorouracil) | Persistence and New Infections of HPV Type Specific Infections | New infections : HPV 45 | 2 Participants |
| Arm B (Fluorouracil) | Persistence and New Infections of HPV Type Specific Infections | New infections : HPV 68 | 4 Participants |
| Arm B (Fluorouracil) | Persistence and New Infections of HPV Type Specific Infections | Persistent : HPV 53 | 4 Participants |
| Arm B (Fluorouracil) | Persistence and New Infections of HPV Type Specific Infections | New infections : HPV 58 | 3 Participants |
| Arm B (Fluorouracil) | Persistence and New Infections of HPV Type Specific Infections | New infections : HPV 39 | 2 Participants |
| Arm B (Fluorouracil) | Persistence and New Infections of HPV Type Specific Infections | Persistent : HPV 68 | 4 Participants |
| Arm B (Fluorouracil) | Persistence and New Infections of HPV Type Specific Infections | New infections: any high-risk HPV | 21 Participants |
| Arm B (Fluorouracil) | Persistence and New Infections of HPV Type Specific Infections | Persistent : HPV 56 | 1 Participants |
| Arm B (Fluorouracil) | Persistence and New Infections of HPV Type Specific Infections | Persistent : HPV 16 | 4 Participants |
| Arm B (Fluorouracil) | Persistence and New Infections of HPV Type Specific Infections | New infections : HPV 51 | 3 Participants |
| Arm B (Fluorouracil) | Persistence and New Infections of HPV Type Specific Infections | Persistent: any high-risk HPV infection | 17 Participants |
| Arm B (Fluorouracil) | Persistence and New Infections of HPV Type Specific Infections | New infections : HPV 66 | 2 Participants |
| Arm B (Fluorouracil) | Persistence and New Infections of HPV Type Specific Infections | New infections : HPV 52 | 4 Participants |
| Arm B (Fluorouracil) | Persistence and New Infections of HPV Type Specific Infections | Persistent : HPV 31 | 5 Participants |
| Arm B (Fluorouracil) | Persistence and New Infections of HPV Type Specific Infections | New infections : HPV 16 | 8 Participants |
| Arm C (Observation) | Persistence and New Infections of HPV Type Specific Infections | New infections : HPV 16 | 8 Participants |
| Arm C (Observation) | Persistence and New Infections of HPV Type Specific Infections | New infections : HPV 66 | 0 Participants |
| Arm C (Observation) | Persistence and New Infections of HPV Type Specific Infections | New infections : HPV 56 | 2 Participants |
| Arm C (Observation) | Persistence and New Infections of HPV Type Specific Infections | New infections : HPV 58 | 3 Participants |
| Arm C (Observation) | Persistence and New Infections of HPV Type Specific Infections | New infections : HPV 59 | 2 Participants |
| Arm C (Observation) | Persistence and New Infections of HPV Type Specific Infections | New infections : HPV 68 | 3 Participants |
| Arm C (Observation) | Persistence and New Infections of HPV Type Specific Infections | New infections: any high-risk HPV | 26 Participants |
| Arm C (Observation) | Persistence and New Infections of HPV Type Specific Infections | Overall number of patients with hrHPV positivity at week 20 | 26 Participants |
| Arm C (Observation) | Persistence and New Infections of HPV Type Specific Infections | New infections : HPV 53 | 5 Participants |
| Arm C (Observation) | Persistence and New Infections of HPV Type Specific Infections | Persistent : HPV 53 | 2 Participants |
| Arm C (Observation) | Persistence and New Infections of HPV Type Specific Infections | Persistent : HPV 56 | 1 Participants |
| Arm C (Observation) | Persistence and New Infections of HPV Type Specific Infections | Persistent : HPV 58 | 3 Participants |
| Arm C (Observation) | Persistence and New Infections of HPV Type Specific Infections | Persistent : HPV 59 | 6 Participants |
| Arm C (Observation) | Persistence and New Infections of HPV Type Specific Infections | Persistent : HPV 66 | 0 Participants |
| Arm C (Observation) | Persistence and New Infections of HPV Type Specific Infections | Persistent : HPV 68 | 0 Participants |
| Arm C (Observation) | Persistence and New Infections of HPV Type Specific Infections | Persistent: any high-risk HPV infection | 25 Participants |
| Arm C (Observation) | Persistence and New Infections of HPV Type Specific Infections | Persistent : HPV 18 | 1 Participants |
| Arm C (Observation) | Persistence and New Infections of HPV Type Specific Infections | New infections : HPV 18 | 2 Participants |
| Arm C (Observation) | Persistence and New Infections of HPV Type Specific Infections | Persistent : HPV 16 | 3 Participants |
| Arm C (Observation) | Persistence and New Infections of HPV Type Specific Infections | Persistent : HPV 31 | 4 Participants |
| Arm C (Observation) | Persistence and New Infections of HPV Type Specific Infections | Persistent : HPV 33 | 2 Participants |
| Arm C (Observation) | Persistence and New Infections of HPV Type Specific Infections | Persistent : HPV 35 | 2 Participants |
| Arm C (Observation) | Persistence and New Infections of HPV Type Specific Infections | Persistent : HPV 39 | 0 Participants |
| Arm C (Observation) | Persistence and New Infections of HPV Type Specific Infections | New infections : HPV 31 | 5 Participants |
| Arm C (Observation) | Persistence and New Infections of HPV Type Specific Infections | Persistent : HPV 45 | 1 Participants |
| Arm C (Observation) | Persistence and New Infections of HPV Type Specific Infections | New infections : HPV 33 | 5 Participants |
| Arm C (Observation) | Persistence and New Infections of HPV Type Specific Infections | Persistent : HPV 51 | 0 Participants |
| Arm C (Observation) | Persistence and New Infections of HPV Type Specific Infections | Persistent : HPV 52 | 1 Participants |
| Arm C (Observation) | Persistence and New Infections of HPV Type Specific Infections | New infections : HPV 35 | 3 Participants |
| Arm C (Observation) | Persistence and New Infections of HPV Type Specific Infections | New infections : HPV 39 | 2 Participants |
| Arm C (Observation) | Persistence and New Infections of HPV Type Specific Infections | New infections : HPV 45 | 0 Participants |
| Arm C (Observation) | Persistence and New Infections of HPV Type Specific Infections | New infections : HPV 51 | 2 Participants |
| Arm C (Observation) | Persistence and New Infections of HPV Type Specific Infections | New infections : HPV 52 | 4 Participants |