Imiquimod, Fluorouracil, or Observation in Treating HIV-Positive Patients With High-Grade Anal Squamous Skin Lesions
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|ClinicalTrials.gov Identifier: NCT02059499|
Recruitment Status : Recruiting
First Posted : February 11, 2014
Last Update Posted : July 18, 2022
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|Condition or disease||Intervention/treatment||Phase|
|Anal Intraepithelial Neoplasia High-grade Squamous Intraepithelial Lesion HIV Infection||Drug: imiquimod Drug: fluorouracil Other: questionnaire administration Other: laboratory biomarker analysis||Phase 3|
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.
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.
|Study Type :||Interventional (Clinical Trial)|
|Estimated Enrollment :||150 participants|
|Intervention Model:||Crossover Assignment|
|Masking:||Single (Outcomes Assessor)|
|Official Title:||A Randomized, Phase III Study of Intra-anal Imiquimod 2.5% vs. Topical 5-fluorouracil 5% vs. Observation for the Treatment of High-grade Anal Squamous Intraepithelial Lesions in HIV-infected Men and Women|
|Actual Study Start Date :||December 28, 2015|
|Estimated Primary Completion Date :||August 2025|
|Estimated Study Completion Date :||September 2025|
Experimental: Arm A (imiquimod)
Patients apply imiquimod intra-anally QD for 16 weeks.
Other: questionnaire administration
Other: laboratory biomarker analysis
Experimental: 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.
Other: questionnaire administration
Other: laboratory biomarker analysis
No Intervention: 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.
- Proportion of participants achieving complete response (Arm A and B) [ Time Frame: At week 20 ]For each treatment comparison (imiquimod vs observation and fluorouracil vs observation) the proportions will be compared across sites using stratified Mantel-Haenszel-Cochran tests at the one-sided 0.025 alpha level.
- Proportion of participants with spontaneous regression (Arm C) [ Time Frame: At week 20 ]For each treatment comparison (imiquimod vs observation and fluorouracil vs observation) the proportions will be compared across sites using stratified Mantel-Haenszel-Cochran tests at the one-sided 0.025 alpha level.
- Presence of intra-anal HSIL on cytology or histology [ Time Frame: At week 20 ]Perianal HSIL will be descriptively reported separately, as well as combined.
- Incidence of adverse events, graded according to the National Cancer Institute Common Terminology Criteria for Adverse Events version 4.0 [ Time Frame: Up to week 44 ]To examine the tolerability and safety of the three arms, descriptive statistics for adverse events will be computed. Adverse events will be summarized at the event level and participant level according to severity. Adverse events will be stratified according to those reported at or before week 20 and after week 20. Proportions and their exact 95% confidence intervals will be calculated. Summary statistics will be computed for the amount of study drug taken.
- Proportion of participants achieving complete response or spontaneous regression [ Time Frame: Up to week 44 ]Proportions will be compared across sites using the stratified Mantel-Haenszel-Cochran test at the two-sided 0.05 alpha level.
- Number of quadrants with HSIL found on biopsies [ Time Frame: Up to week 48 ]Will be compared between arms treating the response as an ordinal variable.
- Proportion of patients achieving complete or partial responses [ Time Frame: Up to week 44 ]The proportion of patients achieving complete or partial responses with imiquimod or fluorouracil will be compared to observation only.
- Persistence of HPV type specific infections [ Time Frame: At week 20 ]The frequency and proportion of HPV types present at baseline that are no longer detected at week 20 will be reported. The frequency and proportion of new HPV infections detected at week 20 that were not present at baseline will also be reported. Proportions and their exact binomial 95% confidence intervals will be calculated.
- Presence of intra-anal HSIL on cytology or histology [ Time Frame: At week 44 ]Perianal HSIL will be descriptively reported separately, as well as combined. Results for the observation arm will be stratified into cross-over treatment groups.
Choosing to participate in a study is an important personal decision. Talk with your doctor and family members or friends about deciding to join a study. To learn more about this study, you or your doctor may contact the study research staff using the contacts provided below. For general information, Learn About Clinical Studies.
|Ages Eligible for Study:||21 Years and older (Adult, Older Adult)|
|Sexes Eligible for Study:||All|
|Accepts Healthy Volunteers:||No|
- 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
- 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)
To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.
Please refer to this study by its ClinicalTrials.gov identifier (NCT number): NCT02059499
|United States, California|
|UCLA CARE Center||Recruiting|
|Los Angeles, California, United States, 90035|
|Contact: Nikkole Valdez 310-557-9027 firstname.lastname@example.org|
|Principal Investigator: Ronald Mitsuyasu, MD|
|San Francisco, California, United States, 94115|
|Contact: Naomi Jay 415-353-7443 email@example.com|
|Sub-Investigator: Naomi Jay|
|Principal Investigator: Joel Palefsky, MD|
|University of California, San Francisco||Recruiting|
|San Francisco, California, United States, 94143|
|Contact: Arezou Sadighi Akha 818-447-5857 Arezou.SadighiAkha@ucsf.edu|
|Principal Investigator: Naomi Jay, PhD, NP|
|United States, Florida|
|University of Miami||Withdrawn|
|Miami, Florida, United States, 33136|
|United States, Georgia|
|Atlanta, Georgia, United States, 30303|
|Contact: Fletcher Neale, CRC II 404-712-3522 firstname.lastname@example.org|
|Principal Investigator: Lisa Flowers, MD|
|United States, Louisiana|
|Louisiana State University Health Sciences Center - New Orleans||Recruiting|
|New Orleans, Louisiana, United States, 70112|
|Contact: Jim Outland 504-568-7634 email@example.com|
|Principal Investigator: Michael Hagensee, MD|
|United States, Massachusetts|
|Boston Medical Center||Recruiting|
|Boston, Massachusetts, United States, 02118|
|Contact: Elizabeth Stier, MD 617-414-5101 firstname.lastname@example.org|
|Principal Investigator: Elizabeth Stier, MD|
|United States, New York|
|Montefiore Medical Center||Recruiting|
|Bronx, New York, United States, 10461|
|Contact: Rikin Gandhi, MSRA 718-862-8840 ext 451 email@example.com|
|Contact: Akash Shah, MSc, CCRP 718-862-8840 ext 436|
|Principal Investigator: Rebecca Levine, MD|
|Laser Surgery Care||Recruiting|
|New York, New York, United States, 10011|
|Contact: Krystal Chuang firstname.lastname@example.org|
|Principal Investigator: Stephen Goldstone, MD|
|Cornell Clinical Trials Unit, New York Presbyterian Hospital||Recruiting|
|New York, New York, United States, 10065|
|Contact: Christina Megill 212-746-7163|
|Principal Investigator: Timothy Wilkin, MD, MPH|
|Weill Medical College of Cornell University||Recruiting|
|New York, New York, United States, 10065|
|Contact: Timothy J. Wilkin 212-746-7202 email@example.com|
|Principal Investigator: Timothy J. Wilkin|
|United States, North Carolina|
|Wake Forest University Health Sciences||Recruiting|
|Winston-Salem, North Carolina, United States, 27157|
|Contact: Elizabeth Zieser-Misenheimer 336-716-5685 firstname.lastname@example.org|
|Principal Investigator: Luis Barroso, MD|
|United States, Texas|
|Baylor College of Medicine||Withdrawn|
|Houston, Texas, United States, 77030|
|United States, Washington|
|Benaroya Research Institute at Virginia Mason Medical Center||Recruiting|
|Seattle, Washington, United States, 98101|
|Contact: Rachel Dowty 206-342-6928 email@example.com|
|Principal Investigator: David Aboulafia, MD|
|University of Puerto Rico||Recruiting|
|San Juan, Puerto Rico, 00936-3027|
|Contact: Maribel Tirado-Gomez 787-772-8300 ext 1108 firstname.lastname@example.org|
|Principal Investigator: Humberto Guiot, MD|
|Principal Investigator:||Timothy Wilkin||AIDS Associated Malignancies Clinical Trials Consortium|
|Responsible Party:||AIDS Malignancy Consortium|
|Other Study ID Numbers:||
NCI-2013-02288 ( Registry Identifier: CTRP (Clinical Trial Reporting Program) )
AMC-088 ( Other Identifier: AIDS - Associated Malignancies Clinical Trials Consortium )
AMC-088 ( Other Identifier: CTEP )
U01CA121947 ( U.S. NIH Grant/Contract )
|First Posted:||February 11, 2014 Key Record Dates|
|Last Update Posted:||July 18, 2022|
|Last Verified:||July 2022|
|Individual Participant Data (IPD) Sharing Statement:|
|Plan to Share IPD:||Undecided|
Squamous Intraepithelial Lesions of the Cervix
Uterine Cervical Dysplasia
Uterine Cervical Diseases
Genital Diseases, Female
Female Urogenital Diseases
Female Urogenital Diseases and Pregnancy Complications
Molecular Mechanisms of Pharmacological Action
Physiological Effects of Drugs