Topical Imiquimod Versus Conization to Treat Cervical Intraepithelial Neoplasia

Study Overview
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Brief Summary
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The purpose of this study is to investigate the non-inferiority of a topical Imiquimod therapy in patients with persistent CIN 2/3 when compared to standard therapy, i.e. conization A randomized, controlled, non-inferiority AGO-Austria trial

Detailed Description
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Background: Alternatives to surgery are needed for the treatment of cervical intraepithelial neoplasia (CIN). CIN is associated with persistent human papillomavirus (HPV) infection and is known to be a potential precursor of cervical cancer. The incidence of CIN has been increasing during the last decades, especially among young women. Patients diagnosed with (persistent) high-grade CIN (CIN2/3) are treated with conization. Conization can be regarded as a safe procedure but peri- and postoperative complications (infections, bleeding, preterm birth) occur. This raises the need for a conservative treatment alternative for patients with high-grade CIN. Preliminary data: Imiquimod (IMQ), a toll-like receptor 7 agonist, is an immune modulating substance approved for the therapy of superficial skin lesions (e.g. basalioma, actinic keratosis) and HPV associated disease (e.g. anogenital condylomata acuminata and vulvar intraepithelial neoplasia). In a randomized, placebo-controlled phase II trial, we previously showed that topical IMQ therapy is an efficacious and feasible treatment for selected patients with CIN 2/3. Methods: In the present open, randomized, non-inferiority trial 500 women with CIN 2/3 will be included. This non-profit, patient-oriented clinical research project will be conducted as an Austrian Gynecologic Oncology Group (AGO-Austria) trial. Participants will be randomized to either 16 weeks treatment with topical IMQ (new treatment) or to standard therapy i.e. conization (active control). This study investigates the non-inferiority of the new treatment, compared to surgical standard treatment. The primary endpoint is the rate of successful treatment, defined as negative HPV test result six months after treatment start. Six months after start of therapy the primary study endpoint is assessed using HPV genotyping. In addition clinical examinations including colposcopy, HPV genotyping, cytology, and if indicated colposcopy-guided biopsies of the uterine cervix will be performed. In addition, rates of CIN persistence/recurrence 6, 12, 18, and 24 months after start of the treatment and rates of negative HPV test results 12 and 24 months after start of the treatment will be evaluated in both treatment groups. Rationale: The need for a conservative treatment modality for patients diagnosed with CIN is obvious, as many young women need surgical treatment. In this randomized controlled, trial we will investigate the non-inferiority of a topical IMQ treatment compared to surgical standard treatment in selected patients diagnosed with CIN 2/3.

Official Title
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ITIC2 Trial - Topical Imiquimod Versus Conization to Treat Cervical Intraepithelial Neoplasia: Randomised Controlled, Non-inferiority Trial

Conditions
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Cervical Intraepithelial Neoplasia

Intervention / Treatment
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* Drug: Topical Imiquimod
* Procedure: Conization


Participation Criteria
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Eligibility Criteria
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Inclusion criteria: Women aged ≥18 years diagnosed with histologically verified CIN 3 and women aged ≥ 30 years diagnosed with CIN 2 Satisfactory colposcopy Signed informed consent Negative pregnancy test Appropriate contraception method for fertile women during active study period Adequate compliance Exclusion criteria: Adenocarcinoma in situ History of previous conization Malignant disease at the time of inclusion Colposcopy suspicious for invasive disease Pregnancy and lactation period Known allergy or intolerance to IMQ Contraindications to conization or IMQ Symptoms of a clinically relevant disease Known HIV infection Evidence of a clinically significant immunodeficiency Current, reported participation in another experimental, interventional protocol

Ages Eligible for Study
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Minimum Age: 18 Years

Sexes Eligible for Study
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Female

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Topical Imiquimod<br>16 weeks topical Imiquimod | Drug: Topical Imiquimod<br>* 16 weeks<br>* Other names: Aldara®;|
| Active Comparator: Conization<br>Large loop excision of the transformation zone | Procedure: Conization<br>* Large loop excision of the transformation zone<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| HPV clearance | non-inferiority of experimental treatment (Imiquimod) to active control (conization) | 6 months after treatment completion | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Rates of CIN remission/regression and/or CIN persistence/regression after treatment | Histologic outcome | 6, 12, and 24 months after treatment completion | 
| HPV clearance |  | 12 and 24 months after treatment completion | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Cervical Intraepithelial Neoplasia, Imiquimod, conization