Randomized Clinical Trial Evaluating the Efficacy of Topical Imiquimod in High Grade Cervical Intraepithelial Lesions

Study Overview
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Brief Summary
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Cervical cancer is one of the leading malignancies affecting women, with 311,000 deaths in 2018, most of them seen in underdeveloped countries. This neoplasm has a pre-invasive state, such as cervical intraepithelial neoplasia (CIN), which is caused by HPV (Human Papillomavirus) infection. The female organism most often is able to eliminate the virus, especially in young patients. However, when the infection becomes persistent, especially for subtypes 16 and 18, the risk of CIN developing an increased. Cytological screening programs can efficiently and wirelessly do this. As high-grade intraepithelial lesions (CIN 2/3) are as demonstrated by worse regression rate, only 13.3% at one year, and higher risk for progression to invasive cancer. As CIN 2/3 need treatment, and as more therapies as they are excisional, which theoretically are better, however, they may compromise the reproductive future of women who are unthreatened, increasing the risk of preterm labor, premature rupture of amniotic membranes, low weight Birth and perinatal mortality. This relationship aroused interest in seeking alternative therapies. Decrease antiviral activity directed against HPV, associated with a higher rate of elimination of the infection. Immediate, an agent that stimulates like dendritic cells to producer cytokines and activates epithelial T cells. Imiquimode, when used in vulvar neoplasias, has been shown to be effective, presenting satisfactory results without treatment of CIN 2/3 of the uterine cervix, requiring a better scientific compilation. Based on these data, this study aims to evaluate the efficacy of topical immunomodulatory treatment for high-grade cervical intraepithelial lesions.

Official Title
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Ensaio clínico Randomizado Avaliando a eficácia do Tratamento tópico Com Imiquimode em lesões Intraepiteliais Cervicais de Alto Grau

Conditions
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High Grade Intraepithelial Neoplasia, Cervix Cancer

Intervention / Treatment
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* Procedure: Control
* Drug: Imiquimod


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Women between the ages of 25 and 50 with histological diagnosis of CIN 2/3; Living 300 km or less from the city of Barretos-São Paulo / Brazil. Exclusion Criteria: Suspected adenocarcinoma (in situ or invasive) or invading squamous cell carcinoma by colposcopy and/or citology; Being pregnant or breastfeeding; Women with some immunodeficiency or transplanted; Previous treatment history for CIN 2/3.

Ages Eligible for Study
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Minimum Age: 25 Years
Maximum Age: 50 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
Interventional Model Description: Patients between 25 and 50 years old with histological diagnosis of high-grade intraepithelial lesion, obtained through satisfactory colposcopy and without previous treatment, who will be selected in the preventive clinic of the Hospital de Cancer de Barretos-SP (HCB ). Eligible patients will be identified at the return visit, when they will come to the hospital to check the result of the examination. In this study the patients will be randomized into two groups: Group 1: Control, where standard treatment will be offered, which is the conization of the uterine cervix with loop electrosurgical excision procedure(LEEP); Group 2: experimental group, which will receive topical treatment in the uterine cervix with immunomodulator (Imiquimod), for a period of 12 weeks, with weekly applications (1x / week). 30 to 60 days after immunomodulatory treatment the patient will be submitted to standard treatment with cervical conization with LEEP.
Masking: Single


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Other: Control<br>Will be offered the standard treatment, which is the conization of the uterine cervix with loop electrosurgical excision procedure (LEEP). | Procedure: Control<br>* Exertion of the cervix transformation zone<br>* Other names: Conization of the cervix;|
| Experimental: Imiquimod<br>Will receive topical uterine cervix (Imiquimod) treatment for a period of 12 weeks with weekly applications (1x / week). 30-60 days afterwards they will be submitted to standard treatment with conization of the uterine cervix with loop electrosurgical excision procedure (LEEP). | Procedure: Control<br>* Exertion of the cervix transformation zone<br>* Other names: Conization of the cervix;Drug: Imiquimod<br>* Application by the doctor of immunomodulatory cream on the uterine cervix 1 time per week for 12 weeks<br>* Other names: Ixium 5%;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Efficacy of immunomodulatory treatment with Imiquimod in high grade intraepithelial lesions of the cervix compared to standard electrosurgical excision procedure (LEEP) treatment. | We will evaluate the efficacy of the Imiquimod treatment applied by the physician after histological examination of the uterine cervix obtained by electrosurgical excision procedure (LEEP) and compare the rate of relapse / reoperation with the control patient only submitted to the standard treatment with LEEP | 30 months | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Local and systemic adverse events | To assess the local and systemic adverse effects of topical immunomodulatory treatment through anamnesis and physical examination. | 30 months | 
| Compare CIN 2 and CIN 3 for the difference in response to immunomodulatory treatment | It will be evaluated separately from the results of the treatment response with Imiquimod in CIN 2 and CIN 3 lesions. | 30 months | 
| Definition of the difference in cost from actual standard treatment compared to Imiquimod | The value in Brazilian reais of treatment with Imiquimod will be defined as compared to the amount spent for the standard treatment with LEEP | 30 months | 
| Evaluation of recurrence of high grade cervical squamous intraepithelial lesion after 2 years of treatment. | To evaluate the recurrence after 2 years of the end of the immunomodulatory topical treatment. | 24 months | 
| Evaluation of reoperation rate after immunomodulatory treatment associated with standard treatment with LEEP compared to LEEP alone. | Evaluation of reoperation rate in post-treatment follow-up. | 24 months | 
| Clearance HPV | To evaluate the persistence or not of the HPV virus and which specific type to relate to the efficacy of the immunomodulatory treatment. | 30 months | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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high grade cervical intraepithelial neoplasia, Immunomodulatory treatment