Imiquimod Treatment of High-grade CIN

Study Overview
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Brief Summary
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This multi-center, open-label, non-randomized controlled intervention study aims to investigate the treatment efficacy, side-effects and quality of life associated with imiquimod treatment of high-grade CIN lesions, as an alternative to surgical treatment by Large Loop Excision of the Transformation Zone (LLETZ). Non-surgical treatment may prevent side-effects associated with surgical treatment, such as premature birth in subsequent pregnancies. The study hypothesis is that approximately 75% of patients with high-grade CIN will be adequately treated with imiquimod. 120 women with a histological diagnosis of CIN2 or CIN3 will be included and allocated to one of two treatment arms according to their preference: Imiquimod treatment arm(60 patients). Patients in this group are treated with vaginal imiquimod 5% cream during 16 weeks. Standard treatment arm (60 patients). Patients in this group will undergo LLETZ treatment.

Detailed Description
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Cervical Intraepithelial Neoplasia (CIN) is the premalignant condition of cervical cancer. The standard treatment of histologically confirmed CIN2-3 is surgical excision by large loop excision of the transformation zone (LLETZ). This procedure has potential complications, such as hemorrhage, infection and preterm birth in subsequent pregnancies. For this reason, non-invasive therapies are needed. Imiquimod cream has been studied as a non-invasive treatment alternative in high-grade CIN, but evidence on treatment efficacy is limited and evidence on disease recurrence and quality of life during and after treatment is lacking. One RCT has been performed and shows that treatment of high-grade CIN with vaginal imiquimod cream leads to disease regression in 73%. Side-effects were generally mild, but common. A recent survey among gynecologists and a patient preference study indicate that imiquimod treatment of high-grade CIN is mainly preferred by a selected population of women with a future pregnancy wish. These women accept a lower treatment efficacy and higher rates of side-effects from imiquimod treatment in order to prevent future preterm birth caused by LLETZ treatment. Ideally, those women with a high probability of successful treatment would be selected. The objective of this study is to investigate the treatment efficacy, side-effects and quality of life associated with imiquimod treatment of high-grade CIN lesions in a selected population of patients who prefer imiquimod treatment instead of LLETZ. The study also aims to identify predictive biomarkers clinical response to imiquimod treatment, in order to select patients in which good treatment response is expected. The study design is a multicenter, open-label, non-randomized controlled intervention study. 120 women with a histological diagnosis of CIN2 or CIN3 will be included and allocated to one of two treatment arms according to their preference: Imiquimod treatment arm(60 patients). Patients in this group are treated with vaginal imiquimod 5% cream during 16 weeks. Standard treatment arm (60 patients). Patients in this group will undergo LLETZ treatment. A control colposcopy will be performed after 10 weeks for the imiquimod group. In case of progressive disease, the treatment will be ended and LLETZ will be performed as treatment. For patients in which the treatment is continued, treatment efficacy will be evaluated after 20 weeks, by colposcopy with diagnostic biopsies. Statistical analysis will be performed based on an intention-to-treat analysis. The primary study endpoints are: Treatment efficacy of imiquimod and LLETZ treatment, defined as regression to CIN1 or less after 20 weeks for imiquimod and no need for additional therapy within 6 months for LLETZ treatment. Identification of predictive biomarkers for the efficacy of imiquimod treatment in the individual patient, based on biomarkers reflecting host, virus and cellular factors. Secondary study endpoints are: Side effects of imiquimod therapy and LLETZ therapy. Disease recurrence at 6, 12 and 24 months follow-up. Quality of life (QoL) before, during and after treatment.

Official Title
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TOPical Imiquimod Treatment of High-grade Cervical Intraepithelial Neoplasia, a Multicenter, Open-label, Non-randomized, Controlled Study (TOPIC-3 Study)

Conditions
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Cervical Intraepithelial Neoplasia

Intervention / Treatment
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* Drug: Imiquimod
* Procedure: Large Loop Excision of the Transformation Zone


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: de novo CIN2 or CIN3 lesion, histologically confirmed by diagnostic biopsy age of 18 years or older Exclusion Criteria: previous histologically confirmed high-grade CIN (CIN 2-3) concomitant vulvar and/or vaginal intraepithelial neoplasia previous cervical malignancy current malignant disease immunodeficiency (including HIV/AIDS and immunodepressive medication) pregnancy or lactation legal incapability

Ages Eligible for Study
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Minimum Age: 18 Years
Maximum Age: 99 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: Non-Randomized
Intervention Model: Parallel Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Imiquimod treatment arm<br>Treatment by vaginal imiquimod cream during 16 weeks. | Drug: Imiquimod<br>* Patients in this group are treated with vaginal imiquimod cream during 16 weeks. A control colposcopy with diagnostic biopsies will be performed after 10 weeks to rule out disease progression. A final colposcopy with diagnostic biopsies will be performed after 20 weeks to evaluate disease efficacy.<br>|
| Active Comparator: Standard treatment arm<br>Treatment by large loop excision of the transformation zone. | Procedure: Large Loop Excision of the Transformation Zone<br>* Patients in this group are treated with LLETZ.<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Treatment efficacy of imiquimod 5% cream for the treatment of CIN2-3 lesions, compared to LLETZ treatment, in selected populations. | Treatment efficacy for the imiquimod group is defined as regression to CIN 1 or less at 20 weeks follow-up. Treatment efficacy for the standard treatment group is defined as no need for additional treatment within 6 months after LLETZ treatment. | 6 months | 
| Identification of predictive biomarkers for treatment efficacy of imiquimod in the individual patient. | Histological biomarkers will be identified in the cervical biopsies performed at baseline. | Baseline (T=0) | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Side effects of imiquimod therapy and LLETZ therapy. | Scored by the Common Terminology Criteria for Adverse Events guidelines. | 20 weeks | 
| Disease recurrence | Defined as abnormal cervical cytology for all treatment groups. | 6, 12 and 24 months | 
| General health-related Quality of life (QoL) before, during and after treatment | Medical Outcomes Study 36-Item Short-Form General Health Survey (RAND 36) | Baseline, 20 weeks and 1 year | 
| Cancer specific Quality of Life, during and after treatment | European Organization for Research and Treatment of Cancer (EORTC) quality-of-life questionnaire: QLQ-C30 | Baseline, 20 weeks and 1 year | 
| Cervical cancer specific Quality of life (QoL), during and after treatment | European Organization for Research and Treatment of Cancer (EORTC) quality-of-life questionnaire: QLQ-CX24 | Baseline, 20 weeks and 1 year | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Cervical intraepithelial neoplasia, Imiquimod, Treatment, Predictive biomarkers