Imiquimod Treatment of CIN Lesions

Study Overview
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Brief Summary
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Rationale: Cervical Intraepithelial Neoplasia (CIN) is the premalignant condition of cervical cancer. High grade CIN (CIN 2-3) is currently treated by large loop excision of the transformation zone (LLETZ). This treatment has potential complications, such as hemorrhage, infection and preterm birth in subsequent pregnancies. For this reason, non-invasive therapies are needed. Imiquimod (an immunomodulator) was proven effective in the treatment of HPV-related vulvar intraepithelial neoplasia (VIN) and may also be effective in HPV-related CIN. [van Seters, 2012] However, the evidence is limited and study results are not consistent. [Grimm, 2012; Pachman, 2012; Lin, 2012] Objectives: Primary objectives: (1) to investigate the efficacy of imiquimod 5% cream for the treatment of CIN2-3 lesions and (2) to develop biomarker panels to predict clinical response to imiquimod therapy. Secondary objectives: to assess side effects of imiquimod treatment and LLETZ, disease recurrence and quality of life. Hypothesis: The investigators hypothesize that imiquimod will be an effective treatment modality in approximately 50-75% of CIN lesions treated without surgical intervention. Study design: Single-centre randomized controlled intervention trial. Study population: 140 women with a histological diagnosis of CIN2-3, equally divided over two study arms. Intervention: Patients will be randomized into one of two arms: Imiquimod treatment arm. Patients in this group are treated by a 16-week regime of imiquimod 5% cream. Standard treatment arm. LLETZ will be performed on patients in this group. Colposcopy with diagnostic biopsies will be performed after 10 weeks for the imiquimod treatment arm. In case progressive disease, the treatment will be ended and appropriate surgical excision will be performed. Treatment efficacy will be evaluated after 20 weeks, by colposcopy with diagnostic biopsies. A histological biomarker panel will be developed, consisting of markers representing both host and viral factors. Main study parameters/endpoints: The primary endpoint of the study is regression-or-not of CIN2-3, defined as CIN1 or less at the colposcopy at 20 weeks for the imiquimod arm and PAP 1 cytology at 6 months for the LLETZ group.

Detailed Description
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The treatment period was set at 20 weeks, in order to realize adequate treatment efficacy of imiquimod, while minimizing the risk of progression of cervical dysplasia to invasive disease in the conservative treatment group. Based on the available literature on the natural history of CIN and several studies on cervical dysplasia that included a conservative treatment group, the risk of disease progression within the treatment period of 20 weeks is estimated to be marginal. Approximately 30% of high-grade CIN progresses to cervical cancer. [Peto, 2004; McCredie, 2008]. This is believed to be a slow process, which can take many years. The annual risk of progression of CIN 3 to invasive cervical cancer is estimated to be less than 1%.[Canfell, 2004]. Ten studies were identified in which a total of 637 patients with high grade CIN were included either as a control group, receiving conservative treatment during 6 weeks to 15 months, or followed during the period between diagnosis and LLETZ.[Grimm, 2012, Follen, 2001; Meyskens, 1994; Keefe, 2001; Alvarez, 2003; Garcia, 2004; Van Pachterbeke, 2009; Kaufmann, 2007; Trimble 2005; Munk, 2012] Three cases of invasive disease were identified: all occured in the same study after 16 weeks of conservative treatment. Other studies showed no progression to invasive disease. One case of progression was reported with undefined disease grade and follow-up term. The possibility of invasive disease already present at the initial colposcopy (biopsy error) cannot be excluded. Based on these results, the investigators selected a treatment period of 20 weeks, with a control colposcopy with diagnostic biopsies after ten weeks. The current study protocol includes a substantial amendment to the original study protocol, which consisted of three study arms: imiquimod treatment arm, LLETZ treatment arm and an observational arm. The purpose of the observational arm was to assess spontaneous regression of high-grade CIN and to develop a prognostic biomarker panel to predict spontaneous regression of high-grade CIN. Patients in the observational arm underwent no treatment for a period of maximum 20 weeks. Histological assessment of disease development was performed after 10 and 20 weeks by colposcopy with diagnostic biopsies. Inclusion of patients into the study was hampered by the observational arm: patients declined the study because they wished to be treated, rather than undergo observational management. The observational arm was removed from the study.

Official Title
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TOPical Imiquimod Treatment of High-grade Cervical Intraepithelial Neoplasm: a Randomized Controlled Trial.

Conditions
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Cervical Intraepithelial Neoplasia

Intervention / Treatment
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* Drug: Imiquimod
* Procedure: LLETZ


Participation Criteria
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Eligibility Criteria
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Inclusion criteria: newly diagnosed high grade CIN lesions (CIN 2-3), histologically confirmed age 18 years or older Exclusion criteria: immunodeficiency pregnancy or lactation legally incapability history of histologically conformed high-grade CIN

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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Accepts Healthy Volunteers

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: Imiquimod treatment arm<br>Patients in this group will be treated with imiquimod during 16 weeks. Colposcopy with diagnostic biopsies will be performed after 10 weeks. In case of progressive disease, the treatment will be ended and appropriate surgical excision will be performed. Treatment efficacy will be evaluated after 20 weeks, by colposcopy with diagnostic biopsies. | Drug: Imiquimod<br>* Imiquimod 5% cream will be administered in a vaginal applicator, containing 12,5 mg of imiquimod (one sachet). The cream will be self-administered three times per week, by use of a vaginal applicator.<br>* Other names: Imiquimod, Aldara.;|
| Active Comparator: Standard treatment arm<br>Large loop excision of the transformation zone (LLETZ) will be performed in this group, as standard treatment. | Procedure: LLETZ<br>* Standard treatment consists of a LLETZ procedure, in which excision of the transformation zone and macroscopic lesions is performed by a monopolar loop electrode, under local anaesthesia. The excision is usually performed in two or three steps, depending on the size of the lesions.<br>* Other names: Loop excision;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Treatment efficacy: histological disease regression | Defined as following: for imiquimod treatment arm: CIN1 or less in diagnostic biopsies at colposcopy at 20 weeks for LLETZ arm: PAP 1 at 6 months follow-up | 20 weeks | 
| Baseline biomarker profile predicting clinical response to imiquimod treatment | The biomarker profiles will consist of markers reflecting host and viral factors, including HPV-genotype, markers of immunologic response (CD4, CD8, CD25, CD138, Fox p3) and markers of cell cycle processes (Rb, p53, Ki67, CK 13/14, IMP3). | 20 weeks | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Prevalence and severity of side effects of imiquimod and LLETZ treatment | The prevalence and severity of side effects of imiquimod and LLETZ treatment, as documented according to Common Terminology Criteria for Adverse Events guidelines. | 6 weeks, 10 weeks, 14 weeks and 20 weeks for imiquimod treatment and 6 weeks for LLETZ treatment | 
| Quality of life for all treatment groups. | Assessed by the following questionnaires: RAND 36, EORTC QLQ-C30 and EORTC QLQ-CX24. | Baseline, 20 weeks and 1 year | 
| Disease recurrence for all treatment groups. | Defined as abnormal cervical cytology. | 6, 12 and 24 months |