Imiquimod Treatment of CIN Lesions (TOPIC)

August 14, 2018 updated by: Maastricht University Medical Center

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

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:

  1. Imiquimod treatment arm. Patients in this group are treated by a 16-week regime of imiquimod 5% cream.
  2. 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.

Study Overview

Status

Terminated

Conditions

Intervention / Treatment

Detailed Description

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.

Study Type

Interventional

Enrollment (Actual)

9

Phase

  • Phase 3

Contacts and Locations

This section provides the contact details for those conducting the study, and information on where this study is being conducted.

Study Locations

  • Netherlands
      • Maastricht, Netherlands, 6202AZ
        • Maastricht University Medical Centre

Participation Criteria

Researchers look for people who fit a certain description, called eligibility criteria. Some examples of these criteria are a person's general health condition or prior treatments.

Eligibility Criteria

Ages Eligible for Study

18 years and older (Adult, Older Adult)

Accepts Healthy Volunteers

No

Genders Eligible for Study

Female

Description

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

Study Plan

This section provides details of the study plan, including how the study is designed and what the study is measuring.

How is the study designed?

Design Details

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

Arms and Interventions

Participant Group / Arm
Intervention / Treatment
Experimental: Imiquimod treatment arm
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
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.
Other Names:
  • Imiquimod, Aldara.
Active Comparator: Standard treatment arm
Large loop excision of the transformation zone (LLETZ) will be performed in this group, as standard treatment.
Procedure: LLETZ
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.
Other Names:
  • Loop excision

What is the study measuring?

Primary Outcome Measures

Outcome Measure
Measure Description
Time Frame
Treatment efficacy: histological disease regression
Time Frame: 20 weeks

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
Time Frame: 20 weeks
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
Time Frame: 6 weeks, 10 weeks, 14 weeks and 20 weeks for imiquimod treatment and 6 weeks for 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.
Time Frame: Baseline, 20 weeks and 1 year
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.
Time Frame: 6, 12 and 24 months
Defined as abnormal cervical cytology.
6, 12 and 24 months

Collaborators and Investigators

This is where you will find people and organizations involved with this study.

Sponsor

Maastricht University Medical Center

Collaborators

MEDA Pharma GmbH & Co. KG

Investigators

  • Study Director: Arnold J Kruse, MD, PhD, Maastricht University Medical Center
  • Study Chair: R.F.P.M. Kruitwagen, Professor, Maastricht University Medical Center

Publications and helpful links

The person responsible for entering information about the study voluntarily provides these publications. These may be about anything related to the study.

General Publications

Study record dates

These dates track the progress of study record and summary results submissions to ClinicalTrials.gov. Study records and reported results are reviewed by the National Library of Medicine (NLM) to make sure they meet specific quality control standards before being posted on the public website.

Study Major Dates

Study Start

December 1, 2014

Primary Completion (Actual)

June 1, 2016

Study Completion (Actual)

June 1, 2016

Study Registration Dates

First Submitted

December 22, 2014

First Submitted That Met QC Criteria

December 30, 2014

First Posted (Estimate)

December 31, 2014

Study Record Updates

Last Update Posted (Actual)

August 15, 2018

Last Update Submitted That Met QC Criteria

August 14, 2018

Last Verified

June 1, 2016

More Information

Terms related to this study

Additional Relevant MeSH Terms

Other Study ID Numbers

  • METC 13-2-031

Drug and device information, study documents

Studies a U.S. FDA-regulated drug product

No

Studies a U.S. FDA-regulated device product

No

product manufactured in and exported from the U.S.

No

This information was retrieved directly from the website clinicaltrials.gov without any changes. If you have any requests to change, remove or update your study details, please contact register@clinicaltrials.gov. As soon as a change is implemented on clinicaltrials.gov, this will be updated automatically on our website as well.

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