Imiquimod Treatment of High-grade CIN (TOPIC-3)

August 14, 2018 updated by: Maastricht University Medical Center

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

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:

  1. Imiquimod treatment arm(60 patients). Patients in this group are treated with vaginal imiquimod 5% cream during 16 weeks.
  2. Standard treatment arm (60 patients). Patients in this group will undergo LLETZ treatment.

Study Overview

Status

Unknown

Conditions

Intervention / Treatment

Detailed Description

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:

  1. Imiquimod treatment arm(60 patients). Patients in this group are treated with vaginal imiquimod 5% cream during 16 weeks.
  2. 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.

Study Type

Interventional

Enrollment (Actual)

120

Phase

  • Not Applicable

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
      • Amersfoort, Netherlands
        • Meander Medical Center
      • Maastricht, Netherlands, 6202AZ
        • Maastricht University Medical Center
      • Rotterdam, Netherlands
        • Erasmus Medical Center

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 to 99 years (ADULT, OLDER_ADULT)

Accepts Healthy Volunteers

No

Genders Eligible for Study

Female

Description

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

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: NON_RANDOMIZED
  • Interventional Model: PARALLEL
  • Masking: NONE

Arms and Interventions

Participant Group / Arm
Intervention / Treatment
EXPERIMENTAL: Imiquimod treatment arm
Treatment by vaginal imiquimod cream during 16 weeks.
Drug: Imiquimod
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.
ACTIVE_COMPARATOR: Standard treatment arm
Treatment by large loop excision of the transformation zone.
Procedure: Large Loop Excision of the Transformation Zone
Patients in this group are treated with LLETZ.

What is the study measuring?

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.
Time Frame: 6 months
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.
Time Frame: Baseline (T=0)
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.
Time Frame: 20 weeks
Scored by the Common Terminology Criteria for Adverse Events guidelines.
20 weeks
Disease recurrence
Time Frame: 6, 12 and 24 months
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
Time Frame: Baseline, 20 weeks and 1 year
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
Time Frame: Baseline, 20 weeks and 1 year
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
Time Frame: Baseline, 20 weeks and 1 year
European Organization for Research and Treatment of Cancer (EORTC) quality-of-life questionnaire: QLQ-CX24
Baseline, 20 weeks and 1 year

Collaborators and Investigators

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

Sponsor

Maastricht University Medical Center

Collaborators

Clinical Trial Center Maastricht B.V.

Investigators

  • Study Director: A.J. Kruse, MD, PhD, 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 (ACTUAL)

November 1, 2016

Primary Completion (ACTUAL)

July 1, 2018

Study Completion (ANTICIPATED)

December 1, 2020

Study Registration Dates

First Submitted

September 16, 2016

First Submitted That Met QC Criteria

September 26, 2016

First Posted (ESTIMATE)

September 28, 2016

Study Record Updates

Last Update Posted (ACTUAL)

August 16, 2018

Last Update Submitted That Met QC Criteria

August 14, 2018

Last Verified

May 1, 2018

More Information

Terms related to this study

Keywords

Additional Relevant MeSH Terms

Other Study ID Numbers

  • NL 57849.068.16

Plan for Individual participant data (IPD)

Plan to Share Individual Participant Data (IPD)?

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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