TOPical Imiquimod treatment of high-grade Cervical intraepithelial neoplasia, a multicenter, open-label, non-randomized, controlled study (TOPIC-3 study)

Cervical Intraepithelial Neoplasia (CIN) is the premalignant condition of
cervical cancer. The standard treatment of histologically confirmed CIN2-3
changes is surgical excision by large loop excision of the transformation zone
(LLETZ), with 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.

This study aims 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 for the clinical
response to imiquimod treatment, in order to select patients in which good
treatment response is expected.

Multicenter, open-label, non-randomized controlled intervention study.

Patients are allocated to one of two treatment groups according to their
preference:
1. Imiquimod treatment. Patients in this group are treated by a 16-week regime
of imiquimod 5% cream. 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.
2. Standard treatment. LLETZ will be performed on patients in this group.

The burden associated with participation includes:
- a questionnaire concerning demographic and behavioral factors for all patients
- contraception in the imiquimod group
- two pregnancy tests in the imiquimod group for sexually active patients
- use of medication with potential side-effects in the imiquimod group
- additional consultations in the imiquimod group (1x for start treatment, 4x
telephone consultation, 1x hospital visit, 1x additional colposcopy with
biopsies)
- documentation of medication use and side effects in the imiquimod group
- documentation of side-effects in the LLETZ group
- quality of life questionnaires at three points in time for all patients

A LLETZ procedure may not be necessary for these participants, when imiquimod
treatment is succesful. This may prevent complications, of which we consider
the reduced risk of premature birth as the most important. The risk of disease
progression in the imiquimod arm is minimalized by the study protocol.