Clinical trial NCT02917746: Imiquimod Treatment of High-grade CIN
Official title: TOPical Imiquimod Treatment of High-grade Cervical Intraepithelial Neoplasia, a Multicenter, Open-label, Non-randomized, Controlled Study (TOPIC-3 Study)
Study type: INTERVENTIONAL
Overall status: UNKNOWN
Phase: NA
Conditions: Cervical Intraepithelial Neoplasia
Keywords: Cervical intraepithelial neoplasia
Imiquimod
Treatment
Predictive biomarkers
Lead sponsor: Maastricht University Medical Center
Sponsor class: OTHER
Collaborators: name: Clinical Trial Center Maastricht B.V.
First posted: 2016-09-28
Enrollment: 120
Sex: FEMALE
Minimum age (years): 18
Maximum age (years): 99
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: NON_RANDOMIZED
Intervention model: PARALLEL
Primary purpose: TREATMENT

Brief summary: 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.

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.

Eligibility criteria: 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

Primary outcomes:
measure: Treatment efficacy of imiquimod 5% cream for the treatment of CIN2-3 lesions, compared to LLETZ treatment, in selected populations.
timeFrame: 6 months
measure: Identification of predictive biomarkers for treatment efficacy of imiquimod in the individual patient.
timeFrame: Baseline (T=0)
Secondary outcomes:
measure: Side effects of imiquimod therapy and LLETZ therapy.
timeFrame: 20 weeks
measure: Disease recurrence
timeFrame: 6, 12 and 24 months
measure: General health-related Quality of life (QoL) before, during and after treatment
timeFrame: Baseline, 20 weeks and 1 year
measure: Cancer specific Quality of Life, during and after treatment
timeFrame: Baseline, 20 weeks and 1 year
measure: Cervical cancer specific Quality of life (QoL), during and after treatment
timeFrame: Baseline, 20 weeks and 1 year
Other outcomes:
Locations:
city: Amersfoort
country: Netherlands
facility: Meander Medical Center
city: Maastricht
country: Netherlands
facility: Maastricht University Medical Center
city: Rotterdam
country: Netherlands
facility: Erasmus Medical Center
Study officials:
affiliation: Maastricht University Medical Center
name: A.J. Kruse, MD, PhD
role: STUDY_DIRECTOR
References:
citation: Crane JM. Pregnancy outcome after loop electrosurgical excision procedure: a systematic review. Obstet Gynecol. 2003 Nov;102(5 Pt 1):1058-62. doi: 10.1016/s0029-7844(03)00741-5.
citation: Kyrgiou M, Koliopoulos G, Martin-Hirsch P, Arbyn M, Prendiville W, Paraskevaidis E. Obstetric outcomes after conservative treatment for intraepithelial or early invasive cervical lesions: systematic review and meta-analysis. Lancet. 2006 Feb 11;367(9509):489-98. doi: 10.1016/S0140-6736(06)68181-6.
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citation: Lin CT, Qiu JT, Wang CJ, Chang SD, Tang YH, Wu PJ, Jung SM, Huang CC, Chou HH, Jao MS, Lai CH. Topical imiquimod treatment for human papillomavirus infection in patients with and without cervical/vaginal intraepithelial neoplasia. Taiwan J Obstet Gynecol. 2012 Dec;51(4):533-8. doi: 10.1016/j.tjog.2012.09.006.
citation: Koeneman MM, van de Sande AJ, van Beekhuizen HJ, Gerestein KG, van de Laar R, Kruitwagen RF, Kruse AJ. Physicians' Awareness, Attitudes, and Experiences Regarding Imiquimod Treatment of Vaginal and Cervical Intraepithelial Neoplasia. J Low Genit Tract Dis. 2016 Jan;20(1):75-9. doi: 10.1097/LGT.0000000000000158.
citation: Koeneman MM, Kruse AJ, Kooreman LF, Zur Hausen A, Hopman AH, Sep SJ, Van Gorp T, Slangen BF, van Beekhuizen HJ, van de Sande AJ, Gerestein CG, Nijman HW, Kruitwagen RF. Preliminary stop of the TOPical Imiquimod treatment of high-grade Cervical intraepithelial neoplasia (TOPIC) trial. BMC Cancer. 2017 Feb 7;17(1):110. doi: 10.1186/s12885-017-3108-9.