Brief Title
Imiquimod Treatment of CIN Lesions
Official Title
TOPical Imiquimod Treatment of High-grade Cervical Intraepithelial Neoplasm: a Randomized Controlled Trial.
Brief Summary
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.
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 Phase
Phase 3
Study Type
Interventional
Primary Outcome
Treatment efficacy: histological disease regression
Secondary Outcome
Prevalence and severity of side effects of imiquimod and LLETZ treatment
Condition
Cervical Intraepithelial Neoplasia
Intervention
Imiquimod
Study Arms / Comparison Groups
Imiquimod treatment arm
Description: 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.
Publications
* Includes publications given by the data provider as well as publications identified by National Clinical Trials Identifier (NCT ID) in Medline.
Recruitment Information
Recruitment Status
Drug
Estimated Enrollment
9
Start Date
December 2014
Completion Date
June 2016
Primary Completion Date
June 2016
Eligibility Criteria
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
Gender
Female
Ages
18 Years - N/A
Accepts Healthy Volunteers
Accepts Healthy Volunteers
Contacts
Arnold J Kruse, MD, PhD, ,
Location Countries
Netherlands
Location Countries
Netherlands
Administrative Informations
NCT ID
NCT02329171
Organization ID
METC 13-2-031
Responsible Party
Sponsor
Study Sponsor
Maastricht University Medical Center
Collaborators
MEDA Pharma GmbH & Co. KG
Study Sponsor
Arnold J Kruse, MD, PhD, Study Director, Maastricht University Medical Center
Verification Date
June 2016