Comparison of Treatment of Cervical Intraepithelial Lesions With Imiquimod or LLETZ

NCT04859361 | Unknown DMC

• 1 other identifier: 2017-01-02
• Study Type: interventional
• Target: 104
• Locations: 1 country
• Sites: 1

Brief Summary

Purpose: There are limited data on the success of conservative treatment of high-grade cervical squamous intraepithelial lesions (HSIL) with imiquimod directly compared to standard of treatment with LLETZ. LLETZ as standard treatment is possibly associated with premature labour, higher subfertility rate and a higher rate of spontaneous abortion. Since premature delivery is one of the most important causes of perinatal morbidity and mortality, alternative conservative methods for SIL treatment are constantly being evaluated. The immunomodulator imiquimod is one of the main target compounds for treating HSIL. Primary objective: to establish the efficacy of treatment with imiquimod (experimental arm) and compare it to the standard treatment with LLETZ (control arm). Secondary objective:

• incidence and severity of the side effects in both groups;
• need for treatment with LLETZ two years after primary treatment with imiquimod in the experimental arm or re-treatment with LLETZ two years after primary treatment with LLETZ in the control arm;
• modulatory effect of imiquimod on immunoregulatory molecules. Study design: Single-centre randomized controlled intervention trial. Study population: 104 women with HSIL (52 in each arm). Intervention: \- randomization in two arms:
• Experimental arm (imiquimod): treatment for 16 weeks with 5% imiquimod.
• Control arm (LLETZ).

Conditions

Intraepithelial Neoplasia, Cervical

Keywords

imiquimod; LLETZ; cervical intraepithelial lesion

Outcome Measures

Primary Outcomes (1)

• Treatment efficacy of 5% imiquimod cream for treatment of HSIL compared to standard treatment with LLETZ defined as absence of HSIL in both arms (histological in experimental arm and cytological in control arm).

  Defined as following: * for experimental (imiquimod) treatment arm: absence of histological HSIL (CIN1 or less) in diagnostic biopsies at colposcopy at 20 weeks; * for control (LLETZ) arm: absence of cytological HSIL at 6 months follow-up.

  20 weeks after treatment initiation in experimental arm and 6 months after LLETZ in control arm.

Secondary Outcomes (3)

• Prevalence and severity of the side effects in both arms.

  10 weeks and 20 weeks after treatment initiation in experimental arm and 20 weeks after LLETZ in control arm.

• Need for LLETZ or repeated LLETZ following primary treatment.

  2 years after primary treatment.

• Immunoregulatory effect of imiquimod.

  2 years after primary treatment.

Study Arms (2)

Treatment with imiquimod

EXPERIMENTAL

Colposcopy with PAP smear and punch biopsy is scheduled at 10 weeks to rule out progression, and at 20 weeks to evaluate treatment success. At 20 weeks, biopsies will be performed at the locations where lesions were previously present and additional biopsies will be performed on any visible lesions. At 20 weeks, in case of disease progression or persistence, treatment with LLETZ will be offered.

Drug: Aldara 5% Topical Cream

Treatment with LLETZ

ACTIVE COMPARATOR

Standard treatment will be scheduled after patients' first period.

Procedure: LLETZ

Interventions

Aldara 5% Topical Cream DRUG

5% Imiquimod cream (1 sachet) will be administered via menstrual cup, before going to sleep, 3 times per week for 16 weeks. Menstrual cup will be inserted in the vagina for a duration of 6-8 hours. In case of severe side effects applications can be reduced to twice per week and if side effects are persistent, to once per week. For maximum control of cervical disease, control colposcopy with a PAP smear and a punch biopsy will be scheduled at 10 weeks to rule out progression, and at 20 weeks after treatment initiation to evaluate treatment success. At 20 weeks, biopsies will be performed at the locations where lesions were previously present, and if there are any new lesions present, additional biopsies will be performed. In case of disease progression or persistence, treatment with LLETZ will be offered.

Also known as: Zyclara, imiquimod

Treatment with imiquimod

LLETZ PROCEDURE

LLETZ will be performed in an outpatient setting with local anesthesia, using KLS Martin Maxium with loop devices ranging from 10 mm to 20 mm in size. The excision will be performed using monopolar current with a cut frequency set to 100-150 W. Treatment success will be evaluated in accordance with our national guidelines 24 weeks after the procedure using a PAP smear with or without a punch biopsy.

Also known as: LEEP

Treatment with LLETZ

Eligibility Criteria

• Age: 18 Years - 40 Years
• Sex: female
• Healthy Volunteers: Yes
• Age Groups: Adult (18-64)

You may qualify if:

• newly diagnosed and previously untreated HSIL in women aged 18 to 35 years or up to 40 years in case of nulliparity;
• satisfactory colposcopy (i.e., fully visible lesion and transformation zone);
• negative pregnancy test;
• safe contraception;
• signed, informed consent.

You may not qualify if:

• previously diagnosed HSIL or AIS;
• previous LLETZ or classical conisation;
• concomitant vulvar or vaginal lesion or neoplasia;
• other malignancies;
• insufficient colposcopy;
• pregnancy or lactation;
• known hypersensitivity to imiquimod;
• any known contraindications to immunotherapy;
• known HIV or acute or chronic hepatitis;
• immune deficiency;
• participation in any other ongoing clinical trial.

Sponsors & Collaborators

• University Medical Centre Maribor: lead

Study Sites (1)

University Medical Centre Maribor

Maribor, 2000, Slovenia

Location

Related Publications (5)

• Grimm C, Polterauer S, Natter C, Rahhal J, Hefler L, Tempfer CB, Heinze G, Stary G, Reinthaller A, Speiser P. Treatment of cervical intraepithelial neoplasia with topical imiquimod: a randomized controlled trial. Obstet Gynecol. 2012 Jul;120(1):152-9. doi: 10.1097/AOG.0b013e31825bc6e8.

  PMID: 22914404 BACKGROUND

• de Witte CJ, van de Sande AJ, van Beekhuizen HJ, Koeneman MM, Kruse AJ, Gerestein CG. Imiquimod in cervical, vaginal and vulvar intraepithelial neoplasia: a review. Gynecol Oncol. 2015 Nov;139(2):377-84. doi: 10.1016/j.ygyno.2015.08.018. Epub 2015 Aug 31.

  PMID: 26335596 BACKGROUND

• Koeneman MM, Kruse AJ, Kooreman LFS, Zur Hausen A, Hopman AHN, Sep SJS, Van Gorp T, Slangen BFM, van Beekhuizen HJ, van de Sande M, Gerestein CG, Nijman HW, Kruitwagen RFPM. TOPical Imiquimod treatment of high-grade Cervical intraepithelial neoplasia (TOPIC trial): study protocol for a randomized controlled trial. BMC Cancer. 2016 Feb 20;16:132. doi: 10.1186/s12885-016-2187-3.

  PMID: 26897518 BACKGROUND

• Jancar N, Mihevc Ponikvar B, Tomsic S. Cold-knife conisation and large loop excision of transformation zone significantly increase the risk for spontaneous preterm birth: a population-based cohort study. Eur J Obstet Gynecol Reprod Biol. 2016 Aug;203:245-9. doi: 10.1016/j.ejogrb.2016.06.005. Epub 2016 Jun 20.

  PMID: 27359080 BACKGROUND

• Cokan A, da Silva NCH, Kavalar R, But I, Pakiz M, Andrade de Oliveira S, Dos Santos Gomes FO, da Silva RS, Peixoto CA, Lucena-Silva N. Modulation of sHLA-G, PD-1, and PD-L1 Expression in Cervical Lesions Following Imiquimod Treatment and Its Association with Treatment Success. Cancers (Basel). 2024 Mar 25;16(7):1272. doi: 10.3390/cancers16071272.

  PMID: 38610950 DERIVED

MeSH Terms

Conditions

Uterine Cervical Dysplasia

Interventions

Imiquimod

Condition Hierarchy (Ancestors)

Precancerous Conditions; Neoplasms; Uterine Cervical Diseases; Uterine Diseases; Genital Diseases, Female; Female Urogenital Diseases; Female Urogenital Diseases and Pregnancy Complications; Urogenital Diseases; Genital Diseases

Intervention Hierarchy (Ancestors)

Aminoquinolines; Quinolines; Heterocyclic Compounds, 2-Ring; Heterocyclic Compounds, Fused-Ring; Heterocyclic Compounds

Study Design

• Study Type: interventional
• Phase: not applicable
• Allocation: RANDOMIZED
• Masking: SINGLE
• Who Masked: INVESTIGATOR
• Purpose: TREATMENT
• Intervention Model: PARALLEL
• Sponsor Type: OTHER
• Responsible Party: SPONSOR

Study Record Dates

• First Submitted: April 21, 2021
• First Posted: April 26, 2021
• Study Start: November 20, 2018
• Primary Completion: April 21, 2020
• Study Completion: September 15, 2023
• Last Updated: May 3, 2021

Record last verified: 2021-04

Locations

SL (1)