Randomized Clinical Trial Evaluating the Efficacy of Topical Imiquimod in High Grade Cervical Intraepithelial Lesions

NCT03233412 | Completed Phase 2 DMC

• 1 other identifier: BarretosCH-20171
• Study Type: interventional
• Target: 90
• Locations: 1 country
• Sites: 1

Brief Summary

Cervical cancer is one of the leading malignancies affecting women, with 311,000 deaths in 2018, most of them seen in underdeveloped countries. This neoplasm has a pre-invasive state, such as cervical intraepithelial neoplasia (CIN), which is caused by HPV (Human Papillomavirus) infection. The female organism most often is able to eliminate the virus, especially in young patients. However, when the infection becomes persistent, especially for subtypes 16 and 18, the risk of CIN developing an increased. Cytological screening programs can efficiently and wirelessly do this. As high-grade intraepithelial lesions (CIN 2/3) are as demonstrated by worse regression rate, only 13.3% at one year, and higher risk for progression to invasive cancer. As CIN 2/3 need treatment, and as more therapies as they are excisional, which theoretically are better, however, they may compromise the reproductive future of women who are unthreatened, increasing the risk of preterm labor, premature rupture of amniotic membranes, low weight Birth and perinatal mortality. This relationship aroused interest in seeking alternative therapies. Decrease antiviral activity directed against HPV, associated with a higher rate of elimination of the infection. Immediate, an agent that stimulates like dendritic cells to producer cytokines and activates epithelial T cells. Imiquimode, when used in vulvar neoplasias, has been shown to be effective, presenting satisfactory results without treatment of CIN 2/3 of the uterine cervix, requiring a better scientific compilation. Based on these data, this study aims to evaluate the efficacy of topical immunomodulatory treatment for high-grade cervical intraepithelial lesions.

Conditions

High Grade Intraepithelial Neoplasia; Cervix Cancer

Keywords

high grade cervical intraepithelial neoplasia; Immunomodulatory treatment

Outcome Measures

Primary Outcomes (1)

• Efficacy of immunomodulatory treatment with Imiquimod in high grade intraepithelial lesions of the cervix compared to standard electrosurgical excision procedure (LEEP) treatment.

  We will evaluate the efficacy of the Imiquimod treatment applied by the physician after histological examination of the uterine cervix obtained by electrosurgical excision procedure (LEEP) and compare the rate of relapse / reoperation with the control patient only submitted to the standard treatment with LEEP

  30 months

Secondary Outcomes (6)

• Local and systemic adverse events

  30 months

• Compare CIN 2 and CIN 3 for the difference in response to immunomodulatory treatment

  30 months

• Definition of the difference in cost from actual standard treatment compared to Imiquimod

  30 months

• Evaluation of recurrence of high grade cervical squamous intraepithelial lesion after 2 years of treatment.

  24 months

• Evaluation of reoperation rate after immunomodulatory treatment associated with standard treatment with LEEP compared to LEEP alone.

  24 months

Study Arms (2)

Control

OTHER

Will be offered the standard treatment, which is the conization of the uterine cervix with loop electrosurgical excision procedure (LEEP).

Procedure: Control

Imiquimod

EXPERIMENTAL

Will receive topical uterine cervix (Imiquimod) treatment for a period of 12 weeks with weekly applications (1x / week). 30-60 days afterwards they will be submitted to standard treatment with conization of the uterine cervix with loop electrosurgical excision procedure (LEEP).

Procedure: Control; Drug: Imiquimod

Interventions

Control PROCEDURE

Exertion of the cervix transformation zone

Also known as: loop electrosurgical excision procedure, Conization of the cervix

Control; Imiquimod

Imiquimod DRUG

Application by the doctor of immunomodulatory cream on the uterine cervix 1 time per week for 12 weeks

Also known as: Imiquimod 5% cream, Ixium 5%

Imiquimod

Eligibility Criteria

• Age: 25 Years - 50 Years
• Sex: female
• Healthy Volunteers: No
• Age Groups: Adult (18-64)

You may qualify if:

• Women between the ages of 25 and 50 with histological diagnosis of CIN 2/3;
• Living 300 km or less from the city of Barretos-São Paulo / Brazil.

You may not qualify if:

• Suspected adenocarcinoma (in situ or invasive) or invading squamous cell carcinoma by colposcopy and/or citology;
• Being pregnant or breastfeeding;
• Women with some immunodeficiency or transplanted;
• Previous treatment history for CIN 2/3.

Sponsors & Collaborators

• Barretos Cancer Hospital: lead
• Farmoquimica S.A.: collaborator

Study Sites (1)

Barretos Cancer Hospital

Barretos, Brazil

Location

Related Publications (23)

• American College of Obstetricians and Gynecologists. Practice Bulletin No. 140: management of abnormal cervical cancer screening test results and cervical cancer precursors. Obstet Gynecol. 2013 Dec;122(6):1338-67. doi: 10.1097/01.AOG.0000438960.31355.9e. No abstract available.

  PMID: 24264713 RESULT

• Martin-Hirsch PP, Paraskevaidis E, Bryant A, Dickinson HO, Keep SL. Surgery for cervical intraepithelial neoplasia. Cochrane Database Syst Rev. 2010 Jun 16;(6):CD001318. doi: 10.1002/14651858.CD001318.pub2.

  PMID: 20556751 RESULT

• 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.

  PMID: 23276555 RESULT

• Pachman DR, Barton DL, Clayton AC, McGovern RM, Jefferies JA, Novotny PJ, Sloan JA, Loprinzi CL, Gostout BS. Randomized clinical trial of imiquimod: an adjunct to treating cervical dysplasia. Am J Obstet Gynecol. 2012 Jan;206(1):42.e1-7. doi: 10.1016/j.ajog.2011.06.105. Epub 2011 Jul 13.

  PMID: 21907959 RESULT

• McCredie MR, Sharples KJ, Paul C, Baranyai J, Medley G, Jones RW, Skegg DC. Natural history of cervical neoplasia and risk of invasive cancer in women with cervical intraepithelial neoplasia 3: a retrospective cohort study. Lancet Oncol. 2008 May;9(5):425-34. doi: 10.1016/S1470-2045(08)70103-7. Epub 2008 Apr 11.

  PMID: 18407790 RESULT

• Arbyn M, Kyrgiou M, Simoens C, Raifu AO, Koliopoulos G, Martin-Hirsch P, Prendiville W, Paraskevaidis E. Perinatal mortality and other severe adverse pregnancy outcomes associated with treatment of cervical intraepithelial neoplasia: meta-analysis. BMJ. 2008 Sep 18;337:a1284. doi: 10.1136/bmj.a1284.

  PMID: 18801868 RESULT

• 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.

  PMID: 16473126 RESULT

• Jin G, LanLan Z, Li C, Dan Z. Pregnancy outcome following loop electrosurgical excision procedure (LEEP) a systematic review and meta-analysis. Arch Gynecol Obstet. 2014 Jan;289(1):85-99. doi: 10.1007/s00404-013-2955-0. Epub 2013 Jul 11.

  PMID: 23843155 RESULT

• Insinga RP, Dasbach EJ, Elbasha EH. Epidemiologic natural history and clinical management of Human Papillomavirus (HPV) Disease: a critical and systematic review of the literature in the development of an HPV dynamic transmission model. BMC Infect Dis. 2009 Jul 29;9:119. doi: 10.1186/1471-2334-9-119.

  PMID: 19640281 RESULT

• Kocken M, Helmerhorst TJ, Berkhof J, Louwers JA, Nobbenhuis MA, Bais AG, Hogewoning CJ, Zaal A, Verheijen RH, Snijders PJ, Meijer CJ. Risk of recurrent high-grade cervical intraepithelial neoplasia after successful treatment: a long-term multi-cohort study. Lancet Oncol. 2011 May;12(5):441-50. doi: 10.1016/S1470-2045(11)70078-X.

  PMID: 21530398 RESULT

• Conner SN, Cahill AG, Tuuli MG, Stamilio DM, Odibo AO, Roehl KA, Macones GA. Interval from loop electrosurgical excision procedure to pregnancy and pregnancy outcomes. Obstet Gynecol. 2013 Dec;122(6):1154-9. doi: 10.1097/01.AOG.0000435454.31850.79.

  PMID: 24201682 RESULT

• Spracklen CN, Harland KK, Stegmann BJ, Saftlas AF. Cervical surgery for cervical intraepithelial neoplasia and prolonged time to conception of a live birth: a case-control study. BJOG. 2013 Jul;120(8):960-5. doi: 10.1111/1471-0528.12209. Epub 2013 Mar 14.

  PMID: 23489374 RESULT

• 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 RESULT

• Mathiesen O, Buus SK, Cramers M. Topical imiquimod can reverse vulvar intraepithelial neoplasia: a randomised, double-blinded study. Gynecol Oncol. 2007 Nov;107(2):219-22. doi: 10.1016/j.ygyno.2007.06.003. Epub 2007 Jul 25.

  PMID: 17655918 RESULT

• van Seters M, van Beurden M, ten Kate FJ, Beckmann I, Ewing PC, Eijkemans MJ, Kagie MJ, Meijer CJ, Aaronson NK, Kleinjan A, Heijmans-Antonissen C, Zijlstra FJ, Burger MP, Helmerhorst TJ. Treatment of vulvar intraepithelial neoplasia with topical imiquimod. N Engl J Med. 2008 Apr 3;358(14):1465-73. doi: 10.1056/NEJMoa072685.

  PMID: 18385498 RESULT

• van Seters M, van Beurden M, de Craen AJ. Is the assumed natural history of vulvar intraepithelial neoplasia III based on enough evidence? A systematic review of 3322 published patients. Gynecol Oncol. 2005 May;97(2):645-51. doi: 10.1016/j.ygyno.2005.02.012.

  PMID: 15863172 RESULT

• Chen FP. Efficacy of imiquimod 5% cream for persistent human papillomavirus in genital intraepithelial neoplasm. Taiwan J Obstet Gynecol. 2013 Dec;52(4):475-8. doi: 10.1016/j.tjog.2013.10.004.

  PMID: 24411029 RESULT

• Diaz-Arrastia C, Arany I, Robazetti SC, Dinh TV, Gatalica Z, Tyring SK, Hannigan E. Clinical and molecular responses in high-grade intraepithelial neoplasia treated with topical imiquimod 5%. Clin Cancer Res. 2001 Oct;7(10):3031-3.

  PMID: 11595691 RESULT

• Gunderson CC, Nugent EK, Elfrink SH, Gold MA, Moore KN. A contemporary analysis of epidemiology and management of vaginal intraepithelial neoplasia. Am J Obstet Gynecol. 2013 May;208(5):410.e1-6. doi: 10.1016/j.ajog.2013.01.047. Epub 2013 Feb 1.

  PMID: 23380265 RESULT

• Haidopoulos D, Diakomanolis E, Rodolakis A, Voulgaris Z, Vlachos G, Intsaklis A. Can local application of imiquimod cream be an alternative mode of therapy for patients with high-grade intraepithelial lesions of the vagina? Int J Gynecol Cancer. 2005 Sep-Oct;15(5):898-902. doi: 10.1111/j.1525-1438.2005.00152.x.

  PMID: 16174242 RESULT

• Darragh TM, Colgan TJ, Cox JT, Heller DS, Henry MR, Luff RD, McCalmont T, Nayar R, Palefsky JM, Stoler MH, Wilkinson EJ, Zaino RJ, Wilbur DC; Members of LAST Project Work Groups. The Lower Anogenital Squamous Terminology Standardization Project for HPV-Associated Lesions: background and consensus recommendations from the College of American Pathologists and the American Society for Colposcopy and Cervical Pathology. Arch Pathol Lab Med. 2012 Oct;136(10):1266-97. doi: 10.5858/arpa.LGT200570. Epub 2012 Jun 28.

  PMID: 22742517 RESULT

• International Agency for Research on Cancer, World Health Organization, Globocan, Estimated Cancer Incidence, Mortality and Prevalence Worldwide in 2012

  RESULT

• Fonseca BO, Possati-Resende JC, Salcedo MP, Schmeler KM, Accorsi GS, Fregnani JHTG, Antoniazzi M, Pantano NP, Santana IVV, Matsushita GM, Dos Reis R. Topical Imiquimod for the Treatment of High-Grade Squamous Intraepithelial Lesions of the Cervix: A Randomized Controlled Trial. Obstet Gynecol. 2021 Jun 1;137(6):1043-1053. doi: 10.1097/AOG.0000000000004384.

  PMID: 33957649 DERIVED

MeSH Terms

Conditions

Uterine Cervical Neoplasms

Interventions

Imiquimod

Condition Hierarchy (Ancestors)

Uterine Neoplasms; Genital Neoplasms, Female; Urogenital Neoplasms; Neoplasms by Site; 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 Officials

• Ricardo D Reis, PhD

  Barretos Cancer Hospital

  STUDY DIRECTOR

• Bruno DO Fonseca, MD

  Barretos Cancer Hospital

  PRINCIPAL INVESTIGATOR

Study Design

• Study Type: interventional
• Phase: phase 2
• Allocation: RANDOMIZED
• Masking: SINGLE
• Who Masked: OUTCOMES ASSESSOR
• Purpose: TREATMENT
• Intervention Model: PARALLEL
• Sponsor Type: OTHER
• Responsible Party: SPONSOR

Model Details: Patients between 25 and 50 years old with histological diagnosis of high-grade intraepithelial lesion, obtained through satisfactory colposcopy and without previous treatment, who will be selected in the preventive clinic of the Hospital de Cancer de Barretos-SP (HCB ). Eligible patients will be identified at the return visit, when they will come to the hospital to check the result of the examination. In this study the patients will be randomized into two groups: Group 1: Control, where standard treatment will be offered, which is the conization of the uterine cervix with loop electrosurgical excision procedure(LEEP); Group 2: experimental group, which will receive topical treatment in the uterine cervix with immunomodulator (Imiquimod), for a period of 12 weeks, with weekly applications (1x / week). 30 to 60 days after immunomodulatory treatment the patient will be submitted to standard treatment with cervical conization with LEEP.

Study Record Dates

• First Submitted: July 6, 2017
• First Posted: July 28, 2017
• Study Start: January 1, 2018
• Primary Completion: January 14, 2020
• Study Completion: January 14, 2020
• Last Updated: February 17, 2021

Record last verified: 2019-04

Data Sharing

• IPD Sharing: Will not share

Locations

BR (1)