Conservative Management of CIN2 Lesions and Biomarkers Evaluation

Completed

• Conditions: CIN2

• Registration Number: NCT04687267
• Lead Sponsor: Istituto Oncologico Veneto IRCCS

Brief Summary

Prospective study including women aged 25-45 years, adherent to the cervical screening program of four different centers of the Veneto region, with a diagnosis of CIN2 lesion. After enrollment according to predefined criteria, and informed consent to participate, the CIN2 lesions are managed by follow-up; cases with progressive lesions will be treated immediately, cases with CIN2 persistence for more than 12 months will be treated as well. Viral, molecular and immunocytochemical biomarkers will be studied, and evaluated in relation to the clinical outcome.

Detailed Description

Women aged 25-45 years, adherent to the organized population-based cervical screening program, with a histological diagnosis of CIN2 and fulfilling the inclusion criteria will be invited to participate to the study, previously providing specific information; in case of acceptance, informed consent is signed.

STUDY PROTOCOL:

The adherent women will attend periodical control visits:

* every 6 months up to 24 months, with performance of: pap test (PT) and colposcopy (with biopsy in case of visible alterations);

* at 6 and 12 months control visit: a liquid-based sample of cervical cells will be collected for the biomarkers' analyses.

BIOMARKERS:

1. - HPV search and partial HPV16/18 genotyping, by cobas 4800 high-risk HPV assay (Roche); PCR with MY09/MY11 consensus primers and full genotyping by restriction fragment length analysis, plus PCR with beta-globin primers (in-house);

2. - methylation analysis of the cellular genes FAM194A and hsa-mir124-2, by methylation-specific quantitative PCR test (qMSP - QIAsure methylation test, Qiagen);

3. - methylation analysis of the L1 and L2 viral genes of HPV types 16 and 18, by pyrosequencing;

4. - immunocytochemical analysis for p16INK4A/Ki67 proteins (dual stain), by p16INK4A/Ki67 immunocytochemical analysis by CINtec Plus kit (Roche).

Study Timeline

• Study Start: 2019-04-15
• Study First Submitted: 2020-12-10
• Study First Submitted QC: 2020-12-23
• Study First Posted: 2020-12-29
• Primary Completion: 2021-10-31
• Study Completion: 2022-12-31
• Status Verified: 2023-09
• Last Update Submitted: 2023-09-27
• Last Update Posted: 2023-09-28

Recruitment & Eligibility

• Status: COMPLETED
• Sex: Female
• Target Recruitment: 319

Inclusion Criteria

• age range 25-45 years,
• CIN2 lesions located in the exocervix and completely visible at colposcopy.

Exclusion Criteria

• age >45 years;
• history of previous high-grade lesions;
• squamo-columnar junction not completely visible (type 3);
• cytology with suspect or indicative for invasive lesion;
• lesions exclusively located in the endocervix;
• lesions located in the exocervix but not completely visible;
• pregnancy

Study & Design

• Study Type: OBSERVATIONAL
• Study Design: Not specified

Primary Outcome Measures

Name	Time	Method
CIN2 clinical outcome by DNA methylation	Through study completion, an average of 2 years.	Rate of CIN2 regression will be calculated in relation to DNA methylation of cellular and viral genes (number of regressed hypermethylated CIN2 lesions / total number of CIN2 lesions with valid result for each gene analyzed).
CIN2 clinical outcome by HPV genotype	Through study completion, an average of 2 years.	Rate of CIN2 regression will be calculated in relation to positivity for HPV16 vs positivity for other high-risk types (number of regressed HPV16-related CIN2 lesions / total number of HPV16-related CIN2 vs number of regressed non-HPV16-related CIN2 lesions / total number of non-HPV16-related CIN2 lesions).
Rate of spontaneous regression of CIN2 lesions	Through study completion, an average of 2 years.	Eligible women will not be treated at diagnosis, but periodically followed-up. Treatment will be provided for progressive lesions and lesions persisting more than 12 months. The rates of lesion regression will be calculated: number of lesions regressed to CIN1 or normal / total number of cases.
CIN2 clinical outcome by p16/ki67 protein expression	Through study completion, an average of 2 years.	Rate of CIN2 regression will be calculated in relation to positivity for p16/ki67 expression (number of regressed p16/ki67-positive CIN2 lesions / total number of CIN2 lesions with valid result for p16/ki67 expression).

Secondary Outcome Measures

Name	Time	Method
Adhesion to CIN2 conservative management.	2 years	The rate of eligible women consenting to participate to the study will be calculated (enrolled women / eligible women)

Trial Locations

Locations (4)

Azienda ULSS 6 Euganea; 🇮🇹 Padova, PD, Italy

Azienda ULSS 2 Marca Trevigiana; 🇮🇹 Treviso, TV, Italy

Azienda ULSS 9 Scaligera; 🇮🇹 Verona, VR, Italy

Azienda ULSS 3 Serenissima; 🇮🇹 Mestre, VE, Italy