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NCT Number: NCT01837693

Cervical Cancer Prevention: From DNA to mRNA? - New Technologies for Cervical Cancer Screening 2

In industrialized countries, cervical cancer is a well controlled disease thanks to the diffusion of Pap test and, in particular, to organized screening programs, which are able to detect and treat pre-invasive lesions (cervical intraepithelial neoplasia, CIN). The human papilloma virus (HPV) has been recognised as the necessary, but not sufficient, cause of cervical cancer, so a new screening test based on the identification of high risk (HR) HPV types has been developed(HPV DNA test). This test has demonstrated to be more effective than cytology in reducing the incidence and the mortality of cervical cancer, but it is less specific, so the use of a test triage is necessary to reduce the number of colposcopies and the risk of over-diagnosis (due to the potential regressivity of pre-invasive lesions). Until now, the triage test used is the cytology (Pap test).

Recently specific biomarkers (mRNA and p16 tests) have been introduced for high grade CIN, targeting the molecular alterations strictly associated to transformation rather than simply detecting HR-HPV infections. These tests are more specific than HPV DNA test with a modest reduction of sensitivity for high-grade lesions.

This is a multicenter randomised trial nested into some Italian screening programs based on the use of HPV DNA test as primary test.

All women with positive HPV DNA test will be tested for cytology and also for mRNA and p16. Women with positive cytology will be referred to colposcopy, while women with negative cytology will be randomized into two arms.

This study aims to evaluate if mRNA and p16 could be used as test of triage of HPV DNA or as a primary screening test with direct sending in colposcopy.

In particular the main objectives are:

* Measuring the cumulative detection rate of CIN2+ in the five years following a HPV DNA positive test and mRNA or p16 negative. * Measuring the potential reduction of overdiagnosis of using mRNA or p16 test instead of DNA, with direct sending in colposcopy * Measuring the reduction of overdiagnosis of cytological triage or triage with mRNA or p16 compared to the direct sending in colposcopy in women with HPV DNA test positive.

Secondary objectives are:

* to assess the feasibility of mRNA testing in primary screening * to validate the sample techniques for the new tests * to standardize quality controls for the the new tests

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Key information

Conditions

Precancerous Conditions Female Urogenital Diseases Female Urogenital Diseases and Pregnancy Complications Genital Diseases Genital Diseases, Female Genital Neoplasms, Female Hypersensitivity Immune System Diseases Neoplasms Neoplasms by Site Urogenital Diseases Urogenital Neoplasms Uterine Cervical Diseases Uterine Cervical Neoplasms Uterine Diseases Uterine Neoplasms

Age range

25 year–59 year

Sex eligibility

Female

Study type

Interventional

Phase

Not applicable

Primary location

Unità Locale Socio-Sanitaria 17 Este Monselice, Este, Italy

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About this study

Individual data about the following study steps are collected according a fixed format:

  • recruited women
  • HPV DNA result
  • cytology and randomization results
  • p16 result
  • mRNA result
  • colposcopies (with relative cytology and histologies) results
  • Women excluded after informed consent
  • Interventions During the first year of recruitment, there will be two semi-annual sending of data, then each year.

To analyze the study progress in each center, summary tables will periodically send to the PI.

All CIN lesions and cancers found in the study will be be blindly reviewed. A set of quality assurance procedures will be implemented for both the molecular tests, including the use of controls provided by the manufacturers with known HPV DNA or mRNA content and the circulation of clinical samples prepared by the laboratories participating in the study.

Who can participate

Healthy volunteers accepted: No

Only the study team can determine whether someone qualifies for participation.

Inclusion criteria

  • women invited for a new screening round based on HPV DNA test

Exclusion criteria

  • women not resident in the screening area, or pregnant, or with treated CIN in the 5 previous years, or in post-colposcopy follow up, or in repetition for unsatisfactory cytology.

Treatment and study plan

Experimental: immediate colposcopy

Procedure

A immediate colposcopy in this arm may detect potentially spontaneous regressive cervical lesions, so may determine an over diagnosis and over treatment, which the study want to estimate

Primary outcomes

  1. cumulative incidence of CIN2+ in women with positive DNA and negative mRNA or p16

    Time frame: 5 years

    Sum of CIN2+ detected in women with positive DNA and negative mRNA or p16 tests during the entire period (5 years) divided by the total number of CIN2+ found in the study. The HPV DNA test will be the final follow-up test, since it is the most sensitive test among the candidates for screening, so it is the one that allows to estimate more accurately the prevalence of lesions.

Secondary outcomes

  1. comparison between CIN2+ detection rates in the two arms in women with p16 or mRNA negative

    Time frame: 1 year

    proportion of CIN2+, HPV DNA positive and p16 or mRNA negative, which regress in a year

  2. comparison between CIN2+ detection rates in the two arms in women with negative cytology

    Time frame: 1 year

    measure of how much the cytological triage can reduce overdiagnosis compared to HPV DNA with direct sending to colposcopy

  3. comparison between CIN2+ detection rate in the two arms in women with p16 or mRNA positive

    Time frame: 1 year

    direct comparison of the effectiveness between a screening based on the HPV mRNA or p16 test followed by cytological triage and a screening with direct sending to colposcopy

Sponsors and collaborators

Lead sponsor

Azienda USL Reggio Emilia - IRCCS

Other Gov

Registry information

Official study title

HPV as Primary Screening Test in Cervical Cancer Prevention: From DNA to mRNA? A Randomised Controlled Trial Nested in a Double Testing Study With Long Term Follow up

Acronym: NTCC2

Important dates

Study start
2013
Primary completion
2017
Study completion
2017
First posted
Apr 23, 2013
Registry last updated
Jun 26, 2025

OpenTrials presents study information sourced from ClinicalTrials.gov. The official registry record should be consulted for the latest information.

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This listing is for discovery and informational purposes only. It is not medical advice, does not guarantee that a study is recruiting, and does not determine eligibility. Contact the study team and a qualified healthcare professional when considering participation.

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