Cervical Cancer Prevention: From DNA to mRNA? - New Technologies for Cervical Cancer Screening 2 (NTCC2)

April 18, 2013 updated by: Azienda Unità Sanitaria Locale Reggio Emilia

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

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

Study Overview

Status

Unknown

Conditions

Intervention / Treatment

Detailed Description

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

  1. recruited women
  2. HPV DNA result
  3. cytology and randomization results
  4. p16 result
  5. mRNA result
  6. colposcopies (with relative cytology and histologies) results
  7. Women excluded after informed consent
  8. 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.

Study Type

Interventional

Enrollment (Anticipated)

60000

Phase

  • Not Applicable

Contacts and Locations

This section provides the contact details for those conducting the study, and information on where this study is being conducted.

Study Contact

Study Locations

  • Italy
      • Este, Italy
        • Unità Locale Socio-Sanitaria 17 Este Monselice
        • Principal Investigator:
          • Antonio Ferro
      • Florence, Italy
        • Istituto per lo Studio e la Prevenzione Oncologica
        • Principal Investigator:
          • Francesca Carozzi
        • Principal Investigator:
          • Massimo Confortini
      • L'Aquila, Italy
        • Azienda Sanitaria Locale 1-L'Aquila
        • Principal Investigator:
          • Vincenzo Maccallini
      • Padua, Italy
        • Istituto Oncologico Veneto
      • Perugia, Italy
        • Azienda Sanitaria Locale 2- Regione Umbria
        • Principal Investigator:
          • Basilio Passamonti
      • Reggio Emilia, Italy
        • Azienda Sanitaria Locale Reggio Emilia
        • Principal Investigator:
          • Luisa Paterlini
      • Rome, Italy
        • Laziosanità - Agenzia di Sanità Pubblica della Regione Lazio
      • Rome, Italy
        • Regina Elena Cancer Institute
      • Tivoli, Italy
        • Azienda Sanitaria Locale Roma G
        • Principal Investigator:
          • Maria Concetta Tufi
      • Trento, Italy
        • Azienda Sanitaria della Provincia Autonoma di Trento
        • Principal Investigator:
          • Paolo Dalla Palma
      • Turin, Italy
        • Centro per la Prevenzione Oncologica del Piemonte
        • Principal Investigator:
          • Guglielmo Ronco

Participation Criteria

Researchers look for people who fit a certain description, called eligibility criteria. Some examples of these criteria are a person's general health condition or prior treatments.

Eligibility Criteria

Ages Eligible for Study

25 years to 59 years (Adult)

Accepts Healthy Volunteers

No

Genders Eligible for Study

Female

Description

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.

Study Plan

This section provides details of the study plan, including how the study is designed and what the study is measuring.

How is the study designed?

Design Details

  • Primary Purpose: Screening
  • Allocation: Randomized
  • Interventional Model: Parallel Assignment
  • Masking: Single

Arms and Interventions

Participant Group / Arm
Intervention / Treatment
No Intervention: one year follow up
A random sample of HPV positive women with negative cytology will be invited to repeat HPV DNA test and biomarkers after a year, as recommended by the current screening protocols based on HPV DNA
Experimental: direct sending in colposcopy
Experimental: immediate colposcopy. A random sample of HPV positive women with negative cytology will be sent to immediate colposcopy
Procedure: Experimental: immediate colposcopy
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

What is the study measuring?

Primary Outcome Measures

Outcome Measure
Measure Description
Time Frame
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.
5 years

Secondary Outcome Measures

Outcome Measure
Measure Description
Time Frame
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
1 year
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
1 year
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
1 year

Collaborators and Investigators

This is where you will find people and organizations involved with this study.

Sponsor

Azienda Unità Sanitaria Locale Reggio Emilia

Investigators

  • Principal Investigator: Paolo Giorgi Rossi, PhD, Epidemiology Service, Local Health Authority of Reggio Emilia, Italy

Publications and helpful links

The person responsible for entering information about the study voluntarily provides these publications. These may be about anything related to the study.

General Publications

Study record dates

These dates track the progress of study record and summary results submissions to ClinicalTrials.gov. Study records and reported results are reviewed by the National Library of Medicine (NLM) to make sure they meet specific quality control standards before being posted on the public website.

Study Major Dates

Study Start

June 1, 2013

Primary Completion (Anticipated)

June 1, 2015

Study Completion (Anticipated)

December 1, 2019

Study Registration Dates

First Submitted

April 18, 2013

First Submitted That Met QC Criteria

April 18, 2013

First Posted (Estimate)

April 23, 2013

Study Record Updates

Last Update Posted (Estimate)

April 23, 2013

Last Update Submitted That Met QC Criteria

April 18, 2013

Last Verified

May 1, 2012

More Information

Terms related to this study

Keywords

Additional Relevant MeSH Terms

Other Study ID Numbers

  • cervicalscreening_mRNA_p16

This information was retrieved directly from the website clinicaltrials.gov without any changes. If you have any requests to change, remove or update your study details, please contact register@clinicaltrials.gov. As soon as a change is implemented on clinicaltrials.gov, this will be updated automatically on our website as well.

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