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

Sponsor

Azienda Unità Sanitaria Locale Reggio Emilia (Other)

Overall Status

Unknown status

CT.gov ID

NCT01837693

Collaborator

(none)

60,000

Enrollment

Locations

Arms

Duration (Months)

5454.5

Patients Per Site

69.9

Patients Per Site Per Month

Study Details

Study Description

Brief Summary

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

Condition or Disease	Intervention/Treatment	Phase
Precancerous Conditions Neoplasms	Procedure: Experimental: immediate colposcopy	N/A

Detailed Description

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.

Study Design

Study Type:

Interventional

Anticipated Enrollment :

60000 participants

Allocation:

Randomized

Intervention Model:

Parallel Assignment

Masking:

Single (Outcomes Assessor)

Primary Purpose:

Screening

Official 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

Study Start Date :

Jun 1, 2013

Anticipated Primary Completion Date :

Jun 1, 2015

Anticipated Study Completion Date :

Dec 1, 2019

Arms and Interventions

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

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

Outcome Measures

Primary Outcome Measures

cumulative incidence of CIN2+ in women with positive DNA and negative mRNA or p16 [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 Outcome Measures

comparison between CIN2+ detection rates in the two arms in women with p16 or mRNA negative [1 year]
proportion of CIN2+, HPV DNA positive and p16 or mRNA negative, which regress in a year
comparison between CIN2+ detection rates in the two arms in women with negative cytology [1 year]
measure of how much the cytological triage can reduce overdiagnosis compared to HPV DNA with direct sending to colposcopy
comparison between CIN2+ detection rate in the two arms in women with p16 or mRNA positive [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

Eligibility Criteria

Criteria

Ages Eligible for Study:

25 Years to 59 Years

Sexes Eligible for Study:

Female

Accepts Healthy Volunteers:

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.

Contacts and Locations

Locations

	Site	City	Country
1	Unità Locale Socio-Sanitaria 17 Este Monselice	Este	Italy
2	Istituto per lo Studio e la Prevenzione Oncologica	Florence	Italy
3	Azienda Sanitaria Locale 1-L'Aquila	L'Aquila	Italy
4	Istituto Oncologico Veneto	Padua	Italy
5	Azienda Sanitaria Locale 2- Regione Umbria	Perugia	Italy
6	Azienda Sanitaria Locale Reggio Emilia	Reggio Emilia	Italy
7	Laziosanità - Agenzia di Sanità Pubblica della Regione Lazio	Rome	Italy
8	Regina Elena Cancer Institute	Rome	Italy
9	Azienda Sanitaria Locale Roma G	Tivoli	Italy
10	Azienda Sanitaria della Provincia Autonoma di Trento	Trento	Italy
11	Centro per la Prevenzione Oncologica del Piemonte	Turin	Italy