Precancerous ConditionsNTCC2NCT01837693
Cervical Cancer Prevention: From DNA to mRNA? - New Technologies for Cervical Cancer Screening 2
A study testing Experimental: immediate colposcopy in people with Precancerous Conditions and Neoplasms, run by Azienda USL Reggio Emilia - IRCCS at 5 sites in Italy.
Trial 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). Read more about this study
- Who is it for?
- Ages 25 to 59 years, women only
- Conditions the study is for
- Precancerous Conditions, Neoplasms
- What is being tested?
- Experimental: immediate colposcopy
- Type of treatment
- Surgery or procedure
- Could I receive a placebo?
- No, everyone receives an active treatment
- How many people
- 41,127 participants
- Where
- 5 sitesItaly
- Study dates
- 1 Jun 2013to 1 Jan 2017
- Phase
- Interventional
- Are there results?
- None posted in the registry
Key requirements
Who can take part, as listed by the sponsor. Only the study team can confirm whether you are eligible, so take this list to your doctor.
- Ages 25 to 59 years
- Women only
- No healthy volunteers
- Adult
Who may be able to join
- women invited for a new screening round based on HPV DNA test
Who cannot join
- 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.
Trial locations and contacts
5 sites in 1 country.
5 sites in 1 country
Italy5 sites
Unità Locale Socio-Sanitaria 17 Este Monselice
Este
Istituto per lo Studio e la Prevenzione Oncologica
Florence
Azienda Sanitaria Locale 2- Regione Umbria
Perugia
Azienda Sanitaria della Provincia Autonoma di Trento
Trento
Centro per la Prevenzione Oncologica del Piemonte
Turin
About this study
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
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.
Read more
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
Read the 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.
- Conditions
- Precancerous Conditions, Neoplasms
- Being tested
- Experimental: immediate colposcopy
- Keywords
- cervical cancer screening, CIN, cervical cancer, biomarkers, sensitivity and specificity
- Medical subject headings
- Precancerous Conditions, Neoplasms, Uterine Cervical Neoplasms, Hypersensitivity
What participants receive
What participants receive. In a randomised study each person is assigned to one group by chance.
Experimental: immediate colposcopyProcedure or surgery
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
| Study group | Role | What they receive |
|---|---|---|
| one year follow up | No intervention | 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 |
| direct sending in colposcopy | Experimental | Experimental: immediate colposcopy. A random sample of HPV positive women with negative cytology will be sent to immediate colposcopy Receives: Procedure: Experimental: immediate colposcopy |
What is being measured
The primary outcome is the main question the study is designed to answer.
cumulative incidence of CIN2+ in women with positive DNA and negative mRNA or p16
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.
Measured: 5 years
Secondary outcomes (3)
comparison between CIN2+ detection rates in the two arms in women with p16 or mRNA negative
proportion of CIN2+, HPV DNA positive and p16 or mRNA negative, which regress in a year
Measured: 1 year
comparison between CIN2+ detection rates in the two arms in women with negative cytology
measure of how much the cytological triage can reduce overdiagnosis compared to HPV DNA with direct sending to colposcopy
Measured: 1 year
comparison between CIN2+ detection rate in the two arms in women with p16 or mRNA positive
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
Measured: 1 year
Timeline
From the start of the study to its completion; the mark is today. Estimated dates are the sponsor’s plan.
- First posted23 Apr 2013 (estimated)
- Study start1 Jun 2013
- Primary completion1 Jan 2017
- Study completion1 Jan 2017
Resources
- Official record on ClinicalTrials.govThe registry entry this page is built from, with its full change history.
- Publications (3)Papers the sponsor has linked to this study.
- Other trials for Precancerous ConditionsStudies of the same condition, open and under way.
- What the trial phases meanHow a treatment moves from first tests in people to approval.
More details
For doctors and researchers: how the study is designed, who runs it, and its registry IDs.
Study design
- Study type
- Interventional
- Phase
- Phase N/A
- Primary purpose
- Screening
- Allocation
- Randomised
- Intervention model
- Parallel groups
- Masking
- Single blind
- Who is masked
- Outcomes assessor
- Enrolment
- 41,127 participants (actual)
Sponsor and investigators
- Lead sponsor
- Azienda USL Reggio Emilia - IRCCS
- Sponsor type
- Other government
- Responsible party
- Sponsor
- Investigators
- Paolo Giorgi Rossi, PhD, Principal investigator, Epidemiology Service, Local Health Authority of Reggio Emilia, Italy
IDs, dates and publications
- ClinicalTrials.gov ID
- NCT01837693
- Sponsor's protocol ID
- cervicalscreening_mRNA_p16
- Acronym
- NTCC2
- Status last verified
- Jun 2017
- First submitted
- 18 Apr 2013
- Last updated
- 26 Jun 2025
- Results posted
- No
- Data monitoring committee
- No
- Individual data sharing
- No
Publications
Del Mistro A, Mancuso P, Carozzi F, De Marco L, Bisanzi S, Pompeo G, Ronco G, Gori S, Allia E, Gustinucci D, Frayle H, Iossa A, Cesarini E, Bulletti S, Passamonti B, Viti J, Toniolo L, Venturelli F, Giorgi Rossi P, Benevolo M; NTCC2 Working Group. Impact of differentiating between persistent and new infections on colposcopy referral in HPV-positive triage-negative women: results from the NTCC2 study. Infect Agent Cancer. 2025 Nov 20;20(1):84. doi: 10.1186/s13027-025-00713-8.
PubMed 41261407De Marco L, Bisanzi S, Ronco G, Mancuso P, Carozzi F, Allia E, Rizzolo R, Gustinucci D, Frayle H, Viti J, Iossa A, Cesarini E, Bulletti S, Passamonti B, Gori S, Toniolo L, Venturelli F, Del Mistro A, Giorgi Rossi P, Benevolo M; NTCC2 Working Group. Extended HPV genotyping by the BD Onclarity assay: concordance with screening HPV-DNA assays, triage biomarkers, and histopathology in women from the NTCC2 study. Microbiol Spectr. 2025 Jan 7;13(1):e0089724. doi: 10.1128/spectrum.00897-24. Epub 2024 Nov 22.
PubMed 39576120Benevolo M, Mancuso P, Allia E, Gustinucci D, Bulletti S, Cesarini E, Carozzi FM, Confortini M, Bisanzi S, Rubino T, Rollo F, Marchi N, Farruggio A, Pusiol T, Venturelli F, Giorgi Rossi P; New Technologies for Cervical Cancer 2 (NTCC2) Working Group. Determinants of p16/Ki-67 adequacy and positivity in HPV-positive women from a screening population. Cancer Cytopathol. 2021 May;129(5):383-393. doi: 10.1002/cncy.22385. Epub 2020 Nov 3.
PubMed 33142029
Study at a glance
From the registry record, last updated by the sponsor on 26 Jun 2025. Recruitment status is as the sponsor reported it: confirm with the study team.
- 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
- ClinicalTrials.gov ID
- NCT01837693
- Acronym / sponsor ID
- NTCC2 / cervicalscreening_mRNA_p16
- Conditions
- Precancerous Conditions, Neoplasms
- Keywords
- cervical cancer screening, CIN, cervical cancer, biomarkers, sensitivity and specificity
- Study type
- Interventional
- Recruitment status
- Completed
- Enrolment
- 41,127 participants (actual)
- Lead sponsor
- Azienda USL Reggio Emilia - IRCCSOther government
- Study start
- 1 Jun 2013 (actual)
- Primary completion
- 1 Jan 2017 (actual)
- Study completion
- 1 Jan 2017 (actual)
- First posted
- 23 Apr 2013 (estimated)
- Results
- Not posted in the source record
Clinical summary
The research question as the sponsor registered it. This describes what the study plans to test, not what it found.
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
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
- Primary purpose
- Screening
- Allocation
- Randomised
- Intervention model
- Parallel groups
- Masking
- Single blind (outcomes assessor)
- Number of arms
- 2
| Arm | Type | Receives |
|---|---|---|
| one year follow up | No intervention | –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 |
| direct sending in colposcopy | Experimental | Procedure: Experimental: immediate colposcopyExperimental: immediate colposcopy. A random sample of HPV positive women with negative cytology will be sent to immediate colposcopy |
Who may qualify
- Ages
- 25 to 59 years
- Sex
- Female only
- Healthy volunteers
- Not accepted
- Age groups
- Adult
Key inclusion criteria (1 listed)
- women invited for a new screening round based on HPV DNA test
Key exclusion criteria (1 listed)
- 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.
Eligibility is decided by the study team after screening; this overview does not establish that a patient qualifies. Full inclusion and exclusion criteria.
Interventions
| Intervention | Type | Arms |
|---|---|---|
| Experimental: immediate colposcopyA 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 | Procedure or surgery | direct sending in colposcopy |
Primary outcome
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.
3 secondary outcomes
comparison between CIN2+ detection rates in the two arms in women with p16 or mRNA negative
Time frame: 1 year
comparison between CIN2+ detection rates in the two arms in women with negative cytology
Time frame: 1 year
comparison between CIN2+ detection rate in the two arms in women with p16 or mRNA positive
Time frame: 1 year
Results and safety
The study is completed, but results are not available in the source record. That does not mean the treatment did or did not work.
Research links
- Official record on ClinicalTrials.govLast updated by the sponsor 26 Jun 2025.
- Derived from this study: PubMed 41261407Del Mistro A, Mancuso P, Carozzi F, De Marco L, Bisanzi S, Pompeo G, Ronco G, Gori S, Allia E, Gustinucci D, Frayle H, Iossa A, Cesarini E, Bulletti S, Passamonti B, Viti J, Toniolo L, Venturelli F, Giorgi Rossi P, Benevolo M; NTCC2 Working Group. Impact of differentiating between persistent and new infections on colposcopy referral in HPV-positive triage-negative women: results from the NTCC2 study. Infect Agent Cancer. 2025 Nov 20;20(1):84. doi: 10.1186/s13027-025-00713-8.
- Derived from this study: PubMed 39576120De Marco L, Bisanzi S, Ronco G, Mancuso P, Carozzi F, Allia E, Rizzolo R, Gustinucci D, Frayle H, Viti J, Iossa A, Cesarini E, Bulletti S, Passamonti B, Gori S, Toniolo L, Venturelli F, Del Mistro A, Giorgi Rossi P, Benevolo M; NTCC2 Working Group. Extended HPV genotyping by the BD Onclarity assay: concordance with screening HPV-DNA assays, triage biomarkers, and histopathology in women from the NTCC2 study. Microbiol Spectr. 2025 Jan 7;13(1):e0089724. doi: 10.1128/spectrum.00897-24. Epub 2024 Nov 22.
- Derived from this study: PubMed 33142029Benevolo M, Mancuso P, Allia E, Gustinucci D, Bulletti S, Cesarini E, Carozzi FM, Confortini M, Bisanzi S, Rubino T, Rollo F, Marchi N, Farruggio A, Pusiol T, Venturelli F, Giorgi Rossi P; New Technologies for Cervical Cancer 2 (NTCC2) Working Group. Determinants of p16/Ki-67 adequacy and positivity in HPV-positive women from a screening population. Cancer Cytopathol. 2021 May;129(5):383-393. doi: 10.1002/cncy.22385. Epub 2020 Nov 3.
- Individual participant dataSharing planned: No
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Referral and contact
AzTrials does not enrol participants or take referrals. Contact the study team or a site listed below; they decide who can take part. This study is not recruiting at the moment.
Paolo Giorgi Rossi, PhD principal investigator
Epidemiology Service, Local Health Authority of Reggio Emilia, Italy
5 sites in 1 country: see every site and its status.
Questions about this trial
What is this clinical trial studying?
A study testing Experimental: immediate colposcopy in people with Precancerous Conditions and Neoplasms, run by Azienda USL Reggio Emilia - IRCCS at 5 sites in Italy.
The full registered description is in the About this study section and the official record.
Who may be eligible to take part?
The sponsor lists 1 inclusion and 1 exclusion criteria. Eligibility is decided by the study team after screening, so read the full criteria and contact a listed site.
Is this clinical trial currently recruiting?
The record says: finished, as of the sponsor's last update on 26 Jun 2025. Status can change between updates, so confirm with the study contact before making plans.
Where is the study taking place?
The record lists 5 sites in Italy. Whether a site is taking part right now should be confirmed with that site. See every site.
What are the possible benefits and risks?
They depend on the study and the treatment, and no study can promise a benefit. The study team explains the known risks during informed consent, before anyone joins; the record itself does not list them.
Are results available for this study?
The study is completed, but results are not available in the source record. That does not mean the treatment did or did not work.
How can a doctor refer a patient or contact the research team?
The record lists no contact. The official record names the sponsor, who can be asked directly. AzTrials does not enrol participants or take referrals.
What does the primary outcome measure?
cumulative incidence of CIN2+ in women with positive DNA and negative mRNA or p16 (time frame: 5 years). It is what the study was designed to measure, not a finding.
Where can I read the original study information?
On the ClinicalTrials.gov record for NCT01837693, which also lists 3 linked publications.
Does a listing mean the treatment is approved or proven to work?
No. A listing means the study is registered. It does not show that the treatment is safe, works, or is approved by a regulator.
How often is this information updated?
AzTrials copies changed records from ClinicalTrials.gov every night and reloads the whole registry every week. The sponsor last updated this record on 26 Jun 2025.