Cervix CancerI-shareNCT05727228
Screening Triage and Risk Stratification
An observational study of Cervix Cancer and HPV Testing, run by University of Aarhus at 1 site in Denmark.
Trial summary
To investigate the performance of cytology, extended genotyping, p16/Ki67 dual stain cytology, DNA methylation and viral load as triage markers in post-menopausal HPV-screen-positive women aged 50-64 years in the organized screening program to predict the risk of developing CIN2+. Read more about this study
- Who is it for?
- Ages 23 to 64 years, women onlyHealthy volunteers can take part
- Conditions the study is for
- Cervix Cancer, HPV Testing, Postmenopausal Women
- What is being tested?
- cytology, p16/ki67 dual stain cytology (DS), extended genotyping, DNA methylation, viral load,
- How many people
- 5,000 participants
- Where
- 1 siteDenmark
- Study dates
- 27 Feb 2023to Feb 2027
- How long will I take part?
- 5 Years
- Phase
- Observational
- Are there results?
- Not yet: the study is under way
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 23 to 64 years
- Women only
- Healthy volunteers accepted
- Adult
Study population: Women aged 50-65 who have been tested HPV-screen positive Women aged 23-64 who undergo test-of-cure or follow-up test after LEEP
Who may be able to join
- HPV-screen-positive (aged 50-64)
- Women who undergo test-of-cure (i.e. HPV and cytology) six months after LEEP in Central Denmark Region (aged 23-64)
- Women who undergo follow-up test (i.e. HPV and cytology) 12 months after LEEP
- A valid cytology-triage result (aged 23-64)
Who cannot join
- Listed in the registry as a person who have rejected to participate in research
- Invalid cytology and HPV result six months after LEEP
- No residual material available
Trial locations and contacts
1 site in 1 country. Contact the study team or a site near you to ask about taking part.
Denmark1 site, 1 recruiting
- Recruiting
Department of Pathology
Randers, Central Jutland, 8930
mette tranberg, post doc, 40113676, mettrani@rm.dk
About this study
Official title: Improving Screening Triage in Older Postmenopausal HPV-screen-positive Women Aged 50-64 and Risk-stratification of Women Aged 23-64 After Excision
- To investigate the performance of cytology, extended genotyping, p16/Ki67 dual stain cytology, DNA methylation and viral load as triage markers in post-menopausal HPV-screen-positive women aged 50-64 years in the organized screening program to predict the risk of developing CIN2+. (work package 1)
- To investigate the performance of cytology, extended genotyping, p16/Ki67 dual stain cytology, DNA methylation and viral load six months after cervical excision to predict the long-term risk of residual/recurrent CIN2+ lesions among women aged 23-64 (work-package 2)
Read the detailed description
As HPV-positive women may have a transient infection which would be cleared with treatment, triage of HPV-positive women are needed to decrease the colposcopy referral. Liquid-based cytology (hereinafter cytology) are often used as triage for HPV-positive women. HPV 16/18 are the predominant HPV types in younger women and are for all aged referred directly for colposcopy. However as women age, hrHPV other types become more prevalent(10) and these types are triaged with cytology. However, as cytology undergo subjective interpretation and as it may have a decreased sensitivity in with increasing age(11, 12) cytology may not be the most optimal triage marker in postmenopausal women.
p16/Ki67 dual stain cytology (hereinafter DS) is another triage marker. p16 is a cell-cycle regulator protein and Ki67 is a proliferation-associated protein which under normal circumstances are mutual exclusive. Thus, in an HPV-transformed cell co-expression of p16 and Ki67 indicates cell deregulation and increased risk of cervical precancer.(13) In several studies DS have shown better sensitivity and negative predictive value (NPV) as compared to cytology in triaging HPV-positive women(14-17) and women with low-grade cytology (ASC-US and LSIL)(18-20).
Methylation of HPV-positive women benefits from a more objective evaluation than both cytology and DS and has in shown promising results in triaging HPV-positive women.(21) Most studies on DS and methylation have however, been conducted in younger women and studies evaluation the performance in postmenopausal women are needed.
Women diagnosed with CIN2+ undergo excisional treatment removing the lesions and thereby reducing the woman's risk of developing cervical cancer. The most frequently used method is loop electrosurgical excision procedure (LEEP). Despite treatment, women previously diagnosed with CIN3+ lesion are at greater risk of developing cervical cancer with the risk increasing with increasing age.(22) Surveillance after LEEP consist of test-of cure (i.e. cytology and HPV test) six months after LEEP in several countries.(23-27) Treatment of CIN2+ is however, not always successful and residual or recurrent high-grade disease (CIN2+) occurs on average in 8% (ranging from 4% to 18%) of treated women, with the majority of treatment failure occurring mainly the first two post-operative years.(28, 29) Persistent HPV infection and positive margins after LEEP are risk factors for residual or recurrent disease after LEEP(28). However, not all women are at the same risk of recurrent disease, but still managed the same way as women at higher risk and therefore a future risk-stratification are needed to individualize the follow-up pathways. Moreover, introduction of a risk-stratification in the follow-up pathway may also decrease the number of open-ended follow-up pathways. In a recent study in HPV-positive women 60-64 years only 26% had follow-up as recommended.(30)
- Conditions
- Cervix Cancer, HPV Testing, Postmenopausal Women
- Being tested
- cytology, p16/ki67 dual stain cytology (DS), extended genotyping, DNA methylation, viral load,
- Keywords
- mass screening, triage biomarkers
- Medical subject headings
- Uterine Cervical Neoplasms
What participants receive
What participants receive. In a randomised study each person is assigned to one group by chance.
cytology, p16/ki67 dual stain cytology (DS), extended genotyping, DNA methylation, viral load,Other
p16/Ki67 dual stain cytology, extended genotyping and DNA methylation will be performed from the residual cell-pellet from the HPV-positive screening samples. If no cytology-triage testing is performed as a part of the screening algorithm, a cytology will be performed at inclusion. If any residual material is left after DS, extended genotyping and DNA methylation, it will be stores at -80 degrees for future purposes.
What is being measured
The primary outcome is the main question the study is designed to answer.
The number of women with CIN2+ diagnosed in either cervical biopsies or cone biopsy
The detection of underlying CIN2 or worse
Measured: at baseline ( within 3 months after index sample)
The number of women with CIN2+ diagnosed in either cervical biopsies or cone biopsy
The detection of underlying CIN2 or worse
Measured: at follow-up ( 1.5 years after index sample)
The number of women with CIN3+ diagnosed in either cervical biopsies or cone biopsy
The detection of underlying CIN3 or worse
Measured: at baseline ( within 3 months after index sample)
The number of women with CIN3+ diagnosed in either cervical biopsies or cone biopsy
The detection of underlying CIN3 or worse
Measured: at follow-up (1.5 years after index sample)
Secondary outcomes (4)
Clinical accuracy (sensitivity and specificity of each triage marker and in different combinations)
sensitivity to detect underlying CIN2+ and specificity to exclude underlying CIN2+
Measured: at baseline (within 3 months after index sample)
Clinical accuracy (sensitivity and specificity of each triage marker and in different combinations)
sensitivity to detect underlying CIN2+ and specificity to exclude underlying CIN2+
Measured: at follow-up (1.5 years after index sample)
HPV genotype distribution
We will measure the distribution of hrHPV types among these older women
Measured: at baseline (within 3 months after index sample)
DS positivity rate
We will measure the DS positivity rate among these older women
Measured: at baseline (within 3 months after index sample)
Timeline
From the start of the study to its completion; the mark is today. Estimated dates are the sponsor’s plan.
- First posted14 Feb 2023
- Study start27 Feb 2023 (estimated)
- Primary completionFeb 2027 (estimated)
- Study completionFeb 2027 (estimated)
Resources
- Official record on ClinicalTrials.govThe registry entry this page is built from, with its full change history.
- Other trials for Cervix CancerStudies 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
- Observational
- Observational model
- Cohort
- Time perspective
- Prospective
- Enrolment
- 5,000 participants (estimated)
- Target duration
- 5 Years
Sponsor and investigators
- Lead sponsor
- University of Aarhus
- Sponsor type
- University, hospital or other
- Collaborators
- Randers Regional Hospital
- Responsible party
- Principal investigator, Mette Tranberg Nielsen, University of Aarhus
- Investigators
- mette tranberg, post doc, Principal investigator, Randers Regional Hospital, Denmark
IDs, dates and publications
- ClinicalTrials.gov ID
- NCT05727228
- Sponsor's protocol ID
- 2704
- Acronym
- I-share
- Status last verified
- Feb 2023
- First submitted
- 16 Jan 2023
- Last updated
- 14 Feb 2023
- Results posted
- No
- Data monitoring committee
- No
- FDA-regulated drug
- No
- FDA-regulated device
- No
- Individual data sharing
- Undecided: This is yet to be decided.
Study at a glance
From the registry record, last updated by the sponsor on 14 Feb 2023. Recruitment status is as the sponsor reported it: confirm with the study team.
- Official title
- Improving Screening Triage in Older Postmenopausal HPV-screen-positive Women Aged 50-64 and Risk-stratification of Women Aged 23-64 After Excision
- ClinicalTrials.gov ID
- NCT05727228
- Acronym / sponsor ID
- I-share / 2704
- Conditions
- Cervix Cancer, HPV Testing, Postmenopausal Women
- Keywords
- mass screening, triage biomarkers
- Study type
- Observational
- Recruitment status
- Recruiting
- Enrolment
- 5,000 participants (estimated)
- Lead sponsor
- University of AarhusUniversity, hospital or other
- Collaborators
- Randers Regional Hospital
- Study start
- 27 Feb 2023 (estimated)
- Primary completion
- Feb 2027 (estimated)
- Study completion
- Feb 2027 (estimated)
- First posted
- 14 Feb 2023 (actual)
- 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.
- To investigate the performance of cytology, extended genotyping, p16/Ki67 dual stain cytology, DNA methylation and viral load as triage markers in post-menopausal HPV-screen-positive women aged 50-64 years in the organized screening program to predict the risk of developing CIN2+. (work package 1)
- To investigate the performance of cytology, extended genotyping, p16/Ki67 dual stain cytology, DNA methylation and viral load six months after cervical excision to predict the long-term risk of residual/recurrent CIN2+ lesions among women aged 23-64 (work-package 2)
Detailed description
As HPV-positive women may have a transient infection which would be cleared with treatment, triage of HPV-positive women are needed to decrease the colposcopy referral. Liquid-based cytology (hereinafter cytology) are often used as triage for HPV-positive women. HPV 16/18 are the predominant HPV types in younger women and are for all aged referred directly for colposcopy. However as women age, hrHPV other types become more prevalent(10) and these types are triaged with cytology. However, as cytology undergo subjective interpretation and as it may have a decreased sensitivity in with increasing age(11, 12) cytology may not be the most optimal triage marker in postmenopausal women.
p16/Ki67 dual stain cytology (hereinafter DS) is another triage marker. p16 is a cell-cycle regulator protein and Ki67 is a proliferation-associated protein which under normal circumstances are mutual exclusive. Thus, in an HPV-transformed cell co-expression of p16 and Ki67 indicates cell deregulation and increased risk of cervical precancer.(13) In several studies DS have shown better sensitivity and negative predictive value (NPV) as compared to cytology in triaging HPV-positive women(14-17) and women with low-grade cytology (ASC-US and LSIL)(18-20).
Methylation of HPV-positive women benefits from a more objective evaluation than both cytology and DS and has in shown promising results in triaging HPV-positive women.(21) Most studies on DS and methylation have however, been conducted in younger women and studies evaluation the performance in postmenopausal women are needed.
Women diagnosed with CIN2+ undergo excisional treatment removing the lesions and thereby reducing the woman's risk of developing cervical cancer. The most frequently used method is loop electrosurgical excision procedure (LEEP). Despite treatment, women previously diagnosed with CIN3+ lesion are at greater risk of developing cervical cancer with the risk increasing with increasing age.(22) Surveillance after LEEP consist of test-of cure (i.e. cytology and HPV test) six months after LEEP in several countries.(23-27) Treatment of CIN2+ is however, not always successful and residual or recurrent high-grade disease (CIN2+) occurs on average in 8% (ranging from 4% to 18%) of treated women, with the majority of treatment failure occurring mainly the first two post-operative years.(28, 29) Persistent HPV infection and positive margins after LEEP are risk factors for residual or recurrent disease after LEEP(28). However, not all women are at the same risk of recurrent disease, but still managed the same way as women at higher risk and therefore a future risk-stratification are needed to individualize the follow-up pathways. Moreover, introduction of a risk-stratification in the follow-up pathway may also decrease the number of open-ended follow-up pathways. In a recent study in HPV-positive women 60-64 years only 26% had follow-up as recommended.(30)
Study design
- Observational model
- Cohort
- Time perspective
- Prospective
- Target follow-up
- 5 Years
Who may qualify
- Ages
- 23 to 64 years
- Sex
- Female only
- Healthy volunteers
- Accepted
- Age groups
- Adult
- Study population
- Women aged 50-65 who have been tested HPV-screen positive Women aged 23-64 who undergo test-of-cure or follow-up test after LEEP
Key inclusion criteria (4 listed)
- HPV-screen-positive (aged 50-64)
- Women who undergo test-of-cure (i.e. HPV and cytology) six months after LEEP in Central Denmark Region (aged 23-64)
- Women who undergo follow-up test (i.e. HPV and cytology) 12 months after LEEP
- A valid cytology-triage result (aged 23-64)
Key exclusion criteria (3 listed)
- Listed in the registry as a person who have rejected to participate in research
- Invalid cytology and HPV result six months after LEEP
- No residual material available
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 |
|---|---|---|
| cytology, p16/ki67 dual stain cytology (DS), extended genotyping, DNA methylation, viral load,p16/Ki67 dual stain cytology, extended genotyping and DNA methylation will be performed from the residual cell-pellet from the HPV-positive screening samples. If no cytology-triage testing is performed as a part of the screening algorithm, a cytology will be performed at inclusion. If any residual material is left after DS, extended genotyping and DNA methylation, it will be stores at -80 degrees for future purposes. | Other | – |
Primary outcome
The number of women with CIN2+ diagnosed in either cervical biopsies or cone biopsy
Time frame: at baseline ( within 3 months after index sample)
The detection of underlying CIN2 or worse
The number of women with CIN2+ diagnosed in either cervical biopsies or cone biopsy
Time frame: at follow-up ( 1.5 years after index sample)
The detection of underlying CIN2 or worse
The number of women with CIN3+ diagnosed in either cervical biopsies or cone biopsy
Time frame: at baseline ( within 3 months after index sample)
The detection of underlying CIN3 or worse
The number of women with CIN3+ diagnosed in either cervical biopsies or cone biopsy
Time frame: at follow-up (1.5 years after index sample)
The detection of underlying CIN3 or worse
4 secondary outcomes
Clinical accuracy (sensitivity and specificity of each triage marker and in different combinations)
Time frame: at baseline (within 3 months after index sample)
Clinical accuracy (sensitivity and specificity of each triage marker and in different combinations)
Time frame: at follow-up (1.5 years after index sample)
HPV genotype distribution
Time frame: at baseline (within 3 months after index sample)
DS positivity rate
Time frame: at baseline (within 3 months after index sample)
Results and safety
This study is still under way. Results are not available in the source record yet.
Research links
- Official record on ClinicalTrials.govLast updated by the sponsor 14 Feb 2023.
- Individual participant dataSharing planned: Undecided. This is yet to be decided.
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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.
mette tranberg, post doc principal investigator
Randers Regional Hospital, Denmark
1 site in 1 country: see every site and its status.
Questions about this trial
What is this clinical trial studying?
An observational study of Cervix Cancer and HPV Testing, run by University of Aarhus at 1 site in Denmark.
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 4 inclusion and 3 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: looking for participants now, as of the sponsor's last update on 14 Feb 2023. Status can change between updates, so confirm with the study contact before making plans.
Where is the study taking place?
The record lists 1 site in Denmark. 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?
This study is still under way. Results are not available in the source record yet.
How can a doctor refer a patient or contact the research team?
Contact mette tranberg, post doc (40113676, mettrani@rm.dk), or a site near the patient. AzTrials does not enrol participants or take referrals.
What does the primary outcome measure?
The number of women with CIN2+ diagnosed in either cervical biopsies or cone biopsy (time frame: at baseline ( within 3 months after index sample)). The study lists 4 primary outcomes in all. It is what the study was designed to measure, not a finding.
Where can I read the original study information?
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 14 Feb 2023.