Cervical Intraepithelial Neoplasia Grade 2 (CIN2)NCT05049252
Biomarkers Predictive for Cervical Intraepithelial Neoplasia Grade 2 (CIN2) Evolvement
An observational study of Cervical Intraepithelial Neoplasia Grade 2 (CIN2), run by University of Aarhus at 1 site in Denmark.
Trial summary
Introduction Cervical intraepithelial neoplasia CIN1 (low grade), CIN2 (moderate grade), CIN3 (severe grade) defines cervical precancer lesions derived from the squamous epithelial cell line. Read more about this study
- Who is it for?
- Ages 23 to 40 years, women only
- Conditions the study is for
- Cervical Intraepithelial Neoplasia Grade 2 (CIN2)
- How many people
- 500 participants
- Where
- 1 siteDenmark
- Study dates
- 1 Jun 2020to 31 Dec 2023
- Phase
- Observational
- 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 23 to 40 years
- Women only
- No healthy volunteers
- Adult
Study population: N=500 women 23-40 years of age with a record of CIN2 in the Danish Pathology Data Bank, at the Department of Pathology, Aarhus University Hospital, managed by active surveillance.
Who may be able to join
- Women
- 23-40 years of age
- First record of CIN2 verified diagnosis (M74B09, T83110)
- Managed by active surveillance (i.e. no surgical treatment within 4 months after index CIN2 diagnosis)
- Record of CIN2 diagnosis during 2000-2010 and at least one record of cervix histological sample during follow-up.
Who cannot join
- Prior record of CIN2+ (i.e. CIN2, CIN3, cervical cancer), hysterectomy or cervical excisional cone biopsy.
- No record of cervical histological sample (cervical punch biopsy of cervical excisional biopsy) within two years after index CIN2 diagnosis.
Trial locations and contacts
1 site in 1 country.
Denmark1 site
Department of Gynecology and Obstetrics, Herning Regional Hospital
Herning, Region of Central Jutland, 7400
About this study
Official title: Performance of HPV E4 and p16INK4a Biomarkers in Predicting Risk of Regression Among Women Diagnosed With Cervical Intraepithelial Neoplasia Grade 2 (CIN2): a Historical Cohort Study
Introduction Cervical intraepithelial neoplasia CIN1 (low grade), CIN2 (moderate grade), CIN3 (severe grade) defines cervical precancer lesions derived from the squamous epithelial cell line. CIN2, represents a heterogenic phenotype expression of both CIN1-like and CIN3-like evolving lesions with different risk of progression. The CIN2 diagnosis has low reproducibility, and current diagnostic tools do not allow for risk-stratification of CIN2.
Risk-profiling is important, to enable targeted management of women with CIN2 at first incidence (surgery or active surveillance) and to avoid risk of over- or undertreatment.
Read more
Preliminary studies show, that the novel tissue biomarker HPV E4 has potential to discriminate CIN1-like (HPV E4 positive) from CIN3-like (HPV E4 negative) evolving CIN2 lesions, suggesting that the biomarker could be vauable for risk-stratification of CIN2.
Aim To examine the potential of the HPV E4 biomarker in predicting risk of CIN2 evolvement.
Materials and Methods Design: Historical cohort study. Study population: N=500 women, 23-40 years of age with a record of incidental CIN2 diagnosis between [2000-2010] in the Danish Pathology Data Bank at Aarhus University Hospital, Region of Central Denmark. All women are defined as managed by active surveillance (i.e. no surgical treatment within 4 months after first CIN2 diagnosis).
Exposure: HPV E4 positive vs HPV E4 negative intraepithelial reaction. Outcome: Regression (normal, CIN1) vs non-regression (CIN2, CIN3, cervical cancer).
Statistical model: Linear regression model (RR (95%CI)).
Perspectives: HPV E4 may act as significant predictor for CIN2 evolvement, and reliable marker for risk-assessment of CIN2. This will be valuable in the clinical management of women with CIN2, enabling to discriminate women, who would most likely regress and could be manged by active surveillance vs women in risk of progression or persistence, who could benefit of immediate surgical treatment.
Read the detailed description
Introduction Persistent infection with high-risk human papillomavirus (hrHPV) is a causative source of cervical cancer [1]. Cervical intraepitehelial neoplasia CIN1 (low), CIN2 (moderate), CIN3 (severe) defines cervical precancer lesions evolved from the squamous epithelium cell line [3]. CIN1 and CIN2 lesions are associated with lower progression rates for cervical cancer than CIN3 [4]. CIN2 poses a major challenge clinically, due to the heterogenic expression of both CIN1-like and CIN3-like evolving lesions, which current diagnostic tools do not enable to stratify in risk of progression [5]. Risk-stratification of CIN2 is highly important for clinical management of CIN2 and to avoid risk of over- or undertreatment. Historically, CIN2 has been the threshold for surgical mangement (cone excisional biopsy). However, since regressions rates of CIN2 lesions are high, and cone excisional biopy is associated with reproductive harm, such as preterm birth, many countries such as Denmark has adopted a more conservative approach in the management of young women with CIN2 (i.e. active surveillance: colposcopy, cervical punch biopsies for every 4-6 monhts up to two years follow-up without any surgical procedure) [6,7]. In the Central Region of Denmark, active surveillance has been recommended for young women since 1995.
The p16 protein plays an important role as inhibitor in cellular regulation and differentiation. p16 is a common surrogat marker for hrHPV E6/E7 oncogenic activity and cellular transformation associated with cancer evolvement. The intrapeithelial expression level of p16 is positively associated with grade of CIN lesion, and may be detected by the p16INK4a immuno-histo-chemical biomarker [7, 8]. Although, the p16INK4a biomarker has added value to diagnostics and grading of cervical precancer lesions, the biomarker is not robust for risk-stratification of CIN2 [9].
Recent studies show, that the novel biomarker HPV E4 may potentially distinguish CIN2 in CIN1-like vs CIN3-like resembling lesions. Suggesting that HPV E4 could be a potential biomarker for risk-stratification of CIN2 [10-12].
However, knowledge is lacking on HPV E4 as predictor for CIN2 evolvement.
Aim To explore whether the HPV E4 biomarker can predict risk of CIN2 evolvement.
Materials and methods Study design: Historical cohort study. Study population: N=500 women 23-40 years of age, with a record of CIN2 in the Danish Patological Data Bank [2000-2010], at the Department of Pathology, Aarhus University Hospital. All women are defined as managed by active surveillance (i.e. colposcopy and cervical punch biopsies for every 4-6 months up to two years follow-up).
Selection: Eligible women with a record of incidental CIN2 diagnosis will be identified in the Danish Pathology Databank among all women with a record of CIN2 diagnosis during 2000-2010.
Laboratory analysis: Formalin-fixed paraffin-embedded (FFPE) tissue samples will be compiled from the archives, at the Department of Pathology, Aarhus University Hospital.
FFPE blocks will be sectioned for morphology analysis (hematoxylin \& eosin (H\&E) and for immuno-histo-chemistry analysis (IHC). We will apply the sandwich technique for the p16INK4a and HPV E4 IHC analysis, using the CINtec® Histology Kit (Roche) and the SILgrade E4 assay (LBP). Subsequently, the stained slides will be evaluated by an expert panel within gynecological pathology (2 from Denmark, 1 from UK and 1 from the US respectively).
Exposure will be defined as expressing a HPV E4 positive (CIN1-like) vs HPV E4 negative (CIN3-like) intraepithelial reaction.
Statistical analysis: Linear regression model, effect measure; relative risk (RR) (95% CI).
Power calculations: At a sample size of N=500 women, a statistical power of 89% is expected, at the significance level 0.05 (alpha). Among women who progress or persist during surveillance, a prevalence of 50% CIN2 HPV E4 positive lesions and 70% p16INK4a positive CIN2 lesions is expected.
Settings and collaborators The project will be carried out at the Department of Gynecology and Obstetrics at Gødstrup Hospital in close collaboration with the Department of Pathology, Aarhus University Hospital including DDL Diagnostic Laboratory; University of Virginia; University of Cambridge and University of Maryland School of Medicine.
Main research group in Denmark
- Associate professor, MD, Anne Hammer Lauridsen, Department of Gynecology and Obstetrics, Gødstrup Hospital, Central Region of Denmark \& Department of Clinical medicine, Aarhus University
- Professor, MD, Lone Kjeld Pedersen, Department of Gynecology and Obstetrics, Odense University Hospital \& OPEN, University of Southern Denmark.
- Professor, MD, Torben Steiniche, Professor, Department of Pathology, Aarhus University Hospital \& Department of Clinical medicine, Aarhus University.
- Ph.d-student, Msch Health Science, Rikke Damgaard, Department of Gynecology and Obstetrics, Gødstrup Hospital, Central Region of Denmark \& Department of Clinical medicine, Aarhus University.
Ethical statement The study is appoved by the Regional Committee on Health Research Ethics, Central Region of Denmark and registered at the Legal Department, Faculty of Health, Aarhus University as required by Danish law.
Perspectives Biomarkers reliable for risk-stratification of CIN2 lesions is important for clinical counseling of women, this will enable a more specific and personalized follow-up strategy to avoid risk of over- or undertreatment. As other countries are moving toward a more conservative approach (active surveillance) with respect to management of young women with CIN2 our results may be valauble in an international perspective as well.
- Keywords
- CIN2, p16INK4a, HPV E4, molecular biomarker, risk stratification
What is being measured
The primary outcome is the main question the study is designed to answer.
Regression: Community diagnosis for normal cells or CIN1 (atypical or dysplasia grade 1) based on pathologists microscopy of tissue of cells (visual examination of cell formation, growth and differentation entailing the epithelial layer).
Regression is identified through the records of community diagnosis of cervical lesion in the Danish Pathology Databank defined by SNOMED codes for normal cervical epithelial cells or CIN1 (atypical or dysplastic cells entailing up to 1/3 of the epithelial layer).
Measured: Time frame is defined from date of index community CIN2 diagnosis to record of last and worst cervical histological diagnosis registred in the Danish Pathology Databank (i.e. 4 months - two years after index CIN2).
Timeline
From the start of the study to its completion; the mark is today. Estimated dates are the sponsor’s plan.
- First posted20 Sep 2021
- Study start1 Jun 2020
- Primary completion31 Dec 2023 (estimated)
- Study completion31 Dec 2023 (estimated)
Resources
- Official record on ClinicalTrials.govThe registry entry this page is built from, with its full change history.
- Publications (12)Papers the sponsor has linked to this study.
- Other trials for Cervical Intraepithelial Neoplasia Grade 2 (CIN2)Studies of the same condition, open and under way.
- More trials run by University of AarhusThe sponsor's other registered studies.
- 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
- Retrospective
- Enrolment
- 500 participants (actual)
Sponsor and investigators
- Lead sponsor
- University of Aarhus
- Sponsor type
- University, hospital or other
- Collaborators
- University of Southern Denmark, DDL Diagnostic Laboratory, University of Cambridge, National Cancer Institute (NCI), University of Virginia
- Responsible party
- Sponsor
IDs, dates and publications
- ClinicalTrials.gov ID
- NCT05049252
- Sponsor's protocol ID
- CIN2-E4
- Status last verified
- May 2023
- First submitted
- 31 Aug 2021
- Last updated
- 7 Dec 2023
- Results posted
- No
- FDA-regulated drug
- No
- FDA-regulated device
- No
- Individual data sharing
- No
Publications
Panczyszyn A, Boniewska-Bernacka E, Glab G. Telomeres and Telomerase During Human Papillomavirus-Induced Carcinogenesis. Mol Diagn Ther. 2018 Aug;22(4):421-430. doi: 10.1007/s40291-018-0336-x.
PubMed 29777397Gravitt PE, Winer RL. Natural History of HPV Infection across the Lifespan: Role of Viral Latency. Viruses. 2017 Sep 21;9(10):267. doi: 10.3390/v9100267.
PubMed 28934151Chaturvedi AK, Kleinerman RA, Hildesheim A, Gilbert ES, Storm H, Lynch CF, Hall P, Langmark F, Pukkala E, Kaijser M, Andersson M, Fossa SD, Joensuu H, Travis LB, Engels EA. Second cancers after squamous cell carcinoma and adenocarcinoma of the cervix. J Clin Oncol. 2009 Feb 20;27(6):967-73. doi: 10.1200/JCO.2008.18.4549. Epub 2008 Dec 29.
PubMed 19114696Lee MH, Finlayson SJ, Gukova K, Hanley G, Miller D, Sadownik LA. Outcomes of Conservative Management of High Grade Squamous Intraepithelial Lesions in Young Women. J Low Genit Tract Dis. 2018 Jul;22(3):212-218. doi: 10.1097/LGT.0000000000000399.
PubMed 29762428van Baars R, Griffin H, Wu Z, Soneji YJ, van de Sandt M, Arora R, van der Marel J, Ter Harmsel B, Jach R, Okon K, Huras H, Jenkins D, Quint W, Doorbar J. Investigating Diagnostic Problems of CIN1 and CIN2 Associated With High-risk HPV by Combining the Novel Molecular Biomarker PanHPVE4 With P16INK4a. Am J Surg Pathol. 2015 Nov;39(11):1518-1528. doi: 10.1097/PAS.0000000000000498.
PubMed 26379150Bruinsma FJ, Quinn MA. The risk of preterm birth following treatment for precancerous changes in the cervix: a systematic review and meta-analysis. BJOG. 2011 Aug;118(9):1031-41. doi: 10.1111/j.1471-0528.2011.02944.x. Epub 2011 Mar 30.
PubMed 21449928Darragh TM, Colgan TJ, Thomas Cox J, Heller DS, Henry MR, Luff RD, McCalmont T, Nayar R, Palefsky JM, Stoler MH, Wilkinson EJ, Zaino RJ, Wilbur DC; Members of the LAST Project Work Groups. The Lower Anogenital Squamous Terminology Standardization project for HPV-associated lesions: background and consensus recommendations from the College of American Pathologists and the American Society for Colposcopy and Cervical Pathology. Int J Gynecol Pathol. 2013 Jan;32(1):76-115. doi: 10.1097/PGP.0b013e31826916c7.
PubMed 23202792Xing Y, Wang C, Wu J. Expression of geminin, p16, and Ki67 in cervical intraepithelial neoplasm and normal tissues. Medicine (Baltimore). 2017 Jun;96(26):e7302. doi: 10.1097/MD.0000000000007302.
PubMed 28658133Cuschieri KS, Cubie HA, Whitley MW, Gilkison G, Arends MJ, Graham C, McGoogan E. Persistent high risk HPV infection associated with development of cervical neoplasia in a prospective population study. J Clin Pathol. 2005 Sep;58(9):946-50. doi: 10.1136/jcp.2004.022863.
PubMed 16126875Griffin H, Soneji Y, Van Baars R, Arora R, Jenkins D, van de Sandt M, Wu Z, Quint W, Jach R, Okon K, Huras H, Singer A, Doorbar J. Stratification of HPV-induced cervical pathology using the virally encoded molecular marker E4 in combination with p16 or MCM. Mod Pathol. 2015 Jul;28(7):977-93. doi: 10.1038/modpathol.2015.52. Epub 2015 May 8.
PubMed 25953390Griffin H, Wu Z, Marnane R, Dewar V, Molijn A, Quint W, Van Hoof C, Struyf F, Colau B, Jenkins D, Doorbar J. E4 antibodies facilitate detection and type-assignment of active HPV infection in cervical disease. PLoS One. 2012;7(12):e49974. doi: 10.1371/journal.pone.0049974. Epub 2012 Dec 3.
PubMed 23226504Damgaard RK, Jenkins D, de Koning MN, Quint WG, Stoler MH, Doorbar J, Kahlert J, Gravitt PE, Steiniche T, Petersen LK, Hammer A. Performance of HPV E4 and p16INK4a biomarkers in predicting regression of cervical intraepithelial neoplasia grade 2 (CIN2): protocol for a historical cohort study. BMJ Open. 2022 Jul 6;12(7):e059593. doi: 10.1136/bmjopen-2021-059593.
PubMed 35793925
Study at a glance
From the registry record, last updated by the sponsor on 7 Dec 2023. Recruitment status is as the sponsor reported it: confirm with the study team.
- Official title
- Performance of HPV E4 and p16INK4a Biomarkers in Predicting Risk of Regression Among Women Diagnosed With Cervical Intraepithelial Neoplasia Grade 2 (CIN2): a Historical Cohort Study
- ClinicalTrials.gov ID
- NCT05049252
- Acronym / sponsor ID
- CIN2-E4
- Keywords
- CIN2, p16INK4a, HPV E4, molecular biomarker, risk stratification
- Study type
- Observational
- Recruitment status
- Unknown status
- Enrolment
- 500 participants (actual)
- Lead sponsor
- University of AarhusUniversity, hospital or other
- Collaborators
- University of Southern Denmark, DDL Diagnostic Laboratory, University of Cambridge, National Cancer Institute (NCI), University of Virginia
- Study start
- 1 Jun 2020 (actual)
- Primary completion
- 31 Dec 2023 (estimated)
- Study completion
- 31 Dec 2023 (estimated)
- First posted
- 20 Sep 2021 (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.
Introduction Cervical intraepithelial neoplasia CIN1 (low grade), CIN2 (moderate grade), CIN3 (severe grade) defines cervical precancer lesions derived from the squamous epithelial cell line. CIN2, represents a heterogenic phenotype expression of both CIN1-like and CIN3-like evolving lesions with different risk of progression. The CIN2 diagnosis has low reproducibility, and current diagnostic tools do not allow for risk-stratification of CIN2.
Risk-profiling is important, to enable targeted management of women with CIN2 at first incidence (surgery or active surveillance) and to avoid risk of over- or undertreatment.
Preliminary studies show, that the novel tissue biomarker HPV E4 has potential to discriminate CIN1-like (HPV E4 positive) from CIN3-like (HPV E4 negative) evolving CIN2 lesions, suggesting that the biomarker could be vauable for risk-stratification of CIN2.
Aim To examine the potential of the HPV E4 biomarker in predicting risk of CIN2 evolvement.
Materials and Methods Design: Historical cohort study. Study population: N=500 women, 23-40 years of age with a record of incidental CIN2 diagnosis between [2000-2010] in the Danish Pathology Data Bank at Aarhus University Hospital, Region of Central Denmark. All women are defined as managed by active surveillance (i.e. no surgical treatment within 4 months after first CIN2 diagnosis).
Exposure: HPV E4 positive vs HPV E4 negative intraepithelial reaction. Outcome: Regression (normal, CIN1) vs non-regression (CIN2, CIN3, cervical cancer).
Statistical model: Linear regression model (RR (95%CI)).
Perspectives: HPV E4 may act as significant predictor for CIN2 evolvement, and reliable marker for risk-assessment of CIN2. This will be valuable in the clinical management of women with CIN2, enabling to discriminate women, who would most likely regress and could be manged by active surveillance vs women in risk of progression or persistence, who could benefit of immediate surgical treatment.
Detailed description
Introduction Persistent infection with high-risk human papillomavirus (hrHPV) is a causative source of cervical cancer [1]. Cervical intraepitehelial neoplasia CIN1 (low), CIN2 (moderate), CIN3 (severe) defines cervical precancer lesions evolved from the squamous epithelium cell line [3]. CIN1 and CIN2 lesions are associated with lower progression rates for cervical cancer than CIN3 [4]. CIN2 poses a major challenge clinically, due to the heterogenic expression of both CIN1-like and CIN3-like evolving lesions, which current diagnostic tools do not enable to stratify in risk of progression [5]. Risk-stratification of CIN2 is highly important for clinical management of CIN2 and to avoid risk of over- or undertreatment. Historically, CIN2 has been the threshold for surgical mangement (cone excisional biopsy). However, since regressions rates of CIN2 lesions are high, and cone excisional biopy is associated with reproductive harm, such as preterm birth, many countries such as Denmark has adopted a more conservative approach in the management of young women with CIN2 (i.e. active surveillance: colposcopy, cervical punch biopsies for every 4-6 monhts up to two years follow-up without any surgical procedure) [6,7]. In the Central Region of Denmark, active surveillance has been recommended for young women since 1995.
The p16 protein plays an important role as inhibitor in cellular regulation and differentiation. p16 is a common surrogat marker for hrHPV E6/E7 oncogenic activity and cellular transformation associated with cancer evolvement. The intrapeithelial expression level of p16 is positively associated with grade of CIN lesion, and may be detected by the p16INK4a immuno-histo-chemical biomarker [7, 8]. Although, the p16INK4a biomarker has added value to diagnostics and grading of cervical precancer lesions, the biomarker is not robust for risk-stratification of CIN2 [9].
Recent studies show, that the novel biomarker HPV E4 may potentially distinguish CIN2 in CIN1-like vs CIN3-like resembling lesions. Suggesting that HPV E4 could be a potential biomarker for risk-stratification of CIN2 [10-12].
However, knowledge is lacking on HPV E4 as predictor for CIN2 evolvement.
Aim To explore whether the HPV E4 biomarker can predict risk of CIN2 evolvement.
Materials and methods Study design: Historical cohort study. Study population: N=500 women 23-40 years of age, with a record of CIN2 in the Danish Patological Data Bank [2000-2010], at the Department of Pathology, Aarhus University Hospital. All women are defined as managed by active surveillance (i.e. colposcopy and cervical punch biopsies for every 4-6 months up to two years follow-up).
Selection: Eligible women with a record of incidental CIN2 diagnosis will be identified in the Danish Pathology Databank among all women with a record of CIN2 diagnosis during 2000-2010.
Laboratory analysis: Formalin-fixed paraffin-embedded (FFPE) tissue samples will be compiled from the archives, at the Department of Pathology, Aarhus University Hospital.
FFPE blocks will be sectioned for morphology analysis (hematoxylin \& eosin (H\&E) and for immuno-histo-chemistry analysis (IHC). We will apply the sandwich technique for the p16INK4a and HPV E4 IHC analysis, using the CINtec® Histology Kit (Roche) and the SILgrade E4 assay (LBP). Subsequently, the stained slides will be evaluated by an expert panel within gynecological pathology (2 from Denmark, 1 from UK and 1 from the US respectively).
Exposure will be defined as expressing a HPV E4 positive (CIN1-like) vs HPV E4 negative (CIN3-like) intraepithelial reaction.
Statistical analysis: Linear regression model, effect measure; relative risk (RR) (95% CI).
Power calculations: At a sample size of N=500 women, a statistical power of 89% is expected, at the significance level 0.05 (alpha). Among women who progress or persist during surveillance, a prevalence of 50% CIN2 HPV E4 positive lesions and 70% p16INK4a positive CIN2 lesions is expected.
Settings and collaborators The project will be carried out at the Department of Gynecology and Obstetrics at Gødstrup Hospital in close collaboration with the Department of Pathology, Aarhus University Hospital including DDL Diagnostic Laboratory; University of Virginia; University of Cambridge and University of Maryland School of Medicine.
Main research group in Denmark
- Associate professor, MD, Anne Hammer Lauridsen, Department of Gynecology and Obstetrics, Gødstrup Hospital, Central Region of Denmark \& Department of Clinical medicine, Aarhus University
- Professor, MD, Lone Kjeld Pedersen, Department of Gynecology and Obstetrics, Odense University Hospital \& OPEN, University of Southern Denmark.
- Professor, MD, Torben Steiniche, Professor, Department of Pathology, Aarhus University Hospital \& Department of Clinical medicine, Aarhus University.
- Ph.d-student, Msch Health Science, Rikke Damgaard, Department of Gynecology and Obstetrics, Gødstrup Hospital, Central Region of Denmark \& Department of Clinical medicine, Aarhus University.
Ethical statement The study is appoved by the Regional Committee on Health Research Ethics, Central Region of Denmark and registered at the Legal Department, Faculty of Health, Aarhus University as required by Danish law.
Perspectives Biomarkers reliable for risk-stratification of CIN2 lesions is important for clinical counseling of women, this will enable a more specific and personalized follow-up strategy to avoid risk of over- or undertreatment. As other countries are moving toward a more conservative approach (active surveillance) with respect to management of young women with CIN2 our results may be valauble in an international perspective as well.
Study design
- Observational model
- Cohort
- Time perspective
- Retrospective
Who may qualify
- Ages
- 23 to 40 years
- Sex
- Female only
- Healthy volunteers
- Not accepted
- Age groups
- Adult
- Study population
- N=500 women 23-40 years of age with a record of CIN2 in the Danish Pathology Data Bank, at the Department of Pathology, Aarhus University Hospital, managed by active surveillance.
Key inclusion criteria (5 listed)
- Women
- 23-40 years of age
- First record of CIN2 verified diagnosis (M74B09, T83110)
- Managed by active surveillance (i.e. no surgical treatment within 4 months after index CIN2 diagnosis)
- Record of CIN2 diagnosis during 2000-2010 and at least one record of cervix histological sample during follow-up.
Key exclusion criteria (2 listed)
- Prior record of CIN2+ (i.e. CIN2, CIN3, cervical cancer), hysterectomy or cervical excisional cone biopsy.
- No record of cervical histological sample (cervical punch biopsy of cervical excisional biopsy) within two years after index CIN2 diagnosis.
Eligibility is decided by the study team after screening; this overview does not establish that a patient qualifies. Full inclusion and exclusion criteria.
Primary outcome
Regression: Community diagnosis for normal cells or CIN1 (atypical or dysplasia grade 1) based on pathologists microscopy of tissue of cells (visual examination of cell formation, growth and differentation entailing the epithelial layer).
Time frame: Time frame is defined from date of index community CIN2 diagnosis to record of last and worst cervical histological diagnosis registred in the Danish Pathology Databank (i.e. 4 months - two years after index CIN2).
Regression is identified through the records of community diagnosis of cervical lesion in the Danish Pathology Databank defined by SNOMED codes for normal cervical epithelial cells or CIN1 (atypical or dysplastic cells entailing up to 1/3 of the epithelial layer).
Results and safety
Results are not available in the source record.
Research links
- Official record on ClinicalTrials.govLast updated by the sponsor 7 Dec 2023.
- Background: PubMed 29777397Panczyszyn A, Boniewska-Bernacka E, Glab G. Telomeres and Telomerase During Human Papillomavirus-Induced Carcinogenesis. Mol Diagn Ther. 2018 Aug;22(4):421-430. doi: 10.1007/s40291-018-0336-x.
- Background: PubMed 28934151Gravitt PE, Winer RL. Natural History of HPV Infection across the Lifespan: Role of Viral Latency. Viruses. 2017 Sep 21;9(10):267. doi: 10.3390/v9100267.
- Background: PubMed 19114696Chaturvedi AK, Kleinerman RA, Hildesheim A, Gilbert ES, Storm H, Lynch CF, Hall P, Langmark F, Pukkala E, Kaijser M, Andersson M, Fossa SD, Joensuu H, Travis LB, Engels EA. Second cancers after squamous cell carcinoma and adenocarcinoma of the cervix. J Clin Oncol. 2009 Feb 20;27(6):967-73. doi: 10.1200/JCO.2008.18.4549. Epub 2008 Dec 29.
- Background: PubMed 29762428Lee MH, Finlayson SJ, Gukova K, Hanley G, Miller D, Sadownik LA. Outcomes of Conservative Management of High Grade Squamous Intraepithelial Lesions in Young Women. J Low Genit Tract Dis. 2018 Jul;22(3):212-218. doi: 10.1097/LGT.0000000000000399.
- Background: PubMed 26379150van Baars R, Griffin H, Wu Z, Soneji YJ, van de Sandt M, Arora R, van der Marel J, Ter Harmsel B, Jach R, Okon K, Huras H, Jenkins D, Quint W, Doorbar J. Investigating Diagnostic Problems of CIN1 and CIN2 Associated With High-risk HPV by Combining the Novel Molecular Biomarker PanHPVE4 With P16INK4a. Am J Surg Pathol. 2015 Nov;39(11):1518-1528. doi: 10.1097/PAS.0000000000000498.
- Background: PubMed 21449928Bruinsma FJ, Quinn MA. The risk of preterm birth following treatment for precancerous changes in the cervix: a systematic review and meta-analysis. BJOG. 2011 Aug;118(9):1031-41. doi: 10.1111/j.1471-0528.2011.02944.x. Epub 2011 Mar 30.
- Background: PubMed 23202792Darragh TM, Colgan TJ, Thomas Cox J, Heller DS, Henry MR, Luff RD, McCalmont T, Nayar R, Palefsky JM, Stoler MH, Wilkinson EJ, Zaino RJ, Wilbur DC; Members of the LAST Project Work Groups. The Lower Anogenital Squamous Terminology Standardization project for HPV-associated lesions: background and consensus recommendations from the College of American Pathologists and the American Society for Colposcopy and Cervical Pathology. Int J Gynecol Pathol. 2013 Jan;32(1):76-115. doi: 10.1097/PGP.0b013e31826916c7.
- Background: PubMed 28658133Xing Y, Wang C, Wu J. Expression of geminin, p16, and Ki67 in cervical intraepithelial neoplasm and normal tissues. Medicine (Baltimore). 2017 Jun;96(26):e7302. doi: 10.1097/MD.0000000000007302.
- Background: PubMed 16126875Cuschieri KS, Cubie HA, Whitley MW, Gilkison G, Arends MJ, Graham C, McGoogan E. Persistent high risk HPV infection associated with development of cervical neoplasia in a prospective population study. J Clin Pathol. 2005 Sep;58(9):946-50. doi: 10.1136/jcp.2004.022863.
- Background: PubMed 25953390Griffin H, Soneji Y, Van Baars R, Arora R, Jenkins D, van de Sandt M, Wu Z, Quint W, Jach R, Okon K, Huras H, Singer A, Doorbar J. Stratification of HPV-induced cervical pathology using the virally encoded molecular marker E4 in combination with p16 or MCM. Mod Pathol. 2015 Jul;28(7):977-93. doi: 10.1038/modpathol.2015.52. Epub 2015 May 8.
- Background: PubMed 23226504Griffin H, Wu Z, Marnane R, Dewar V, Molijn A, Quint W, Van Hoof C, Struyf F, Colau B, Jenkins D, Doorbar J. E4 antibodies facilitate detection and type-assignment of active HPV infection in cervical disease. PLoS One. 2012;7(12):e49974. doi: 10.1371/journal.pone.0049974. Epub 2012 Dec 3.
- Derived from this study: PubMed 35793925Damgaard RK, Jenkins D, de Koning MN, Quint WG, Stoler MH, Doorbar J, Kahlert J, Gravitt PE, Steiniche T, Petersen LK, Hammer A. Performance of HPV E4 and p16INK4a biomarkers in predicting regression of cervical intraepithelial neoplasia grade 2 (CIN2): protocol for a historical cohort study. BMJ Open. 2022 Jul 6;12(7):e059593. doi: 10.1136/bmjopen-2021-059593.
- 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.
The record lists no contact. Use the official record to reach the sponsor.
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 Cervical Intraepithelial Neoplasia Grade 2 (CIN2), 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 5 inclusion and 2 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: status not confirmed, as of the sponsor's last update on 7 Dec 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?
Results are not available in the source record.
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?
Regression: Community diagnosis for normal cells or CIN1 (atypical or dysplasia grade 1) based on pathologists microscopy of tissue of cells (visual examination of cell formation, growth and differentation entailing the epithelial layer). (time frame: Time frame is defined from date of index community CIN2 diagnosis to record of last and worst cervical histological diagnosis registred in the Danish Pathology Databank (i.e. 4 months - two years after index CIN2).). 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 NCT05049252, which also lists 12 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 7 Dec 2023.