Neoplasms

All Conditions

Urinary Tract, Sexual Organs, and Pregnancy Conditions

Rare Diseases

Carcinoma

Uterine Cervical Dysplasia

Precancerous Conditions

Uterine Cervical Diseases

Uterine Diseases

Genital Diseases, Female

Genital Diseases

Urogenital Diseases

Female Urogenital Diseases

Pregnancy Complications

Female Urogenital Diseases and Pregnancy Complications

Cervical Intraepithelial Neoplasia

No intervention, group 24-29 years. Women will receive the written invitation to screening only

Messenger text message reminder, group 24-29 years.

No intervention group 30-64 years, Women will receive the written invitation to screening only

Messenger text message reminder, group 30-64

Social Norms (population proportion) text message reminder, group 30-64 years

Social Norms (population total) text message reminder, group 30-64 years

Framed gain text message reminder, group 30-64 years

Framed loss text message reminder, group 30-64 years

"Your cervical smear test is due. To book please call \<xxxxxxxxxxx\>"

Neutral text message reminder

"\<GP NAME\>: Your cervical smear test is due. To book please call \<xxxxxxxxxxx\>"

Messenger text message reminder

"Last year in Hillingdon 7 out of 10 women took part in cervical screening. Your cervical smear test is due. To book please call \<xxxxxxxxxxx\>"

Social Norms A reminder

"Last year 12000 women in Hillingdon took part in cervical screening. Your cervical smear test is due. To book please call \<xxxxxxxxxxx\>"

Social Norms B reminder

"Cervical cancer screening saves 4500 lives in England every year. Your cervical smear test is due. To book please call \<xxxxxxxxxxx\>"

Framed Gain text reminder

"Failing to attend cervical screening could lead to 4500 avoidable deaths in England each year. Your cervical smear test is due. To book please call \<xxxxxxxxxxx\>"

Framed Loss text reminder

Deborah Cunningham

Cervical cancer is the most common cancer in women under 35 years and is a major public health concern. Fortunately, the natural history of this malignancy can be beneficially improved through cytological screening. However, the success of screening programmes depends on their ability to attract the "at risk" population, as well as the analytical sensitivity and specificity of the screening test. In the UK, screening consistently falls short of the 80% national target and recent evidence shows uptake is decreasing, in part due to the introduction of HPV vaccination programmes. In the under 30s London population, average coverage only reached 50% in 2013. Given this information, the cervical screening programme is under increasing pressure to improve uptake, and need an evidence based intervention.

We aim to improve the uptake of cervical screening using SMS messaging through a randomised controlled trial. The trail will evaluate both the prevalent and incident rounds of screening and within the intervention group, analyse how the content of text reminders influences their effectiveness. Specifically we will evaluate a) neutral b) messenger c) social norms d) framed gain/loss reminders. Unlike our previous trial, this SMS reminder will encourage the booking of an appointment which has never been tested, rather than simply reminding women to attend. All women being invited for cervical screening, registered at participating GPs within Hillingdon will be eligible to participate. Women will also be provided with a 2 week window during which they can opt out of the research. Given the sample sizes we predict the trial will take 9 months.

In Hillingdon specifically, where this randomised controlled trial (RCT) will be set, the uptake of the prevalent population of women (24-29 years as a proxy), was only 35% in 2012, whilst the incident population (30-64years as a proxy) was slightly higher at 51% (HSCIC2, 2013).

One strategy which healthcare has previously employed to improve uptake of both screening and routine appointments is the use of SMS or "text message" reminders. Standard reminders have often been used in healthcare and act as "primers", prompting people to make healthier choices (Blumenthal-Barby \& Burroughs, 2012). They also serve to reduce the practical barriers preventing women from attending i.e. failure to book or remember the time/location of the appointment. Previous research investigating the effectiveness of appointment reminders demonstrated that both telephone and postal reminders, although at times effective, were often impractical, unsustainable, and/or unaffordable (Gurol-Urganci et al, 2013, Perron et al, 2013).

SMS interventions have been effective at improving medication adherence, disease management and smoking cessation (Krishna et al, 2013; Abroms et al, 2014). They have also proven effective at reducing "Do Not Attends" (DNAs) within healthcare, estimated to cost the NHS £600 million per year in wasted time and resources (Dr Foster Research, 2009). SMS reminders were also found to be very successful at increasing the attendance of breast screening appointments, increasing the uptake by 17% compared to usual care (Kerrison et al, 2013). As well as improving attendance, SMS reminders have also proved effective at reducing costs, increasing the efficiency of clinics, enabling more effective booking, reducing mismatches between demand and capacity, and generally helping to increase productivity within healthcare.

SMS interventions have many benefits over alternative mediums. Firstly an SMS is cheap, roughly 3p per text whilst a letter can cost 10 times that. SMS is also capable of reaching the recipient wherever they are whilst letters can only be delivered to recipients last known address. This is particularly important, as people are more likely to retain their mobile numbers nowadays even if they change address, especially in London where the population is notoriously mobile. Mobile phone use is also ubiquitous in the UK, with a recent report estimating that over 99% of adults in London owned a mobile phone in 2013 (Ofcom, 2013). Another advantage of SMS is that there is evidence that people increasingly use electronic day planners and therefore a message direct to a person's phone encourages people to promptly record appointments and even allowing them to set alarms creating their own reminder. SMS interventions would therefore be as wide reaching as a postal intervention (if not more so) at a fraction of the cost and with greater accuracy.

Although previous evidence provides a sound rationale that SMS interventions have great potential for cervical screening, there is still a considerable amount of information required in order to introduce this intervention as standard practice.

The research also aims to evaluate whether minor differences in wording affect women's response to these messages. This idea stems from "Nudge" theory, a form of Libertarian Paternalism or "Asymmetric Paternalism" (Thaler and Sunstein, 2003). This concept is derived from a mix of cognitive psychology and behavioural science which is based on the principal that humans, due to a lack of information, experience, cognitive ability and self-control, often fail to act in a way that promotes their own welfare (Sunstein and Thaler, 2003). Libertarian paternalisms therefore encourages individuals to act in their, and/or societies, best interests whilst maintaining freedom of choice (Aggarwal et al 2014). Although the use of "nudge" has been viewed as controversial within healthcare by some, this study has justified its use by avoiding any form of coercion, and making it clear that this text is simply a reminder of the normal invitation process.

There is mounting evidence demonstrating that even small changes in the content and framing heavily influences people decisions (Haynes et al, 2013; Hallsworth et al, 2014). Whether the positive effects of small wording changes or "nudging" is reflected in women's attitudes towards cervical screening programs has yet to be evaluated. This information will be crucial in order to maximise efficiency of this intervention and knowledge gained could be applied to similar interventions in healthcare making them more cost effective. We also hope to evaluate whether people with different levels of deprivation respond differently to the different messages. This is hugely important, as tailoring the message to the population is crucial to improving the efficiency of the intervention and to reduce health inequalities within London.

In light of this evidence we have chosen seven different text message options, all of which have according to research great potential to improve the uptake of screening. These include a control of no text message, a neutral reminder and five reminders with behavioural messages to prompt uptake. The intervention arms according to research have great potential to improve the uptake of screening. It is well established that reducing the effort required to perform an action increases the likelihood of follow-through (Leventhal et al, 1965).

All text messages begin with the test message, followed by a standard reminder message that is constant across the messages and the participants GP practice phone number.

The chosen messages are no text message, a neutral message; a messenger; two social norms; a gain frame and a loss frame highlighting the benefits of cervical screening.

Neutral Reminder

The neutral message will not "nudge" but simply remind the woman to book a cervical screening appointment, acting as a direct reminder of the letter invitation sent out as normal practice. It will act as a control for the other types of message.

"Your cervical smear test is due. To book please call \<xxxxxxxxxxx\>"

Messenger Reminder

Some evidence suggests that people respond better to invitations from their personal practice rather than a centralised NHS organisation (Segan et al, 1998; Arbyn et al, 2010). This is especially true of young women, immigrants, urban residents and those with low socioeconomic status, which are key demographics we hope to improve uptake in through this intervention (Bosgraaf et al, 2013).

"\<GP NAME\>: Your cervical smear test is due. To book please call \<xxxxxxxxxxx\>"

Social Norms Messages

Social norms messages focus on the principal that people have a tendency to overestimate the extent to which their peers perform acts, causing themselves or others harm. Evidence suggests educating people about the actual degree to which people perform these acts can alter behaviour (Perkins et al, 2002). This theory, combined with the fact that people are strongly influenced by comparison to what others do will hopefully prompt women to take up the offer of cervical screening. We have also chosen to use a local statistics as personalised messages have a greater influence as they increase the relevance of the message to the women (Institute for government: Cabinet Office, 2010)

1. Social Norms (local, proportion) reminder:

   "Last year in Hillingdon 7 out of 10 women took part in cervical screening. Your cervical smear test is due. To book please call \<xxxxxxxxxxx\>"
2. Social Norms (local, total number) reminder:

"Last year 12000 women in Hillingdon took part in cervical screening. Your cervical smear test is due. To book please call \<xxxxxxxxxxx\>"

Gain and Loss Frame Messages

The role gain and loss frame messengers to encourage uptake of good health behaviour is not entirely clear. Some evidence points to humans having "have a stronger aversion to losses than we do affinity to gains" therefore highlighting losses may have a greater impact (Blumenthal-Barby \& Burroughs, 2012). On the other hand a meta-analysis found that gain frame was more likely to be effective in changing prevention behaviour. (Gallagher, 2001). To evaluate this further a gain and loss frame message were included above. Statistics included in these messages were taken from (Peto, 2004) and correlate to widely used statistics on cancerscreening.nhs.uk to maintain consistency with other information women might be seeing.

1. Gain frame

   "Cervical cancer screening saves 4500 lives in England every year. Your cervical smear test is due. To book please call \<xxxxxxxxxxx\>"
2. Loss frame

"Failing to attend cervical screening could lead to 4500 avoidable deaths in England each year. Your cervical smear test is due. To book please call \<xxxxxxxxxxx\>"

POTENTIAL ETHICAL ISSUES

The main ethical issue is that in order to analyse the data, the researcher will need to access minimal amounts of patient data. The researcher will specifically need to access a list of women in Hillingdon who are sent an invitation to cervical screening on a weekly basis, if they are registered with a consenting GP. All participating GPs (which to date include over 85% of those approached for the trial) have consented to share relevant data with the research team and are happy with the safeguards put in place to protect confidentiality. These include NHS secure emails, password protection on all patient data, anonymisation of data (identifiable by NHS number only) and strict adherence to all NHS information governance regulations.

On this list, each participant will be identified by their NHS number, and this will be the only unique identifier. The researcher will also need information about their age (not date of birth), participants "attended/not attended status" at the end of the 18 week follow up period and the GP practice code, to ensure we only include women registered with consenting GPs. We would also like to access the second half of participants' postcode to allow for a basic deprivation analysis.

Before accessing this information we will offer women the option to opt out of the research and therefore not share this data or receive a text message reminder. This will be achieved by the cervical screening (call-recall) team adding an insert on behalf of the GP, into the screening invitation letter to all eligible women. This insert will provide informed consent slip and contact details of the researcher if women would like further information. They will have 2 weeks to respond and be removed from the study.

As an extension of this research, the trial will also investigate how variations in the wording of the text messages affect uptake. This wording has been carefully selected with the guidance of the NHS Cervical Screening Program (NHSCSP) as well as Public Health England psychology experts and any data within the text messages is up to date and sourced from the NHSCS.

Can Text Reminders Improve Uptake of Cervical Screening?

Can Text Reminders Improve Uptake of Cervical Screening? A RCT.

Analysis of the rate of cervical screening by trial arm at the end of the screening round (32 weeks)

Attendance within different groups by trial arm

Attendance within groups of different levels of deprivation (using IMD) by trial arm

Analysis of the rate of cervical screening by trial arm using SMS delivery status data to compared the rate of cervical screening in women who receive the SMS at the end of the screening round (32 weeks from screening invitation)

Sarah Huf

Clinical Research Fellow

Infections

Symptoms and General Pathology

Immune System Diseases

Uterine Cervical Neoplasms

Communicable Diseases

Acquired Immunodeficiency Syndrome

HIV Infections

Papillomavirus Infections

Disease Attributes

Sexually Transmitted Diseases

Sexually Transmitted Diseases, Viral

Virus Diseases

Uterine Neoplasms

Genital Neoplasms, Female

Urogenital Neoplasms

DNA Virus Infections

Tumor Virus Infections

Women with perinatally acquired HIV aged 18 or over who are sexually active

Women with perinatally acquired HIV aged 18 or over who are not sexually active

HPV test from cervical sample using Cepheid GeneXpert HPV

Human papillomavirus testing

Cervical cytology

HPV type specific serology (16/18) using ELISA from serum samples

HPV serology

Tamara Elliott

Sarah Fidler

This is a cross-sectional, observational study of high-risk HPV status, cervical cytology and HPV vaccine uptake and response in young women with perinatally acquired HIV.

This is an observational study of cervical cytology assessment, high risk human papilloma virus (hr-HPV) status, and HPV antibody titres amongst adult women living with perinatally acquired HIV infection (PaHIV). Eligible consenting participants will have two samples taken; firstly, a cervical sample tested for cytology and Hr-HPV with the Cepheid GeneXpert HPV; secondly serum will be assessed for hr-HPV serology. All women with PaHIV, vaccinated and unvaccinated for HPV, over the age of 18 years will be eligible and will be recruited into one of two cohorts: (1) sexually active women: full study, cervical and blood sampling (n=50) or (2) non-sexually active women, blood sampling only (n=30). Follow up for abnormal smear results or hr-HPV positivity will be arranged through colposcopy.

Screening for HPV and Cervical Cancer in Young Women With Perinatally Acquired HIV

Screening for Human Papillomavirus and Cervical Cancer in Young Women With Perinatally Acquired HIV

Public Health England

Imperial College London

Cobas HPV-DNA test is performed on the cervical sample in addition to the routine cytology

Screening with cytology as usual in the cervical screening program

Cobas HPV-DNA testing device from Roche is already in standard use in the Danish screening program for purpose of triage and primary screening of women 60+. It has four signals; HPV-negative, HPV-16, HPV-18 and "other"

Cobas HPV-DNA test

Elsebeth Lynge, Professor

In Denmark, the first birth cohorts of women offered HPV-vaccination as girls are entering the cervical screening program. These women are expected to be better protected against cervical cancer. It has not yet been decided how to screen these women.

This method study will investigate a possible screening scheme that could provide a reduced burden of screening for HPV-vaccinated birth cohorts.

In Denmark, women aged 23-49 are offered cervical screening with liquid-based cytology (LBC) every 3rd year, and women aged 50-59 every 5th year. Women aged 60-64 are offered an exit HPV-DNA test.

In 2008 vaccination against Human papilloma virus (HPV) was offered free of charge to girls aged 13-15. HPV-vaccination has been part of the child vaccination program for 12-year old girls since 2009. Women born in 1994 were offered HPV-vaccination at age 14, and approximately 80% are HPV-vaccinated. These women entered the screening program in 2017.

HPV-testing is shown to provide a better protection against cervical cancer than cytology testing, and the 6-year protection against CIN3+ after a negative HPV-test has been observed to be higher than the 3-year protection after a negative cytology test (ref).

The aim of the study is to evaluate if primary screening with HPV-testing and LBC triage every 6 years in women offered HPV-vaccination as girls would provide at least the same protection as the present screening, measured by cumulative number of cervical intraepithelial neoplasia (CIN). This screening scheme would allow HPV-negative women to benefit from a prolonged screening interval and thereby reduce the burden of screening for HPV-vaccinated birth cohorts.

The study is deemed a method study by the ethical committee of the Capital region and informed consent is, therefore, not required. The study is approved by the Danish data protection agency.

The study will be undertaken as a method study embedded in the existing cervical screening program in the study area: Region Zealand, Northern Denmark region, Central Denmark region and part of region of Southern Denmark. The study is planned to run over three screening rounds. We expect 12000 women to be screened in the baseline screening round.

The study includes all women born in 1994 who live in the study area and participate in cervical screening. For a random half of these women, an HPV-DNA test is performed in addition to routine cervical cytology. The result of the HPV-test will not affect screening or follow-up, but is performed solely for purposes of the method study. CINtec p16 histology will be performed on all cervical biopsies in the study to ensure the quality of the diagnosis.

When screening samples are received at the pathology labs the allocation (HPV+/- in addition to cytology) will appear automatically in the IT-system.

The study will be conducted a non-inferiority study. If non-inferiority is declared, analysis for superiority will be conducted. Censoring will be performed in the event of death, emigration, end of study and at first cervical intraepithelial neoplasia grade 3 or above (CIN3+) or conization. Data on primary and secondary endpoints will be collected from National Health registers.

The project is supported by funds from 'Det Frie forskningsråd', 'Helsefonden' and 'Johannes Clemmesens Forskningsfond'. Cobas HPV-DNA and CINtec p16 histology test-kits are sponsored by Roche. Both tests were in standard use in the pathology departments prior to the project.

Results of the baseline screening round and final results from the study will be published in relevant peer-reviewed journals.

Trial23 - A Method Study on Cervical Screening in Women Offered HPV-vaccination as Girls

Trial23 - A Method Study on the Use of Primary HPV-testing With Cytology Triage in Women Offered HPV-vaccination as Girls

Number of women with the secondary outcome in the two study arms at baseline (baseline screening round).

Prevalence of HPV-infections; HPV-16, -18 and other

Number of women with the secondary outcome in the two study arms after baseline screening.

Histologically proven CIN3+ is chosen as primary outcome measure because it is the diagnostic threshold above which conization is recommended by the Danish Society of Gynecology and Obstetrics. Primary outcome will be based on intention-to-treat and per protocol analysis and stratified by region of residence. Primary HPV-testing with cytology triage every six years compared to cytology every three years will be approximated from the observed data.

Intention-to-treat and per protocol analysis. Stratified by region of residence.

Intention-to-treat and per protocol analysis. Stratified by region of residence

Naestved Hospital

Aalborg University Hospital

Soenderjylland Hospital

Hospital of South West Jutland

Randers Regional Hospital

University of Copenhagen

Professor

Molecular testing for HPV with partial genotyping for types 16/18, with referral of the HPV16/18-positive group for diagnostic evaluation, and secondary randomisation of women testing positive for other oncogenic HPV infection (not 16/18), to either image-read cytology screening or dual-stained (DS) cytology testing with p16/Ki67 - the "HPV arm". Screening performed 5 yearly.

Image-read liquid based cytology (LBC) screening with reflex HPV triage testing for low grade smears, the "LBC arm." Screening performed 2.5 yearly.

Molecular testing for HPV with a test allowing partial genotyping for separate identification of types 16/18 from cervical samples. The technology used in this trial will be approved by the Therapeutic Goods Administration (TGA) Australia. It will identify the major HPV oncogenic genotypes in a pool and separately identify HPV 16 and 18. It will also satisfy performance criteria for relative sensitivity and specificity compared to Hybrid Capture 2 (HC2 ) as articulated by Meijer et al, 2009, Guidelines for human papillomavirus DNA test requirements for primary cervical cancer screening in women 30 years and older.

Molecular testing for HPV

The liquid based cytology (LBC) used in this trial will be will be approved by the Therapeutic Goods Administration (TGA) Australia for LBC and appropriately validated and (TGA approved) to perform human papillomavirus testing from a cytology sample.

Liquid Based Cytology

Karen Canfell, BE, D.Phil.

Marion Saville, M.B., Ch.B

Compass is a randomised controlled trial of primary HPV testing for cervical cancer screening in Australia. A pilot study involving 5,000 women was carried out in 2013-2014. The trial will involve recruiting 76,300 women from primary health clinics. Women aged 25-69, attending for cervical screening or for routine follow-up will be invited to participate in the 2-arm trial. A liquid-based cytology (LBC) sample will be taken from consenting women and sent to VCS Pathology. Women will be randomised in a 1:2 parallel group allocation to LBC and HPV arms using randomisation with the minimisation procedure, with stratification by birth cohort according to whether offered HPV vaccination in Australia's national publicly-funded HPV vaccination program (date of birth \>=July 1st 1980 and \<1st July 1980). In the LBC (active control) arm, women will undergo 2.5 yearly image read cytology screening with reflex HPV triage testing for low grade cytology. In the HPV (intervention) arm women will undergo 5 yearly HPV screening with partial genotyping enabling separate identification of HPV16 and HPV18 and referral of this group for diagnostic evaluation, and secondary randomisation of "intermediate risk" women testing positive for oncogenic HPV (but not HPV 16 or 18) to either image read LBC screening or dual-stained (DS) cytology testing with p16/Ki67. The laboratory reports issued to practitioners will specify the recommended management for women, according to study arm and test results.Participating women will be flagged and clinical outcomes will be tracked via the Compass Register. Data linkage between the Compass Register and HPV vaccination records held on the Australian Immunisation Register will be performed in order to integrate vaccination and screening histories for trial participants. Participants will be actively followed for an anticipated 5 years from the time of recruitment and the primary outcome is based on the total cumulative detection of CIN3+ after exit testing at 5 years. The anticipated study completion date of March 2027 takes into consideration the final migration of participants to the National Cancer Screening Register and allows for two years to follow-up any intermediate risk results occurring in the last of the recruited trial participants.

Compass is a randomised controlled trial of primary HPV testing for cervical cancer screening versus cytology screening in Australia. A pilot study involving 5,000 women was carried out in 2013-2014. The main trial will involve recruiting 76,300 women from primary health clinics. Women aged 25-69, attending for cervical screening or for routine follow-up will be invited to participate in the 2-arm trial. A liquid-based cytology (LBC) sample will be taken from consenting women and sent to VCS Pathology, at VCS Foundation. On receipt of a woman's first Compass sample at VCS Pathology she will be randomised in a 1:2 parallel group allocation to LBC and HPV arms using randomisation with the minimisation procedure, with stratification by birth cohort according to whether offered HPV vaccination in Australia's national publicly-funded HPV vaccination program (date of birth \>=July 1st 1980 and DOB \<1st July 1980).

The screening and management algorithms for the two study arms will be as follows:

LBC Arm: 2.5 yearly image-read cytology screening with reflex HPV triage testing for low grade cytology.

HPV Arm: 5 yearly HPV screening for potentially oncogenic types with partial genotyping enabling separate identification of HPV16 and HPV18 and referral of this group for diagnostic evaluation, and secondary randomisation of "intermediate risk" women testing positive for oncogenic HPV (but not HPV 16 or 18) to either image read LBC screening or dual-stained (DS) cytology testing with p16/Ki67.

The laboratory reports issued to practitioners will specify the recommended management for women, according to study arm and test results.

Participating women will be flagged on the Compass Register and invitation letters will be issued 3 months prior to the designated time for re-screening or follow-up. Clinical outcomes (screening test, colposcopy and histology results) will be tracked via the Compass Register. Data linkage between the Compass Register and HPV vaccination records held on the Australian Immunisation Register will be performed in order to integrate vaccination and screening histories for trial participants. Participants will be followed for an anticipated 5 years from the time of recruitment.

Previous trials in unvaccinated populations have demonstrated increased detection of CIN2+ in HPV-screened (or co-tested) women vs. cytology-alone screened women in the baseline screening round, followed by decreased rates of incident CIN3+ in HPV-screened vs. Pap screened women thereafter. This potentially reflects (i) the increased detection of disease at the CIN2 (treatment) threshold at baseline in HPV-screened women, leading to increased prevention of future CIN3 in the group of women treated for CIN2 at baseline; and (ii) the association, demonstrated in multiple cohort studies, between HPV positivity (especially for types 16/18) and the development of CIN3+ in the future. In the Compass trial, HPV-positive women without verified disease at baseline undergo increased surveillance until testing HPV negative.

A total of 36,300 women in the birth cohorts not offered vaccination and 40,000 women in the cohorts offered vaccination, who are presenting for routine screening, will be recruited, to bring the total number recruited to 76,300 (updated August 2019) (with the additional women representing those presenting for routine follow-up and those recruited for a safety monitoring sample). The sample size requirements for the trial are based on assessment of the cumulative proportion of CIN3+ (including CIN3 and invasive cervical cancer) in women who were screen-negative at baseline. A major impact of this study will be value of extended screening intervals in patients who are screen-negative at baseline. Logistically, it would be difficult to randomise patients after baseline screening and as such, the cumulative 5-year CIN3+ rates in baseline screen-negative patients may no longer be strictly comparative. However, this is a critical scientific question and so the trial is powered for this secondary outcome: the cumulative proportion of CIN3+ (including CIN3 and invasive cervical cancer) in screen-negative women, adjusted for censoring after CIN2+ treatment.

The primary outcome is based on the total cumulative detection of CIN3+. Because the primary outcome includes precancer, there remains a potential benefit from early detection in the baseline screening round, and although this benefit is not explicitly factored into the primary outcome it will be highlighted in the assessment of outcomes in baseline screen-negative women (i.e. in the analysis for Secondary Outcome 1). When assessing total cumulative rates of CIN3+, including both the baseline round and longitudinal follow-up in each arm, the follow-up duration is a critical determinant of the expected relative outcomes for CIN3+ when the two arms are compared. A second critical determinant is the disease ascertainment process at trial exit, and a consistent process using a sensitive screening test followed by equivalent referral and management processes must be performed in both arms. Therefore all women enrolled in Compass will be offered HPV exit testing at 5 years (as the standard recommendation for cervical screening in Australia from December 2017, the HPV exit test will also act as a routine cervical screening test).

A Scientific Advisory Committee will advise the investigator team on issues related to protocol, operations and any other issues brought by the investigators to the Committee. An Independent Data Safety and Monitoring Committee (IDSMC) has been configured to monitor the safety of participants in the trial.

Compass is sponsored by the VCS Foundation, a government-funded health promotion charity. The VCS have received equipment and a funding contribution for the Compass trial from Roche Molecular Systems and Ventana Inc USA.

The following technologies have been selected for use in the trial. All devices used in the trial will be listed on the Australian Register of Therapeutic Goods (ARTG) and will be used within their listed approved use. However, during the course of the trial, alternative products may potentially be used, as appropriate, if they fulfil these criteria and if they are successfully pre-qualified at the VCS in accordance with NATA laboratory requirements, and if they satisfy the Quality Assurance Processes currently being established for new technologies to be used in the Renewal National Cervical Screening Program (since alternate ARTG-listed LBC medium and HPV test technologies are available).

Specimen Collection Technology: Samples in the trial will be collected using a liquid-based sample medium. The technology to be used will be PreserveCyt/ThinPrep (Hologic Inc, Bedford MA) (included on the ARTG).

Image read LBC technology: The Hologic Thinprep Imaging (TPI) System will be used for image read analysis (included on the ARTG).

HPV DNA testing technology: Primary HPV DNA testing will be performed using the COBAS 4800 HPV Test (Roche Molecular Systems Inc., Pleasanton, CA (listed on the ARTG) and incorporating:

* Cobas 4800 System, Sample Preparation Kit: c4800 SMPL PREP
* Cobas 4800 System, Amplification/Detection Kit: c4800 HPV AMP/DET
* Cobas 4800 System, Preparation Kit: c4800 LIQ CYT
* Cobas 4800 System, Wash Buffer Kit: c4800 WB

Dual-stained cytology (DS). Analysis of dual stained cytology for p16/Ki-67 markers in the trial will involve use of the CINtec® PLUS kit (VENTANA MEDICAL SYSTEMS, INC., AZ) (this in-vitro diagnostic medical device is included on the ARTG).

Compass - Randomised Controlled Trial of Primary HPV Testing for Cervical Screening in Australia

Compass - Randomized Controlled Trial of 5-yearly Cervical Screening With Primary HPV Testing Versus Cervical Screening With 2.5-yearly Liquid Based Cytology Testing, in HPV-Unvaccinated and HPV-Vaccinated Women in Australia

The primary outcome will be cumulative CIN3+ at 5 years following a 5 year HPV exit testing round in both arms, in women randomised to the HPV arm vs. women randomised to the LBC arm, adjusted for censoring after CIN2+ treatment. For the primary outcome, intention to treat analysis will be performed with closed loop testing for non-inferiority and superiority if non-inferiority is declared. Assuming a total average CIN3+ rate in the LBC arm (across unvaccinated and vaccinated women) of 0.94%, and an absolute non-inferiority margin of 0.22%, the trial will have 78% power with 97.5% confidence to detect non-inferiority for the HPV arm, allowing for a 15% non-compliance rate.

Cumulative CIN3+ in women presenting for routine screening randomised to the HPV arm who were HPV-negative at baseline, vs. CIN3+ in those randomised to the LBC arm and who were LBC-negative at baseline, adjusted for censoring after CIN2+ treatment and stratified by recruitment group (date of birth \>=July 1st 1980 and \<1st July 1980). Intention to treat analysis will be performed with closed loop testing for non-inferiority and superiority if non-inferiority is declared.

Cumulative CIN3+ in women presenting for routine screening randomised to the HPV arm who were HPV-negative at baseline, vs. CIN3+ in those randomised to the LBC arm and who were LBC-negative at baseline and at 2.5 years, adjusted for censoring after CIN2+ treatment and stratified by recruitment group (date of birth \>=July 1st 1980 and \<1st July 1980). Per-protocol analysis will be performed in women screened and followed up within a defined tolerance period according to protocol recommendations.

Cumulative CIN2+ in women randomised to the HPV arm who were HPV-negative at baseline, vs. CIN2+ in women who were randomised to the LBC arm and were LBC-negative at baseline, adjusted for censoring after CIN2+ treatment and stratified by recruitment group (date of birth \>=July 1st 1980 and \<1st July 1980).

Cross-sectional outcomes for CIN 2+ and CIN3+ detection in each arm, stratified by recruitment group (date of birth \>=July 1st 1980 and \<1st July 1980).

CIN2+ in women randomised to HPV testing at baseline who have other HPV (not 16/18), stratified by recruitment group (date of birth \>=July 1st 1980 and \<1st July 1980).

CIN2+ and CIN3+ in women who have an abnormal test result at baseline, adjusted for censoring after CIN2+ treatment and stratified by recruitment group (date of birth \>=July 1st 1980 and \<1st July 1980).

CIN2+ and CIN3+ in women who were in follow-management for a previous abnormality at baseline, adjusted for censoring after CIN2+ treatment and stratified by recruitment group (date of birth \>=July 1st 1980 and \<1st July 1980).

Cancer Council New South Wales

VCS Foundation

Associate Professor

Vaginal Discharge

Vaginal Diseases

We enroll a total of 1,200 women, as follows,

1. 120 cases with no history or current cervical intraepithelial lesion or malignancy.
2. 180 cases with a history of abnormal Pap test including ASCUS, CIN1, or atypical glandular cell.
3. 240 cases with a history of atypical squamous cells favor HSIL, dysplasia cannot exclude HSIL, CIN2, CIN3, cervical carcinoma in situ, squamous cell carcinoma, atypical glandular cells favor neoplasm, adenocarcinoma in situ, or cervical adenocarcinoma.
4. 240 cases with current ASCUS, CIN1, or atypical glandular cell.
5. 420 cases with current abnormal Pap test as atypical squamous cells favor HSIL, dysplasia cannot exclude HSIL, CIN2, CIN3, cervical carcinoma in situ, squamous cell carcinoma, atypical glandular cells favor neoplasm, adenocarcinoma in situ, or cervical adenocarcinoma.

A device to collect exfoliative cells from vaginal fornix that can self-operated with ease and comfort.

Self sampling kit for collecting discharge from vaginal fornix

Hung-Hsueh Chou, MBBS, VS

Hygeia Touch Inc. developed a safe and comfortable vaginal self-sampling device "Hygeia Touch Self Sampling Kit for Women" to self-collect the vaginal discharge sample for high-risk Human Papillomavirus (hrHPV) detection.

This clinical trial aimed to evaluate the agreement of hrHPV detections between vaginal self-sampling using "Hygeia Touch Self Sampling Kit for Women" and physician sampling, and these results will be applied for TFDA registration approval.

Primary end-point:

1. Agreement of hr-HPV types, including types 16, 18, 31, 33, 35, 39, 45, 51, 52, 56, 58, 59, 66, and 68, between the physician-collected sample and self-collected sample
2. Agreement of the presence of hr-HPV between the physician-collected sample and self-collected sample

Secondary end-point:

1. Percentage of the valid sample between self-collected and physician-collected specimens
2. Agreement of all (N = 27) HPV types between the paired samples
3. Adverse events associated with sample collection
4. Questionnaire of the appreciation and satisfaction of using self-collecting vaginal discharge sample using "Hygeia Touch Self Sampling Kit for Women" through a short movie and a brief illustration
5. Correlation between histological diagnosis and HPV types

Two samples were collected, one by the study investigator using a cervical swab and another one by the patient using the study device immediately after viewing the instruction video and illustration. The association of the self-collected sample and the physician-collected sample was blinded to the laboratory personnel.

the specimen was marked by code which was intended to mask the sample pairing

Detection of HPV in female genital tract.

Agreement of hrHPV Type Between Self-collected Sample From Vaginal Fornix and Physician Collected Sample From the Cervical Surface

Evaluate the Agreement of High-risk Human Papillomavirus Type Between Self-collected Vaginal Discharge Sample Using "HygeiaTouch Self Sampling Kit for Woman" and Physician Collected Sample From the Cervix

Rate of the "agreement". The "agreement" is defined as either (1) presence of any high-risk HPV type in physician collected specimen, and the patient sampled specimen, or (2) absence of high-risk HPV in physician collected specimen and the patient sampled specimen.

Rate of the "agreement". The "agreement" is defined as either (1) presence of any HPV type in physician collected specimen, and the patient sampled specimen, or (2) absence of any HPV in physician collected specimen and the patient sampled specimen.

Percentage of the presence of the beta-globin gene. The ratio could be calculated between self-collected and physician-collected specimens.

The number of participants with any adverse event.

Hygeia Touch Inc.

Skin and Connective Tissue Diseases

Breast Neoplasms

Catherine WOLLJUNG-BOUR, Nurse

Madeline KETTERLIN, Nurse

Céline BOSCO, Nurse

The hypothesis of the investigators is that women don't have all the needfull knowledge to understand the importance of a regular gynaecological aftercare.

The main objective is to assess women's knowledge's about gynaecological aftercare.

The second objective is to identify barriers that prevent women of a regular gynaecological aftercare

Women's Knowledges About Gynaecological Aftercare

Women's Knowledges About Gynaecological Aftercare, Hospitalized in Maternity Service, or Consulting in Policlinic, in University Hospitals of Strasbourg

Assessment of women's knowledge of gynecological follow-up via a questionnaire. The score is calculated from the questionnaire 24 hours before the discharge of patients from the gynecology department

University Hospital, Strasbourg, France

Women aged 30-64 years who signed informed consent and comply with inclusion and exclusion criteria.

Women who signed informed consent will be screened with HPV testing.

HPV screening

Rolando Herrero, MD, PhD

HPV testing for primary cervical cancer screening of women over 30 years of age is likely to become the standard of care in the near future in many areas of the world. Its high sensitivity can significantly improve the effectiveness of screening programs and its prolonged negative predictive value can allow extension of screening intervals. However, a single HPV test has low positive predictive value and can lead to unnecessary workup and over-treatment and generate unnecessary distress. This multi-centric study will screen 50,000 women with HPV testing and compare several triage approaches that can follow HPV testing in order to make an HPV-based screening programme efficient, affordable and sustainable.

The study will be conducted in several Latin American countries. Currently, the study has started in one site in Colombia and soon another site in Mexico will start. In each participating center, women aged 30-64 years who are attending clinics for cervical screening will be invited to participate in the study. Women who agree to participate and sign the corresponding Institutional Review Board (IRB) approved consent forms will undergo a pelvic examination, and cervical cells for primary screening and triage will be collected. Recruitment specimens will be used for primary screening with an established HPV DNA test (Food and Drug Administration FDA approved). All women who are HPV-positive by the recruitment test will be referred for a standardized colposcopy examination for diagnosis. At the colposcopy visit, but before colposcopy is performed, a risk factor interview will be administered and participants will undergo visual inspection of the cervix with acetic acid (VIA) and collection of additional cervical cells and a blood specimen. The results of VIA will not be disclosed to the colposcopist. During colposcopy, the colposcopists will obtain (2-4) biopsies from any abnormally-appearing areas to ascertain neoplastic outcomes (CIN3+) and to direct treatment as required. All women who attend colposcopy will have a second round of HPV testing approximately 18 months after recruitment and those who are HPV-positive will be referred to colposcopy for final diagnosis. Data management and study supervision will be the responsibility of the International Agency for Research on Cancer (IARC) and the local Principal Investigators, most of whom are experienced HPV researchers.

The combined number of histologically-confirmed diagnoses of CIN3+, including CIN2 lesions positive for p16, (estimated n=500) will be the outcome of primary interest for evaluation of the performance of the various triage modalities. Our initial analyses will focus on comparisons of triage strategies that employ a single method: VIA, conventional/liquid-based cytology, HPV DNA genotyping, HPV RNA detection, detection of E6 proteins of high risk HPV types, or markers of HPV-induced cell-cycle alterations (e.g., p16, ki67, etc). To the extent possible, molecular testing for HPV triage will be carried out on the recruitment specimens to simulate a 'reflex testing' approach wherein screening and triage are done on the same specimen without additional visits. Subsequent analyses will consider various alternative strategies that employ more than one triage methodology; e.g., HPV DNA genotyping followed by cytology. The effectiveness and costs of each alternative strategy will be assessed under various scenarios of feasibility, cost, and effectiveness.

One dry and two liquid cervical samples will be collected at entry. Sample fate will depend on a liquid HPV test. If positive: the dry sample will be used for the E6 protein strip test, the liquid sample for liquid-based cytology and the p16/ki67 test, and 10 aliquots from the second liquid sample will be stored. If negative: the dry sample will be stored for the E6 strip test until the end of the study. Testing will be done based on evidence towards usefulness in primary screening, two aliquots from the first liquid sample will be stored and, the second liquid sample will be discharged. At initial colposcopy, a cervical sample (6 aliquots) and a 10mL blood sample (serum, plasma and buffy-coat) will be collected and stored. All samples will be used for testing of triage techniques.

Cervical Cancer Screening With Human Papillomavirus Testing

Multicentric Study of Cervical Cancer Screening and Triage With Human Papillomavirus (HPV) Testing

There will be two HPV screening rounds. Women who test negative for HPV at initial screening will finish their participation. HPV positive women will be: 1) referred to colposcopy, 2) invited for a second HPV screening round if not yet treated, and 3) referred to final colposcopy if HPV positive at second screening. Clinical management will be based on local histology.

Histology specimens will be externally reviewed by one highly experience international pathologist. If the local and external results are the same, this will become the final histology. If there is disagreement, the specimen will be sent to a third pathologist (be blinded to previous readings). The final diagnosis will then be that agreed by two pathologists (local and either external or both external). Remaining discrepancies will be solved by adjudication at a multi-headed microscope. Worst histology on review will be used to define outcome measures.

International Agency for Research on Cancer

HIV Seropositivity

Central Nervous System Depressants

All Drugs and Chemicals

Anti-Arrhythmia Agents

Channel Blockers

Anti-Infective Agents

Antineoplastic Agents

Micronutrients

Coagulants

Vitamins

Anesthetics

Lidocaine

Anesthetics, Local

Acetic Acid

Retinol acetate

Iodine

Lugol's solution

Cadexomer iodine

those who serologically tested positive for HIV

those who serologically tested negative for HIV

those with no available serological test for HIV

Cervical specimen obtained using speculum examination and cervical collection bush.

Screening

Vaginal speculum examination followed by application of 2% acetic acid and lugol's iodine with inspection with colposcope and punch biopsies taken of abnormal areas.

Colposcopy

The above (see colposcopy) is followed by local anaesthetic with two dentist's ampoules of lignocaine and large loop excision using coagulation of the abnormal area (usually 2 x 3 x 1 cm).

LLETZ

Greta Dreyer, PhD

Cathy Visser, MSc

Leon C Snyman, MMedO&G;FCOG

Greta D Dreyer, PhD

Nearly 8 000 new cervical cancer cases are diagnosed in South Africa per year; many are still undiagnosed and about 50% of diagnosed cases succumb per year. Although the current prevalence of pre-cancer cervical disease is largely unknown, data from local studies suggest regional differences and an increase in the prevalence of cytological abnormalities when compared with historical data. Low frequency in cytology screening is the primary factor attributable to development of invasive cervical cancer and almost one-third of all cervical cancer patients had previous negative cytology. Due to the low sensitivity of cytology it can be assumed that the true prevalence of pre-cancer disease is underestimated by all available data. One round of optimal cervical cytology will detect around 50% of existing pre-cancer cervical disease as identified and proven using colposcopy and directed biopsy. It is now widely accepted that primary screening with a human papilloma virus (HPV) test can improve the sensitivity of screening and that even a single round of HPV screening can rapidly reduce the incidence of invasive cervical cancer and related mortality within a few years.

South Africa has a high prevalence of HIV infection and a delay in or failure to initiate antiretroviral therapy (ART). These facts, together with the largely unscreened status of the female population and the high incidence of cervical cancer all suggest that HPV infection and precursors to cervical cancer are both unusually common among South African women. Accurate current knowledge of the performance of newer generation HPV based screening tests in HIV-infected and general female population are essential for cost-analysis and planning for national prevention and screening programs. This study will aim to demonstrate the feasibility and efficacy of new generation HPV deoxyribonucleic acid (DNA) based screening assays in a South African setting.

The investigators hypothesize that HPV testing followed by normal and special cytology tests will be a successful screening model for a South African population.

Study title	NCT ID	Conditions	Interventions	Eligibility	Organization
Can Text Reminders Improve Uptake of Cervical Screening?	NCT02363088	Cervical Carcin... Cervical Dyspla...	Neutral text me... Messenger text ... Social Norms A ... Social Norms B ... Framed Gain tex... Framed Loss tex...	24 Years - 64 Years	Imperial College Healthcare NHS Trust
Screening for HPV and Cervical Cancer in Young Women With Perinatally Acquired HIV	NCT04587050	HIV Infections Human Papilloma... Cervical Cancer	Human papilloma... Cervical cytolo... HPV serology	18 Years -	Imperial College London
Screening for HPV and Cervical Cancer in Young Women With Perinatally Acquired HIV	NCT04587050	HIV Infections Human Papilloma... Cervical Cancer	Human papilloma... Cervical cytolo... HPV serology	18 Years -	Imperial College London
Trial23 - A Method Study on Cervical Screening in Women Offered HPV-vaccination as Girls	NCT03049553	Cervical Intrae...	Cobas HPV-DNA t...	23 Years - 23 Years	University of Copenhagen
Compass - Randomised Controlled Trial of Primary HPV Testing for Cervical Screening in Australia	NCT02328872	Cancer of the C... Cervical Intrae...	Molecular testi... Liquid Based Cy...	25 Years - 69 Years	VCS Foundation
Agreement of hrHPV Type Between Self-collected Sample From Vaginal Fornix and Physician Collected Sample From the Cervical Surface	NCT04472377	Human Papilloma... Self Sampling Vaginal Dischar...	Self sampling k...	21 Years - 65 Years	Hygeia Touch Inc.
Women's Knowledges About Gynaecological Aftercare	NCT03589352	Gynecology		18 Years -	University Hospital, Strasbourg, France
Cervical Cancer Screening With Human Papillomavirus Testing	NCT01881659	CIN3 CIN2 Cervical Cancer	HPV screening	30 Years - 64 Years	International Agency for Research on Cancer
Compass - Randomised Controlled Trial of Primary HPV Testing for Cervical Screening in Australia	NCT02328872	Cancer of the C... Cervical Intrae...	Molecular testi... Liquid Based Cy...	25 Years - 69 Years	VCS Foundation
Screening Study for Cervical Pre-cancer and Cancer Prevention in South African Women.	NCT02956031	Cervical Cancer High Grade Sil CIN2	Screening Colposcopy LLETZ	25 Years - 75 Years	University of Pretoria

Spots Global Cancer Trial Database for cervical screening