Compass - Randomised Controlled Trial of Primary HPV Testing for Cervical Screening in Australia
Compass - Randomised Controlled Trial of Primary HPV Testing for Cervical Screening in Australia
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.
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.
Inclusion Criteria:

 -  Australian residents with a cervix, aged 25-69 years who are attending for routine
 cervical screening. (Note: since April 2016 recruitment has been confined to the
 younger strata, i.e. women age-eligible for HPV vaccination aged at least 25 and born
 on or after 1st July 1980, as the recruitment target of the older cohort was met).

 -  Participants may have been previously enrolled in the Compass Pilot but must have been
 discharged to routine screening. Women may also be in follow-up management for a
 previous abnormality or unsatisfactory cytology.

 Exclusion Criteria:

 -  Previous total hysterectomy (uterus and cervix).

 -  The presence of symptoms or signs for which cervical cancer must be excluded.

 -  Currently undergoing treatment for cervical cancer.

 -  Currently enrolled in the Compass Pilot Study.