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

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Brief Title

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

Official Title

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

Brief Summary

      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.
    

Detailed Description

      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.
    


Study Type

Interventional


Primary Outcome

Cumulative CIN3+ (Cervical Intraepithelial Neoplasia Grade 3 or invasive cervical cancer) (ITT)

Secondary Outcome

 Cumulative CIN3+ in baseline screen-negative women (ITT)

Condition

Cancer of the Cervix

Intervention

Molecular testing for HPV

Study Arms / Comparison Groups

 Intervention (HPV Arm)
Description:  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.

Publications

* Includes publications given by the data provider as well as publications identified by National Clinical Trials Identifier (NCT ID) in Medline.

Recruitment Information


Recruitment Status

Device

Estimated Enrollment

76181

Start Date

January 2015

Completion Date

December 2023

Primary Completion Date

December 2022

Eligibility Criteria

        Inclusion Criteria:

          -  Australian female residents 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.
      

Gender

Female

Ages

25 Years - 69 Years

Accepts Healthy Volunteers

Accepts Healthy Volunteers

Contacts

Karen Canfell, BE, D.Phil., , 

Location Countries

Australia

Location Countries

Australia

Administrative Informations


NCT ID

NCT02328872

Organization ID

Exec-PP-12


Responsible Party

Principal Investigator

Study Sponsor

VCS Foundation

Collaborators

 Cancer Council New South Wales

Study Sponsor

Karen Canfell, BE, D.Phil., Principal Investigator, Cancer Council New South Wales


Verification Date

January 2020