HPV FOCAL study: human papillomavirus testing for cervical cancer screening

ISRCTN	ISRCTN79347302
DOI	https://doi.org/10.1186/ISRCTN79347302
ClinicalTrials.gov (NCT)	NCT00461760
Protocol serial number	MCT-82072
Sponsor	Provincial Health Services Authority (Canada)
Funder	Canadian Institutes of Health Research (ref: MCT-82072)

Submission date: 20/04/2007
Registration date: 20/04/2007
Last edited: 11/10/2021

Recruitment status: No longer recruiting
Overall study status: Completed
Condition category: Cancer

Prospectively registered

Protocol

Statistical analysis plan

Results

Individual participant data

Plain English summary of protocol

Background and study aims
Cervical cancer is a type of cancer that develops in a woman's cervix (the entrance to the womb from the vagina). Almost all cases of cervical cancer are caused by the human papilloma virus (HPV). The aim of this study is to evaluate primary HPV testing for cervical cancer screening in an organized program setting in Canada.

Who can participate?
Women aged 25 to 65 attending a collaborating BC healthcare provider for regular cervical cancer screening (pap tests)

What does the study involve?
Participants have a cervical sample obtained from their usual health care provider. Upon receipt at the lab, the cervical sample (liquid based collection device) is randomly allocated to either HPV testing or cytology testing (Pap test, to detect abnormal cells that may develop into cancer if left untreated). Participants with negative results are recalled at either 2 years or 4 years after their first sample. Participants with positive results are managed according to a specific study protocol. The incidence of cervical cancer is measured after four years.

What are the possible benefits and risks of participating?
Participants have access to close monitoring and enhanced screening. Some participants may be recommended for colposcopies they would not have received outside of the study setting.

Where is the study run from?
BC Cancer (Canada)

When is the study starting and how long is it expected to run for?
August 2007 to December 2014

Who is funding the study?
Canadian Institutes of Health Research (Canada)

Who is the main contact?
1. Dr Andrew J Coldman (scientific)
acoldman@bccancer.bc.ca
2. Ms Laurie Smith (public)
lsmith3@bccancer.bc.ca

Contact information

Dr Andrew J Coldman
Scientific

BC Cancer
711-750 West Broadway
Vancouver
V5Z 1G1
Canada

Phone	+1 (0)604 877 6000 x4829
Email	acoldman@bccancer.bc.ca

Ms Laurie Smith
Public

BC Cancer
711-750 West Broadway
Vancouver
V5Z 1H6
Canada

Phone	+1 (0)604 877 6098 ext. 4829
Email	lsmith3@bccancer.bc.ca

Study information

Primary study design	Interventional
Study design	Multicentre three-arm randomised parallel-trial on diagnostic strategy with data analyst blinding
Secondary study design	Randomised controlled trial
Study type	Participant information sheet
Scientific title	A multicentre randomised controlled parallel group evaluation of Human PapillomaVirus testing for cervical cancer screening
Study acronym	HPV FOCAL
Study objectives	1. Establish efficacy of human papillomavirus (HPV) testing as stand alone screening test with cytology triage of HPV positive women 2. Establish an appropriate screening interval for HPV negative women 3. Determine cost-effectiveness of HPV testing as a primary screening test
Ethics approval(s)	Research Ethics Board of the University of British Columbia-British Columbia Cancer Agency, 03/04/2007, ref: H06-04032
Health condition(s) or problem(s) studied	Human papillomavirus (HPV), cervical cancer
Intervention	1. HPV testing two-year safety check arm - liquid based cytology (LBC) sample tested only for HPV: Those who are HPV negative will be screened again in two years for their exit screen, only with cytology so the results correlate with women in the control arm. Those who are HPV positive on the initial screening test will be managed the same way as HPV positive women in the four-year intervention arm. 2. HPV testing four-year intervention arm - 24. a.2.d. experimental intervention dose, duration, etc - LBC sample will only be tested for HPV: HPV negatives will have their exit screen at four years (or earlier if deemed by Data Safety and Monitoring Committee) when they will be screened with HPV and cytology testing and those positive on either test referred for Colposcopy. HPV positive on their initial screen will have the residual of that specimen analysed with cytology. Initial information at time of registration: a. If cytology negative they will be recalled at six month intervals for HPV/cytology testing and referred for colposcopy if greater than or equal to abnormal squamous cells of undetermined significance (ASCUS-US) at any recall or persistently HPV positive after three recalls Amended as of 12/03/2018: 2. a: If cytology negative they will be recalled at twelve month intervals for HPV/cytology testing and referred for colposcopy if greater than or equal to abnormal squamous cells of undetermined significance (ASCUS-US) at any recall or persistently HPV positive b. If cytology is greater than or equal to ASCUS-US they will be immediately referred for colposcopy and managed according to those results. Initial information at time of registration: 3. Control arm - Conventional cytology with liquid based cytology - 24. b.1.cd. control intervention dose, duration, etc: Liquid based cytology sample processed for cytology and followed according to existing provincial guidelines. Recalled again at two years for their second routine screen and at four years for their exit screen where they will be screened with cytology and HPV testing. Amended as of 19/03/2009: 3. Control arm - Conventional cytology with liquid based cytology - On the basis of this result women will be managed as follows: Within normal limits (negative results): Recalled for their next routine screen at 2 years, where the sample will undergo cytology testing. If negative again at the 2 year screen, recalled, for the exit screen at 4 years. At the 4 year exit screen, the sample obtained will undergo both HPV and cytology testing with those positive on either test being referred for colposcopy and then treated based on the colposcopy results. ASC-H or greater than LSIL (12/03/2018: changed to greater than or equal to LSIL): (at recruitment visit or at the 2 year screen) will receive immediate colposcopy and treated based on the colposcopy results. ASC-US: (at recruitment visit or at the 2 year screen) the residual of the specimen collected will undergo HPV testing. Follow-up based on the result of the HPV test: a. HPV-positive: referred for immediate colposcopy and treated based on the colposcopy results b. HPV-negative: recalled for repeat cytology testing in 12 months. If greater than or equal to ASC-US, referred for colposcopy and treated based on the colposcopy results. If cytology negative they will be returned to the routine screening pool for this arm. Added 10/01/2011: Recruitment to the safety arm will terminate 31/12/2010 and from that point forward, women will be randomized 1:1 into the cytology or intervention arms only. A total of ~28,000 women (11,000 each in the Control and Intervention arms respectively, and ~6,000 in the Safety arm) will be enrolled in the FOCAL trial. Added 12/03/2018: (Ethics board approved amendment 2011): After review and modifications to safety analysis plan, the overall sample size calculation was revised. Revising this calculation and using an 80% power threshold for the comparisons originally included, indicates that a sample size of ~9,140 subjects in the cytology and intervention arms is appropriate.
Intervention type	Other
Primary outcome measure(s)	Current primary outcome measures as of 12/03/2018: 1. CIN grade 3 or greater (CIN3+) detected over the four years post recruitment in the control and intervention arms evaluated and compared as a surrogate marker for estimating reductions in incidence of cervical cancer, measured at four years Previous primary outcome measures: 1. Histologically confirmed cervical intraepithelial neoplasia (CIN) greater than or equal to grade two detected at two years in both the control and safety-check arms 2. CIN grade three (CIN3) or greater detected over the four years post recruitment in the control and intervention arms evaluated and compared as a surrogate marker for estimating reductions in incidence of cervical cancer, measured at four years 3. Detection of histologically confirmed greater than or equal to CIN3 in the participants allocated to six month re-testing, measured at two years 4. Total estimated cost per woman screened and total estimated cost per quality-adjusted life-year gained for each technology, measured at four years
Key secondary outcome measure(s)	Current secondary outcome measures: 1. Histologically confirmed cervical intraepithelial neoplasia grade 2 or greater (CIN2+) two detected at two years in both the control and safety-check arms 2. CIN2+ detected in the control and intervention arms over the four years post recruitment 3. Clearance of HPV infection in women who are HPV positive at recruitment, measured at two and four years 4. Detection of histologically confirmed greater than or equal to CIN3 in the participants allocated to 12 month re-testing, measured at two years 5. Evaluation of the impact of primary HPV testing on colposcopy services through evaluation of colposcopy referral rates in each arm through the trial follow-up period 6. Total estimated cost per woman screened and total estimated cost per quality-adjusted life-year gained for each technology, measured at four years Previous secondary outcome measures: Clearance of HPV infection in women who are HPV positive at recruitment, measured at two and four years
Completion date	31/12/2014

Eligibility

Participant type(s)	Patient
Age group	Adult
Sex	Female
Target sample size at registration	28000
Key inclusion criteria	Current information as of 04/11/2008: 1. Women aged 25 to 65 years 2. Registered with MSP 3. Attending a collaborating BC healthcare provider for regular cervical cancer screening (pap tests) Initial information at time of registration: 1. Women aged 25 to 65 years 2. British Columbia residents 3. Eligible for routine cervical screening
Key exclusion criteria	Current information as of 01/12/2009 (effective 25/11/2009): 1. Pap smear less than one year ago 2. Pregnant (at time of initial sample) 3. History of moderate to severe cervical intraepithelial neoplasia (greater than CIN2) requiring treatment less than 5 years ago 4. History of invasive cervical cancer at any time 5. Complete hysterectomy with cervix removal 6. Human immunodeficiency virus (HIV) positive or receiving immunosuppressive treatments 7. Unable or unwilling to sign the Information and Consent form Information as of 04/11/2008: 1. Pap smear less than one year ago 2. Pregnant 3. History of moderate to severe cervical intraepithelial neoplasia (greater than CIN2) requiring treatment less than 5 years ago 4. History of cervical cancer at any time 5. Complete hysterectomy with cervix removal 6. Human immunodeficiency virus (HIV) positive or receiving immunosuppressive treatments 7. Received HPV vaccination 8. Unable or unwilling to sign the Information and Consent form Initial information at time of registration: 1. Pregnant 2. History of cervical cancer 3. Hysterectomy 4. Human immunodeficiency virus (HIV) positive 5. Unable to give informed consent
Date of first enrolment	01/01/2008
Date of final enrolment	30/05/2012

Locations

Countries of recruitment

Canada

Study participating centres

BC Cancer

750 West Broadway
Vancouver
V5Z 4G8
Canada

Cervical Cancer Screening Laboratory

686 West Broadway
Vancouver
-
Canada

BC Centre for Disease Control Public Health Laboratory

655 West 12th Ave
Vancouver
V5Z 4R4
Canada

BC Cancer Pathology Laboratory

600 West 10th Avenue
Vancouver
-
Canada

Royal Jubilee Pathology Laboratory

1952 Bay St.
Victoria
-
Canada

Results and Publications

Individual participant data (IPD) Intention to share	No
IPD sharing plan summary	Data sharing statement to be made available at a later date
IPD sharing plan	The data sharing plans for the current study are unknown and will be made available at a later date.

Study outputs

Output type	Details	Date created	Date added	Peer reviewed?	Patient-facing?
Results article	preliminary results	24/03/2010		Yes	No
Results article	results	16/12/2015		Yes	No
Results article	results	03/07/2018		Yes	No
Results article		07/10/2021	11/10/2021	Yes	No
Participant information sheet	Participant information sheet	11/11/2025	11/11/2025	No	Yes
Study website	Study website	11/11/2025	11/11/2025	No	Yes

Editorial Notes

11/10/2021: Publication reference and ClinicalTrials.gov number added.
05/07/2018: Publication reference added.
11/04/2018: Plain English summary, recruitment dates, trial participating centres, publication and dissemination plan and IPD sharing statement were added,
12/03/2018: Contact details, interventions, outcome measures updated.
01/09/2016: Publication reference added.
10/01/2011: The target number of participants was changed from 33,000 to ~28,000.