Reengineering Cervical Cancer Screening for the 21st Century: Joint Action for a Novel Up-to-date and Sustainable Screening Program

NCT ID: NCT06915610

Last Updated: 2025-04-23

Basic Information

• Recruitment Status: ENROLLING_BY_INVITATION
• Clinical Phase: NA
• Total Enrollment: 5700 participants
• Study Classification: INTERVENTIONAL
• Study Start Date: 2025-04-10
• Study Completion Date: 2027-03-31

Brief Summary

Cervical cancer screening (CCS) is important to prevent and control cervical cancer (CC). In Portugal, CCS starts with the assessment of the presence of Human Papillomavirus (HPV) in cervical-vaginal samples, collected by a health professional. However, self-sampling (self-collection of vaginal samples by the participants in CCS), is being considered in several settings, aiming to improve participation in CCS, while also exploring its potential to reduce costs.

The goal of this study is to learn how self-sampling could be introduced in the CCS program in Portugal, by testing different strategies to combine the self-collection of samples with the collection of samples by a health professional, which is currently the standard of care.

Researchers will conduct a study comparing the following ways of conducting CCS:

• Sample collection by health professionals - SOC;
• Self-sampling - SS;
• Asking the participants if they prefer to collect their own samples, or to have the samples collected by a health professional, and then proceed as they prefer - CHOICE.

After assessing the adherence to CCS in each of the groups define above, the participants will be given the possibility to participate through a method different from the initially proposed or chosen, as follows:

• SOC will be complemented with invitation for SS;
• SS will be complemented with invitation for the SOC;
• CHOICE participants will be invited again to CHOICE, being given a new opportunity to choose how they prefer to be screened.

This study design allows for comparisons between these groups, to understand how using these strategies alone and complementarily works, and also for comparisons within each group, to understand how one strategy being used on the top of the previous may contribute to increase adherence to screening. The researchers will additionally collect information of the adherence to CCS in the year before the study is conducted, to be used as an additional benchmark.

For a better understanding on the potential barriers and facilitators to incorporating self-sampling in the CCS program, this study will also comprise interviews with the health professionals involved in the study, as well as with females eligible for screening who had been invited to participate.

Depending on the results of HPV testing and complementary cytological evaluations, participants may be referred for further assessment, according to the standard of care in the Portuguese National Health Service. This study will address the possibility of improving the yielding of the referral for further assessment, by testing, in parallel to the current standard of care, a method that is expected to contribute to reducing the number of referrals of false-positives.

Therefore, this study is expected to provide evidence based on different methods of assessment, showing the extent to which SS may contribute to improve adherence do CCS, and testing new methods that may reduce the referral of false-positives for further assessment.

Detailed Description

Vaccination against human papillomavirus (HPV) is highly effective and is expected to reduce substantially the burden of cervical cancer (CC), but cervical cancer screening (CCS) remains necessary for females who were not covered by the vaccination plans, those who remain non-adherent to vaccination, and for early detection of the cervical lesions not prevented by the vaccine. However, the sustainability of CCS programs will be challenged by the expectedly dramatic reduction in frequency of cervical precancerous lesions. A paradigm shift for CCS programs, towards a substantial improvement of efficiency, and ability to reach those more in need of screening, is essential to maintain their cost-effectiveness. We will implement a state-of-the-art approach to population-based CCS, with potential to broaden screening coverage, lower costs and increase efficiency, compared to the current standard of care, by including self-sampling and state-of-the-art molecular methods for triage.

The investigation is based on a pragmatic parallel cluster randomized controlled trial (RCT), including nearly 6,000 participants (2,000 in each arm), implemented at Local Health Unit Gaia e Espinho (ULSGE) in collaboration with the Research Center of Portuguese Institute of Oncology of Porto (CI-IPOP). Family doctors will be randomly allocated to one of the three study arms, and all females from their lists of patients who are eligible for screening, as defined by the current guidelines for the organized screening program, will be invited.

CCS screening will be based on high-risk HPV (HrHPV) testing, according to the Portuguese CCS program. Referral to colposcopy will follow the standard of care (based on HrHPV and liquid based cytology [LBC]), regardless of the strategy used for CCS; females testing non-HPV16/18 HrHPV-positive in self-sampling will undergo a new sample collection by a health professional, so that a LBC evaluation can be performed to support the decision of referral to colposcopy, as defined by the standard of care. Deoxyribonucleic acid (DNA) methylation will be conducted in parallel.

Intention to treat analysis will be the primary strategy of analysis for comparison between the groups, based on crude comparisons, or controlling for confounding through multivariable binary logistic regression, when an imbalance between the distribution of confounders between study arms is observed. Methylation accuracy estimates will be computed with 95% confidence intervals. The cutoffs for each biomarker will be those defined in our previous studies.

The sample size was defined to address the primary objectives that involve the comparison of study arms, with a 1:1:1 allocation ratio, considering a statistical power of 90% and a design effect of 1.1 (assuming an average cluster size of 50 and an intracluster correlation coefficient of 0.002). For a non-inferiority hypothesis, considering an alpha (one-sided) of 5% and assuming an adherence of 50% and a non-inferiority margin of 5%, a sample of 5,700 females is needed.

Family doctors from a total of 10 to 20 primary health care units are expected to be enrolled to achieve the sample size needed, depending on the adherence of the medical doctors and the number of eligible females in their lists of patients.

The study will be initially implemented in 2 to 3 primary health care units, to achieve an expected sample of at least 600 participants, for piloting and adjustment of the overall sample size based on the empirical data on the proportions of adherent females in each arm.

The assessment of the adherence according to the different strategies to incorporate self-sampling in the CCS program will be complemented by a qualitative study to assess barriers and facilitators to the implementation of CCS and adherence to CCS in different formats. This will involve the family doctors who have collaborated in the study and females selected among those invited for screening in the different study arms, based on focus groups and individual semi-structured interviews.

Also, a quantitative assessment of the invited females experiences with CCS within the study and determinants of adherence will be conducted on a subsample including approximately 10% of the invited females, who will be asked to answer a structured questionnaire.

Conditions

Cervical Cancer Screening

Study Design

• Allocation Method: RANDOMIZED
• Intervention Model: PARALLEL
• Primary Study Purpose: SCREENING
• Blinding Strategy: NONE

Study Groups

Standard of care (followed by self-sampling for the non-adherent) - SOC+SS

CCS screening according to the standard of care (sample collected by a health professional). Participants not adhering will be subsequently invited to perform self-sampling for screening.

When considering only the initial use of the SOC for CCS, this corresponds to arm type "active comparator". When considering the use of the SOC, followed by SS for participants not adhering to CCS according to the SOC, this corresponds to arm type "experimental".

Group Type: OTHER

Invitation of all participants to CCS according to the standard of care (active comparator)

Intervention Type: OTHER

Invitation of all participants to CCS according to the standard of care

Invitation of all participants to CCS according to the standard of care, followed by invitation of those non-adherent to CCS through self-sampling

Intervention Type: OTHER

Participants not adhering to CCS after the first invitation (SOC) will be additionally invited for CCS screening through self-sampling (as in SS)

Self-sampling (followed by the standard of care for the non-adherent) - SS+SOC

CCS screening by self-sampling. Participants not adhering will be subsequently invited for screening according to the standard of care (sample collected by a health professional).

Group Type: EXPERIMENTAL

Invitation of all participants to CCS through self-sampling

Intervention Type: OTHER

A self-sampling kit mailed to the participants, with a prepaid envelope for returning them after sample collection. Participants may also return the kits by depositing them in a container that will be available in their Health Care Center.

The invitation for CCS through self-sampling is accompanied by written instructions, SMS reminders and navigation support (dedicated telephone line, WhatsApp, website)

Invitation of all participants to CCS through self-sampling, followed by invitation of those non-adherent to CCS according to the standard of care

Intervention Type: OTHER

Participants not adhering to CCS after the first invitation for self-sampling (SS) will be additionally invited for CCS screening according to the standard of care (as in SOC)

Choice (2x) between CCS through sample collected by health professional and self sampling - CHOICEx2

Participants will be asked for their preference for CCS through sample collected by a health professional or by self-sampling, and will undergo CCS accordingly. Those not adhering will be invited again to choose between one of the two methods of CCS.

Group Type: EXPERIMENTAL

Invitation of all participants to CCS, asking them to choose between self-sampling and the standard of care

Intervention Type: OTHER

In a telephone contact, prompted by an SMS, participants will be given the opportunity to schedule CCS according to the standard of care or to ask for a self-sampling kit to be mailed to them. Depending on their choice, the procedure will be similar to what is described for arm SOC or for arm SS, as applicable

Invitation of all participants to CCS, asking them to choose between self-sampling and the standard of care; this mode of invitation is repeated when participants do not adhere to the first invitation

Intervention Type: OTHER

Participants not adhering to CCS after a first invitation for screening through a method of their choice (CHOICE) will be invited again, also being given the opportunity to choose between the standard of care or self-sampling (as in the first CHOICE invitation). Depending on the participants' choice, the procedure will be similar to what is described for arm SOC or for arm SS, as applicable, both in the first and in the second CHOICE invitations

Interventions

Invitation of all participants to CCS according to the standard of care (active comparator)

Invitation of all participants to CCS according to the standard of care

Intervention Type: OTHER

Invitation of all participants to CCS through self-sampling

A self-sampling kit mailed to the participants, with a prepaid envelope for returning them after sample collection. Participants may also return the kits by depositing them in a container that will be available in their Health Care Center.

The invitation for CCS through self-sampling is accompanied by written instructions, SMS reminders and navigation support (dedicated telephone line, WhatsApp, website)

Intervention Type: OTHER

Invitation of all participants to CCS, asking them to choose between self-sampling and the standard of care

In a telephone contact, prompted by an SMS, participants will be given the opportunity to schedule CCS according to the standard of care or to ask for a self-sampling kit to be mailed to them. Depending on their choice, the procedure will be similar to what is described for arm SOC or for arm SS, as applicable

Intervention Type: OTHER

Invitation of all participants to CCS according to the standard of care, followed by invitation of those non-adherent to CCS through self-sampling

Participants not adhering to CCS after the first invitation (SOC) will be additionally invited for CCS screening through self-sampling (as in SS)

Intervention Type: OTHER

Invitation of all participants to CCS through self-sampling, followed by invitation of those non-adherent to CCS according to the standard of care

Participants not adhering to CCS after the first invitation for self-sampling (SS) will be additionally invited for CCS screening according to the standard of care (as in SOC)

Intervention Type: OTHER

Invitation of all participants to CCS, asking them to choose between self-sampling and the standard of care; this mode of invitation is repeated when participants do not adhere to the first invitation

Participants not adhering to CCS after a first invitation for screening through a method of their choice (CHOICE) will be invited again, also being given the opportunity to choose between the standard of care or self-sampling (as in the first CHOICE invitation). Depending on the participants' choice, the procedure will be similar to what is described for arm SOC or for arm SS, as applicable, both in the first and in the second CHOICE invitations

Intervention Type: OTHER

Other Intervention Names

SOC; SS; Evalyn Brush; CHOICE; SOC+SS; SS+SOC; CHOICEx2

Eligibility Criteria

Inclusion Criteria

• Females fulfilling the eligibility criteria for CCS, as defined by the current guidelines for the organized screening program in Portugal.

Exclusion Criteria

• Not having a Portuguese mobile phone number or a Portuguese address available in the clinical/administrative records of the primary healthcare units;

• Minimum Eligible Age: 30 Years
• Maximum Eligible Age: 69 Years
• Eligible Sex: FEMALE
• Accepts Healthy Volunteers: Yes

Sponsors

Instituto Portugues de Oncologia, Francisco Gentil, Porto

OTHER

Sponsor Role: collaborator

Universidade do Porto

OTHER

Sponsor Role: collaborator

Unidade Local de Saude de Gaia e Espinho EPE

OTHER

Sponsor Role: collaborator

Instituto de Saude Publica da Universidade do Porto

OTHER

Sponsor Role: lead

Responsible Party

Nuno Lunet

Professor

Responsibility Role: PRINCIPAL_INVESTIGATOR

Principal Investigators

Nuno Lunet, PhD

Role: PRINCIPAL_INVESTIGATOR

Universidade do Porto

Locations

Unidade Local de Saúde Gaia e Espinho

Vila Nova de Gaia, , Portugal

Countries

Portugal

Other Identifiers

MPr-2023-12-15422

Identifier Type: -

Identifier Source: org_study_id