Clinical trial NCT06915610: Reengineering Cervical Cancer Screening for the 21st Century: Joint Action for a Novel Up-to-date and Sustainable Screening Program
Official title: Reengineering Cervical Cancer Screening for the 21st Century: Joint Action for a Novel Up-to-date and Sustainable Screening Program
Study type: INTERVENTIONAL
Overall status: ENROLLING_BY_INVITATION
Phase: NA
Conditions: Cervical Cancer Screening
Keywords: Cervical cancer
Human papillomavirus
Self-sampling
DNA methylation
Lead sponsor: Instituto de Saude Publica da Universidade do Porto
Sponsor class: OTHER
Collaborators: name: Instituto Portugues de Oncologia, Francisco Gentil, Porto
name: Universidade do Porto
name: Unidade Local de Saude de Gaia e Espinho EPE
First posted: 2025-04-08
Enrollment: 5700
Sex: FEMALE
Minimum age (years): 30
Maximum age (years): 69
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: yes
Allocation: RANDOMIZED
Intervention model: PARALLEL
Intervention model description: Within each group, participants will be initially invited for CCS though one of the methods under evaluation, and those not adhering will be invited again for CCS through another method. This design will allow for between-group comparisons, both after the first invitation and considering the two invitations, as well as within-group comparisons to assess the extent to which the second (complementary) invitation may contribute to improve participation in CCS. Additionally, data on the participation in CCS in the same settings in the previous years will be retrospectively collected, allowing further ("before-after") comparisons within each group.

A qualitative study will be conducted involving medical doctors and females invited for CCS within the study to assess barriers and facilitators to CCS implementation and participation.

An observational design nested within the RCT will be used to assess the experience of females invited for CCS, and determinants of adherence.
Primary purpose: SCREENING

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.

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;
* Any of the exclusion criteria for CCS, as defined by the current guidelines for the organized screening program in Portugal.

Primary outcomes:
measure: Adherence to screening, after the first invitation for CCS in the study
timeFrame: 45 days after first scheduling/invitation
measure: Adherence to CCS, after two invitations for screening in the study
timeFrame: 45 days after first scheduling/invitation or 45 days after the second scheduling/invitation (for those not adhering to the first scheduling/invitation within 45 days)
measure: Performance of DNA methylation markers for high-grade squamous intraepithelial lesions or worse (HSIL+) detection
timeFrame: 45 days after cytological or histological results, as applicable
Secondary outcomes:
measure: Identification of barriers and facilitators to the implementation and participation in CCS
timeFrame: 90 days after the last invitation for CCS in the study
measure: Proportion of HPV infection, overall and for each genotype tested
timeFrame: 45 days after first scheduling/invitation or 45 days after the second scheduling/invitation (for those not adhering to the first scheduling/invitation within 45 days)
measure: Adherence to follow-up appointments (%), overall and among participants referred for follow-up
timeFrame: 45 days after the appointment date
measure: Variation in adherence and HPV test result outcomes between the first and the second invitation for screening
timeFrame: 45 days after first scheduling/invitation or 45 days after the second scheduling/invitation (for those not adhering to the first scheduling/invitation within 45 days)
measure: Variation in adherence from the previous year to the study period
timeFrame: 45 days after first scheduling/invitation or 45 days after the second scheduling/invitation (for those not adhering to the first scheduling/invitation within 45 days)
measure: Subgroup analyses of all comparisons of adherence between groups
timeFrame: 45 days after first scheduling/invitation or 45 days after the second scheduling/invitation (for those not adhering to the first scheduling/invitation within 45 days)
measure: Subgroup analyses of DNA methylation accuracy outcomes, according to the adherence to self-sampling and to the standard of care
timeFrame: 45 days after cytological or histological results, as applicable
measure: Characterization of the experience with CCS and determinants of adherence
timeFrame: 120 days after the last invitation for CCS in the study
Other outcomes:
measure: Process indicators
timeFrame: Up to 45 days after first scheduling/invitation or up to 45 days after the second scheduling/invitation (for those not adhering to the first scheduling/invitation within 45 days)
Locations:
city: Vila Nova de Gaia
country: Portugal
facility: Unidade Local de Saúde Gaia e Espinho
Study officials:
affiliation: Universidade do Porto
name: Nuno Lunet, PhD
role: PRINCIPAL_INVESTIGATOR
References: