Community-based intervention for cervical cancer screening uptake in a semi-urban area of Pokhara Metropolitan, Nepal (COBIN-C): study protocol for a cluster-randomized controlled trial

Background Previous studies suggest that health intervention designed to increase cervical cancer screening has been effective to reduce cervical cancer incidence and mortality. The aim of this study is to determine the effect of a home-based health education intervention for increasing cervical cancer screening uptake delivered by trained female community health volunteers (FCHVs), a category of community health worker in Nepal. Methods A community-based, open-label, two-armed, cluster-randomized trial [seven clusters (geographical wards) randomized for the intervention, and seven for the control arm]. The participants are recruited from a population-based survey with a sample size of 884. Based on population proportion size, 277 women will be recruited for the intervention group and 413 women recruited for the control group. A 12-month community-based health education intervention will be administered mobilizing the FCHVs, based on the Health Belief Model. The primary outcome measure of the study will be the difference in percentage of cervical cancer screening uptake between the two study arms. The primary outcomes will be modeled by using mixed-effect logistic regression analysis. Discussion COBIN-C is the first study investigating the effect of a community-based health education intervention by FCHVs on increasing cervical cancer screening uptake among women in Nepal. The purpose of this study is to develop and implement a home-based, culturally sensitive program to increase cervical cancer screening coverage at the community level. Trial registration ClinicalTrials.gov NCT03808064. Registered on January 14, 2019. Supplementary Information The online version contains supplementary material available at 10.1186/s13063-021-05049-3.


Background
Cervical cancer is a common cancer among women in most low-and middle-income countries (LMICs) in Asia, Africa, and Latin America [1]. It is the major cause of cancer deaths among women in Nepal with an estimated 2942 new cases and 1928 deaths in 2018 [1]. Screening is one of the most effective tools for early diagnosis, prevention, and treatment [2,3]. However, there are very limited tools and skilled health professionals available for cervical cancer screening in many LMICs, including Nepal. The World Health Organization (WHO) and the Alliance for Cervical Cancer Prevention (ACCP) recommend that countries, areas, or institutions seeking to initiate or strengthen cervical cancer screening programs should consider introducing or expanding visual inspection with acetic acid (VIA) until more appropriate and affordable HPV-based tests become available [4,5]. A single-visit approach with VIA and cryotherapy has been shown to be a safe, acceptable, feasible and is a potentially efficient method of cervical cancer prevention in Nepal [6]. National guidelines for the prevention and screening of cervical cancer includes VIA as a screening method for cervical cancer [7]. Studies reveal that participation of Nepalese women for cervical cancer screening is still low [2.8% (25-64 years); 1.5% (15-49 years); 5.4% (30-65 years)] [8][9][10]. Thus, there is a need for appropriate, cost-effective, and sustainable interventions to increase VIA screening uptake at the primary health care level across Nepal.
Studies suggest that mobilizing lay health workers and empowering them with integrated training could contribute in expansion of the knowledge base on non-communicable diseases (NCDs) at the community level and harmonize the community-based interventions [11][12][13]. In Nepal, female community health volunteers (FCHVs) have carried out community-based public health initiatives for more than 25 years and are willing to contribute to help mitigate NCDs [14]. FCHVs, a category of community health workers in Nepal, are married women, locally selected and trained through the Ministry of Health and Population. Previous studies demonstrated that FCHVs are able to screen for diabetes and hypertension: this has provided a favorable platform to explore the possible roles of FCHVs for increasing cervical cancer screening uptake [15,16].
Mobilizing FCHVs to educate women and encourage them to participate in cervical cancer screening, and thus strengthening grass root level primary health provision, could be an acceptable and culturally appropriate intervention, which needs to be tested. Furthermore, it may contribute in the implementation of the National Cervical Cancer Screening and Prevention policy and ultimately help to reduce cervical cancer mortality in Nepal. The health promotion package will be a simple, feasible and effective approach.
In our study, we will conduct a community based cluster-randomized controlled trial (cRCT) to explore the roles of FCHVs in educating and empowering women through home visits to increase the uptake of VIA screening. Therefore, the primary outcome of the study is to increase the cervical cancer-screening uptake in the study area.

Methods
This manuscript adheres to the Consolidated Standards of Reporting Trials (CONSORT) 2010 statement: extension to cRCT [17].

Study design and setting
The proposed trial is a community-based, 12-month, open label, two-arm cRCT with an equal allocation of clusters (geographical wards) between intervention and control arms in a semi-urban area of Pokhara Metropolitan city (former Lekhnath municipality, administratively divided in to 15 wards). It is one of the two areas where the Cervical Cancer Screening and Prevention (CCSP) pilot program was first initiated in Nepal. The total population of Lekhnath municipality is 59,498 (female 32,104 and male 27,394) with the total number of households being 14,958 as per the 2011 census [18]. Each ward will be considered as one cluster. Although the study area is composed of 15 clusters, only 14 will be selected for the cluster randomization (one cluster that is comparatively different from others in sociodemography and health service availability is excluded). Allocation of the clusters into intervention and control arms is described below. The study area is limited to health services comprising one recently upgraded 25bedded hospital from a primary health care center, three health posts, and six urban health care centers. According to the District Public Health Office, Kaski in 2018, there were 123 FCHVs in the municipality.

Participants
The populations targeted in our study area are women aged 30-60 years (the age range recommended for VIA screening in Nepal), listed in the Community-Based Intervention for Non-communicable diseases study for hypertension (COBIN-H) [7,16]. We will invite all the selected women participants for a baseline survey. During the baseline survey, knowledge, attitude, and screening practice on cervical cancer will be obtained and eligible women will be invited to participate in the trial. The flow of trial participants is shown in Fig. 1, which includes the number of participants eligible, surveyed, excluded, recruited, randomized, and analyzed for the primary outcome. The SPIRIT checklist for this trial is provided as an Additional file 1.

Recruitment
A sampling framework was adopted from the COBIN-H trial that has taken a population framework of all eligible participants from the voter list prepared by the Election Commission in 2017 [16]. As of 31 December 2018, all the women of age group 30-60 years were included in the study. Trained women public health professionals (data enumerators) will carry out a baseline survey. The data enumerators will receive 4 days of intensive training before data collection. The survey tool is adapted from a joint survey report of Family Health Division of Nepal's Ministry of Health and United Nations Population Fund (UNFPA) [8,[19][20][21]. It includes questions on survey information, consent, socio-demographic information, questions related to sexual and reproductive health, health-seeking behavior, knowledge, attitude and cervical cancer screening practice, and sign and symptoms. The questionnaire was modified as per the Nepalese settings, translated to the Nepali language and back to English to ensure content validity. Baseline data will be used for possible confounder adjustment and stratification by effect modifiers. The data enumerators will identify eligible participants, ask about their willingness to participate in the cRCT, receive informed consent, and recruit in the trial. The required number of participants will be randomly selected from those willing to participate in the cRCT: FCHVs will visit each household, meet the selected participant, and obtain consent to participate in the trial.

Randomization
Clusters will be randomly assigned to intervention and control areas using a 1:1 allocation ratio. Randomization will be done before the participants are recruited. Research teams responsible for identifying potential participants, obtaining consent, and recruiting trial participants will be blinded to the participants' allocation status. The following steps will be taken to avoid selection bias during random allocation: (a) clusters will be randomized only after the baseline survey, (b) clusters will not be withdrawn from or added to the study, and (c) a statistician from abroad who is not familiar to the study will randomize the clusters.

Inclusion and exclusion criteria
Women aged 30-60 years who are listed in COBIN-H and who indicated they planned to reside in a cluster in the study area for at least the next 12 months are eligible for inclusion in the baseline survey and for the invitation to participate in the study. Women who are severely ill, pregnant, less than 6 weeks after delivery, who are already diagnosed with cervical pre-cancer and cancer, with a history of total hysterectomy, as well as those who decline to participate in the study or unable to complete the interview, will be excluded from the study.

Primary and secondary outcomes
The primary outcome of the study is percentage change in cervical cancer screening uptake from baseline to follow-up in the intervention group compared to the control group in a 12-month home-based health education intervention. The baseline survey will be conducted before the cluster randomization, and a follow-up survey of similar method will be conducted after 12-month intervention. The response of each participant for cervical cancer screening in the baseline survey and the follow-up survey will be compared to evaluate the percentage. In addition, FCHV will provide a referral slip to the participants in the intervention group (keeping a copy of the referral slip to submit to the field supervisor) during the home visit, which they take with them and submit to the health facility for VIA screening. The referral slip contains study code, name, age, address, and signature of both FCHV and the participant. FCHV will inform the participants about the health facility where the services are freely available. The key health personnel providing the VIA screening services are oriented about the study. Furthermore, confidentiality about the participants' information will be maintained throughout the intervention. The field supervisor will collect the referral slip to confirm that the participants have received VIA screening and results from all the health facilities of the intervention ward as a reference to the participants' response.
The secondary outcomes of the study are change in the level of knowledge and awareness among women on cervical cancer screening and prevention. The response of each participant for knowledge and awareness on cervical cancer screening in the baseline survey and the follow-up survey will be compared to evaluate the change using the validated questionnaire [19,20].

Sample size calculation
The sample size for the baseline survey is calculated based on the method suggested by the WHO STEPWI SE Approach [22]: for our study, we calculate 884 participants with 20% non-response. A systematic random sampling method will be performed as a sampling technique. For the power calculation, we took reference from a quasi-experimental study from Nigeria that reported an effect size of 5% between intervention and control group during a 13-week period [23]. We expect an effect size of 10% increase in our study with a 1-year follow-up where FCHVs are mobilized to conduct home visit counseling once every 3 months and the intervention takes place in an ongoing community-based program for non-communicable diseases from 2014 [16]. Assuming, 20% loss to follow-up and ICC of 0.01 and seven clusters per arm will provide 90% power resulting to 49 women per cluster. The total sample size needed for the intervention study is 690 that will be recruited from the 884 participants (baseline survey), which is enough to obtain 90% power.

Interventions
After randomization, the FCHVs in intervention wards will receive training coordinated by the research team in collaboration and close supervision of the local health authority. The training manual is designed under the guidance of experts in cervical cancer and public health from the national and international organizations. The training manual is based on the following: training of community health workers, WHO, 2017 training manual [24] and Cervical Cancer Screening and Prevention (CCSP) A Reference Manual 2015 [25]. The FCHVs will receive a 3-day training package highlighting: (a) an introduction to NCDs and cervical cancer, (b) cervical cancer causes and risk factors, (c) cervical cancer screening and service availability, (d) providing health education and counseling women (30-60 years), and (e) recording, reporting, and follow-up. An overview of program content is presented in Table 1. Educational sessions are guided by the use of the Health Belief Model [26], and training materials will be reviewed and validated by experts and major stakeholders. The developed training materials will be pretested with the FCHVs from a nearby area not included in the study. In addition, the FCHVs will also receive health education materials (pamphlets), referral cards, and a recording register during the training session.
At the end of the training, FCHVs will assign the number of households that have to be visited based on the baseline survey. Participants in the intervention clusters will receive a 12-month, home-based, health education package administered by FCHVs in a household setting. FCHVs will visit each household, meet the selected participant, receive approval, and provide the health education. On average, one FCHV will meet 18 participants three times a year. FCHV will complete the three visits to provide health education even if the participants have already received VIA screening. During the visit, FCHVs will deliver the health education intervention, to encourage and empower women for cervical cancer screening uptake available free of cost at their local health facility.
They will also conduct two reinforcement visits every 4 months from the first visit (three home visits in a year).
Health workers conducting cervical cancer screening at the local health facility in the intervention group will receive orientation about the study to make sure that the women attending the health facility receive screening. They will ensure that the equipment is functional and reagents are available, record information, provide psychosocial counseling to the case positives, and refer for further confirmation and treatment. The recorded information at the health facility will be tallied using the referral slip to confirm women's participation for cervical cancer screening. The collected data will be kept strictly confidential and will only be accessed by the members of the trial team. Each participant is assigned an individual trial identification number, which is securely stored. The principal investigator reserves the right to the data set and could share upon reasonable request.
There will be no special criteria for discontinuing or modifying allocated interventions. Furthermore, the implementing community-based intervention for cervical cancer screening uptake will not require alteration to usual care pathways (including use of any medication) and will continue for both the trial arms.
A field supervisor will routinely visit each FCHV in order to maintain motivation and collection of records from the health facilities. The supervisor also provides ad hoc help to the FCHVs when needed during the intervention period. We will also use a supervision checklist to track and update the knowledge and skill levels of FCHVs as well as to ensure fidelity to the study protocol.
In the control clusters, participants will receive "usual care." The usual care means the current health education and promotion practices for cervical cancer screening at the community level provided by the government health system. They will not receive further contact, information, or educational materials from FCHVs until the 12-month assessment.

Minimization of contamination
The risk and level of contamination will be monitored at the levels of FCHVs and participants. FCHVs will be instructed not to share information about the study and not to provide any support to people from other clusters in the community, other than the ones who are assigned. The risk of contamination will also be minimized by the cluster design, whereby the intervention and control clusters will be geographically separated and the chance of intervention cluster participants regularly meeting control cluster participants will be negligible. All possible means of contamination between intervention and control participants will be collected during the followup survey and adjustments will be made for estimating the effect.

Intervention fidelity
The intervention is designed under the guidance of experts in cervical cancer and public health from the national and international organizations. The subject experts and major stakeholders reviewed and validated the training materials. The education session were delivered under the close supervision of the local level health authority and the research team, who will monitor the intervention. The Data Safety and Monitoring Board (DSMB) along with a member from the Nepal Health Research Council will evaluate the progress of the trial, including periodic assessments of data quality and timeliness, participant recruitment, accrual and retention, participant risk versus benefit, performance of the trial site, and other factors that can affect study outcome. Each FCHV in the intervention cluster will be advised of the importance of following the intervention steps and content during the training session. The field supervisor will monitor FCHVs tasks. FCHVs will deliver the services guided by a register that keeps them reminded of stages of the intervention and will report every 4 months.

Data analysis
STATA version 15 software (StataCorp, College Station, TX, USA) will be used for quantitative analysis following the Consolidated Standards of Reporting Trials (CON-SORT) guidelines for cluster-randomized trials. Flowcharts ( Fig. 1) will include the number of participants seen at each stage of the trial, eligible, randomized, and analyzed for the primary outcome. In the initial analysis, we will compare baseline characteristics of enrolled participants in the study arms and follow-up status. We will use mixed-effect logistic regression to compare between the groups as the outcome (the primary outcome would be the difference in the proportion of women who participate in the cervical cancer-screening program between intervention and control within 1 year). Comparison of the knowledge scores between baseline and follow-up, after 1-year intervention, will measure the knowledge level. Estimation will take into account the effect of potential confounders (age, ethnicity, education, parity, income, location, etc.).

Interim analyses and stopping rules
There is no plan for interim analysis, as we do not expect a situation that would lead us to stop the study. However, in the event of an extreme situation such as a natural disaster, a conflict, or duplication of similar interventions in our control area, we will temporarily stop the study to assess the implications on the study design.

Trial management
We have a robust mechanism to ensure data quality. At first, the data enumerators will receive intensive training on the process of data collection. The principal investigator will monitor the data enumerators on a day-to-day basis. The research assistant assigned for data entry will inspect the data manually and enter the data in EpiData software file (EpiData Association, Odense, Denmark). Double entry for 10% of the data will qualify potential errors in data entry quality. The research officer will crosscheck the data quality on the spot and in our field office for any incomplete, inconsistent, and invalid data. Any deviation in the data quality will require recollecting in the field.

Indemnities
The study carries minimal risk to the study participants, which is why we have no compensation or insurance plan for the participants. However, we will provide medical insurance and US$5 per home visit to FCHVs for transportation expenses.

Publication plan
The results of the trial will be published in a peerreviewed journal.

Discussion
The COBIN-C study is the first investigation of a community-based intervention to increase cervical cancer screening uptake in Nepal. We expect that a community-based, culturally tailored education intervention delivered by community health workers such as FCHVs will play a key role in increasing cervical cancer screening uptake in the study area. Indeed, community health workers can play an important role in understanding the cultural barriers including community health practices, cultural identity, and coping practices that can promote positive health outcomes [27].
Furthermore, studies from Iran, Kenya, and Nigeria have reported health education interventions and behavior change frameworks provide an effective base for cervical cancer prevention [23,[28][29][30]. In our study, FCHV in the intervention group will make three home visits to educate and empower women for cervical cancer screening uptake that is available free of cost at the local health facilities. Previous study reveals that appropriate and structured training program motivates FCHVs to contribute in addressing non-communicable diseases [14].
The health promotion package is a simple, feasible, and potentially effective approach. It may contribute in the implementation of the National Cervical Cancer Screening and Prevention policy and help reduce cervical cancer mortality in the long term in Nepal and if successful may be adapted to similar settings elsewhere.

Trial status
The trial is now closed to participant accrual, but the trial is ongoing. The endpoint assessment of all the participants will be completed by the end of August 2021. The schedule of enrollment, interventions, and assessments is presented in Table 2. The protocol has been submitted for publication after the end of recruitment due to manuscript preparation and author's travel plan.
The protocol version number and date-V1, 28 December 2020.