Effect of a Brief Web-Based Educational Intervention on Willingness to Consider Human Papillomavirus Vaccination for Children in Japan: Randomized Controlled Trial

Background The human papillomavirus (HPV) vaccination rate in Japan has fallen to nearly zero since the suspension of governmental proactive recommendations in 2013, owing to the development of purported adverse events. Objective This study aimed to evaluate the effects of a brief web-based educational intervention using the theory of behavioral insights on the willingness of adults to consider the HPV vaccine for their daughters and sons. Methods We recruited 1660 participants aged 20 years or older in March 2018 via a webpage and provided them with a 10-item questionnaire related to the following aspects: awareness regarding HPV infection and vaccination, willingness for immunization, and actions for prevention. We randomly stratified participants based on sex and age with or without a brief educational intervention involving scientific information presented in an easy-to-read format. Results Only 484 (29.2%) of the respondents were aware of the benefits of HPV vaccination. Although only 352 (21.2%) of the respondents displayed a willingness for immunization of their daughters, there were 40 (4.8%) more respondents in the intervention group with this willingness (adjusted odds ratio [aOR] 1.32, 95% CI 1.04-1.69). In a subanalysis, the willingness toward vaccination for daughters in men was significantly higher in the intervention group (aOR 1.46, 95% CI 1.05-2.02). However, such a difference was not observed among women (aOR 1.20, 95% CI 0.83-1.73). Conclusions This study suggests that a brief web-based educational intervention increases the willingness of adults to consider the HPV vaccine for their children, especially among men. Thus, providing adequate information to men may be a useful strategy to improve the currently low rates of HPV vaccination. Trial Registration UMIN Clinical Trials Registry UMIN000049745 (UMIN-CTR); https://upload.umin.ac.jp/cgi-open-bin/ctr_e/ctr_view.cgi?recptno=R000049745


2a-i) Problem and the type of system/solution
This study aimed to assess the effects of these behavioral insights utilizing fundamental scientific information on vaccine benefits, along with statistics on cervical cancer.

2a-ii) Scientific background, rationale: What is known about the (type of) system
Intervention used in this study is not a system but just a easy-to-read format.

Does your paper address CONSORT subitem 2b?
Vaccine awareness programs are necessary and campaigns through the media and social network services can play significant roles. In an information-overloaded society, people frequently take decisions related to health issues based on limited information. Therefore, it is critical to consider the influence of behavioral insights to promote change [12]. This broadly refers to concrete approaches based on the knowledge of behavioral science and economics. The Easy, Attractive, Social and Timely (EAST) principles are a simple way of applying behavioral insights to interventions and have been used to change human awareness and behavior [12]. This study aimed to assess the effects of these behavioral insights utilizing fundamental scientific information on vaccine benefits, along with statistics on cervical cancer.

3a) CONSORT: Description of trial design (such as parallel, factorial) including allocation ratio
We randomly assigned each participant to respond to an identical questionnaire after (Intervention group) or prior to (Control group) providing behavioral insights material (BI-material) using fundamental scientific information presented in an easy-to-read format (as displayed in Figures 1 and 2).
Participants were randomly allocated (1:1) to each group. Intervention was performed using an automatic web-based allocation system stratified with sex (female/women, male/men) and age (20s, 30s, 40s, 50s, and 60s) of the participants. Randomization was performed by Macromill, Inc web-research system. 3b) CONSORT: Important changes to methods after trial commencement (such as eligibility criteria), with reasons No change. 3b-i) Bug fixes, Downtimes, Content Changes 4a) CONSORT: Eligibility criteria for participants These were registered members of the research panel owned by Macromill, Inc. (Tokyo, Japan). The participants were 20 years old or above as on March 12th-13th, 2018. 4a-i) Computer / Internet literacy 4a-ii) Open vs. closed, web-based vs. face-to-face assessments: We recruited a total of 1,660 participants in March 2018 via a specially designed webpage for this study. These were registered members of the research panel owned by Macromill, Inc. (Tokyo, Japan). Our study was obviously closed. 4a-iii) Information giving during recruitment Participants were randomly allocated (1:1) to each group after providing their consent. 4b) CONSORT: Settings and locations where the data were collected We recruited a total of 1,660 participants in March 2018 via a specially designed webpage for this study. These were registered members of the research panel owned by Macromill, Inc. (Tokyo, Japan).

4b-i) Report if outcomes were (self-)assessed through online questionnaires
Our study is performed as web-based trial. 4b-ii) Report how institutional affiliations are displayed 5) CONSORT: Describe the interventions for each group with sufficient details to allow replication, including how and when they were actually administered 5-i) Mention names, credential, affiliations of the developers, sponsors, and owners These were registered members of the research panel owned by Macromill, Inc. (Tokyo, Japan). 5-ii) Describe the history/development process I described the process in the discussion session about behavioral insights. "Informational materials are designed primarily to increase effectiveness; they are based on a specific purpose rather than a template."

5-iii) Revisions and updating
This intervention material is the first edition.

5-iv) Quality assurance methods
Our intervention material is designed primarily to increase effectiveness; they are based on a specific purpose rather than a template.
The intervention method (BI-material) was designed by us, resulting in a moderate cost; therefore, this intervention is more reliable and cost-effective than those used in previous studies. The first author of this article (YS) is a core member of the behavioral design team in Yokohama, which was established as the first non-governmental nudge unit in Japan. Thus, this BI-material is reliable in view of the BI methodology. 5-v) Ensure replicability by publishing the source code, and/or providing screenshots/screen-capture video, and/or providing flowcharts of the algorithms used We displayed the source and flowchart in the manuscript.

5-vi) Digital preservation
This material is freely used as a material for the education in our department. However we have not provided yet in free access website.

5-vii) Access
Participants were registered members of the research panel owned by Macromill, Inc. (Tokyo, Japan).

5-viii) Mode of delivery, features/functionalities/components of the intervention and comparator, and the theoretical framework
Participants were registered members of the research panel owned by Macromill, Inc. (Tokyo, Japan). If this manuscript would be published, we will provide this material through our department website and through SNS.

5-ix) Describe use parameters
Not applicable for our study.

5-x) Clarify the level of human involvement
This material was provided through web-site. There were no human involvement.

5-xi) Report any prompts/reminders used
Not applicable for our study.

5-xii) Describe any co-interventions (incl. training/support)
Not applicable for our study.
In the intervention group, we provided the BI-material prior to answering questions related to preventive awareness, following consent for the online study. The control group was provided with the same material as that provided to the intervention group after all responses were completed.
There are little possibility existing any co-interventions. 6a) CONSORT: Completely defined pre-specified primary and secondary outcome measures, including how and when they were assessed The primary outcome is the rate of willingness on the HPV vaccine for their daughters. The secondary outcome is the sub-analysis of sexes. 6a-i) Online questionnaires: describe if they were validated for online use and apply CHERRIES items to describe how the questionnaires were designed/deployed Not applicable for our study. 6a-ii) Describe whether and how "use" (including intensity of use/dosage) was defined/measured/monitored Not applicable for our study. 6a-iii) Describe whether, how, and when qualitative feedback from participants was obtained Not applicable for our study. 6b) CONSORT: Any changes to trial outcomes after the trial commenced, with reasons We recruited a total of 1,660 participants in March 2018 via a specially designed webpage for this study. These were registered members of the research panel owned by Macromill, Inc. (Tokyo, Japan). 7a) CONSORT: How sample size was determined 7a-i) Describe whether and how expected attrition was taken into account when calculating the sample size The sample size was calculated as powered 80% to detect a 10% effect in the intervention group (increased from 40% in the control to 50% in the intervention group) with a two-sided p value of 0.05. P values less than 0.05 were regarded as significant. The hypothetical baseline willingness rate in the control group was determined based on our previous study. The sample size was calculated as 776 when the effect of intervention estimated a 10% increase. The number of participants recruited was double of the calculated sample size because of the difficulty of estimating the baseline willingness and the intervention effect.

7b) CONSORT: When applicable, explanation of any interim analyses and stopping guidelines
The primary outcome is the rate of willingness on the HPV vaccine for their daughters. The secondary outcome is the sub-analysis of sexes. 8a) CONSORT: Method used to generate the random allocation sequence Participants were randomly allocated (1:1) to each group after providing their consent. Intervention was performed using an automatic web-based allocation system stratified with sex (female/women, male/men) and age (20s, 30s, 40s, 50s, and 60s) of the participants. Randomization was performed by Macromill, Inc web-research system. Participants and investigators were blinded to the distribution (double-blinded). Once the upper limit of each stratum was reached, new participants could not be added to the web system. This ensured uniform distribution of the stratification factors. In the intervention group, we provided the BI-material prior to answering questions related to preventive awareness, following consent for the online study. The control group was provided with the same material as that provided to the intervention group after all responses were completed. 8b) CONSORT: Type of randomisation; details of any restriction (such as blocking and block size) Participants were randomly allocated (1:1) to each group after providing their consent. Intervention was performed using an automatic web-based allocation system stratified with sex (female/women, male/men) and age (20s, 30s, 40s, 50s, and 60s) of the participants. Randomization was performed by Macromill, Inc web-research system. Participants and investigators were blinded to the distribution (double-blinded). Once the upper limit of each stratum was reached, new participants could not be added to the web system. This ensured uniform distribution of the stratification factors. In the intervention group, we provided the BI-material prior to answering questions related to preventive awareness, following consent for the online study. The control group was provided with the same material as that provided to the intervention group after all responses were completed. 9) CONSORT: Mechanism used to implement the random allocation sequence (such as sequentially numbered containers), describing any steps taken to conceal the sequence until interventions were assigned Not applicable for our study. 10) CONSORT: Who generated the random allocation sequence, who enrolled participants, and who assigned participants to interventions Randomization was performed by Macromill, Inc web-research system. 11a) CONSORT: Blinding -If done, who was blinded after assignment to interventions (for example, participants, care providers, those assessing outcomes) and how 11a-i) Specify who was blinded, and who wasn't Participants and investigators were blinded to the distribution (double-blinded). 11a-ii) Discuss e.g., whether participants knew which intervention was the "intervention of interest" and which one was the "comparator" Not applicable for our study.

11b) CONSORT: If relevant, description of the similarity of interventions
Not applicable for our study. 12a) CONSORT: Statistical methods used to compare groups for primary and secondary outcomes Statistical evaluation comprised the student's t-test, the chi-square (χ2) test, and multiple regression analyses. 12a-i) Imputation techniques to deal with attrition / missing values Not applicable for our study. There were no missing values.

12b) CONSORT: Methods for additional analyses, such as subgroup analyses and adjusted analyses
Same as the primary outcome analysis. RESULTS 13a) CONSORT: For each group, the numbers of participants who were randomly assigned, received intended treatment, and were analysed for the primary outcome Not applicable for our study. All participants receive intended treatment.

13b) CONSORT: For each group, losses and exclusions after randomisation, together with reasons
Not applicable for our study.

13b-i) Attrition diagram
Not applicable for our study.

14a) CONSORT: Dates defining the periods of recruitment and follow-up
From March 12th to 13th 2018, 1,660 participants were recruited.
We have no follow-up period.

14a-i) Indicate if critical "secular events" fell into the study period
Not applicable for our study. 14b) CONSORT: Why the trial ended or was stopped (early) Not applicable for our study.

15-i) Report demographics associated with digital divide issues
Not applicable for our study. 16a) CONSORT: For each group, number of participants (denominator) included in each analysis and whether the analysis was by original assigned groups 16-i) Report multiple "denominators" and provide definitions Not applicable for our study. All participants answered questionnaire and received intervention as allocated.

16-ii) Primary analysis should be intent-to-treat
Not applicable for our study. All participants answered questionnaire and received intervention as allocated. 17a) CONSORT: For each primary and secondary outcome, results for each group, and the estimated effect size and its precision (such as 95% confidence interval) Only 21.2% of the respondents displayed a favorable attitude toward HPV immunization for their daughters (Q6). However, an additional 40 (4.8%) participants responded affirmatively in the intervention group (aOR=1.32, 95% CI=1.04-1.69) compared to those in the control group (Table 2). For Q7, there were additional 33 (3.9%) satisfied respondents willing for their sons' vaccination in the intervention group (aOR=1.38, 95% CI=1.05-1.80) compared to those in the control group (Table 2).

17a-i) Presentation of process outcomes such as metrics of use and intensity of use
Not applicable for our study. 17b) CONSORT: For binary outcomes, presentation of both absolute and relative effect sizes is recommended Only 21.2% of the respondents displayed a favorable attitude toward HPV immunization for their daughters (Q6). However, an additional 40 (4.8%) participants responded affirmatively in the intervention group (aOR=1.32, 95% CI=1.04-1.69) compared to those in the control group (Table 2). For Q7, there were additional 33 (3.9%) satisfied respondents willing for their sons' vaccination in the intervention group (aOR=1.38, 95% CI=1.05-1.80) compared to those in the control group (Table 2).
There were no additional analysis other than planned analysis.

18-i) Subgroup analysis of comparing only users
Not applicable for our study.

19) CONSORT: All important harms or unintended effects in each group
Not applicable for our study.

19-i) Include privacy breaches, technical problems
Not applicable for our study.

19-ii) Include qualitative feedback from participants or observations from staff/researchers
Not applicable for our study. DISCUSSION 20) CONSORT: Trial limitations, addressing sources of potential bias, imprecision, multiplicity of analyses 20-i) Typical limitations in ehealth trials Third, selection bias existed as the respondents were Japanese enrolled by an internet survey company.

21) CONSORT: Generalisability (external validity, applicability) of the trial findings 21-i) Generalizability to other populations
Our study reveals a positive outlook towards the HPV vaccination following brief, web-based educational intervention, especially among male participants. Such an approach is extremely effective to overcome challenges related to communication and information overload.

21-ii) Discuss if there were elements in the RCT that would be different in a routine application setting
Not applicable for our study.

22) CONSORT: Interpretation consistent with results, balancing benefits and harms, and considering other relevant evidence 22-i) Restate study questions and summarize the answers suggested by the data, starting with primary outcomes and process outcomes (use)
We conducted a web-based randomized controlled trial (RCT) to assess the benefits of BI-material employing fundamental scientific information and motivate individuals to take the HPV vaccine. Our results showed that providing brief scientific information could increase the positive awareness of HPV vaccination. This effect was observed typically among male participants. Similar minor interventions may potentially modify mindsets favorably. However, such brief digital information failed to affect the mindset in women. In terms of the coronavirus disease (COVID-19) pandemic, a difference in awareness of prevention strategies was observed between the sexes; therefore, it is essential to build a method appropriate for sex subgroups to transform general behavior via the internet and social networking service (SNS).

22-ii) Highlight unanswered new questions, suggest future research
We recognize several limitations in this study. First, the sustainability of effective change was not evaluated. Typically, with respect to health issues, taking action requires time. Therefore, a study should assess not only a change in mindset but also the appropriate course of action. We have already performed a RCT (UMIN000039273) assessing the sustainability of general acceptance and concrete behavior for HPV vaccination. Other information 23) CONSORT: Registration number and name of trial registry UMIN000049745 URL; https://www.umin.ac.jp/english/ 24) CONSORT: Where the full trial protocol can be accessed, if available Not applicable for our study.

25) CONSORT: Sources of funding and other support (such as supply of drugs), role of funders
We received research funding from the Japan Agency for Medical Research and Development (grant no. 15ck0106103h0102).

X26-i) Comment on ethics committee approval
The study protocol was approved by the Institutional Research Ethics Committee of Yokohama City University School of Medicine (A180200004). The trial registration number is UMIN000049745.

x26-ii) Outline informed consent procedures
In the intervention group, we provided the BI-material prior to answering questions related to preventive awareness, following consent for the online study. The control group was provided with the same material as that provided to the intervention group after all responses were completed.

X26-iii) Safety and security procedures
Not applicable for our study.

X27-i) State the relation of the study team towards the system being evaluated
We have no COI between study team and the survey company.