A Web-Based Human Papillomavirus Vaccination Intervention for Young Gay, Bisexual, and Other Men Who Have Sex With Men: Protocol for a Randomized Controlled Trial

Background Gay, bisexual, and other men who have sex with men experience several disparities related to human papillomavirus (HPV) infection, including high incidence rates of anal cancer. Although the HPV vaccine is currently recommended for young adults, HPV vaccine coverage is modest among young gay, bisexual, and other men who have sex with men (YGBMSM). Objective We describe the design and methods for a randomized controlled trial (RCT) to rigorously evaluate Outsmart HPV, a population-targeted, individually tailored, Web-based HPV vaccination intervention for YGBMSM. The RCT is designed to determine the efficacy of the intervention, the mechanism by which the intervention has an effect (ie, mediation), and whether efficacy varies by participant characteristics (ie, moderation). Methods Outsmart HPV was previously developed and pilot-tested. This study is a 3-arm prospective RCT that will enroll a projected 1995 YGBMSM who are aged 18 to 25 years, live in the United States, and have not received any doses of the HPV vaccine. Participants will be recruited by means of paid advertisements on social media sites and randomized to receive (1) standard information on the Web about HPV vaccine (control group), (2) Outsmart HPV content on the Web with monthly unidirectional vaccination reminders sent via text messages, or (3) Outsmart HPV content on the Web with monthly interactive vaccination reminders sent via text messages. Participants will complete Web-based surveys at 4 time points during the study: baseline, immediately after engaging with Web-based content, 3 months after randomization, and 9 months after randomization. Primary outcomes will include both HPV vaccine initiation (ie, receipt of 1 or more doses of the HPV vaccine) and completion (receipt of all 3 doses recommended for this age range). We will examine constructs from the intervention’s theoretical framework as potential mediators and demographic and health-related characteristics as potential moderators of intervention effects. Results The institutional review board at The Ohio State University has approved the study. Materials have been developed and finalized for all study groups. Recruitment for the RCT began in fall 2019. Conclusions If shown to be efficacious, Outsmart HPV has the potential to fill an important gap by promoting HPV vaccination among a population at increased risk of HPV infection and HPV-related disease. Trial Registration ClinicalTrials.gov NCT04032106; http://clinicaltrials.gov/show/NCT04032106 International Registered Report Identifier (IRRID) PRR1-10.2196/16294


DESCRIPTION (provided by applicant):
Our overall goal is to increase human papillomavirus (HPV) vaccination among young sexual minority men (YSMM). Sexual minority men (i.e., men who have sex with men or identify as gay or bisexual) have high rates of HPV infection and HPV-related disease, including anal cancer. HPV vaccine is recommended for sexual minority men through age 26, yet fewer than 21% of YSMM ages 18-26 have received any HPV vaccine doses (i.e., initiation) and fewer than 10% have received all three recommended doses (i.e., completion). To address this issue, we recently developed and pilot tested a theoretically-informed mobile health HPV vaccine intervention for YSMM (Outsmart HPV). To our knowledge, Outsmart HPV is the first HPV vaccine intervention developed for this population. The pilot study established the intervention's feasibility and acceptability and produced very promising preliminary data. However, the pilot nature of this study precluded us from formally establishing intervention efficacy or examining additional intervention mechanism processes. The proposed study is a critical next step in this line of research because it will build upon our pilot study to comprehensively evaluate Outsmart HPV via a well-powered randomized controlled trial. We will recruit 1995 unvaccinated YSMM ages 18-25 from the US via social media and randomize each participant to either: a) standard information about HPV and HPV vaccine via a mobile-friendly website (control group); b) Outsmart HPV with unidirectional vaccine reminders; or c) Outsmart HPV with interactive vaccine reminders. Aim 1 will determine the efficacy of Outsmart HPV on increasing HPV vaccine initiation and completion. In doing so, the aim will determine which type of HPV vaccine reminders (unidirectional or interactive) most effectively increases vaccination as part of the Outsmart HPV intervention. Aim 2 will identify mediators that explain the relationship between study arm and HPV vaccine initiation and completion. This will identify the mechanism by which the intervention affects HPV vaccination (i.e., how the intervention leads to changes in theoretical constructs which in turn lead to vaccination). Aim 3 will determine if intervention efficacy differs across key demographic and healthrelated characteristics of participants (i.e., moderation). This will allow us to determine if Outsmart HPV has differential efficacy across subgroups and, if so, to identify those men for whom the intervention may require further adaptation in the future. Results of the proposed study will provide an evidence base regarding intervention efficacy, mediators, and moderators. These findings will offer a 1 R01 CA226682-01 3 HDEP REITER, P sophisticated understanding of Outsmart HPV that is needed to effectively and efficiently disseminate this innovative intervention to YSMM in the future.

PUBLIC HEALTH RELEVANCE:
The proposed study will comprehensively evaluate Outsmart HPV, an innovative mobile health HPV vaccine intervention that was recently developed for young sexual minority men. In doing so, the proposed study will provide an evidence base regarding the intervention's efficacy, mediators, and moderators. Results will provide a sophisticated understanding of the intervention that is needed to effectively and efficiently disseminate the intervention in the future.

CRITIQUE 2
Significance: 1 Investigator(s): 1 Innovation: 1 Approach: 2 Environment: 1 Overall Impact: This outstanding application seeks to test the efficacy of a theory-based, targeted and tailored, mobile health HPV vaccine intervention ("Outsmart HPV") for young sexual minority men (YSMM) over a 4 year timeline. The intervention will be tested in a 3-arm RCT that is powered to detect differences in initiation and completion rates and includes comparison with an appropriate control arm as well as an arm that is responsive to emerging science in the area of mHealth. Additionally, the trial is adequately powered to identify theory-based mediators and demographic moderators of the intervention effect, which will provide needed evidence for dissemination efforts. The intervention targets a significant population: at-risk young men who are vulnerable to disparities in HPV vaccination and HPV-related diseases, including several cancers for which routine screening is not available. The proposed trial is rigorously designed, the intervention elements are reproducible and well-justified based on health behavior theory, and the underlying premise for the work is supported by strong preliminary data from a feasibility study conducted by the team in preparation for the randomized trial. The investigative team is exceptionally and uniquely well-qualified to conduct the study, with a strong MPI plan and clear contributions made by nationally recognized experts in men's reproductive health and HPV vaccination through the inclusion of an Expert Advisory Board. The environment and resources available will ensure success with each critical element of this trial, from enrollment to intervention delivery, analysis, and dissemination and implementation planning. The strengths of this application far outweigh a few minor weaknesses noted in the approach.

Significance: Strengths
 Preliminary results support the feasibility of the Outsmart HPV intervention among YSMM and provide sound, relevant estimates for planning the proposed trial  Interventions for HPV vaccination have not targeted YSMM, who are at high risk of HPV-related diseases and less aware of HPV vaccination, thus, a successful intervention with understanding of mediators and moderators of intervention efficacy would have a high impact on the field of male sexual minority health Weaknesses  None noted.

Investigator(s): Strengths
 Highly accomplished investigative team containing all of the necessary expertise to conduct the proposed work, including behavioral interventions, HPV vaccination, YSMM health, medicine, mHealth/health communication, and biostatistics 1 R01 CA226682-01 4 HDEP REITER, P  Drs. Reiter and McRee collaborated successfully on the feasibility study (NCI R21) for the Outsmart HPV intervention, have numerous co-authored papers, and a detailed MPI Leadership Plan  An Expert Advisory Board will be actively engaged with the investigators throughout the duration of the project with meaningful and specific responsibilities to enhance the rigor of the study; of note exceptional relevant expertise includes Drs. Zimet and Bell who have provided letters of support Weaknesses  None noted.

Innovation: Strengths
 Interventions specifically targeting HPV vaccination among YSMM have not been developed  Conducting an appropriately powered comparison of unidirectional vs. interactive vaccine reminders in a randomized design is novel, responsive to recent evidence, and would inform the field of mHealth research more generally Weaknesses  None noted.

Approach: Strengths
 Strong preliminary data support the feasibility of the Outsmart HPV intervention; the underlying rationale for the intervention components is well-justified by 3 relevant theoretical/conceptual frameworks (PMT, IMB, MSM)  Trial is adequately (>80%) powered to determine efficacy (initiation and completion), identify theory-based mediators, and evaluate effect-modifiers of the intervention (demographic and health-related)  Intervention content and recruitment methods will be finalized in response to sequential qualitative input from YSMM via online focus groups  Two intervention arms have a strong scientific rationale based in mHealth literature (interactive vs. unidirectional reminders), control arm offers access to VIS (standard-of-care HPV vaccine materials from CDC)  Rigorous development of interactive response message library ensures accurate and "standard" replies are given in response to participant needs Weaknesses  Recruitment methods will exclude YSMM who are not engaged with social media; this is a minor weakness, as it will be a small minority of individuals who will likely not be responsive to mHealth approaches and require other strategies for reach/intervention  Vaccination records (signature of release of medical information) will not be required for study participation which could threaten the validity of self-reported outcome data

Environment: Strengths
 The Ohio State University provides outstanding physical, human, and intellectual resources to the investigative team including secure storage, grants administration, human subjects review, and resources inherent to having a Comprehensive Cancer Center  Technologies needed to carry out the research are available through itracks (online focus groups) and the Center for Health Communications Research at the University of Michigan (mHealth intervention) Weaknesses Acceptable o An adequate plan is provided to regularly monitor the integrity of the data and the safety of the subjects; appropriate and timely reporting of adverse events, data breaches, and protocol deviations is described, a board seems unnecessary. Overall Impact: Overall this application has several strengths. This application addresses YSMM, an understudied population that faces greater disease burden and disparities from HPV related cancers. It 1 R01 CA226682-01 6 HDEP REITER, P has a strong team of investigators with the appropriate expertise and relevant experience to conduct the project. And finally, the scientific premise is clear. Aims and hypotheses are clearly articulated and justified. Minor weaknesses that dampen enthusiasm for this application include that the project includes both a unidirectional and interactive condition that inflates the sample size needed to conduct a fully powered test of the intervention. Efficacy was established in the pilot for unidirectional messages; it is unclear why the interactive component needs a different intervention group since it includes the unidirectional message and then provides additional intervention. The investigators do not use statistical controls to account for the variance contributed by the interactive messages. Then the required sample size would be more manageable. The recruitment plan does not appear feasible given the team's own experience with this population. Finally, additional information is needed on the power analysis. The investigators note that "projections are based on pilot results (with slight increases)" but we do not know how "slight." These weaknesses dampen enthusiasm for an otherwise impactful application.

Significance: Strengths
 This application addresses YSMM an understudied population that faces greater disease burden and disparities from HPV related cancers  CDC supports the need for catch up vaccines in this population through age 26  The application is built on a strong scientific premise Weaknesses  The investigators should justify the need to examine unidirectional versus interactive messages.

Investigator(s): Strengths
 Strong team of investigator with appropriate expertise and relevant experience to conduct the project.

Weaknesses
 None noted.

Innovation: Strengths
 This a multicomponent intervention targeting all steps need to complete the HPV vaccination process: information, planning and follow-up  The intervention will help participants locate a provider in order to obtain vaccination.  This project will develop an intervention for YSMM, a population that will benefit from increased vaccine coverage.

Weaknesses
 None noted

Approach: Strengths
 The intervention is based on strong preliminary evidence of intervention efficacy from a previous pilot study.  Phase I and Phase II are clearly delineated. The project has well articulated aims and testable hypotheses.  The scientific premise is clear.

Weaknesses
 Efficacy was established in the pilot for unidirectional messages; it is unclear why the interactive component needs a different intervention group since it includes the unidirectional message and then provides additional intervention. It is unclear if the investigators are suggesting that adding the interactive component to the existing intervention changes it significantly from the pilot. The 1 R01 CA226682-01 7 HDEP REITER, P recruitment plan does not appear feasibly given the teams own experience with this population. In 7 months, the team recruited 150 study participants (however in 2.5 years they plan to recruit 1995)  The investigators state that their desired sample size is 1398, however, it is not clear what the sample sized based on. Additional information on the power analysis is needed. The investigators note that "projections are based on pilot results (with slight increases..)" but we do not know how "slight"

Environment:
Strengths  Environment appears adequate to conduct the proposed work.
 The team has a strong track record of collaboration with the Principal Investigator Weaknesses  None noted.