Study design

The TRAP-HPV study is a randomised, placebo-controlled, double-blinded trial being conducted in Montreal, Canada. This protocol follows the Standard Protocol Items: Recommendations for Intervention Trials checklist of recommended items to address in a clinical trial protocol.11 The study received ethical approval by institutional review boards at McGill University (A04-M37-12A), Concordia University (30001405), and Centre Hospitalier de l’Université de Montréal (2014–2019, CE 13.016). Amendments to the protocol are approved by the previously mentioned review boards. The protocol was last revised on 12 June 2018 (10th revised version). Before taking part in this exploratory clinical trial, all participants provide informed written consent to the research nurse (online supplementary appendix 1–3 for women, men and the addendum for active study participants during the COVID-19 pandemic, respectively).

Study setting and participant recruitment

Participant’s enrolment started in January 2014, and is ongoing. Our study coordinator enrols participants. Initially, participants attended one of two venues for their clinic visit, which provide medical care year-round to students: the McGill University Health Services Clinic or Concordia University Health Services Clinic. At present, starting in September 2018, all participants are seen at the Division of Cancer Epidemiology’s research clinic at the Gerald Bronfman Department of Oncology, McGill University.

Recruitment is bolstered through campus-wide appeals, including posters, emails to student lists, promotional videos, online-classified advertising services and word-of-mouth advertising. Additional efforts include mail-outs to students living in residence, classroom presentations in professional schools and information booths at student activities where promotional products are distributed (ie, brochures, promo-button pins and keychains). In July 2017, we implemented a new strategy to boost enrolment. Traditionally, study coordinator(s) would ask potential participants a set of questions to determine their eligibility during the enrolment or screening phase (online supplementary appendix 4). We opted to complement this approach with an online pre-eligibility survey that consists of nine eligibility questions that are answered by potential participants on their own (online supplementary appendix 5). Eligibility is then assessed using a predefined automatically generated algorithm. Potential participants are contacted and informed of their eligibility. This questionnaire is posted on social media, the McGill Cancer Epidemiology website (https://www.mcgill.ca/traphpv/), and online-classified advertising services. To promote participant retention, we send reminder emails to participants before their scheduled study visits and reschedule appointments with participants when they cannot attend their visit.

Eligibility criteria

To be eligible, volunteer couples must (1) not have received the intervention vaccine (Gardasil prior to 8 July 2015 and Gardasil 9 afterwards); (2) plan on remaining in Montreal for at least 1 year; (3) be in a new relationship (onset of sexual activity) that started no more than 6 months prior to study entry; (4) plan on having continued sexual contact with partner; (5) be between 18 and 45 years old; (6) have no history of cervical, penile, oral or anal cancers and (7) be willing to comply with study procedures. Additionally, the female must not be pregnant or plan on immediately becoming pregnant. Concerning criteria 3 and 4, we screen couples based on the Dyadic Adjustment Scale (DAS), a validated instrument to measure the stability of couples’ relationships.12–14 Although the questionnaire is intended for married and common-law couples, participants answer 4 questions (in English or French) applicable to non-cohabitating couples from the Dyadic Satisfaction subscale of the DAS (table 1). These questions gauge the degree of confidence in the partner, likelihood of a separation, and overall satisfaction with the relationship. Couples in which one of the partners scores less than 80% of the maximum score are not enrolled.

Interventions

Once recruited, couples were randomised to one of four treatment or placebo vaccine combinations (table 2) via a 2-by-2 design where both partners either receive the intervention vaccine or the placebo vaccine, or receive discordant vaccination regimens from the research nurse. Prior to 8 July 2015, Gardasil was used as the intervention vaccine, which allowed for the observation of four infection outcomes (HPVs 6, 11, 16, 18). Henceforth, intervention has been defined as vaccination with Gardasil 9 (Merck).7 This vaccine allows for the observation of nine HPV outcomes (HPVs 6, 11, 16, 18, 31, 33, 45, 52, 58). The placebo vaccine is the hepatitis A vaccine Avaxim (Sanofi Pasteur). Initially, Havrix (GlaxoSmithKline) was administered as the placebo vaccine until 11 June 2018 (refer to discussion and table 3 for more details regarding intervention and placebo vaccine amendments). Hepatitis A vaccine was chosen as the placebo vaccine because hepatitis A immunisation provides a similar health prevention incentive to study participants as HPV vaccination while preserving the scientific cogency of a ‘placebo’ comparator. Gardasil 9 requires administration of three doses, while Avaxim only requires 2 doses. Hence, a placebo injection (saline solution) is administered between the hepatitis A vaccination regimen. Accordingly, both treatment and control vaccines have similar regimens, that is, at study entry, 2 months and 6 months.

To ensure that all study participants gain similar health benefits and incentives, and in keeping with ethical values, a crossover of interventions is implemented at the end of the study; the HPV vaccine is offered to all control participants and hepatitis A vaccine to all HPV-immunised participants. The benefit of HPV vaccination would not be significantly delayed for control participants since the study is relatively short (12 months).

Incentives for participation

HPV and hepatitis A vaccines are provided free of charge and participants receive a monetary incentive at every visit. Remuneration per participant is distributed as follows: CAN$120 at enrolment visit; CAN$60 for visits 2, 3 and 4; CAN$80 at visit 5; and CAN$120 at the last visit. In total, individuals are each given CAN$500 (CAN$1000 per couple) as a cash incentive for their participation, if all study visits were to be completed.

Randomisation and blinding

Random allocation of study participants is determined via computer-assisted simple randomisation. Treatment assignment is done via a secure web-based programme at the time the couple is enrolled. Participants, investigators and outcome assessors are blinded to vaccination assignment. Participant blinding is assured because both vaccines (HPV and hepatitis A) and their syringes look identical (previously drawn from blinded vials in a separate room by the nurse) so that participants are unaware of their content. Furthermore, injection pain is expected to be similar for both vaccines. At the end of the study, participants are informed of their allocation.

Data collection procedures

Figure 1 shows the study design, procedures and schedule. Blood samples are collected only at the first visit, whereas oral and penile/vaginal samples are collected at every visit. Anal sampling was discontinued in July 2016 due to its hindering effect on recruitment. Vaginal samples are self-collected at the clinic after participants receive verbal and written instructions from the study nurse. All other samples are collected by trained research nurses. Pending transfer to the laboratory, oral and blood samples are stored in a −20°C freezer while penile and vaginal samples are stored in a 4°C fridge. On arrival to the lab, samples are kept at similar temperature conditions until being processed.

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Figure 1

Study design and time points of data collection. Participants in a relationship no longer than 6 months are enrolled in the study. The assigned vaccination regimen is administered at the 0, 2 and 6 months marks. oral, penile, penile (men) and vaginal (women) samples are collected from participants at every study visit. Blood samples are collected from participants only at enrolment. HPV, human papillomavirus.

HPV testing

DNA is extracted from samples using the Master Pure extraction kit (Epicentre, Madison, Wisconsin, USA).24 HPV genotyping is done using the Linear Array HPV Genotyping Test (Roche Molecular Systems, Indianapolis, Indiana, USA).25 Using the PGMY09/11 consensus primer system which targets the L1 gene of the HPV genome, this assay can detect 36 types (HPVs 6, 11, 16, 18, 26, 31, 33–35, 39, 40, 42, 44, 45, 51–54, 56, 58, 59, 61, 62, 66–73, 81–84 and 89). Coamplification of β-Globin is performed to assess specimen quality.

Study outcomes

For each anatomic site, the primary outcome will be transmission reduction of HPV infections of target HPV vaccine types (HPVs 6, 11, 16, 18, 31, 33, 45, 52, and 58) over time in Avaxim-administered sexual partners of HPV vaccinated individuals, corresponding to the combinations M^TF^P and M^PF^T (table 2). The control group consists of couples randomised to both participants receiving Avaxim, denoted as the M^PF^P group. The fully protected group is represented by the combination M^TF^T. We will also measure prevalence and incidence of HPV types covered by the intervention vaccine in all collected samples, for each visit and among all participants.

Reduction in HPV type concordance (for the nine target types) will be evaluated over time between vaccination groups. These comparisons will be done with due attention to the enrolment HPV type-specific infection status of participants. For instance, we expect that an Avaxim-treated woman who is positive for HPV6 in the oral specimen, but negative for this type in the vaginal specimen, may derive benefit if her partner had received the intervention vaccine, even if he is HPV6 positive in the penile sample. We assume that protection via vaccination is pan-mucosal, via transudation of neutralising antibodies and may mediate transmission.

Data management

Data management and project coordination is done at the McGill’s Division of Cancer Epidemiology coordination centre. Study oversight and data management are led by the study director (ME-Z) and principal investigator (ELF). The research staff have access to the secure study-designated website containing participant and study visit information. Along with laboratory results, all participant information is confidential and stored in a secure location. All participant data are checked monthly for quality assurance.

Sample size

There are no published empirical estimates of the expected level of transmission reduction. Our informal consultation with experts in the field indicated that 40% reduction in transmission would be a conservative estimate; it would represent the expected magnitude of a protective effect in the discordant vaccination groups where the partner receiving a placebo is the one to be protected. Using the Bernstein and Lagakos approach,26 we determined that a total of 500 couples (125 couples per group/cell in table 2) are required for 90% power, with type 1 error of 0.05, and one-sided hypothesis for a 40% reduction in transmission rate, assuming a cumulative 16% lost to follow-up at month 12 (attrition rate of 2.7% per-visit). Empirically based estimates of parameters for sample size calculation were obtained from our unit’s molecular epidemiological investigations of the HITCH cohort study.27–29 We also assumed gender equivalent rates of transmission as per findings in the HITCH study.29

Statistical methods

We hypothesise that HPV vaccination would be effective in reducing the risk of HPV transmission to sexual partners. The study design offers the opportunity to measure transmission events in multiple mucosal sites for multiple HPV types, over multiple clinic visits, and for both directionalities (ie, male to female and female to male). We will take advantage of advanced regression methods as a framework for measuring the effects expected via HPV vaccination.

In the simplest core formulation (eg, analysing a single HPV type and a single mucosal site), we will use the Kaplan-Meier technique to plot the cumulative probability of HPV infection in sexual partners of vaccinated versus unvaccinated individuals against follow-up time. Using the layout in table 2, this implies comparing HPV infection histories of women in the M^TF^P and M^PF^P groups and men in the M^PF^T and M^PF^P groups. Expectedly, protection is also likely to occur via cumulative effects observable via HPV detection in multiple mucosal sites; we will address this by conducting time to event analysis.

We will use the log-rank test for statistical comparisons in HPV transmission between vaccine and control groups. Cox proportional hazard regression models will be used to estimate the effect of vaccination on HPV transmission to sexual partners based on HRs and their respective 95% CIs. Time to HPV infection in days will be defined as the time from study enrolment to infection date. In addition to the intention-to-treat analysis approach, we will perform regression models to examine the role of several candidate determinants in mediating transmission and protective effects.

Furthermore, cumulative risk models will be fitted with type-specific transmission as an outcome. Generalised estimating equations (GEE) models will be used to incorporate data across multiple HPV types,30 to account for repeated HPV prevalence data across types and study visits involving the same participant. In a single GEE logistic regression model, we will consider type-specific infection events for each vaccine HPV type as separate transmission endpoints and then estimate the exposure effect on selected HPVs as a group, as we have published.27 28 Mixed-effects models will also be fitted incorporating repeated HPV transmission data across HPV types and visits involving the same participant.31 Couples who break-up and end their relationship before their last visit will be censored of the study. Since vaccination protection is expected to begin as early as the first dose, we can expect to analyse reductions in transmission with a subset of visits for a few couples before the full set of visits is completed, which will allow for an interim analysis to be conducted before study termination.

Data monitoring and adverse events

An independent data safety monitoring board will review the interim analysis results. The analysis is planned for when we have recruited half of the target sample size (250 couples) or when 100 couples complete all six visits. We will use all available data when either condition occurs first. We will seek advice from McGill University’s Research Ethics Board concerning the composition of this board; members will likely be nominated outside of our purview. The type 1 error for concluding efficacy will be controlled by the Lan-Demets spending function32 with O’Brien and Fleming type boundaries.33

Patient and public involvement

Prior to commencement of the TRAP-HPV study, we conducted a qualitative assessment to explore the acceptability of proposed study procedures and invite recommendations on ways to improve them. We held a focus group with 13 heterosexual couples within the eligible age range of the TRAP-HPV study to resemble potential participants. Focus group participants attended a presentation of the proposed trial procedures then engaged in discussions regarding potential concerns and improvements. Topics discussed related to inclusion criteria, censoring due to break-up, lost of follow-up, ethical considerations regarding the placebo and attractiveness of the study to similar couples. Results from the focus group inform our trial procedures.

Dissemination policy

Information gained from this study will be published in peer-reviewed journals and presented at national and international conferences. In the context of knowledge translation, the generated empirical evidence could be used in mathematical models of vaccination to inform policymakers in Canada and elsewhere. The implications for mathematical models is discussed further in the discussion.

Preliminary recruitment findings

As of April 2020, we have enrolled 167 couples since recruitment commenced in January 2014. Our records show that 81 couples have been recruited via posters, 47 via online-classified ads (Kijiji, McGill Classified ads and Facebook), 18 couples via word of mouth, and one via a study promotion during a university orientation event, while 12 couples did not specify the recruitment method. So far, 71 couples have completed all six visits, 62 couples withdrew before their last visit and 31 couples with ongoing participation.