Title: Human papillomavirus infection: a randomised controlled trial of Imiquimod versus Podophyllotoxin, in combination with quadrivalent human papillomavirus vaccination in the treatment and prevention of recurrence of anogenital warts (HIPvac Trial)
Funder: Department of Health and Social Care

Abstract: The project aims to address the following questions: 1. Is topical therapy with imiquimod or podophyllotoxin more effective in clearing and preventing recurrence of anogenital warts? 2. Does the addition of quadrivalent human papillomavirus (HPV) vaccination to topical therapy provide additional benefits in terms of either higher clearance or reduced recurrence rates? 3. What is the comparative cost-effectiveness of the topical treatment and vaccination strategies? Design: A randomised, controlled partially blinded 2 x 2 factorial trial with an accompanying economic analysis. The two factors are: type of topical cream for self-application (16 weeks of imiquimod 5%, or 4 weeks of podophyllotoxin 0.15% as active control, according to the licence); type of vaccination (either a 3 dose regimen of a quadrivalent HPV vaccine (Gardasil – Sanofi Pasteur at 0, 2 and 6 months), or hepatitis A vaccine), starting at the same time as the topical wart treatment. Patients will be randomised to one of 4 groups: imiquimod cream plus HPV vaccine; podophyllotoxin cream plus HPV vaccine; imiquimod cream plus hepatitis A vaccine; podophyllotoxin cream plus hepatitis A vaccine. Health technologies being assessed: Podophyllotoxin and imiquimod creams will be used according to current clinical practice and British Association for Sexual Health and HIV guidelines. The quadrivalent HPV (qHPV) vaccine will be given according to label at 0, 2 and 6 months. Topical treatment will not be blinded owing to the different dosing schedule; vaccine allocation will be double blind, with a hepatitis A vaccine control arm. Measurement of costs and outcomes: The primary analysis for the two factors will be by intention to treat, based on comparisons at the margins of the 2 x 2 table: subjects randomised to imiquimod versus podophyllotoxin cream, and subjects randomised to qHPV vaccine versus control vaccine. The primary outcome measure will be complete wart clearance by 16 weeks and freedom from any recurrence of anogenital warts between 16 and 48 weeks. As this is a pragmatic trial addressing the question of which treatment should be used as initial therapy, further treatment with cryotherapy(liquid nitrogen spray) will be permitted in either arm, as will additional doses of podophyllotoxin cream in the podophyllotoxin arm, if there is a failure to respond, or intolerance, in accordance with standard clinical practice. Switching between the randomised topical treatments will not be permitted before 16 weeks; subsequent therapy will be at the discretion of the investigator. Secondary outcome measures will include: proportion wart-free at the end of the assigned treatment course (4 or 16 weeks); proportion wart-free at 16 weeks after use of additional treatment as required; quantity of additional treatment (number of cryotherapy applications, additional weeks of podophyllotoxin or imiquimod) required to achieve clearance by 16 weeks; proportion wart-free at 24 weeks; proportion wart-free at 24 weeks after use of additional treatment as required; quantity of additional treatment (number of cryotherapy applications, additional weeks of podophyllotoxin or imiquimod) required to achieve clearance by 24 weeks; time to complete wart clearance; proportion experiencing wart recurrence/relapse after wart clearance; proportion experiencing wart recurrence/relapse at 48 weeks after wart clearance at 24 weeks; time from complete wart clearance to recurrence/relapse; adverse events; health-related quality of life, as measured by the AUC for EQ-5D; symptom score; total costs of treatment including prescribed agents and clinic visits. Analysis for the primary outcome, and other binary outcomes, will be based on logistic regression, and will be adjusted for gender and previous occurrence of warts as stratification factors, and will include both factors (topical treatment and vaccination) as covariates. If participants do not attend or provide follow-up information, missing data will be dealt with by multiple imputation. Odds ratios with 95% confidence intervals will be reported. For the time-to-event secondary outcomes Kaplan-Meier curves will be produced and Cox regression used to calculate hazard ratios for each of the two effects. We do not anticipate any substantial interaction between topical treatment and vaccination, so that the effect of each factor can be assessed by a simple analysis adjusting for the main effect of the other, along with site and any pre-specified known prognostic factors. Economic outcomes will be collected in the same way as previous studies by the investigators (Woodhall, 2011). Health-related quality of life will be assessed using the EuroQol EQ-5D. Information on types of treatments given, staff attending and number of visits made will be collected. These will be combined with unit costs from standard NHS sources as well as previous economic studies (ibid.) to evaluate treatment costs. Clinical, quality of life and cost data will be used to assess the relative cost-effectiveness of alternative treatment options, with or without vaccination. Cost-effectiveness analyses will be conducted according to the reference case used by the National Institute for Health and Clinical Excellence to ensure comparability with other economic evaluations. Project timetable including recruitment rate: Start-up to first patient enrolment: 6 months Recruitment period: 18 months (55 patients/month) Follow-up from last patient recruitment: 12 months Last follow-up attendance to study completion: 6 months Total study period: 3.5 years from start-up. Setting: Genitourinary medicine clinics, where about 80% cases of anogenital warts treated in the NHS in England and Wales are seen (Health Protection Agency, 2010; 2011). Sites will be invited initially from the network of clinics participating in the HTA-funded PIVOT trial, where these sites also have a sexual health clinic. Target Population: Patients presenting with external anogenital warts, aged 18 or over, males and females, with either a first or subsequent episode of anogenital warts. Exclusion criteria will include wart treatment in the previous 6 months, current or planned pregnancy or lactation, previous quadrivalent HPV vaccine, and known HIV seropositivity. Sample size: The study will recruit 1000 participants with equal numbers randomised to each of the four groups in the 2x2 factorial design, so that allowing for 20% loss to follow-up 800 patients will contribute primary outcome data. The anticipated proportion achieving the primary endpoint in the less favourable treatment arm is 35%, assuming a wart clearance rate of 50% within 16 weeks and a 30% subsequent recurrence rate. The proposed sample size provides 80% power (at the 5% significance level) to detect an increase to 45% with the better treatment. This sample size also provides 80% power to detect an increase from 35% to 45% in the primary endpoint from vaccination, as would arise if vaccination reduces the recurrence rate from 30% to 10% whilst leaving the wart clearance rate unchanged.

Lay abstract: Genital warts are a very common sexually transmitted disease (130,000 cases/year treated in genitourinary medicine clinics in England) and are caused in over 90% cases by human papillomavirus (HPV) types 6 or 11. Podophyllotoxin (as a cream or solution) and imiquimod cream are the most frequently used topical treatments for genital warts, but they have never been adequately compared to determine their relative effectiveness with respect to the clearance or recurrence rate. A vaccine is available to prevent HPV 6 and 11 (as well as HPV 16 and 18, the viruses that cause most cervical cancer), but it is not known whether it will increase the rate of clearance of genital warts if it is given at the same time as topical treatment, or whether it can prevent recurrences. We propose to conduct a 2 x 2 factorial randomised trial of patients with genital warts. The first factor is randomisation to topical treatment with either imiquimod cream or podophyllotoxin cream. The second factor is randomisation to either a course of quadrivalent HPV vaccine (active against HPV types 6/11/16/18) or a control vaccine (against hepatitis A) which has no effect on HPV. This will result in four treatment groups: imiquimod cream plus HPV vaccine; podophyllotoxin cream plus HPV vaccine; imiquimod cream plus hepatitis A vaccine; podophyllotoxin cream plus hepatitis A vaccine. The topical treatment cannot be blinded because of differences in the dosing schedule and treatment duration, whereas the vaccination will be double blinded (i.e. both researcher and patient will be unaware of which vaccine is being given). One thousand patients will be recruited in 25 genitourinary medicine (GUM) clinics in England and Wales. Successful treatment will be defined as clearance of anogenital warts by 16 weeks from randomisation and start of treatment and no relapse between 16 and 48 weeks. The study will also compare the time taken for warts to be cleared with each treatment, the number of patients switching treatment because of non-response to treatment or side-effects, and a standardised measure of health-related quality of life (EQ-5D). An economic analysis will be conducted to compare the cost effectiveness of each treatment. Imiquimod is currently more expensive than podophyllotoxin (although the cost difference is expected to reduce as it is now off patent). The economic benefit of HPV vaccination will be studied if it is demonstrated to be more effective than control. These results will for the first time allow an informed decision on the preferred first line topical genital wart treatment, and in addition will demonstrate whether use of HPV vaccine in patients with warts is beneficial. The study team has conducted clinical and health economic studies of HPV infection, and includes a clinical trials unit (UCL CTU). The research costs of the study are determined by the cost of running a study recruiting 1000 patients, with contributions from NHS Support and Excess Treatment costs. An application to cover the cost of vaccines has been made to the manufacturer.

Research activity codes: 3.4 VACCINES;6.1 PHARMACEUTICALS
Health categories: INFECTION