Multicenter, randomized, double-blinded, placebo-controlled phase 3 trial to evaluate nonavalent HPV vaccine as a secondary prevention in patients treated for human papilloma virus related high-grade squamous intraepithelial lesions.(BioHPV)

The primary objective of this phase 3 trial is to assess the efficacy of nonavalent HPV vaccination as secondary prevention in patients with gynecological or anal high-grade squamous intraepithelial lesions (HSIL). This evaluation is clinically relevant for determining whether vaccination can prevent disease recurrence or progression in patients who have already been treated for HPV-related HSIL affecting the vulva, vagina, penis, cervix, or anus.

The secondary objectives include:

• Further characterization of efficacy through assessment of HPV clearance

• Evaluation of HSIL occurrence at different anatomical sites

• Assessment of the occurrence of invasive HPV-related cancer

• Safety evaluation based on reported adverse events

• Cost-utility analysis (cost per QALY) of HPV vaccination compared to no vaccination in patients undergoing HSIL treatment in France

• Budget impact assessment of HPV vaccination in patients undergoing HSIL treatment in France

The sponsor did not provide information regarding the total number of participants enrolled in this clinical trial. The study population includes **women**, **men**, and **transgender** individuals aged **18 to 55 years** diagnosed with biopsy-proven **HPV-related high-grade squamous intra-epithelial lesions (HSIL)** at any anatomical site, including **vulvar**, **vaginal**, **cervical**, **anal**, or **penile** locations at baseline. Participants must have an **ECOG performance status** of 1 or lower, indicating relatively good functional capacity. The trial accepts patients with **HIV infection** provided they are on **antiretroviral therapy** with an **undetectable viral load**. Women of childbearing potential are required to have a negative pregnancy test prior to vaccination, and sexually active participants must use appropriate contraception throughout the study period. Eligible participants must have a life expectancy exceeding five years and be affiliated with a social security system. The study population represents a vulnerable group requiring specialized clinical consideration.

This clinical trial is designed as a multicenter, randomized, double-blind, placebo-controlled phase 3 study to evaluate the efficacy of a nonavalent human papillomavirus vaccine as secondary prevention in patients treated for high-grade squamous intraepithelial lesions related to human papillomavirus. The trial investigates whether HPV vaccination can prevent recurrence of HSIL at various anatomical sites including vulvar, vaginal, cervical, anal, and penile locations in patients who have undergone treatment for these lesions. The study population includes women, men, and transgender individuals aged 18 to 55 years with biopsy-proven HPV-related HSIL at any site at baseline. Patients with an ECOG performance status of 1 or less are eligible, and HIV-infected individuals receiving antiretroviral therapy with undetectable viral load may participate. The trial employs Gardasil 9 suspension for injection as the investigational product, administered intramuscularly at a dose of 0.5 ml per injection, with a maximum total dose of 1.5 ml over the treatment period of 1 year. The placebo formulation contains water for injection, polysorbate 80, propylene glycol, and soya oil, administered via the same route and dosing schedule.

The primary endpoint is the time to HPV type-specific recurrence of HSIL at the initial site after completed HSIL treatment, with centralized HPV genotyping performed on both initial and recurrent lesions. Secondary endpoints include time to HPV clearance, time to HSIL occurrence at different anatomical sites, time to occurrence of invasive HPV-related cancer, and safety assessment based on reported adverse events according to the National Cancer Institute Common Terminology Criteria for Adverse Events version 5.0. Additional secondary outcomes encompass a 50% decrease in HSIL recurrence rate within 2 years of follow-up post-treatment, evaluation of viral and immune signatures for HSIL stratification, assessment of sexual health of enrolled patients and their current sexual partners at baseline and follow-up time points, and resource use and costs through linkage to the French National Health Data System.

The estimated recruitment start date is March 1, 2026, with an estimated study completion date of September 1, 2030, yielding an overall trial duration of approximately 4.5 years. Participant involvement is expected to extend up to 5 years, including a 2-year primary follow-up period and an extended 5-year follow-up period. Study visits include a screening and inclusion visit at baseline where eligibility criteria are verified, biopsy-proven HSIL is confirmed, and baseline assessments are conducted including HPV genotyping and sexual health evaluation. Women of childbearing potential undergo pregnancy testing 24 hours prior to the first vaccine injection. Follow-up visits are scheduled at regular intervals to monitor for HSIL recurrence, assess HPV clearance, evaluate adverse events, and conduct sexual health assessments at 2-year and 5-year time points. An end-of-study visit occurs at the completion of the 5-year follow-up period to finalize all assessments and document final outcomes. Early termination from the study may occur due to withdrawal of informed consent, development of unacceptable toxicity, pregnancy during the vaccination period, protocol violations, loss to follow-up, or at the discretion of the investigator if continuation poses risk to the participant.

The experimental treatment consists of Gardasil 9, a Human Papillomavirus 9-valent Vaccine (Recombinant, adsorbed), available in multiple pharmaceutical presentations. The vaccine is formulated as a suspension for injection and is supplied either in vials or in pre-filled syringes. The active substances comprise nine types of Human Papillomavirus L1 proteins (types 6, 11, 16, 18, 31, 33, 45, 52, and 58), all in adsorbed form as virus-like particles produced in yeast cells (Saccharomyces cerevisiae CANADE 3C-5, strain 1895) by recombinant DNA technology. The vaccine is administered via the intramuscular route. Each single dose contains 0.5 millilitres of the suspension. The maximum daily dose is 0.5 millilitres, and the maximum total dose across the treatment period is 1.5 millilitres, corresponding to three separate administrations. The treatment period extends over 1 year. The marketing authorization number for the European Union is EU/1/15/1007, and the product is manufactured by MERCK SHARP & DOHME B.V.

The control treatment consists of a placebo formulation designed to match the Gardasil vaccine. The placebo is presented as an injection and contains the following inactive components: water for injection, polysorbate 80, propylene glycol, and soya oil. This placebo formulation does not contain any active immunogenic components and serves as a comparator in this double-blinded study. The placebo is administered via the intramuscular route, identical to the active vaccine. The dosing regimen mirrors that of the experimental vaccine, with a maximum daily dose of 0.5 millilitres and a maximum total dose of 1.5 millilitres over the 1-year treatment period, also corresponding to three separate administrations.

Efficacy will be assessed through the evaluation of time to human papillomavirus type-specific recurrence of high-grade squamous intraepithelial lesions at the initial site following completed treatment. Centralized human papillomavirus genotyping of both the initial lesion and any recurrent lesion will be performed to determine type-specific recurrence. Additional efficacy parameters include time to human papillomavirus clearance, time to occurrence of high-grade squamous intraepithelial lesions at different anatomical sites, and time to occurrence of invasive human papillomavirus-related cancer. The reduction in recurrence rate of high-grade squamous intraepithelial lesions by 50% within 2 years of follow-up after completion of treatment will also be evaluated. Safety will be monitored based on reported adverse events according to the National Cancer Institute Common Terminology Criteria for Adverse Events, version 5.0. Viral and immune signatures for high-grade squamous intraepithelial lesion stratification will be assessed. Sexual health of enrolled patients and their current sexual partners will be evaluated at baseline, end of 2-year follow-up, and end of 5-year follow-up. Resource use and costs will be assessed through linkage to the French National Health Data System.