Evaluation of Adjuvant Nonavalent Human Papillomavirus Vaccination in Preventing Recurrence of Vulvar High-Grade Squamous Intraepithelial Lesion in Women

The primary objective of the VulVaccin study is to evaluate the **efficacy** of adjuvant nonavalent HPV vaccination in women undergoing treatment for pathology-proven **Vulvar High-Grade Squamous Intraepithelial Lesion (vHSIL)** in preventing clinical recurrence of HSIL up to 24 months. This is clinically relevant as it aims to reduce the recurrence rate of vHSIL, a precursor to vulvar cancer, thereby potentially decreasing the incidence of vulvar malignancies.

Secondary objectives include:

• Assessing the effectiveness (complete remission) after treatment in vaccination versus placebo at 6 and 12 months.
• Evaluating complete remission after treatment in vaccination versus placebo at 6 and 12 months in primary episode vHSIL versus recurrence.
• Determining the effectiveness of adjuvant vaccination in different treatments of vHSIL (laser, imiquimod, excision) after 24 months.
• Identifying additional treatment for vHSIL needed during the study period and differences between the study groups.
• Examining the effect of vaccination versus placebo on different HPV types (HPV type of primary and recurrence).
• Comparing the immune response in HPV vaccination versus placebo vaccination.
• Evaluating cost-effectiveness using the IMTA Medical Consumption Questionnaire (iMCQ) and IMTA Productivity Cost Questionnaire (iPCQ).
• Assessing quality of life (measured by Euroqol 5D-5L questionnaire) and sexual health (measured by Female Sexual Function Index, FSFI questionnaire) improvement after vaccination compared to placebo.
• Investigating the effect of vaccination versus placebo on CIN/cervical cytology of the uterine cervix.
• Conducting long-term follow-up to determine the difference between vaccination and placebo groups in the number of recurrences of vHSIL (5 and 10 years) and the occurrence of vulvar malignancies (2, 5, and 10 years).

The clinical trial focuses on evaluating the efficacy of adjuvant nonavalent HPV vaccination in preventing clinical recurrence of **vulvar high-grade squamous intraepithelial lesion (vHSIL)** in women. The study population consists exclusively of female participants aged 18 years or older, who have been histologically diagnosed with vHSIL and are scheduled for treatment, which may include surgical, laser, or imiquimod interventions. The trial does not include male participants or vulnerable populations. The sponsor has not provided information regarding the total number of participants. Participants were selected based on their diagnosis and planned treatment for vHSIL, with no specific lifestyle considerations such as diet or physical activity mentioned. Key inclusion criteria include being a woman aged 18 or older with a confirmed diagnosis of vHSIL and a treatment plan in place.

The clinical trial is designed to evaluate the efficacy of **adjuvant nonavalent HPV vaccination** in women undergoing treatment for vulvar High-Grade Squamous Intraepithelial Lesion (vHSIL) in preventing clinical recurrence of HSIL up to 24 months. This is a randomized, placebo-controlled trial, ensuring that participants are randomly assigned to either the treatment group receiving the Gardasil 9 vaccine or a placebo group. The trial is double-blind, meaning neither the participants nor the researchers know who is receiving the actual vaccine or the placebo, which helps to eliminate bias. The trial is expected to last until January 2029, with recruitment starting in December 2023.

Participants will be involved in the study for a maximum of 52 weeks, with the possibility of early termination if they experience adverse effects or if they choose to withdraw consent. The study visits are structured as follows: an initial inclusion (screening) visit to confirm eligibility based on criteria such as age (18 years or older) and histologically proven vHSIL, followed by treatment planning. Subsequent follow-up visits will occur at 6 and 12 months post-treatment to assess the primary endpoint, which is the difference in clinical recurrence rates of vHSIL between the vaccine and placebo groups. Secondary endpoints will be evaluated at these visits as well, including the recurrence rate of vHSIL and other HPV-related diseases, as well as the cost-effectiveness of the intervention.

The end-of-study visit will occur at 24 months post-treatment, where the final assessment of the primary and secondary endpoints will be conducted. Participants will be monitored for any additional treatments required after the primary intervention and changes in HPV types and antibody levels. The trial aims to provide comprehensive data on the vaccine's effectiveness in reducing recurrence rates and improving the quality of life for women treated for vHSIL. Conditions that may lead to early termination from the study include significant adverse reactions to the vaccine or placebo, non-compliance with study procedures, or withdrawal of consent by the participant.

The clinical trial involves the administration of **Gardasil 9**, a **Human Papillomavirus (HPV) 9-valent Vaccine** (Recombinant, adsorbed), which is utilized as the experimental treatment. This vaccine is presented as a suspension for injection and is administered via **intramuscular injection**. The vaccine contains virus-like particles of HPV types 6, 11, 16, 18, 31, 33, 45, 52, and 58, produced in yeast cells (Saccharomyces cerevisiae) by recombinant DNA technology. The maximum daily dose is 1 ml, with a total maximum dose of 3 ml over a treatment period of up to 52 weeks. The vaccine is manufactured by Merck Sharp & Dohme BV and is authorized under the marketing authorization number EU/1/15/1007/001.

In this study, **Sodium Chloride 0.9%** is used as the placebo comparator. The pharmaceutical form and route of administration for Sodium Chloride 0.9% are not specified in the provided data. However, it is typically used in clinical trials as a control to match the administration method of the experimental treatment, which in this case is likely to be an intramuscular injection. The use of a placebo is essential to evaluate the efficacy of the experimental vaccine by providing a baseline for comparison.

The clinical trial aims to assess the efficacy of adjuvant nonavalent HPV vaccination in women undergoing treatment for vulvar **High-grade Squamous Intraepithelial Lesion (HSIL)**. The primary endpoint for evaluating efficacy is the difference in the number and percentage of patients experiencing clinical recurrence of vulvar HSIL between the HPV vaccination group and the placebo group, monitored up to 24 months post-treatment. Secondary endpoints include the recurrence rate at 6 and 12 months, differences in recurrence rates between primary and recurrent HSIL, and the necessity for additional treatment post-primary intervention.

Additional secondary endpoints involve the description and percentage of different HPV types, the percentage clearance of primary HPV type post-vaccination versus placebo, and the correlation between HPV antibody levels and recurrence rates. The trial will also assess the incremental cost-effectiveness ratio (ICER), quality of life, sexual impact, productivity impact, and changes in HPV types in cervical cytology and HSIL before and after vaccination. The recurrence rate of vulvar HSIL and vulvar cancer, as well as other HPV-related diseases, will be compared between the vaccination and placebo groups.