Evaluation of Nonavalent Human Papillomavirus Vaccine Efficacy in Refractory Palmar and Plantar Warts in Immunocompetent Patients

The primary objective of this study is to evaluate whether the **nonavalent HPV vaccine**, compared to placebo, leads to complete remission of difficult-to-treat palmar or plantar warts in immunocompetent patients, one month after the third injection. This is clinically relevant as it addresses the challenge of managing warts that have not responded to at least two prior treatments, potentially offering a new therapeutic option for these persistent cases.

Secondary objectives include:

• Assessing the improvement of quality-of-life.
• Evaluating the improvement of pain.
• Assessing the improvement for walking and hand impairment.
• Evaluating if the nonavalent HPV vaccine leads to partial remission of difficult-to-treat palmar or plantar warts one month after the third injection in immunocompetent patients.
• Assessing the number of new warts.

The clinical trial involves a study population comprising **immunocompetent** individuals aged 15 years and 3 months or older, both male and female, who are experiencing difficult-to-treat palmar or plantar warts. These participants have had warts for more than one year, with either five or more warts or a total surface area of warts measuring at least 4 cm². The trial population was selected based on their history of receiving two lines of treatment within the past year, with the last treatment administered no more than three weeks prior to inclusion. Participants are required to have painful warts or experience functional or social discomfort due to their condition. The study excludes individuals on systemic immunosuppressive or immunomodulating drugs. Women of childbearing potential must have a negative pregnancy test and use effective contraception throughout the vaccination period. Participants must be affiliated with a social security regimen and capable of adhering to the study protocol. The sponsor has not provided information regarding the total number of participants in the trial.

The clinical trial is designed to evaluate the efficacy of the nonavalent **HPV vaccine** in the treatment of difficult-to-treat palmar or plantar warts. This study is a randomized, double-blind, controlled trial comparing the vaccine to a placebo. The trial is expected to last approximately four years, with an estimated recruitment start date of June 29, 2022, and an estimated end date of June 29, 2026. Participants will be involved in the study for a maximum treatment period of six months.

The sequence of study visits includes an initial screening visit to confirm eligibility based on specific inclusion criteria, such as age, number and size of warts, and previous treatment history. Following the screening, participants will receive three injections of the investigational product or placebo, administered intramuscularly. Follow-up visits are scheduled at months 0, 2, 6, and 7 to assess primary and secondary endpoints, including complete remission of warts, quality of life, pain, and functional discomfort. The end-of-study visit will occur seven months after the first injection to evaluate the primary endpoint of complete remission of cutaneous warts.

Participants are expected to adhere to the study schedule and complete all visits. Conditions that may lead to early termination from the study include the use of systemic immunosuppressive or immunomodulating drugs, non-compliance with study procedures, or withdrawal of consent. Women of childbearing potential must maintain effective contraception throughout the study period. The trial aims to provide valuable insights into the potential benefits of the nonavalent HPV vaccine for patients with challenging wart conditions.

The clinical trial involves the administration of two treatments. The first treatment is **Sodium Chloride**, which is utilized as a comparator in the study. This treatment is provided in the form of a solution for injection. The **Sodium Chloride** solution is administered intramuscularly. The dosage is set at a maximum daily dose of 0.5 ml, with a total maximum dose of 1.5 ml over the course of the treatment. The treatment period is limited to a maximum of six months. The **Sodium Chloride** solution is a chemically derived substance and does not have a marketing authorization number.

The second treatment is the **Gardasil 9** vaccine, which is the experimental medication in this trial. This vaccine is a suspension for injection provided in a pre-filled syringe. It is a nonavalent **Human Papillomavirus (HPV)** vaccine, recombinant and adsorbed, designed to target nine different HPV types. The vaccine is administered intramuscularly. The dosage is consistent with a maximum daily dose of 0.5 ml and a total maximum dose of 1.5 ml, similar to the comparator. The treatment period is also capped at six months. The **Gardasil 9** vaccine is produced by Merck Sharp & Dohme B.V. and holds the marketing authorization number EU/1/15/1007/002. The active substances in the vaccine are structurally diverse and produced in yeast cells using recombinant DNA technology.

The efficacy of the nonavalent HPV vaccine in the treatment of difficult-to-treat palmo-plantar warts will be assessed through a series of primary and secondary endpoints. The primary endpoint is the complete remission of cutaneous warts seven months after the first injection of the vaccine. Secondary endpoints include the evaluation of Quality of Life using the DLQI Questionnaire at months 0, 2, 6, and 7, assessment of pain using the Visual Analogue Scale (VAS) at the same timepoints, and evaluation of functional discomfort for walking and functional disability in hands using the Revised Foot Function Index or Cochin Hand Function Scale, respectively, also at months 0, 2, 6, and 7. Additionally, partial remission of cutaneous warts and the number of new warts appearing at months 2, 6, and 7 will be recorded.