Efficacy of 2LPAPI on Clearance of Genital High-Risk Human Papillomavirus Infections: A Randomized, Double-Blind, Placebo-Controlled Trial

The primary objective of this randomized, placebo-controlled, double-blind study is to evaluate the **efficacy** of 2LPAPI® compared to placebo in achieving the clearance of genital high-risk **Human Papillomavirus (HPV)** infections after 12 months of follow-up. This is clinically relevant as persistent HR-HPV infections are associated with the development of cervical cancer and other anogenital cancers, making effective clearance a critical endpoint for reducing cancer risk.

Secondary objectives include:

• Comparison of 2LPAPI® versus placebo on the HR-HPV infection clearance rate at the 6-month visit.
• Assessment of HR-HPV infection clearance rate by HPV type at 6-month and 12-month visits.
• Evaluation of the evolution of cytology.
• Normalization of cytology for the subpopulation of patients with a baseline non-normal cytology.
• Safety assessment through the monitoring of adverse events (AEs) and serious adverse events (SAEs), whether related or not to the study drug.

The clinical trial focuses on evaluating the efficacy of **2LPAPI®** compared to a placebo in the clearance of genital high-risk **Human Papillomavirus (HPV)** infections over a 12-month period. The study population consists exclusively of female participants, specifically women aged between 25 and 45 years. Participants are required to be of childbearing age and must be using effective contraception. The trial does not include a vulnerable population. Participants are expected to have a stable sexual relationship throughout the study duration. The sponsor has not provided information regarding the total number of participants. Key inclusion criteria include having a recent cytology with results ranging from normal to low-grade squamous intraepithelial lesion (LSIL) or cervical intraepithelial neoplasia (CIN) I, and a current diagnosis of high-risk HPV. Participants must also demonstrate the ability to understand and comply with study requirements and have signed the informed consent form. The trial does not involve male subjects, and no specific lifestyle considerations such as diet or physical activity are highlighted.

The clinical trial is designed as a **randomized, placebo-controlled, double-blind** study to evaluate the efficacy of 2LPAPI on the clearance of genital high-risk **Human Papillomavirus (HPV)** infections. The trial aims to compare the efficacy of 2LPAPI versus placebo over a 12-month follow-up period. Participants will be randomly assigned to receive either the active treatment or a placebo, with neither the participants nor the investigators aware of the group assignments, ensuring the double-blind nature of the study. The trial is expected to run from October 15, 2020, to April 30, 2027, with participant involvement lasting up to 12 months.

Study visits are structured to include an initial screening visit, followed by regular follow-up visits at 6 and 12 months, and an end-of-study visit. The screening visit will determine eligibility based on criteria such as age, cytology results, and HPV diagnosis. Follow-up visits will assess the primary endpoint of HPV infection clearance at 12 months, as well as secondary endpoints including infection clearance at 6 months, cytology evolution, and safety assessments. The end-of-study visit will conclude the participant's involvement in the trial.

Participants are expected to remain in the study for the full 12-month duration unless specific conditions necessitate early termination. These conditions may include adverse events, withdrawal of consent, or non-compliance with study protocols. The trial will monitor for adverse events and serious adverse events, which will be evaluated for their relation to the study drug. The study's rigorous design and comprehensive follow-up schedule aim to provide robust data on the efficacy and safety of 2LPAPI in treating high-risk HPV infections.

The clinical trial involves the administration of **2LPAPI granules en gélules à ouvrir**, an experimental medication formulated as granules in capsules designed to be opened. The active substances in this formulation include **interferon alfa**, **ciclosporin A**, **interleukin-1**, **interleukin-2**, **ribonucleic acid**, **specific nucleic acid SNA-HLA II**, and **specific nucleic acid SNA-PAPI**. These substances are derived from proteins and nucleic acids, with ciclosporin A being a chemical compound. The medication is administered via the oromucosal route, with a maximum daily dose of 380 mg and a total maximum dose of 68.4 g over a treatment period of up to 6 months. The pharmaceutical form is described as pillules, and the product is not a pediatric formulation.

The study also includes a **placebo** treatment, referred to as **Placebo 2LPAPI**, which is used as a comparator to evaluate the efficacy of the experimental medication. The placebo is administered in the same manner as the experimental treatment, via the oromucosal route, with identical dosing schedules to ensure blinding and consistency in the trial. The placebo does not contain any active substances and serves to provide a baseline for assessing the therapeutic effects of the 2LPAPI granules.

The efficacy of the investigational product, 2LPAPI, will be assessed in a randomized, placebo-controlled, double-blind clinical trial aimed at evaluating its effect on the clearance of genital high-risk human papillomavirus (**HR-HPV**) infections. The primary endpoint for efficacy evaluation is the clearance of **HR-HPV** infection at the 12-month visit. Secondary endpoints include **HR-HPV** infection clearance at the 6-month visit, clearance by HPV type at both 6-month and 12-month visits, and the evolution of cytology, which will be assessed for normalization, stagnation, or aggravation at these timepoints. Additionally, the normalization of cytology at 6-month and 12-month visits will be specifically evaluated for the subpopulation of patients with a baseline non-normal cytology.

Data collection will occur at specified intervals, with assessments conducted at the 6-month and 12-month visits. The trial will utilize laboratory tests to determine **HR-HPV** infection status and cytology evaluations to monitor changes in cellular morphology. Safety will also be monitored through the recording of adverse events (AEs) and serious adverse events (SAEs), whether related or unrelated to the study drug. The trial is designed to provide comprehensive data on the efficacy and safety of 2LPAPI in the target population over the course of the study period.