Efficacy Evaluation of 2LEBV and 2LXFS on Asthenia in Epstein-Barr Virus-Infected Patients: A Randomized, Double-Blind, Placebo-Controlled Trial

The primary objective of this randomized, placebo-controlled, double-blind study is to evaluate the **efficacy** of 2LEBV® and 2LXFS® in reducing fatigue severity in patients with **Epstein-Barr Virus infection** at the end of the treatment period. This is clinically relevant as fatigue is a significant symptom impacting the quality of life in patients with this viral infection.

Secondary objectives include:

• Comparison of the treatment's efficacy on other dimensions of the CIS questionnaire, excluding fatigue, at the end of treatment between the 2LEBV® or 2LXFS®/2LEBV® group versus the placebo group.
• Assessment of the treatment's efficacy on fatigue severity and other CIS questionnaire dimensions at 3 and 12 months between the treatment groups and placebo.
• Evaluation of the treatment's efficacy on other symptoms related to EBV infection and their duration, as well as the evolution of lymphocyte typing, between the treatment groups and placebo at various visits.
• Comparison of the evolution of IgG levels between the treatment groups and placebo at specified visits.
• Assessment of safety issues associated with the treatment.

The clinical trial focuses on individuals diagnosed with **Epstein-Barr Virus infection**, specifically targeting a population experiencing significant fatigue for one month or more. The study includes both male and female participants aged 12 years and older. The trial does not involve a vulnerable population. Participants are required to have a positive serology for EBV, with either IgG or IgM antibodies present. The sponsor has not provided information regarding the total number of participants. The selection criteria include individuals who exhibit at least two additional symptoms such as long-lasting exhaustion, subfebrile state, fever, or loss of appetite, among others. Participants must agree to undergo serology and lymphocyte typing as part of the study requirements. The trial does not specify any particular lifestyle considerations such as diet or physical activity. The sponsor has not disclosed further details regarding the general health status of the participants.

The clinical trial is designed as a **randomized, double-blind, placebo-controlled** study to evaluate the efficacy of two investigational products, 2LEBV and 2LXFS, in patients with **Epstein-Barr Virus infection**. The primary objective is to compare the efficacy of these treatments on fatigue severity at the end of the treatment period, which spans six months. The trial is expected to conclude by June 15, 2026, with recruitment having commenced on November 11, 2020.

Participants will undergo a series of study visits, beginning with an inclusion visit (V0) to confirm eligibility based on criteria such as age, significant fatigue, and positive serology for EBV. Follow-up visits are scheduled at regular intervals, including V1, V3, V4, and V5, to monitor various endpoints. The primary endpoint is assessed using the general fatigue scale of the MFI-20 questionnaire at the six-month visit (V4). Secondary endpoints include assessments of physical fatigue, reduced activity, motivation, mental fatigue, and other EBV-related symptoms at specified visits. Safety evaluations, including the occurrence of adverse events, are conducted throughout the study.

Participant involvement is expected to last for the entire six-month treatment period unless early termination is warranted. Conditions for early termination include the occurrence of severe adverse events or non-compliance with study protocols. The study employs a rigorous methodology to ensure the reliability and validity of the results, with blinding maintained for both participants and investigators to minimize bias.

The clinical trial involves the administration of **2LEBV granules en gélules à ouvrir**, which is an experimental medication formulated as granules in capsules designed to be opened. The active substances in this formulation include **deoxyribonucleic acid (DNA)**, **interleukin-1**, **interleukin-2**, **ribonucleic acid (RNA)**, **specific nucleic acid SNA-EBV**, and **specific nucleic acid SNA-HLA II**. The pharmaceutical form is classified as pillules, and the medication is administered via the oromucosal route. The maximum daily dose is 380 mg, with a total maximum dose of 68.4 g over a treatment period of up to 6 months. Participant compliance is monitored through regular assessments to ensure adherence to the dosing schedule.

Another experimental treatment used in the study is **2LXFS**, also formulated as pillules. This medication contains a combination of active substances, including **interferon alfa**, **deoxyribonucleic acid (DNA)**, **interferon gamma**, **interleukin-1**, **interleukin-2**, **ribonucleic acid (RNA)**, **specific nucleic acids SNA-XFSA**, **SNA-XFSB**, **SNA-XFSC**, **ribonucleic acid K10**, **ribonucleic acid K30**, and **tumor necrosis factor-alpha**. Similar to 2LEBV, 2LXFS is administered oromucosally, with a maximum daily dose of 380 mg and a total maximum dose of 68.4 g over a 6-month period. Compliance is monitored to ensure proper administration and adherence to the treatment regimen.

The study also includes a **placebo** group, which serves as a comparator to evaluate the efficacy of the experimental treatments. The placebo is administered in a form that mimics the experimental medications, ensuring blinding of the study participants and investigators. The placebo is also administered via the oromucosal route, with dosing schedules aligned with those of the active treatments to maintain consistency across the study arms. Compliance with placebo administration is similarly monitored to ensure the integrity of the trial results.

The efficacy of the clinical trial will be assessed by comparing the treatment effects on fatigue severity between the groups receiving 2LEBV® or 2LXFS®/2LEBV® and the placebo group. The primary endpoint for evaluating efficacy is the general fatigue scale of the MFI-20 questionnaire, which will be measured at the end of the treatment during the 6-month visit (V4). Secondary endpoints include assessments of physical fatigue, reduced activity, reduced motivation, and mental fatigue scales on the MFI-20 questionnaire at V4, as well as at V3 and V5. Additionally, other symptoms related to Epstein-Barr Virus (EBV) infection, such as long-lasting exhaustion, fever, and sore throat, will be evaluated at V3, V4, and V5.

Further assessments will include lymphocyte typing and immune status (normo, hypo, or hyperactive immune system) at V1, V3, V4, and V5, along with measurements of IgG anti-EA, anti-VCA, anti-EBNA, and IgM anti-VCA at V0, V1, and V4. Safety will be monitored through the occurrence of Adverse Events (AEs) and Severe Adverse Events (SAEs), whether related or not to the study drug. The trial is designed as a randomized, placebo-controlled, double-blind study to ensure the reliability and validity of the efficacy assessments.