Contribution of an antiviral drug (Valaciclovir) in the treatment of generalized periodontitis (stage III or IV and grade A, B or C): prospective, randomized and double blind clinical trial.

The primary objective of this clinical trial is to compare the **efficacy** of antiviral treatment with **valaciclovir** in conjunction with conventional non-surgical treatment (scaling and root surfacing) against conventional treatment with a placebo in patients with generalized periodontitis (stage III or IV and grade A, B or C). This evaluation will occur 28 days post-antiviral treatment and 2 months following root surfacing, during the periodontal re-evaluation visit. The clinical relevance of this objective lies in determining whether the addition of valaciclovir can enhance treatment outcomes in managing advanced stages of generalized periodontitis, potentially leading to improved periodontal health and reduced disease progression.

Secondary objectives include:

• Comparing the efficacy of valaciclovir combined with conventional treatment to conventional treatment alone with placebo, assessed 6 and 8 months after root surfacing using conventional periodontal clinical indices.
• Analyzing changes in the levels of EBV, CMV, and HSV-1 viruses, referred to as "periodontal viral load," between the two patient groups throughout the follow-up period.
• Evaluating changes in the quantity of main bacterial species in the periodontal biofilm before, at the end, and after antiviral treatment between both groups.
• Comparing the frequency of periodontal surgery from the periodontal reassessment visit between the two groups.
• Assessing changes in the impact of oral health on the quality of life of patients between both groups.
• Evaluating the medico-economic impact of using valaciclovir with conventional treatment compared to conventional treatment alone.

The clinical trial involves participants diagnosed with **generalized periodontitis** at stage III or IV and grade A, B, or C. The study population includes both male and female subjects aged 18 years and older. Participants are required to have a diagnosis of periodontitis induced by bacterial biofilms of dental plaque. The trial does not include a vulnerable population. Participants of childbearing age are required to use an effective method of contraception during their study participation. The total number of participants is not provided by the sponsor. The selection criteria include the signature of informed consent and membership in a social security scheme. Lifestyle considerations such as diet, physical activity, or habits are not specified in the available data.

The clinical trial is designed to evaluate the efficacy of **valaciclovir**, an antiviral drug, in the treatment of generalized periodontitis, specifically stages III or IV and grades A, B, or C. This study is a prospective, randomized, double-blind, controlled trial comparing the antiviral treatment with conventional non-surgical treatment, such as scaling and root surfacing, against a placebo. The trial is expected to run from July 2023 to August 2026, with a maximum treatment period of 28 days for each participant. The primary endpoint is the measurement of periodontal pocket depth using a calibrated probe at low pressure during the third visit. Secondary endpoints include conventional periodontal clinical indices, viral and bacterial levels in periodontal samples, and the impact on oral health-related quality of life.

Participants will be involved in the study for a period of up to 28 days, with follow-up visits extending to two months post-treatment for periodontal re-evaluation. The sequence of study visits includes an initial screening visit to confirm eligibility based on criteria such as age (≥18 years), diagnosis of periodontitis, and informed consent. Follow-up visits will assess treatment efficacy and safety, with the end-of-study visit occurring after the final evaluation of periodontal health. Conditions that may lead to early termination from the study include non-compliance with the study protocol, withdrawal of consent, or adverse events that compromise participant safety.

The clinical trial involves the administration of **Valaciclovir**, an antiviral medication, in the form of a film-coated tablet. The active substance in this medication is **Valaciclovir**, chemically known as L-valine ester with 9-((2-hydroxyethoxy)methyl)guanine. The pharmaceutical form is a film-coated tablet, with each tablet containing 500 mg of the active substance. The medication is administered orally, with a maximum daily dose of 1000 mg and a total maximum dose of 28000 mg over a treatment period of 28 days. The medication is produced by Mylan Pharmaceuticals Limited and is identified by the marketing authorization number RVG 100108. The trial aims to evaluate the efficacy of this antiviral treatment in comparison to conventional non-surgical treatment for generalized periodontitis.

In addition to the experimental treatment, the study utilizes **Cellulose, Microcrystalline** as a placebo. This substance is provided in the form of an oral powder and serves as an excipient in the trial. The placebo is administered orally, with a maximum daily dose of 1000 mg and a total maximum dose of 28000 mg over the same 28-day treatment period. The use of cellulose, microcrystalline, as a placebo allows for a double-blind study design, ensuring that neither the participants nor the investigators are aware of the treatment assignments, thereby reducing bias in the evaluation of the antiviral treatment's efficacy.

Efficacy in this clinical trial will be assessed by evaluating the impact of antiviral treatment with **valaciclovir** compared to conventional non-surgical treatment for generalized periodontitis. The primary endpoint for efficacy assessment is the measurement of periodontal pocket depth using a graduated and colored probe at low pressure (<0.2N) during visit 3. This measurement will be conducted 28 days after the end of antiviral treatment and 2 months after root surfacing, during the periodontal re-evaluation visit.

Secondary endpoints include conventional periodontal clinical indices such as Bleeding on Probing (BOP), plaque index (PI), Clinical Attachment Level (CAL), and pocket depth at sounding. These indices will be collected from the same tooth used for the primary objective. Additionally, the levels of EBV, CMV, and HSV1 viruses in periodontal samples will be measured through quantitative PCR of their viral genomes. The levels of twenty bacterial species in periodontal samples will also be assessed using quantitative PCR of bacterial genomes. The oral health impact on quality of life will be evaluated using the Oral Health Impact Profile 14 (OHIP-14) questionnaire. Furthermore, the medico-economic impact will be assessed by calculating the incremental cost-effectiveness ratio, relating the cost difference of each strategy to the difference in efficiency, specifically the number of patients who underwent therapeutic surgery during the follow-up period.