Evaluation of Aciclovir and Valaciclovir Hydrochloride in the Treatment of HSV-2 Meningitis: A Double-Blind, Randomized Controlled Trial

The primary objective of this study is to evaluate whether active treatment with **(val)acyclovir** is superior to placebo in the management of **HSV-2 meningitis**. This will be assessed by the number of patients with a Total Morbidity Score (TMS) greater than 6 at 7 days post-randomization. The clinical relevance of this objective lies in determining the efficacy of antiviral therapy in reducing morbidity associated with viral meningitis, which can significantly impact patient outcomes and healthcare strategies.

Secondary objectives include determining the proportions of patients with a favorable outcome during a 3-month follow-up, assessing the completion of allocated treatment (oral or intravenous), evaluating safety, and measuring quality of life through secondary endpoints. These objectives aim to provide a comprehensive understanding of the treatment's long-term benefits and potential risks, thereby informing clinical decision-making and patient care strategies.

The clinical trial focuses on participants diagnosed with **HSV-2 meningitis**. The sponsor has not provided information regarding the total number of participants. The study population includes both male and female subjects, with an age range that encompasses adults and older adults. Participants were selected based on a clinical presentation consistent with viral meningitis, confirmed by cerebrospinal fluid pleocytosis and a positive HSV-2 PCR test. All participants are required to have a Glasgow Coma Scale score of 15 and the ability to absorb oral medications. The trial does not specifically target a vulnerable population, and no particular lifestyle considerations such as diet or physical activity are highlighted as part of the selection criteria.

The clinical trial is designed to evaluate the efficacy of **aciclovir** and its oral prodrug, **valaciclovir**, in treating **HSV-2 meningitis**. This study is a randomized, double-blind, controlled trial, comparing the active treatments with their respective placebos. The trial is expected to commence on June 1, 2025, and conclude by May 31, 2030. Participants will be involved in the study for a maximum of 7 days, corresponding to the treatment period. The primary endpoint is the proportion of patients with a Total Morbidity Score (TMS) greater than 6 at 7 days post-randomization. Secondary endpoints include a reduction in TMS, unfavourable outcomes, and quality of life assessments at various intervals.

Study visits are structured as follows: an initial inclusion (screening) visit will confirm eligibility based on criteria such as clinical presentation consistent with viral meningitis, cerebrospinal fluid pleocytosis, and a positive HSV-2 PCR result. Participants must also have a Glasgow Coma Scale score of 15 and the ability to absorb oral medications. Follow-up visits will occur at 7 days, 3 months, and 12 months post-randomization to assess outcomes and adverse events. The end-of-study visit will coincide with the final follow-up assessment.

Participants may be withdrawn from the study early if they experience severe adverse events, are unable to comply with the study protocol, or if the investigator deems it necessary for their safety. The trial will utilize both intravenous and oral administration routes for the active substances and placebos, ensuring blinding is maintained throughout the study. The trial's design and methodology aim to provide robust data on the effectiveness of aciclovir and valaciclovir in managing HSV-2 meningitis, contributing valuable insights into treatment strategies for this condition.

The clinical trial involves the administration of **Aciclovir** and **Valaciclovir** as experimental medications, alongside a placebo. **Aciclovir** is provided in the form of a solution for infusion, specifically as "Aciclovir Pfizer 25 mg/ml, koncentrat till infusionsvätska, lösning." This pharmaceutical form is a concentrate for solution for infusion, administered intravenously. The maximum daily dose is 5 grams, with a total maximum dose of 35 grams over a treatment period of up to 7 days. The active substance, **Aciclovir**, is of chemical origin and is classified under the ATC code J05AB01. The product is manufactured by Pfizer AB and holds the marketing authorization number 14837 in Sweden.

**Valaciclovir** is administered in the form of film-coated tablets, marketed as "Valaciclovir Sandoz 500 mg compresse rivestite con film." The route of administration is oral, with a maximum daily dose of 3 grams and a total maximum dose of 21 grams over a 7-day treatment period. The active substance, **Valaciclovir Hydrochloride**, is also of chemical origin and is classified under the ATC code J05AB11. This product is manufactured by Sandoz S.P.A. and holds the marketing authorization number 039149188 in Italy.

The placebo used in the study is designed to be identical in appearance to the active products, both in intravenous and tablet forms. It is produced by Euromed Pharma Services S.R.L. The placebo serves as a comparator treatment to evaluate the efficacy of the active medications in the context of the trial. Compliance with the dosing schedule and administration is monitored throughout the study to ensure adherence to the protocol.

Efficacy in the clinical trial titled "Aciclovir for HSV-2 MENingitis: A double-blinded randomised controlled trial (AMEN)" will be assessed using several parameters. The primary endpoint is the proportion of patients with a **Total Morbidity Score (TMS)** greater than 6 at 7 days post-randomisation. Secondary endpoints include the proportion of patients achieving a 50% reduction in TMS score after 7 days compared to the score at randomisation, unfavourable outcomes defined by an Extended Glasgow Outcome Scale (E-GOS) score of less than 7, and all-cause mortality at 7 days, 3 months, and 12 months post-randomisation. Additional secondary endpoints involve the proportion of patients with a headache score greater than 2 at 7 days, persisting neurological symptoms at specified timepoints, completion of the assigned treatment strategy, complications related to peripheral venous lines, duration of hospital admission, severe adverse events during treatment, and quality of life scores and cognitive evaluations using SF-36, EQ-5D-5L, and the Mental Fatigue Scale at 7 days, 3 months, and 12 months post-randomisation.