Evaluation of the Efficacy and Safety of Extended-Release Levetiracetam as Adjunctive Therapy in Refractory Partial Onset Epilepsy: A Randomized, Double-Blind Study

The primary objective of this study is to assess the reduction in weekly **Focal Onset Seizures** (FOS) frequency of **levetiracetam** extended release (XR) compared to levetiracetam immediate release (IR) in subjects with drug-resistant FOS. This is clinically relevant as it aims to determine the efficacy of a once-daily extended-release formulation in managing refractory partial onset epilepsy, potentially offering improved seizure control and patient compliance.

Secondary objectives include:

• Assessing the reduction in weekly FOS frequency of levetiracetam XR compared to placebo in subjects with drug-resistant FOS.
• Evaluating the efficacy of levetiracetam XR compared to placebo.
• Exploring the effect of levetiracetam XR compared to levetiracetam IR and placebo on health-related quality of life (HRQoL).

The clinical trial involves a total of **79 participants** diagnosed with **Refractory Partial Onset Epilepsy**. The study population includes both male and female subjects, with an age range of 12 to 80 years for participants from Spain, Poland, and Bulgaria, while other countries include only adult subjects. Participants are required to have a confirmed diagnosis of epilepsy with **Focal-onset seizures** (FOS), with or without secondary generalization, and must be on stable doses of anti-seizure medication for at least four weeks prior to screening. The trial population was selected based on their drug-resistant FOS status, having experienced at least six seizures during an eight-week observational period. Lifestyle considerations include the requirement for females of childbearing potential to use highly effective contraception, and sexually active males with partners of childbearing potential to use acceptable birth control methods. Participants with a Vagal Nerve Stimulator must have stable settings for more than three months prior to screening. The trial includes a vulnerable population, ensuring comprehensive informed consent and compliance with study procedures.

The clinical trial is designed to evaluate the **efficacy** and safety of once-daily, extended-release **levetiracetam** as an add-on therapy in patients with refractory partial onset epilepsy. This study is a double-blind, randomized, placebo, and active-controlled trial. The trial will involve a 12-week double-blind treatment period, with the primary objective being the assessment of the reduction in weekly focal onset seizures (FOS) frequency of levetiracetam extended release (XR) compared to levetiracetam immediate release (IR) in subjects with drug-resistant FOS. The trial is expected to commence recruitment on January 31, 2025, and conclude by July 31, 2026.

Participants will undergo a series of study visits, beginning with an inclusion (screening) visit to confirm eligibility based on criteria such as age, diagnosis of epilepsy with focal-onset seizures, and stable doses of anti-seizure medication (ASM). Following the screening, participants will be randomized to receive either the test product, levetiracetam XR, or a comparator, which includes Keppra 500 mg film-coated tablets or placebo formulations. The study will include follow-up visits to monitor the participants' response to the treatment, adherence to the study protocol, and any adverse events. The end-of-study visit will assess the overall outcomes and collect final data on seizure frequency and quality of life.

The expected length of participant involvement is approximately 12 weeks, corresponding to the duration of the double-blind treatment period. Conditions that may lead to early termination from the study include non-compliance with study procedures, significant adverse events, or withdrawal of consent. The primary endpoint is the percent change from baseline in FOS frequency per week over the 12-week period, while secondary endpoints include changes in absolute FOS, the proportion of subjects with at least a 50% reduction in seizure frequency, and improvements in quality of life measures. The trial will adhere to rigorous scientific standards to ensure the reliability and validity of the results.

The clinical trial involves the administration of several treatments to evaluate the efficacy and safety of **Levetiracetam** in patients with refractory partial onset epilepsy. The primary experimental medication is **Levetiracetam XR**, which is provided in the form of prolonged-release granules in a sachet. The active substance is **Levetiracetam**, a chemical compound, with a maximum daily dose of 1000 mg and a total maximum dose of 8400 mg over a 12-week treatment period. The medication is administered orally once daily. Participant compliance is monitored through regular assessments and adherence checks.

In addition to the experimental medication, the study includes a comparator treatment, **Keppra 500 mg film-coated tablets**, which also contains the active substance **Levetiracetam**. These tablets are repackaged into capsules to maintain the double-blind study design. The dosage and administration route are consistent with the experimental medication, with a maximum daily dose of 1000 mg and a total maximum dose of 8400 mg over the same treatment period.

The trial also utilizes two placebo treatments to ensure the integrity of the double-blind design. The first placebo is **Masked Keppra® placebo film-coated tablets**, which are encapsulated to mimic the appearance of the active treatment. The second placebo is **Levetiracetam prolonged-release placebo granules**, designed to match the experimental medication's form and administration route. Both placebos are administered orally, with dosing schedules aligned with the active treatments to maintain blinding and study integrity.

The efficacy of the clinical trial will be assessed by evaluating the reduction in weekly **Focal Onset Seizures (FOS)** frequency in patients with drug-resistant FOS. The primary endpoint is the percent change from baseline in FOS frequency per week over a 12-week double-blind period. Secondary endpoints include the change from baseline in absolute FOS over the same period, the proportion of subjects achieving at least a 50% reduction in total seizure frequency per week, and the number of days free of FOS during the treatment period. Additionally, the response in weekly FOS frequency will be categorized into six categories according to reduction over the 12 weeks.

Quality of life will be assessed using the Quality of Life in Epilepsy (QoLIE-31) scale for patients aged 18 years and older, and the QoLIE-AD-48 for those under 18, throughout the study period. Patient satisfaction and medication compliance will also be evaluated. These efficacy parameters will be measured and collected at specified timepoints, including baseline and the end of the 12-week treatment period, using validated scales and patient-reported outcomes. The analysis will focus on comparing the efficacy of levetiracetam extended release (XR) to levetiracetam immediate release (IR) as an add-on therapy in the study population.