Efficacy and Safety Evaluation of BHV-7000 as Adjunctive Therapy in Adults with Refractory Focal Onset Epilepsy: A Randomized, Double-Blind, Placebo-Controlled Study

The primary objective of this study is to evaluate the **efficacy** of two dose strengths of BHV-7000 compared to placebo as an adjunctive therapy for patients with **refractory focal onset epilepsy**. This is measured by the proportion of subjects achieving at least a 50% reduction in seizure frequency per month (28 days). This objective is clinically relevant as it aims to determine the potential of BHV-7000 to significantly reduce seizure frequency, thereby improving the quality of life for patients with this challenging form of epilepsy.

Secondary objectives include comparing the efficacy of the two dose strengths of BHV-7000 to placebo by assessing the change in 28-day average seizure frequency from the Observation Phase. This further evaluation helps to understand the dose-response relationship and optimize treatment strategies for refractory focal onset epilepsy.

The clinical trial involves a total of **180 participants** diagnosed with **refractory focal onset epilepsy**. The study population includes both male and female subjects aged between 18 to 75 years. Participants were selected based on their ability to comply with study requirements, including maintaining accurate seizure diaries. The trial population is characterized by individuals who have been diagnosed with focal onset epilepsy for at least one year and meet the criteria for drug-resistant epilepsy as defined by the International League Against Epilepsy. Participants are currently undergoing treatment with no more than four epilepsy treatments, which may include anti-seizure medications, dietary regimens, or neurostimulation devices. The study does not specify any particular lifestyle considerations such as diet or physical activity beyond the epilepsy treatments mentioned. The trial includes a vulnerable population, ensuring a comprehensive evaluation of the adjunctive therapy's efficacy across a diverse group of individuals.

The clinical trial is designed as a **randomized**, **double-blind**, **placebo-controlled** study to evaluate the efficacy, safety, and tolerability of BHV-7000 in subjects with **refractory focal onset epilepsy**. The trial aims to compare two dose strengths of BHV-7000 to a placebo, with the primary endpoint being the proportion of subjects achieving at least a 50% reduction in seizure frequency over a 28-day period. Secondary endpoints include changes in seizure frequency and the proportion of subjects achieving higher reductions or complete seizure freedom.

The trial is expected to commence recruitment on July 18, 2024, and conclude by August 18, 2025. Participants will be involved for a maximum treatment period of 12 weeks, with the study drug administered orally in the form of a prolonged-release tablet. The trial will include an initial screening visit to confirm eligibility based on criteria such as age, ability to swallow the tablet, and compliance with seizure diary entries. Following the screening, participants will enter a double-blind period (DBP) where they will receive either BHV-7000 or a placebo.

Study visits will be scheduled to monitor the participants' health and response to the treatment. These visits will include assessments of seizure frequency, safety evaluations, and compliance checks. The end-of-study visit will occur at the conclusion of the 12-week DBP, where final assessments will be conducted. Participants may be withdrawn from the study if they experience severe adverse events, fail to comply with the study protocol, or choose to withdraw consent.

The trial will adhere to strict inclusion and exclusion criteria to ensure the safety and reliability of the results. Participants must have a documented diagnosis of focal onset epilepsy for at least one year and meet the International League Against Epilepsy's definition of drug-resistant epilepsy. The study will not include individuals with more than four concurrent epilepsy treatments or those unable to comply with the study requirements.

The clinical trial involves the administration of **BHV-7000**, a **prolonged-release tablet** developed by Biohaven Therapeutics Ltd. This experimental medication is designed for oral administration and is available in two dosage strengths. The first dosage strength is 50 mg, with a maximum total dose of 4200 mg over a 12-week treatment period. The second dosage strength is 25 mg, with a maximum total dose of 2100 mg over the same treatment period. The active substance in both formulations is chemically derived and is consistently referred to as BHV-7000. The administration schedule is structured to ensure participant compliance, with dosing occurring at regular intervals as per the study protocol.

In addition to the experimental medication, a **placebo** is utilized as a comparator treatment in this double-blind, placebo-controlled study. The placebo is designed to mimic the appearance of the BHV-7000 tablets but contains no active pharmaceutical ingredients. The use of a placebo is critical in evaluating the efficacy and safety of BHV-7000 by providing a baseline for comparison. Participants are randomly assigned to receive either the active medication or the placebo, ensuring the integrity of the study's blinding process. Compliance with the dosing regimen is monitored throughout the trial to maintain the validity of the results.

The efficacy of the investigational product **BHV-7000** in the treatment of refractory focal onset epilepsy will be assessed through a series of primary and secondary endpoints. The primary endpoint is the proportion of subjects achieving at least a 50% reduction in the 28-day average seizure frequency during the double-blind period (DBP) compared to the open-label period (OP). Secondary endpoints include changes in log-transformed 28-day adjusted seizure frequency from the OP over the 12-week DBP and the first month of the DBP, as well as the proportion of subjects with at least a 75% reduction in seizure frequency and those who are seizure-free during the DBP. Additionally, the change in log-transformed 7-day adjusted seizure frequency from the OP over the first week of the DBP will be evaluated. The proportion of subjects at week 12 with a Patient Global Impression of Change (PGI-C) response of "minimally improved," "much improved," or "very much improved" will also be assessed. Efficacy assessments will be conducted using validated scales and patient-reported outcomes at specified timepoints throughout the trial.