Efficacy and Safety Evaluation of BHV-7000 in Adults with Refractory Focal Onset Epilepsy: A Phase 2/3 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 **refractory focal onset epilepsy**. This is measured by the proportion of subjects achieving at least a 50% reduction in seizures per month (28 days). This objective is clinically relevant as it aims to determine the potential of BHV-7000 to significantly reduce seizure frequency, which is a critical outcome for improving the quality of life in patients with refractory focal onset epilepsy.

Secondary objectives include:

• Comparing the efficacy of each of two dose strengths of BHV-7000 to placebo as an adjunctive therapy for refractory focal onset epilepsy, measured by the change from the baseline in 28-day average seizure frequency.
• Comparing the efficacy of BHV-7000 to placebo during the first month of treatment.
• Comparing the efficacy of BHV-7000 to placebo as measured by the proportion of subjects achieving at least a 75% reduction in seizures per month (28 days).
• Comparing the efficacy of BHV-7000 to placebo on seizure freedom, defined as a 100% seizure reduction during the double-blind phase.
• Comparing the efficacy of BHV-7000 to placebo during the first week of treatment.
• Comparing the efficacy of BHV-7000 to placebo on the patient global impression of change (PGI-C) at week 8.
• Assessing the safety and tolerability of BHV-7000.

The clinical trial involves a total of **206 participants** diagnosed with **Refractory Focal Onset Epilepsy**. The study population comprises both male and female subjects, aged between 18 to 75 years. Participants were selected based on their diagnosis of Focal Onset Epilepsy for at least one year prior to the screening visit, as defined by the 2017 International League Against Epilepsy (ILAE) Classification. The trial includes individuals who meet the 2009 ILAE definition of drug-resistant epilepsy, having failed adequate trials of two tolerated and appropriately chosen anti-seizure medication schedules. Participants are required to be currently treated with at least one and up to three anti-seizure medications, with a total of up to four epilepsy treatments, which may include a diet regimen or device. The ability to maintain accurate seizure diaries is also a prerequisite. The trial population includes a vulnerable group, ensuring a comprehensive evaluation of the adjunctive therapy's efficacy across a diverse demographic.

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 the efficacy of two dose strengths of BHV-7000 to placebo as adjunctive therapy, with the primary endpoint being the proportion of subjects achieving at least a 50% reduction in seizures per month. The trial is expected to commence recruitment on September 1, 2024, and conclude by September 30, 2025, with an overall duration of approximately 13 months.

Participants will undergo a series of study visits, beginning with an inclusion (screening) visit to assess eligibility based on criteria such as age, diagnosis, and current treatment regimen. Following successful screening, participants will be randomized to receive either BHV-7000 or placebo in a prolonged-release tablet form, administered orally. The study will include multiple follow-up visits to monitor safety and efficacy, with assessments of seizure frequency and adverse events. The end-of-study visit will conclude the participant's involvement, during which final evaluations will be conducted.

The expected length of participant involvement is approximately 8 weeks, corresponding to the maximum treatment period. Conditions that may lead to early termination from the study include the occurrence of severe adverse events, non-compliance with study procedures, or withdrawal of consent. The trial will adhere to rigorous scientific standards to ensure the reliability and validity of the results, contributing valuable data to the understanding and management of refractory focal onset epilepsy.

The clinical trial involves the evaluation of **BHV-7000**, an experimental medication, in subjects with refractory focal onset epilepsy. **BHV-7000** is administered in the form of a **prolonged-release tablet**. The active substance, also named **BHV-7000**, is of chemical origin and is provided by Biohaven Therapeutics Ltd. The medication is administered orally, with a maximum daily dose of 75 mg and a total maximum dose of 4200 mg over the treatment period. The treatment duration is set for a maximum of 8 weeks. Participant compliance with the dosing schedule is monitored throughout the trial to ensure adherence to the prescribed regimen.

In addition to the experimental medication, the study includes a **placebo** group to serve as a comparator. The placebo, referred to as **Placebo BHV-7000**, is designed to match the experimental medication in appearance but does not contain the active substance. The placebo is administered under the same conditions as the experimental drug to maintain the double-blind nature of the study. This ensures that neither the participants nor the investigators are aware of the treatment assignments, thereby reducing bias and allowing for an accurate assessment of the efficacy and safety of **BHV-7000**.

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 8-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, along with the proportion of subjects at Week 8 with a Patient Global Impression of Change (PGI-C) response of "minimally improved," "much improved," or "very much improved."

Data collection will occur at specified intervals throughout the trial, with efficacy assessments being conducted using validated scales and patient-reported outcomes. The analysis will focus on comparing the efficacy of two dose strengths of **BHV-7000** to placebo as adjunctive therapy. The trial is designed as a Phase 2/3 multicenter, randomized, double-blind, placebo-controlled study, ensuring rigorous evaluation of the investigational product's efficacy in the target population. The study will adhere to the International League Against Epilepsy (ILAE) criteria for defining focal onset epilepsy and drug-resistant epilepsy, ensuring that participants meet the necessary diagnostic criteria for inclusion in the trial.