A Randomized Phase 2 Study of Adjunctive EQU-001 for Uncontrolled Focal Onset Seizures

The primary objective of this randomized Phase 2 study is to evaluate the **efficacy** of EQU-001, administered at doses of 20 mg and 60 mg per day, as an adjunctive therapy compared with placebo for **focal onset seizures** in subjects with **epilepsy**. This objective is clinically relevant as it aims to determine the potential of EQU-001 to improve seizure control in patients who experience focal onset seizures, which are often challenging to manage with existing treatments.

Secondary objectives include:

• Assessing the efficacy of EQU-001 at doses of 20 mg and 60 mg during a maintenance phase.
• Evaluating the efficacy of EQU-001 at doses of 20 mg and 60 mg in specified seizure types.
• Assessing the subject's impression of change at doses of 20 mg and 60 mg.
• Evaluating the effect on quality of life of EQU-001 in subjects with focal onset seizures at doses of 20 mg and 60 mg daily.
• Assessing the safety and tolerability of EQU-001 in doses of 20 mg and 60 mg per day in subjects with focal onset seizures.

The clinical trial involves a total of **140 participants** diagnosed with **epilepsy**, specifically focusing on those experiencing focal onset seizures. The study population includes both male and female subjects, aged between 18 and 65 years. Participants were selected based on their diagnosis of focal epilepsy according to the ILAE 2017 criteria, with a requirement of having at least eight countable, observable focal seizures during the 8-week baseline period prior to randomization. The trial includes individuals whose seizures have remained uncontrolled despite an adequate trial of at least one anti-seizure medication (ASM) within the last two years. Participants are currently receiving treatment with 1-3 ASMs, with doses stable for at least four weeks prior to screening. Lifestyle considerations include the stability of any implanted devices such as vagal nerve stimulators, responsive neurostimulators, or deep brain stimulators, which must have been implanted and activated more than one year prior to screening. The trial also includes a vulnerable population, ensuring that all participants or their legal representatives are capable of providing informed consent and maintaining an accurate study diary. The study does not specify any particular dietary or physical activity requirements for participants.

The clinical trial is designed to evaluate the efficacy of **EQU-001**, an adjunctive therapy for patients with **epilepsy** experiencing uncontrolled focal onset seizures. This is a randomized, double-blind, placebo-controlled Phase 2 study. Participants will be randomly assigned to receive either EQU-001 at doses of 20 mg or 60 mg per day, or a placebo, with the primary objective being the assessment of the median percentage change in the overall number of countable observable seizures per 28-day period relative to baseline during the double-blind treatment period. The trial is expected to conclude by February 28, 2027, with recruitment having commenced on April 15, 2023.

Participants will undergo a series of study visits, beginning with an inclusion (screening) visit to confirm eligibility based on criteria such as age, seizure history, and current treatment regimen. Following successful screening, participants will enter an 8-week baseline period during which seizure frequency will be monitored. The treatment phase will last 16 weeks, during which participants will continue their stable anti-seizure medication regimen alongside the study drug or placebo. Follow-up visits will occur at regular intervals to monitor safety, efficacy, and any adverse events. The end-of-study visit will conclude the participant's involvement, with assessments to evaluate the overall impact of the treatment.

Participant involvement is expected to last approximately 24 weeks, including the baseline and treatment periods. Conditions that may lead to early termination from the study include significant adverse events, non-compliance with the study protocol, or withdrawal of consent. The study aims to provide valuable insights into the potential benefits of EQU-001 as an adjunctive treatment for focal onset seizures in epilepsy, with secondary endpoints including responder rates and quality of life assessments.

The clinical trial involves the administration of **EQU-001**, an experimental medication formulated as a soft capsule. The active substance in EQU-001 is **ivermectin**, a chemical product provided by Equilibre Biopharmaceuticals B.V. The medication is administered orally, with a maximum daily dose of 60 mg and a total maximum dose of 94,860 mg over a treatment period of up to 1581 days. The trial aims to evaluate the efficacy of EQU-001 as an adjunctive therapy for focal onset seizures in subjects with epilepsy. Participant compliance with the dosing schedule will be monitored throughout the study.

In addition to EQU-001, the trial includes a **placebo** group to serve as a comparator. The placebo is designed to be identical in appearance to the experimental medication but does not contain the active substance. The placebo is also administered orally, following the same dosing schedule as EQU-001, to ensure blinding and maintain the integrity of the study results.

Two auxiliary treatments are included in the study, both classified as chemical products. The first auxiliary treatment is an anxiolytic, categorized under the ATC code N05B, with a pharmaceutical form denoted as PHF00007MIG. This treatment is administered orally, with a maximum daily dose of 60 mg and a total maximum dose of 94,860 mg over the same treatment period. The second auxiliary treatment is an antiepileptic, classified under the ATC code N03A, with a pharmaceutical form denoted as PHF00082MIG. This treatment is also administered orally, with a maximum daily dose of 3 g and a total maximum dose of 4743 g over the treatment period. Both auxiliary treatments are included to support the primary objective of the trial and are not the focus of efficacy evaluation.

The efficacy of EQU-001 as an adjunctive therapy for **focal onset seizures** in subjects with epilepsy will be assessed through a series of primary and secondary endpoints. The primary endpoint is the median percentage change in the overall number of countable observable seizures per 28-day period relative to baseline in each treatment arm during the double-blind treatment period compared with placebo. Secondary endpoints include the median percentage change in seizure frequency during the maintenance phase (treatment weeks 5 through 16), responder rates (≥50%, ≥70%, and ≥90%) in treated arms compared with placebo, and the percentage of subjects who are seizure-free by study days 29-112.

Additional secondary endpoints involve the Patient Global Impression of Change Scale Score at days 56 and 112, changes in the Patient weighted Quality of Life in Epilepsy (QOLIE 31-P) scale score, and the Columbia-Suicide Severity Rating Scale responses. The number of subjects withdrawing due to adverse events and the number of adverse events (CTCAE grade 2 or higher) will also be evaluated. Efficacy assessments will be conducted at specified timepoints, including days 56 and 112, to ensure comprehensive data collection and analysis.