Evaluation of Clemizole Hydrochloride (EPX-100) as Adjunctive Therapy in Pediatric and Adult Dravet Syndrome: A Randomized, Double-Blind, Placebo-Controlled Trial

Trial ID: 2024-518628-57-00
Protocol: EPX-100-001
Sponsor: Epygenix Therapeutics Inc.

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Diseases & Conditions

Severe myoclonic epilepsy of infancy

Objectives

The primary objective of this study is to evaluate the **efficacy** of EPX-100 (Clemizole Hydrochloride) compared with placebo as adjunctive therapy in children and adult participants with **Dravet syndrome**. The evaluation focuses on the mean percent change in countable convulsive seizure frequency during the Titration and Maintenance periods relative to baseline. This is clinically relevant as it aims to determine the potential of EPX-100 to reduce seizure frequency, which is a significant concern in managing Dravet syndrome.

Participants

The clinical trial involves a total of **37 participants** diagnosed with **Dravet syndrome**, a severe form of epilepsy. The study population includes both male and female participants aged 2 years and older. Participants were selected based on a clinical diagnosis of Dravet syndrome, with seizures not fully controlled by antiepileptic drugs (AEDs). The trial includes individuals with a documented genetic mutation of the SCN1A gene and a history of specific seizure types. Participants are required to be on a stable AED regimen for at least 30 days prior to the study and must generally be in good health. The trial population is composed of both children and adults, and it includes a vulnerable population. Lifestyle considerations such as maintaining an accurate daily seizure calendar are essential for participation. The study excludes pregnant women, and sexually active women of child-bearing potential must use medically acceptable birth control methods. The selection process ensures that participants meet specific health and lifestyle criteria to accurately assess the efficacy of EPX-100 as an adjunctive therapy.

Plans and Procedures

The clinical trial is designed as a **randomized**, **double-blind**, **placebo-controlled** study to evaluate the efficacy of EPX-100 (**clemizole hydrochloride**) as an adjunctive therapy in children and adult participants with **Dravet syndrome**. The trial will span a total duration of 20 weeks, with the primary objective being to assess the mean percent change in countable convulsive seizure frequency during the Titration and Maintenance periods relative to baseline. Participants will be randomly assigned to receive either the investigational medicinal product or a placebo, which is identical in appearance apart from the active substance.

The sequence of study visits begins with an inclusion (screening) visit, where participants are assessed for eligibility based on specific criteria, including age, clinical diagnosis, and seizure history. Following successful screening, participants will enter the baseline observational phase, during which seizure frequency is documented. Subsequent visits will occur throughout the Titration and Maintenance periods, where the investigational product or placebo is administered, and efficacy and safety assessments are conducted. The trial concludes with an end-of-study visit, where final evaluations are performed, and data is collected for analysis.

Participant involvement is expected to last for the entire 20-week duration of the trial, provided they meet all ongoing eligibility criteria and do not experience any adverse events or conditions that necessitate early termination. Conditions that may lead to early withdrawal include significant protocol deviations, adverse reactions, or withdrawal of consent. The trial is structured to ensure rigorous data collection and analysis, with the primary endpoint being the comparison of seizure frequency changes between the EPX-100 and placebo groups.

Treatment

The clinical trial involves the administration of **EPX-100**, an investigational medicinal product containing the active substance **clemizole hydrochloride**. This compound is provided in the form of an **oral solution**. The maximum daily dose of EPX-100 is 160 mg, with a total maximum dose of 192.64 g over the course of the study. The treatment period extends up to 172 days. The route of administration is oral, and the medication is to be taken as per the dosing schedule outlined in the study protocol. Participant compliance with the dosing regimen will be monitored throughout the trial.

The study also includes a **placebo** group, where participants receive a placebo that is identical in appearance and administration to the investigational medicinal product, except for the absence of the active substance. The placebo is administered orally, following the same schedule as the EPX-100 group, to maintain the double-blind nature of the trial. The placebo serves as a comparator to evaluate the efficacy of EPX-100 in reducing the frequency of convulsive seizures in participants with Dravet Syndrome.

Efficacy

The efficacy of EPX-100 (Clemizole Hydrochloride) as an adjunctive therapy in children and adult participants with **Dravet Syndrome** will be assessed by evaluating the mean percent change in countable convulsive seizure frequency (CCSF1) during the Titration and Maintenance (T+M) periods relative to baseline. This primary endpoint will be measured to determine the difference in seizure frequency between the EPX-100 treatment group and the placebo group. The trial is designed as a 20-week multicenter, randomized, double-blind, placebo-controlled study.

Inclusion and Exclusion Criteria

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Inclusion Criteria

Male and female outpatient participants 2 years and older at time of consent. 2. Clinical diagnosis of Dravet Syndrome. Participants must have seizures which are not completely controlled by AEDs with the following criteria: • Onset of seizures prior to 18 months of age, • Normal development at onset, • History of seizures that are generalized, unilateral clonic, and/or hemiclonic, • Brain MRI without cortical malformation, and • Genetic mutation of the SCN1A gene must be documented. 3. The participant must be approved to participate by the PI after review of the medical history, baseline seizure diaries and inclusion/exclusion criteria. The Independent Reviewer will confirm Dravet Syndrome diagnosis for each participant enrolled in the study and adjudicate all seizure types on the seizure diaries. 4. #X countable convulsive seizures with observable motor signs) per 4-week baseline period (Observational Phase). 5. Participants should be on a stable regimen of AEDs #30 days prior to Visit 1 and generally in good health. 6. Parent or LAR is able and willing to maintain an accurate and complete daily seizure calendar. 7. Sexually active women of child-bearing potential (WCBP) must be using a medically acceptable method of birth control and have a negative urine pregnancy test at the screening visit. AWCBP is defined as a female who is biologically capable of becoming pregnant. A medically acceptable method of birth control includes intrauterine devices in place for at least 3 months, surgical sterilization, or adequate barrier methods (e.g.,diaphragm and foam). Use of oral contraceptives in combination with another method (e.g., a spermicidal cream) is acceptable. In participants who are not sexually active, abstinence is an acceptable form of birth control and urine will be tested per protocol. Women who are of non-child-bearing potential, i.e., post-menopause, must have this condition captured in their medical history.Pregnant women are excluded from this study. 8. Have parent or LAR available and willing to give written informed consent, after being properly informed of the nature and risks of the study and prior to engaging in any study- related procedures.

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Exclusion Criteria

Known sensitivity, allergy, or previous exposure to EPX-100 (clemizole HCl). 2.Exposure to any investigational drug or device <90 days prior to screening or plans to participate in another drug or device trial at any time during the study. 3. Seizures secondary to illicit drug or alcohol use, infection, neoplasm, demyelinating disease, degenerative neurological disease, or central nervous system (CNS) disease deemed progressive, metabolic illness, or progressive degenerative disease. 4. Concurrent use of drugs known to interfere with EPX-100, including moderate or severe inducers or inhibitors of CYP3A4/5/7. Specifically, concurrent use of carbamazepine, oxcarbazepine, phenytoin, and/or phenobarbital, as well as refraining from grapefruits and grapefruit juice during the study period. Refer to Appendix 1 for a list of prohibited drugs. 5. Prior or concurrent use of fenfluramine or lorcaserin. 6. Concurrent use of fenfluramine. Participants with prior use of fenfluramine within the previous 3 months, or without proper documentation of an echocardiogram, at minimum 3 months following the last dose of fenfluramine, to ensure that the participant does not meet any criteria for drug-related (fenfluramine) cardiac valvular heart disease and/or drug-related pulmonary arterial hypertension (PAH) as indicated by any of the following: • documented mild or greater aortic regurgitation [AR] or moderate or greater mitral regurgitation [MR] • significant (greater than mild) tricuspid regurgitation • abnormally thickened cardiac valve and/or has restricted motion of the valve leaflets • elevated right heart/pulmonary artery pressure >35mmHg 7. Has any medical condition that, in the PI's judgment, is considered to be clinically significant and could potentially affect participant safety or study outcome, including but not limited to: clinically significant cardiac disease (including angina, congestive heart failure, uncontrolled hypertension, and history of arrhythmias), renal, pulmonary, gastrointestinal, hematologic or hepatic conditions; or a condition that affects the absorption, distribution, metabolism, or excretion of drugs. 8. Has an active suicidal plan/intent or have had active suicidal thoughts in the past 6 months or a suicide attempt in the past 3 years.