EPX-100 (Clemizole Hydrochloride) as Add-on Therapy to Control Convulsive Seizures in Patients With Dravet Syndrome

Study Overview
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Brief Summary
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The purpose of this study is to evaluate the safety and efficacy of EPX-100 as adjunctive therapy in children and adult participants with Dravet Syndrome.

Detailed Description
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This is a global, multicenter, randomized, double-blind, placebo-controlled study to evaluate the safety and efficacy of EPX-100 as adjunctive therapy in children and adult participants with Dravet Syndrome. The study consists of a 4-week observational period, a 16-week double blind period and a 3-year open label extension.

Official Title
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A 20-Week Multicenter, Randomized, Double-Blind, Placebo-Controlled Trial of EPX-100 (Clemizole Hydrochloride) as Adjunctive Therapy in Children and Adult Participants With Dravet Syndrome (ARGUS Trial)

Conditions
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Dravet Syndrome

Intervention / Treatment
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* Drug: EPX-100 (Clemizole HCl)
* Drug: Placebo


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Male and female participants 2 years and older at time of consent. Participant or parent/Legally Authorized Representative (LAR) willing and able to provide written informed consent, assent (if applicable) prior to initiation of any study related procedures. 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 (not including mild atrophy associated with the natural progression of Dravet Syndrome), and Genetic mutation of the SCN1A gene must be documented. The participant must be approved to participate by the Independent Reviewer, in collaboration with the PI. Participants will be approved for participation following review of the participant's medical and seizure history, historical neuroimaging, historical EEGs, genetic report confirming SCN1A mutation, and review and classification of at least 28 days of baseline seizures. ≥4 countable convulsive seizures within minimum 28-day screening/baseline period (e.g., hemiclonic, secondarily generalized tonic-clonic, generalized tonic-clonic, tonic, clonic, tonic/atonic (resulting in a drop), and focal with clear observable motor signs). Participants should be on a stable regimen of AEDs ≥30 days prior to Visit 1 and generally in good health. Participant or parent/ LAR is able and willing to maintain an accurate and complete daily seizure and medication diary for the duration of the trial. Sexually active women of child-bearing potential (WCBP) must be using a medically acceptable method of birth control and have a negative serum or urine pregnancy test at the screening (Visit 1) and Randomization (Visit 2). A WCBP 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. Exclusion Criteria: The presence of any of the following excludes a participant from study enrollment: Known sensitivity, allergy, or previous exposure to EPX-100 (clemizole HCl). 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. 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. 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 and/or phenytoin, as well as refraining from grapefruits and grapefruit juice during the study period. Refer to Appendix 1 for a list of prohibited drugs. Prior or concurrent use of lorcaserin. 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 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. 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.

Ages Eligible for Study
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Minimum Age: 2 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Parallel Assignment
Interventional Model Description: Patients are randomized 1:1 to EPX-100 or placebo.
Masking: Triple


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Active arm with EPX-100 (Clemizole HCl)<br>EPX-100 oral solution | Drug: EPX-100 (Clemizole HCl)<br>* Daily dose of EPX100<br>* Other names: Clemizole;|
| Placebo Comparator: Placebo arm<br>Color- and taste-matched placebo oral solution dosed to match the active arm. | Drug: Placebo<br>* Daily dose of Placebo<br>* Other names: Placebo to match EPX-100 solution;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| The mean percent change in countable convulsive seizure frequency (CCSF1) in the Titration and Maintenance (T+M) periods relative to baseline. | The mean percent change in countable convulsive seizure frequency (CCSF1) in the Titration and Maintenance (T+M) periods relative to baseline. | 20 weeks | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| The difference between EPX-100 vs placebo in the number of countable convulsive seizure-free days in the T+M periods relative to baseline. | The difference between EPX-100 vs placebo in the number of countable convulsive seizure-free days in the T+M periods relative to baseline. | 20 weeks | 
| The difference between EPX-100 vs placebo in proportion of participants with >50% reduction in the mean CCSF in the T+M periods relative to baseline. | The difference between EPX-100 vs placebo in proportion of participants with >50% reduction in the mean CCSF in the T+M periods relative to baseline. | 20 weeks | 
| The total change in Seizure Severity using Hague Seizure Severity Scale (HASS). | The total change in Seizure Severity using Hague Seizure Severity Scale (HASS). | 20 weeks | 
| The improvement in Clinical Global Impression (CGI). | The improvement in Clinical Global Impression (CGI). | 20 weeks | 
| The total change in Quality of Life in Childhood Epilepsy short form (QOLCE 55). | The total change in Quality of Life in Childhood Epilepsy short form (QOLCE 55). | 20 weeks | 
| The difference between EPX-100 vs placebo in proportion of participants with >25% reduction in the mean CCSF in the T+M periods relative to baseline. | The difference between EPX-100 vs placebo in proportion of participants with >25% reduction in the mean CCSF in the T+M periods relative to baseline. | 20 weeks | 
| The mean difference between EPX-100 vs placebo per 28-days in the percent change of all seizures in the T+M periods relative to the baseline. | The mean difference between EPX-100 vs placebo per 28-days in the percent change of all seizures in the T+M periods relative to the baseline. | 20 weeks | 
| The change in the number of episodes of status epilepticus, in the T+M periods relative to the baseline. | The change in the number of episodes of status epilepticus, in the T+M periods relative to the baseline. | 20 weeks | 
| The incidence of rescue anti-epileptic drug (AED) use between EPX-100 and placebo, as measured by the number of days on rescue AEDs in the T+M periods relative to the baseline. | The incidence of rescue anti-epileptic drug (AED) use between EPX-100 and placebo, as measured by the number of days on rescue AEDs in the T+M periods relative to the baseline. | 20 weeks | 
| The individual item changes in Quality of Life in Childhood Epilepsy short form (QOLCE 55). | The individual item changes in Quality of Life in Childhood Epilepsy short form (QOLCE 55). | 20 weeks | 
| The individual item changes in Seizure Severity using Hague Seizure Severity Scale (HASS). | The individual item changes in Seizure Severity using Hague Seizure Severity Scale (HASS). | 20 weeks | 
| The change in the Sleep Disturbance Scale for Children (SDSC) between EPX-100 and placebo by each scheduled visit | The change in the Sleep Disturbance Scale for Children (SDSC) between EPX-100 and placebo by each scheduled visit | 20 weeks | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Clemizole Hydrochloride, Convulsive Seizure, Pediatric epilepsy, Dravet