A Trial of EPX-100 (Clemizole Hydrochloride) as an Add-on Therapy in Children With Dravet Syndrome

• ClinicalTrials.gov Identifier: NCT04462770
• Recruitment Status: Recruiting
• First Posted: July 8, 2020
• Last Update Posted: September 23, 2020
• Sponsor: Epygenix
• Collaborator: GreenLight Clinical PTY LTD
• Information provided by (Responsible Party): Epygenix

Study Description

Brief Summary:

The purpose of this study is to compare the efficacy of EPX-100 against placebo as adjunctive therapy in patients with Dravet Syndrome.

Condition or disease	Intervention/treatment	Phase
Dravet Syndrome	Drug: EPX-100 (Clemizole HCl); Drug: Placebo	Phase 2

Detailed Description:

This is a multicenter, randomized, double-blind, placebo-controlled, proof of concept trial to evaluate the efficacy of EPX-100 (clemizole hydrochloride) in children with Dravet Syndrome. The 20-week study begins with a 4-week Observational Phase which will establish seizure frequency and eligibility for treatment, followed by a 4-week Titration Phase to identify the maximum tolerated dose in each patient. Thereafter, the patient will enter into a 12-week Maintenance Phase. A battery of chemistries, hematology, urinalysis, pharmacokinetics, and ECG's will be monitored throughout the 20-week study. The patient will have the opportunity to enter a 52-week Open-Label Extension phase at the end of the Maintenance Phase. The primary endpoint is the percent change in the 28-day seizure frequency in the final 4-weeks of the 12-week Maintenance Phase relative to the 4-week Observational Phase in the modified intent-to-treat (mITT) population between active and placebo (3:1) therapy.

Study Design

• Study Type: Interventional (Clinical Trial)
• Estimated Enrollment: 24 participants
• Allocation: Randomized
• Intervention Model: Parallel Assignment
• Intervention Model Description: Participants are randomized 3:1 to EPX-100 or placebo dose finding titration starting at 2.0mg /kg/day increasing by 1.0mg/kg/day every 7 days until the maximum tolerated dose (MTD) is reached. If the participant cannot tolerate the 2 mg/kg/day starting dose, he/she will be initiated with 1 mg/kg/day and titrated by 0.5 mg/kg/day weekly until MTD is reached.
• Masking: Triple (Participant, Care Provider, Investigator)
• Masking Description: Matching active vs placebo solutions have been prepared including color and taste.
• Primary Purpose: Treatment
• Official Title: A 20-Week Multicenter, Randomized, Double-Blind, Placebo- Controlled, Proof of Concept Trial of EPX-100 (Clemizole Hydrochloride) as Adjunctive Therapy in Children With Dravet Syndrome
• Estimated Study Start Date: September 2020
• Estimated Primary Completion Date: October 2021
• Estimated Study Completion Date: October 2022

Arms and Interventions

Arm	Intervention/treatment
Active Comparator: Active arm with EPX-100 (Clemizole HCl); EPX-100 oral solution 5mg/mL starting at 2.0 mg/kg/day increasing 1 mg/kg/day every 7 days until the maximum tolerated dose is found. Those intolerant of the 2.0 mg/kg/day starting dose will drop to a dose of 1.0 mg/kg/day and increasing by 0.5 mg/kg every 7 days or to MTD.	Drug: EPX-100 (Clemizole HCl); Daily dose of EPX100; Other Names: Clemizole Hydrochloride; Clemizole HCl
Placebo Comparator: Placebo arm; Color- and taste-matched placebo oral solution dosed to match the active arm at 2.0 mg/kg/day increasing 1 mg/kg/day for every 7 days until the maximum tolerated dose is found.	Drug: Placebo; Daily dose of Placebo; Other Name: Placebo to match EPX-100 solution

Outcome Measures

Primary Outcome Measures :

1. Percent change in 28-day seizure frequency [ Time Frame: 4 weeks ]
   The percent change in seizure frequencies of the final 4 weeks of the 12-week treatment period (Maintenance Phase) relative to the baseline period (Observational Phase) in the modified intent-to-treat (mITT) and per protocol populations.

Secondary Outcome Measures :

1. Proportion of participants with >50 percent reduction in mean seizure frequency in the last 4 weeks compared to the first 4 weeks [ Time Frame: 4 weeks ]
   Mean seizure frequencies >50 percent reduction in the final 4 weeks of the Maintenance Phase are compared with the 4 weeks in the Observational Phase between active and placebo groups
2. Proportion of participants with >25 percent reduction in mean seizure frequency in the last 4 weeks compared to the first 4 weeks [ Time Frame: 4 weeks ]
   Mean seizure frequencies >25 percent reduction in the final 4 weeks of the Maintenance Phase are compared with the 4 weeks in the Observational Phase between active and placebo groups
3. Number of convulsive seizure-free days [ Time Frame: 12 weeks ]
   The number of convulsive seizure-free days during the 12-week Maintenance Phase compared with the Observational Phase compared with placebo
4. Reduction in episodes of status epilepticus [ Time Frame: 4 weeks ]
   Defined as a seizure lasting up to 30 minutes or a series of recurrent seizures lasting ≥5 minutes without return to normalcy between seizures between the 4-week Baseline period (Observational Phase) and the final 4-week period of the 12-week Maintenance Phase and compared with Placebo
5. The incidence of rescue anti-epileptic drug (AED) as measured by the number of days on AEDs [ Time Frame: 12 weeks ]
   The incidence of AEDs as measured by the number of days on rescue AEDs during the 12-week Maintenance Phase as compared with the 4-week Observational Phase on EPX-100 compared with placebo
6. Improvement in Clinical Global Impression (CGI) [ Time Frame: Baseline and 12 weeks ]
   Improvement in Clinical Global Impression compared with baseline and placebo group, scored from 1 to 7 with 1 being the best outcome
7. Change in the Quality of Life in Childhood Epilepsy Questionnaire (QOLCE-55) [ Time Frame: Baseline and 12 weeks ]
   Change in Quality of Life in Childhood Epilepsy Questionnaire compared with baseline and the placebo group, scored from 0 to 100 with higher scores reflecting better quality of life
8. Change in Targeted Behaviour using a Visual Analogue Scale (VAS) [ Time Frame: Baseline and 12 weeks ]
   Change in Targeted Behaviour using Visual Analog Scale compared with baseline and the placebo group, scored 1 to 4 with higher scores reflecting a better outcome
9. Change in the Sleep Disturbance Scale for Children (SDSC) [ Time Frame: Baseline and 12 weeks ]
   Change in the Sleep Disturbance Scale for Children compared with baseline and the placebo group, scored from 1 to 5 with 1 being the best outcome

Eligibility Criteria

• Ages Eligible for Study: 2 Years to 17 Years (Child)
• Sexes Eligible for Study: All
• Accepts Healthy Volunteers: No

Criteria

Inclusion Criteria:

1. Clinical diagnosis of Dravet Syndrome. Participants must have seizures which are not completely controlled by anti-epileptic drugs (AEDs) with the following criteria:

   • Onset of frequent seizures prior to 18 months of age,
   • Normal development at onset,

   • History of seizures that are generalized, unilateral clonic, and/or hemi-clonic, namely:

     • Hemi-clonic (Note: Lateralization - right body, left body, or independent R and L)
     • Focal with clear, observable motor signs (i.e., automatisms, dystonic posturing, focal tonic stiffening)
     • Secondarily generalized tonic clonic (evolving to bilateral convulsive seizure from focal seizure)
     • Generalized tonic clonic convulsion
     • Tonic
     • Clonic (note bilateral: symmetric R and L)
     • Tonic/Atonic - aka 'drop attacks'
   • Brain MRI without cortical malformation, and
   • Genetic mutation of the sodium voltage-gated channel alpha subunit 1 (SCN1A) gene must be documented.
2. The participant must be approved to participate by the PI after a review of the medical history, baseline seizure calendars and inclusion/exclusion criteria. The Independent Reviewer will confirm Dravet Syndrome diagnosis for each participant enrolled in the study.
3. Seizure criteria of ≥4 countable convulsive seizures (tonic-clonic, tonic, clonic, atonic, focal with observable motor signs) per 4-week baseline period (Observational Phase).
4. Participants should be on a stable regimen of AEDs≥30days prior to Visit 1 and generally in good health.
5. Parent or Legal Authorised Representative (LAR) is willing and able to maintain an accurate and complete daily seizure calendar.
6. 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. 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.
7. 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.

Exclusion Criteria:

The presence of any of the following excludes a participant from study enrollment:

1. 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, or fenfluramine as an investigational drug, are excluded, as well as refraining from grapefruits and grapefruit juice during the study period.
5. Has any medical condition that, in the PI's judgement, 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.
6. 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.

Contacts and Locations

Contacts

Contact: Hahn-Jun Lee, M.Sc, Ph.D.; (201) 724-1786; hahnjun7@epygenix.com

Contact: David R Luke, Pharm.D; (860)464-8402; DLuke4@Comcast.net

Locations

United States, New Jersey

NorthEast Epilepsy Group; Recruiting

Hackensack, New Jersey, United States, 07601

Contact 201-343-6676 ext 1 epilepsyNJ@epilepsygroup.com

Principal Investigator: Eric Segal, MD

United States, Texas

Child Neurology Associates; Recruiting

Austin, Texas, United States, 78749

Contact: Maria Alvarado-Garcia 512-494-4000 ext 265 malvaradogarcia@childneurotx.com

Principal Investigator: Aaron Cardon, MD

Sponsors and Collaborators

Epygenix

GreenLight Clinical PTY LTD

Investigators

• Study Director: Hahn-Jun Lee, M.Sc, Ph.D.; Epygenix Therapeutics, Inc.

More Information

• Responsible Party: Epygenix
• ClinicalTrials.gov Identifier: NCT04462770
• Other Study ID Numbers: EPX-100-001
• First Posted: July 8, 2020
• Last Update Posted: September 23, 2020
• Last Verified: September 2020

Individual Participant Data (IPD) Sharing Statement:

• Plan to Share IPD: No

• Studies a U.S. FDA-regulated Drug Product: Yes
• Studies a U.S. FDA-regulated Device Product: No

Keywords provided by Epygenix:

Clemizole; Seizure; Pediatric epilepsy; Dravet

Additional relevant MeSH terms:

Epilepsies, Myoclonic; Syndrome; Disease; Pathologic Processes; Epilepsy, Generalized; Epilepsy; Brain Diseases; Central Nervous System Diseases; Nervous System Diseases; Epileptic Syndromes