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

• ClinicalTrials.gov Identifier: NCT04462770
• Recruitment Status: Recruiting
• First Posted: July 8, 2020
• Last Update Posted: December 19, 2022
• Sponsor: Epygenix
• Information provided by (Responsible Party): Epygenix

Study Description

Brief Summary:

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.

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

Detailed Description:

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.

Study Design

• Study Type: Interventional (Clinical Trial)
• Estimated Enrollment: 100 participants
• Allocation: Randomized
• Intervention Model: Parallel Assignment
• Intervention Model Description: Patients are randomized 1:1 to EPX-100 or placebo.
• 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 Trial of EPX-100 (Clemizole Hydrochloride) as Adjunctive Therapy in Children and Adult Participants With Dravet Syndrome (ARGUS Trial)
• Actual Study Start Date: September 15, 2020
• Estimated Primary Completion Date: December 2024
• Estimated Study Completion Date: December 2024

Arms and Interventions

Arm	Intervention/treatment
Experimental: Active arm with EPX-100 (Clemizole HCl); EPX-100 oral solution	Drug: EPX-100 (Clemizole HCl); Daily dose of EPX100; Other Names: Clemizole Hydrochloride; Clemizole HCl; Clemizole
Placebo Comparator: Placebo arm; Color- and taste-matched placebo oral solution dosed to match the active arm.	Drug: Placebo; Daily dose of Placebo; Other Name: Placebo to match EPX-100 solution

Outcome Measures

Primary Outcome Measures :

1. The mean percent change in countable convulsive seizure frequency (CCSF1) in the Titration and Maintenance (T+M) periods relative to baseline. [ Time Frame: 20 weeks ]
   The mean percent change in countable convulsive seizure frequency (CCSF1) in the Titration and Maintenance (T+M) periods relative to baseline.

Secondary Outcome Measures :

1. The difference between EPX-100 vs placebo in the number of countable convulsive seizure-free days in the T+M periods relative to baseline. [ Time Frame: 20 weeks ]
   The difference between EPX-100 vs placebo in the number of countable convulsive seizure-free days in the T+M periods relative to baseline.
2. 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. [ Time Frame: 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.
3. The total change in Seizure Severity using Hague Seizure Severity Scale (HASS). [ Time Frame: 20 weeks ]
   The total change in Seizure Severity using Hague Seizure Severity Scale (HASS).
4. The improvement in Clinical Global Impression (CGI). [ Time Frame: 20 weeks ]
   The improvement in Clinical Global Impression (CGI).
5. The total change in Quality of Life in Childhood Epilepsy short form (QOLCE 55). [ Time Frame: 20 weeks ]
   The total change in Quality of Life in Childhood Epilepsy short form (QOLCE 55).
6. 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. [ Time Frame: 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.
7. 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. [ Time Frame: 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.
8. The change in the number of episodes of status epilepticus, in the T+M periods relative to the baseline. [ Time Frame: 20 weeks ]
   The change in the number of episodes of status epilepticus, in the T+M periods relative to the baseline.
9. 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. [ Time Frame: 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.
10. The individual item changes in Quality of Life in Childhood Epilepsy short form (QOLCE 55). [ Time Frame: 20 weeks ]
    The individual item changes in Quality of Life in Childhood Epilepsy short form (QOLCE 55).
11. The individual item changes in Seizure Severity using Hague Seizure Severity Scale (HASS). [ Time Frame: 20 weeks ]
    The individual item changes in Seizure Severity using Hague Seizure Severity Scale (HASS).
12. The change in the Sleep Disturbance Scale for Children (SDSC) between EPX-100 and placebo by each scheduled visit [ Time Frame: 20 weeks ]
    The change in the Sleep Disturbance Scale for Children (SDSC) between EPX-100 and placebo by each scheduled visit

Eligibility Criteria

• Ages Eligible for Study: 2 Years and older (Child, Adult, Older Adult)
• Sexes Eligible for Study: All
• Accepts Healthy Volunteers: No

Criteria

Inclusion Criteria:

1. Male and female participants 2 years and older at time of consent.
2. 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.

3. 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.
4. 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.
5. ≥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).
6. Participants should be on a stable regimen of AEDs ≥30 days prior to Visit 1 and generally in good health.
7. 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.
8. 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:

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 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.
5. Prior or concurrent use of 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.

Contacts and Locations

Contacts

Contact: Lorianne Masuoka, M.D.; (415) 933-0826; lm@epygenix.com

Contact: Rebekah DeVitry Fries; rfries@epygenix.com

Locations

United States, California

Children's Hospital of Los Angeles; Recruiting

Los Angeles, California, United States, 90027

Contact: Martha Arellano-Garcia 323-361-5812 margarcia@chla.usc.edu

Principal Investigator: Deborah L Holder, MD

UCSF Medical Center; Recruiting

San Francisco, California, United States, 94158

Contact: Lucy Liu 415-353-8440 Lucy.Liu3@UCSF.edu

Principal Investigator: Ernesto Gonzalez-Giraldo, MD

United States, Illinois

Ann & Robert H. Lurie Children's Hospital of Chicago; Recruiting

Chicago, Illinois, United States, 60611

Contact: Maya Stosic 312-227-4525 mstosic@luriechildrens.org

Principal Investigator: Linda C Laux, MD

United States, Michigan

University of Michigan- Mott Children's Hospital; Recruiting

Ann Arbor, Michigan, United States, 48109

Contact: Brittany Nordhaus 734-936-4179 nbrittan@med.umich.edu

Principal Investigator: Julie Ziobro, MD, PhD

United States, North Carolina

Wake Forest Baptist Health Sciences Department of Neurology; Recruiting

Winston-Salem, North Carolina, United States, 27157

Principal Investigator: Gautam Popli, MD

United States, Ohio

Cincinnati Children's Hospital; Recruiting

Cincinnati, Ohio, United States, 45229

Contact: Samantha Ballard, BSN, RN, CPN 513-803-3177 samantha.ballard@cchmc.org

Principal Investigator: Gewalin Aungaroon, MD

United States, Tennessee

Le Bonheur Children's Hospital; Recruiting

Memphis, Tennessee, United States, 38105

Contact: Kenisha Guy 901-287-7484 Kenisia.Guy@lebonheur.org

Principal Investigator: James Wheless, MD

United States, Texas

Child Neurology Consultants of Austin; Recruiting

Austin, Texas, United States, 78757

Contact: Victoria Henderson 210-416-4163 Victoria_Henderson@mednax.com

Principal Investigator: Karen Keough, MD

United States, Washington

Seattle Children's; Recruiting

Seattle, Washington, United States, 98105

Contact: Laurie Guidry 206-987-0058 laurie.guidry@seattlechildrens.org

Principal Investigator: Russell P Saneto, DO, PhD

Canada, British Columbia

Children's and Women's Health Centre of British Columbia; Recruiting

Vancouver, British Columbia, Canada, V6H 3V4

Contact: Inderpal Gill 604-875-2345 ext 6834 laurie.guidry@seattlechildrens.org

Principal Investigator: Mary Connolly, MD

Canada, Ontario

Children's Hospital of Eastern Ontario; Recruiting

Ottawa, Ontario, Canada, K1H 8L1

Contact: Sarah Healy 613-738-4297 shealy@cheo.on.ca

Principal Investigator: Sharon Whiting, MD

The Hospital for Sick Children; Recruiting

Toronto, Ontario, Canada, M5G 1X8

Contact: Laura MacDougall, PhD, CCRP 416-813-7996 laura.macdougall@sickkids.ca

Contact: Christine Kowal 416-813-7654 christine.kowal@sickkids.ca

Principal Investigator: Elizabeth Donner, MD

Toronto Western Hospital, University Health Network; Recruiting

Toronto, Ontario, Canada, M5T 2S8

Contact: Quratulain Zulfiqar Ali, MD 4166035800 ext 5906 quratulain.zulfiqar_ali@uhn.ca

Principal Investigator: Danielle M Andrade, MD

Sponsors and Collaborators

Epygenix

More Information

• Responsible Party: Epygenix
• ClinicalTrials.gov Identifier: NCT04462770
• Other Study ID Numbers: EPX-100-001
• First Posted: July 8, 2020
• Last Update Posted: December 19, 2022
• Last Verified: August 2022

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 Hydrochloride; Convulsive 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