Study of EQU-001 for Uncontrolled Focal Onset Seizures

Sponsor

Equilibre Biopharmaceuticals B.V. (Industry)

Overall Status

Not yet recruiting

CT.gov ID

NCT05473442

Collaborator

(none)

300

Enrollment

Arms

Anticipated Duration (Months)

Study Details

Study Description

Brief Summary

This study is a Phase 2 multinational, double-blind, placebo-controlled, randomized (1:1:1), efficacy and safety study of adjunctive EQU-001 for the treatment of focal onset seizures in subjects aged 18 to 65 years, who have been diagnosed with epilepsy according to International League Against Epilepsy (ILAE) Classification of the Epilepsies 2017 criteria This study is designed to test the efficacy and safety of EQU-001 20 mg and 60 mg as compared with placebo as an add-on anti-seizure medication (ASM) in subjects with uncontrolled focal onset seizures.

The treatment portion of the study will be comprised of a 4-week double-blind medication activation period and a 12-week double-blind maintenance period.

Condition or Disease	Intervention/Treatment	Phase
Focal Onset Seizures	Drug: EQU-001 Other: Matching Placebo	Phase 2

Study Design

Study Type:

Interventional

Anticipated Enrollment :

300 participants

Allocation:

Randomized

Intervention Model:

Parallel Assignment

Intervention Model Description:

Double-blind, placebo-controlled, randomized at a 1:1:1 ratio to receive 20 mg of EQU-001, 60 mg of EQU-001 or a matched placeboDouble-blind, placebo-controlled, randomized at a 1:1:1 ratio to receive 20 mg of EQU-001, 60 mg of EQU-001 or a matched placebo

Masking:

Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor)

Primary Purpose:

Treatment

Official Title:

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

Anticipated Study Start Date :

Nov 1, 2022

Anticipated Primary Completion Date :

Nov 1, 2024

Anticipated Study Completion Date :

Nov 1, 2026

Arms and Interventions

Arm	Intervention/Treatment
Experimental: EQU-001 60 mg EQU-001 60 mg (3 x 20 mg pills)	Drug: EQU-001 20 mg pills of EQU-001
Experimental: EQU-001 20 mg EQU-001 20 mg (1 x 20 mg pill + 2 x matching placebo pills)	Drug: EQU-001 20 mg pills of EQU-001 Other: Matching Placebo 20 mg matching placebo pills
Placebo Comparator: EQU-001 0 mg EQU-001 0 mg (3 x matching placebo pills)	Other: Matching Placebo 20 mg matching placebo pills

Arm

Intervention/Treatment

Experimental: EQU-001 60 mg

EQU-001 60 mg (3 x 20 mg pills)

Drug: EQU-001

20 mg pills of EQU-001

Experimental: EQU-001 20 mg

EQU-001 20 mg (1 x 20 mg pill + 2 x matching placebo pills)

Drug: EQU-001

20 mg pills of EQU-001

Other: Matching Placebo

20 mg matching placebo pills

Placebo Comparator: EQU-001 0 mg

EQU-001 0 mg (3 x matching placebo pills)

Other: Matching Placebo

20 mg matching placebo pills

Outcome Measures

Primary Outcome Measures

Median percentage change in the overall number of countable observable seizures [Every 4 weeks from week 1 up to week 16]
per 28-day period relative to baseline in each treatment arm during the double-blind treatment period compared with placebo.

Secondary Outcome Measures

Median percentage change in the overall number of countable observable seizures [Every 4 weeks from week 5 up to week 16]
per 28-day period relative to baseline in each treatment arm during the maintenance phase compared with placebo
≥ 50% responder rates [Week 1 to 16]
In the treated arms as compared with placebo during double blind components of the study, which consist of the medication activation and maintenance period
≥ 50% responder rates [Week 5 to 16]
In the treated arms as compared with placebo during the maintenance period alone
Difference in PGI-C Scale: Patient's Global Impression of Change (PGIC) [Week 6 to 16]
In each treated cohort as compared with placebo at days 42 and 112. PGI-C Scale ranges from 'Very much improved' to 'Very much worse'
Median percentage change in the number of countable observable seizures by subtype [Week 1 to 16]
Subtype (focal aware with motor component, focal impaired aware, and focal to bilateral tonic-clonic) per 28 days during the maintenance period (treatment weeks 5-16) and during the entire double blind period in the treated and placebo arms
Percent (%) of subjects who are seizure free [Week 5 to 16]
by study days 29-112
Percent (%) of subjects who are seizure free in treated arms as compared with placebo [Week 5 to 16]
≥ 70% and ≥ 90% response rates in treated arms compared with placebo [Week 5 to 16]
during the maintenance period
Change from visit 2 (enrollment) in the Patient weighted Quality of Life in Epilepsy (QOLIE 31-P) scale score [Week 6 to 16]
at days 42 and 112 in each treated arm as compared with placebo
Number of subjects who withdraw from treatment [Week 1 to 16]
because of an AE in each treatment arm
Number of adverse events (CTCAE grade 2 or higher) [Week 1 to 16]
in the treatment arms compared with placebo
Change in Columbia-Suicide Severity Rating Scale (C-SSRS) [Week 1 to 16]
from visit 2 in each treated arm as compared with placebo at each measured timepoint

Eligibility Criteria

Criteria

Ages Eligible for Study:

18 Years to 65 Years

Sexes Eligible for Study:

All

Accepts Healthy Volunteers:

Inclusion Criteria:

Age 18- 65 years at time of informed consent
The subject or designee is willing and able to keep an accurate study diary, the subject is able to adhere to the protocol, the subject or the subject's legal representative is able read, understand, and sign informed consent, as applicable.
Diagnosed with focal epilepsy according to ILAE (2017) criteria. Diagnosis to include clinical history and an EEG consistent with focal epilepsy. A normal interictal EEG is allowed when the clinical history is consistent with focal epilepsy.
Subject has no seizures that are not focal by the ILAE 2017 criteria
Subject must have 8 countable, observable focal seizures during the 8-week baseline period prior to randomization, including at least 3 in each 4-week period with no 21-day seizure-free period. These seizures must be observable (focal aware with motor component, focal impaired awareness, focal to bilateral tonic-clonic) and as such may not include focal aware seizures without a detectable motor component, aphasia, or other observable symptom.
Must have had a brain MRI or contrast-enhanced head CT scan with an available report (images need not be available) that has been performed within the past 10 years and that is negative for confounding conditions such as tumor, infection, demyelinating disease, or other progressive neurological disease. Remote stroke that may represent the etiology for epilepsy is allowed. If no such CT or MRI report is available, a potential subject will be asked to undergo a head CT scan with intravenous contrast to meet eligibility criteria prior to study enrollment.
Seizures uncontrolled after an adequate trial of at least 1 ASM within the last 2 years.
Currently receiving treatment with 1-3 ASMs with doses stable for at least 4 weeks prior to screening. These medications must stay stable during the 8-week baseline period and during the 16-week treatment period. In the case that the plasma level of a concomitant ASM changes, the subject and their physician may then modify the dose to maintain the plasma level that was present prior to beginning the study drug. and must document the change in the EDC system.
If participant has a vagal nerve stimulator (VNS), responsive neurostimulator (RNS) or deep brain stimulator (DBS), it must have been implanted and activated >1 year prior to screening, and stimulation parameters that have been stable for >3 months, and battery life of unit anticipated to extend for duration of trial.
Females of childbearing potential who are not sexually inactive (abstinent) for 14 days prior to the first dose, throughout the study, and then for 14 days following the last dose, must agree to use acceptable birth control methods:

Exclusion Criteria:

Pregnant or lactating
History of hypersensitivity to ivermectin or to any of the excipients in the EQU-001 gelcap
History of status epilepticus in the past 1 year from screening
History of pseudo- or nonepileptic seizures, or other nonepileptic events that could be confused with epileptic seizures, within the past 5 years
History of traumatic brain injury within 30 days prior to screening
Resective epilepsy surgery within 1 year; epilepsy-related radiosurgery within 2 years
Presence of progressive neurological disorder or other progressive disorder or unstable medical condition(s) that may confound study results. History of long QT syndrome, family history of sudden death of unknown cause.
Psychiatric disorder where changes in pharmacotherapy are needed or anticipated during the study or which would interfere with the subject's ability to participate in the trial
Active suicidal plan/intent in the past 6 months, a history of suicide attempt in the last 2 years, or more than 1 lifetime suicide attempt as evidenced by a positive response to C-SSRS questions 4 or 5
History of substance use disorder, including alcohol, within the past 2 years
Currently in another investigational drug study
Currently on felbamate for less than one year before visit 1 (aplastic anemia and hepatic failure usually occur within 6 months to one year). If on felbamate, documentation of stable hemogram and liver enzyme tests must be present.
Currently on vigabatrin for less than 2 years before visit 1, as most visual field changes occur between 6 months and 2 years Subjects on vigabatrin should have available, appropriate documentation of visual fields.
Currently taking retigabine/ezogabine
History of intermittent use of rescue benzodiazepines (i.e., 1 to 2 doses over a 24-hour period is considered a 1-time rescue) more than once in the 4 weeks prior to the baseline visit or more than once per 4 weeks during the 8-week baseline period
Currently taking ivermectin, or has taken it within the last 4 weeks prior to visit 1
Has had a COVID-19 vaccination within the past 2 weeks prior to visit 1 (allowable to rescreen or to delay randomization) 18a.Use of the following medications within 4 weeks of the baseline visit and throughout the study that may interfere with study drug metabolism (please note ASMs with CYP3A4 metabolism are not excluded from this study, as drug levels and safety are monitored throughout the study): i. CYP3A4 inducers: rifampin, lumacaftor, mitotane, enzalutamide, apalutamide, St. John's wort, glucocorticoids ii. Medications with PGP interactions: amiodarone, apalutamide, verapamil, lorlatinib, rifampin, St. John's wort 18b. Use of the following medications/foods is not strictly prohibited but is discouraged. Please make every attempt to refrain and to record each incidence of use of any of these (along with all medications and supplements).

CYP3A4 inhibitors, including, but not limited to clarithromycin, ceritinib, idelalisib, lonafarnib, tucatinib, erythromycin, telithromycin, diltiazem, posaconazole, voriconazole, nefazodone, itraconazole, ketoconazole, anti-retroviral drugs (atazanavir, darunavir, indinavir, lopinavir, nelfinavir, ritonavir, saquinavir, tipranavir), grapefruit and grapefruit juice, pomegranate fruit and pomegranate juice iii. Additional medications that may interact with CYP3A4, PGP, or Vitamin K: fluconazole, isavuconazole, cyclosporine, imatinib, warfarin, acenocoumarol 19. Has any of the following laboratory or exam abnormalities: i. Positive urine drug screen (methamphetamines, amphetamines, cocaine, PCP, opioids, barbiturates) at screening without a therapy related explanation ii. Positive hCG (female participants) (at screening or visit 2/enrollment) iii. QTcF > 450 msec at visit 2/enrollment 20. Subject is not approved for study inclusion by the Epilepsy Consortium based on the diagnostic review form 21. Any condition that, in the opinion of the investigator, may impact a subject's safety or ability to follow study procedures