EQU-001 as an Add-On Drug for People with Focal Seizures while on Medication

Overview

Sponsor-declared trial summary

Key facts

Sponsor

Equilibre Biopharmaceuticals B.V.

Participant type

Patients

Age range

18-64 years, 65+ years

Gender

Male and Female

Therapeutic area

Diseases [C] - Nervous System Diseases [C10]

Trial duration

completed 7 Jul 2023

Decision date (initial)

2023-02-15

Transition trial

No

Low-intervention

No

Rare-disease indication

No

Vulnerable population

Yes

Funding sources

Equilibre Biopharmaceuticals B.V.

External identifiers

EU CT number

2022-500302-18-00

WHO UTN

U1111-1278-1904

Trial design

CTIS Part I — objectives, methods, condition coding

Main objective

Scope: Safety, Others, Pharmacodynamic, Efficacy, Pharmacokinetic

To evaluate the efficacy of EQU-001 in doses of 20 mg and 60 mg per day as adjunctive therapy compared with placebo for focal onset seizures in subjects with epilepsy

Secondary objectives 5

1. 1. To assess the efficacy of EQU-001 at doses of 20 mg and 60 mg during a maintenance phase
2. 2. To assess the efficacy of EQU-001 at doses of 20 mg and 60 mg in specified seizure types
3. 3. To assess the subject’s impression of change at doses of 20 mg and 60 mg
4. 4. To assess the effect on quality of life of EQU-001 in subjects with focal onset seizures at doses of 20 mg and 60 mg daily
5. 5. To assess the safety and tolerability of EQU-001 in doses of 20 mg and 60 mg per day in subjects with focal onset seizures

Conditions and MedDRA coding

Epilepsy

Regulatory references

Scientific advice from competent authorities

European Medicines Agency

Eligibility criteria

Principal inclusion / exclusion criteria as submitted by sponsor

Inclusion criteria 10

1. 1. Age 18- 65 years at time of informed consent.
2. 8. 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.
3. 9. 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.
4. 10. Females of childbearing potential who are not sexually inactive (abstinent) for 30 days prior to the first dose, throughout the study, and then for 30 days following the last dose, must agree to use of one of the following acceptable birth control methods from 30 days prior to the first dose through 30 days after the last dose of study drug: i. Combined estrogen and progestogen containing hormonal contraception associated with inhibition of ovulation (oral, intravaginal, transdermal) together with a condom or other barrier method ii. Progestogen-only hormonal contraception associated with inhibition of ovulation (oral, injectable, implantable) together with a condom or other barrier method iii. Intrauterine device (IUD) together with a condom or other barrier method iv. Intrauterine hormone releasing system (IUS) together with a condom or other barrier method v. Bilateral tubal occlusion, hysterectomy, bilateral oophorectomy vi. Vasectomized partner (vasectomy >6 months ago)  For this study, pre-menopausal is defined as not meeting the clinical criteria for postmenopausal, that is, no menstrual period for at least one year, in the absence of other identifiable cause(s) of not having a period, together with the absence of typical symptoms of menopause, such as hot flashes and mood instability.  True abstinence is allowable when in line with the preferred and usual lifestyle of the subject. Periodic abstinence (such as calendar, ovulation, symptothermal, post-ovulation methods) and withdrawal are not acceptable methods of contraception.
5. 2. 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.
6. 3. 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.
7. 4. Subject has no seizures that are not focal by the ILAE 2017 criteria.
8. 5. 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.
9. 6. 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 (but not prior to the subject’s diagnostic assessment for epilepsy)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.
10. 7. Seizures uncontrolled after an adequate trial of at least 1 ASM within the last 2 years.

Exclusion criteria 21

1. 1. Pregnant or lactating
2. 18. 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 iv. Serum albumin of 25 g/L or less at screening or visit 2/enrollment v. CTP score of 10 or greater at visit 2/enrollment
3. 2. History of hypersensitivity to ivermectin or to any of the excipients in the EQU-001 gelcap
4. 19. Subject is not approved for study inclusion by the Epilepsy Consortium based on the diagnostic review form
5. 21. Any condition that, in the opinion of the investigator, may impact a subject’s safety or ability to follow study procedures
6. 3. History of status epilepticus in the past 1 year from screening
7. 4. History of pseudo- or nonepileptic seizures, or other nonepileptic events that could be confused with epileptic seizures, within the past 5 years
8. 5. History of traumatic brain injury within 30 days prior to screening
9. 6. Resective epilepsy surgery within 1 year; epilepsy-related radiosurgery within 2 years or Ventriculoperitoneal shunt placement within 1 year
10. 7. 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.
11. 8. 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
12. 10. History of substance use disorder, including alcohol, within the past 2 years
13. 9. 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
14. 11. Currently in another investigational drug study
15. 12. 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
16. 13. 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
17. 14. Currently taking retigabine/ezogabine
18. 15. 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. If a subject is taking benzodiazepines for an indication other than epilepsy (e.g., anxiety, sleep), the dose should be stable for at least 4 weeks prior to screening and remain stable throughout screening and double blind periods of the study.
19. 16. Currently taking ivermectin, or has taken it within the last 4 weeks prior to visit 1
20. 17a. 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 (except if given as a rescue anti-seizure medication) ii. Medications with PGP interactions: amiodarone, apalutamide, verapamil, lorlatinib, rifampin, St. John’s wort, elacridar, valspodar, zosuquidar 17b. 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). ii. CYP3A4 inhibitors, including, but not limited to clarithromycin, ceritinib, idelalisib, lonafarnib, tucatinib, erythromycin, telithromycin, diltiazem, dronedarone, 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, dronedarone, cyclosporine, imatinib, warfarin, acenocoumarol, fexofenadine, edoxaban, dabigatran etexilate
21. 20. History of 14 or more consecutive days in Angola, Equatorial Guinea, Gabon, Cameroon, the Central African Republic, the Republic of Congo, the DR of Congo, Nigeria, Chad, and/or South Sudan within the past 17 years and did not take diethylcarbamazine prophylaxis or has not been evaluated for/found to be negative for or treated for loa loa and subsequently evaluated as resolved since the most recent stay of at least 14 days.

Endpoints

Primary and secondary outcome measures (English text)

Primary endpoints 1

1. Median percentage change in the overall number of countable observable seizures per 28 day period relative to baseline in each treatment arm during the double-blind treatment period compared with placebo

Secondary endpoints 12

1. 1. Median percentage change in the overall number of countable observable seizures per 28 day period relative to baseline in each treatment arm during the maintenance phase (treatment weeks 5 through 16) compared with placebo
2. 2. ≥ 50% responder rates in the treated arms as compared with placebo during double blind components of the study, which consist of the medication activation and maintenance period
3. 3. ≥ 50% responder rates in the treated arms as compared with placebo during the maintenance period alone (treatment weeks 5-16)
4. 4. Difference in Patient Global Impression of Change Scale Score between each treated cohort and placebo at days 56 and 112
5. 5. Median percentage change in the number of countable observable seizures by 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
6. 6. Percent (%) of subjects who are seizure free by study days 29-112 (treatment weeks 5-16)
7. 7. Percent of subjects who are seizure free in treated arms as compared with placebo during treatment weeks 5-16
8. 8. ≥ 70% and ≥ 90% response rates in treated arms compared with placebo during the maintenance period (treatment weeks 5-16)
9. 9. Change from visit 2 (enrollment) in the Patient weighted Quality of Life in Epilepsy (QOLIE 31-P) scale score at days 56 and 112 in each treated arm as compared with placebo
10. 10. Number of subjects who withdraw from treatment because of an AE in each treatment arm
11. 11. Number of adverse events (CTCAE grade 2 or higher) in the treatment arms compared with placebo
12. 12. Change from visit 2 in Columbia-Suicide Severity Rating Scale responses in each treated arm as compared with placebo at each measured timepoint

Investigational products

Investigational medicinal products (IMPs), comparators, placebo, auxiliary

Test 1

Placebo 1

Auxiliary 2

Sponsors and contacts

Sponsor organisations, regulatory contacts, third parties

Equilibre Biopharmaceuticals B.V.

Sponsor organisation

Equilibre Biopharmaceuticals B.V.

Address

Herengracht 540

City

Amsterdam

Postcode

1017 CG

Country

Netherlands

Scientific contact point

Organisation

Equilibre Biopharmaceuticals B.V.

Contact name

EQ Clinical Trials

Public contact point

Organisation

Equilibre Biopharmaceuticals B.V.

Contact name

EQ Clinical Trials

Third parties 4

Locations

8 EU/EEA countries · 27 investigational sites

By country

Investigational sites

Results and documents

Annex IV summary of results, Annex V layperson summary, and all documents registered in CTIS for this trial

Summary of results Art. 37(4) CTR

Layperson summary Annex V

Documents 2 files

Public protocol annexes, IB summaries, regulatory submissions and post-authorisation documents registered in CTIS.

Application history

3 submissions — initial application plus substantial / non-substantial modifications