The ENACT Trial: A Randomized, double-blind, placebo-controlled adjunctive treatment trial to evaluate the efficacy and safety of ENX-101 in patients with focal (partial onset) seizures

Overview

Sponsor-declared trial summary

Key facts

Sponsor

Engrail Therapeutics Inc.

Participant type

Patients

Age range

18-64 years

Gender

Male and Female

Therapeutic area

Diseases [C] - Nervous System Diseases [C10]

Decision date (initial)

2022-12-12

Transition trial

No

Low-intervention

No

Rare-disease indication

No

Vulnerable population

Yes

Funding sources

Engrail Therapeutics, Inc.

External identifiers

EU CT number

2022-501028-95-00

ClinicalTrials.gov

NCT05481905

Trial design

CTIS Part I — objectives, methods, condition coding

Main objective

Scope: Efficacy, Pharmacokinetic, Safety

To evaluate the efficacy of ENX-101 administered adjunctively with 1 to 4 antiseizure medications for the treatment of focal seizures [ Time Frame: Treatment Period (Day 1 to Day 56) compared to placebo ]

Secondary objectives 3

1. To evaluate the efficacy of ENX-101 administered adjunctively with 1 to 4 antiseizure medications for the treatment of focal seizures [ Time Frame: Day 1 to end of the Treatment Period (Day 56) compared to placebo ]
2. To evaluate the efficacy of ENX-101 [ Time Frame: Treatment Period (Day 29 to Day 56) compared to placebo ]
3. To evaluate the efficacy of ENX-101 [ Time Frame: Treatment Period (Day 1 to Day 56) compared to placebo ]

Conditions and MedDRA coding

focal (partial onset) epilepsy

Study design 2 periods

Regulatory references

Eligibility criteria

Principal inclusion / exclusion criteria as submitted by sponsor

Inclusion criteria 14

1. 1. Male or female aged 18 to 75 years, inclusive, at Screening
2. 10. Body mass index of 18 to 40 kg/m2 at Screening
3. 11. Capable of giving written informed consent
4. 12. Is willing to give written consent to have data entered into a study participant database
5. 13. Patient is able to keep accurate seizure eDiary for duration of study
6. 2. Diagnosed with focal (partial onset) epilepsy according to the International League Against Epilepsy (ILAE) 2017 classification of Epilepsy, as confirmed by the Epilepsy Study Consortium
7. 3. Able to provide an imaging study(ies) [magnetic resonance imaging (MRI) scan strongly preferred yet computed tomography (CT) acceptable] obtained within the previous 10 years that can rule out a progressive cause of epilepsy
8. 5. During the 3 months (84 days) immediately prior to Screening: • ≥ 3 observable focal onset seizures per 28-day period; • <10 seizures per day; • Any seizure-free interval no more than 21 days in length
9. 6. During the 8-week Baseline Period prior to Day 1: • ≥ 6 observable focal onset seizures; • < 10 seizures per day; • No seizure-free interval of ≥ 21 days
10. 6. Has been treated with approved ASMs ≥ 2 years and is currently being treated with: at least one and no more than 4 ASMs at stable doses for at least 28 days before Screening (not including the rescue medication); dose adjustments should not be expected during the study
11. 7. Use of benzodiazepines as rescue medication is allowed if such use is, on average, ≤ 1 time per week
12. 8. Female patients a. Of non-childbearing potential, defined as either permanently sterilized (at least 4 months after surgical sterilization including bilateral salpingectomy, tubal ligation, or oophorectomy with or without hysterectomy) or post-menopausal (defined as amenorrhea for 12 consecutive months and documented plasma follicle-stimulating hormone level >40 IU/mL; in the event a patient's menopausal status has been clearly established and yet serum follicle-stimulating hormone levels are not consistent with a post-menopausal status, determination of the patient’s eligibility to be included in the study will be at the Investigator’s discretion following consultation with the Medical Monitor), and with a negative pregnancy test at Screening and Day 1 pre-dose; OR b. Of childbearing potential and willing to use 2 effective methods of contraception (i.e., established method of contraception + condom) or remain abstinent (where abstaining from sexual intercourse is in line with the preferred and usual lifestyle of the patient) from the start of the Baseline Period through 3 months after the last dose of study drug, and with a negative pregnancy test at Screening and Day 1 pre-dose
13. 9. Male patients who, if fertile (defined as post-pubertal and not permanently sterile by orchidectomy or vasectomy) must be willing to use a condom or remain abstinent (where abstaining from sexual intercourse is in line with the preferred and usual lifestyle of the patient) from Day 1 through to 3 months after the last dose of study drug
14. 4. Experiencing poorly controlled focal onset seizures [focal aware (simple partial) seizures with an observable component, focal impaired awareness (complex partial) seizures, or focal to bilateral tonic-clonic (secondarily generalised) seizures] despite adequate trials of proven effective medicines

Exclusion criteria 27

1. 1. EEG shows any pattern not consistent with focal etiology of seizures (e.g., generalized spike-wave)
2. 18. Has clinically significant, abnormal findings in serum chemistry, coagulation, hematology, or urinalysis results at Screening or Day 1 (pre-dose) including, but not limited to, elevated (> 3x upper limit of normal) alanine aminotransferase and/or aspartate aminotransferase and/or bilirubin at Screening or Day 1 (pre-dose); isolated gamma-glutamyl transferase elevation, chronic mild anemia or mild hyperglycaemia is acceptable
3. 19. Has evidence of renal impairment defined as estimated glomerular filtration rate (eGFR) <60 mL/min/1.73m2
4. 2. Has history of focal onset seizures which involve subjective sensory or psychic phenomena without impairment of consciousness or awareness (formerly referred to as simple partial seizures without observable component) as their only seizure type
5. 20. Has evidence of hepatic impairment defined as bilirubin levels >1.5 times the upper limit of the normal and/or AST, ALT and/or alkaline phosphatase > 2 times the upper limit of the normal
6. 21. Has clinically significant, abnormal findings in vital sign assessments, at Screening or Day 1 (pre-dose)
7. 22. Has history of hepatitis B or hepatitis C or demonstration of hepatitis B surface antigen or hepatitis C antibody at Screening
8. 23. Has history of HIV infection or demonstration of HIV antibodies at Screening
9. 24. Has a positive test for COVID-19 at Screening or Day 1 (pre-dose)
10. 25. Received an investigational drug within 90 days or 5 half lives, whichever is longer, prior to Screening, activation of an investigational device within 90 days prior to Screening, or currently in the follow up period of another interventional clinical trial at the time of Screening
11. 3. Has genetic/idiopathic generalized epilepsies or combined generalized and focal epilepsies, including a history of Lennox-Gastaut syndrome
12. 10. Had Vagus Nerve Stimulation (VNS), Deep Brain Stimulation (DBS), Responsive Neurostimulator System (RNS), or other neurostimulation for epilepsy device implanted or activated < 1 year prior to Screening, stimulation parameters have been stable for < 3 months, or battery life of unit not anticipated to extend for duration of trial
13. 4. Has history of seizures that occur at such a high frequency they cannot be reliably counted (e.g., repetitive, cluster seizures) within the year prior to Screening
14. 5. Has history of psychogenic non-epileptic seizures
15. 6. Has history of status epilepticus within two years prior to Screening
16. 7. Treatment of epilepsy with ASM was initiated < 2 years prior to Screening
17. 8. Ingested excluded concomitant medication within 5 half lives or 28 days (whichever is longer) prior to Screening including: a. Chronic benzodiazepine (including clobazam) b. Felbamate initiated < 1 year prior to Screening c. Vigabatrin or ezogabine/retigabine d. Phenobarbital e. Primidone f. Oncologic medications g. Schizophrenia or psychosis medications h. Antiarrhythmic medications i. Medications used to treat malaria (except for chloroquine and hydroxychloroquine when used for Systemic lupus erythematosus [SLE] or rheumatoid arthritis) j. Medications for tuberculosis or HIV/AIDS k. Systemic corticosteroids (occasional use of topical corticosteroids is allowed) l. Medications that can increase intraocular pressure (Table 6 of the protocol) m. Medications known to prolong the QTc interval and with a known risk related to cause torsade de points (Table 7 of the protocol))
18. 9. Had epilepsy surgery for tissue resection < 1 year prior to Screening or radiosurgery < 2 years prior to Screening
19. 27. Unable to comply with the requirements of the study or, in the opinion of the Investigator, is unsuitable for the study
20. 11. Initiated dietary therapy for epilepsy (e.g., ketogenic diet) < 3 months prior to Screening
21. 12. Has significant progressive disorders or unstable medical conditions requiring acute intervention or that, in the Investigator’s opinion, may place the patient at risk or interfere with study outcome variables; including, but not limited to, cardiac, renal, neurologic (other than epilepsy), psychiatric, gastrointestinal, pulmonary, endocrinologic, hematologic, infectious, or immunologic disease or active malignancy requiring current or planned oncologic therapy Note: stable medical conditions (other than active malignancy) may be allowed as long as any pharmacologic therapy is at a stable dose and dosing regimen for at least 28 days prior to the start of Screening with no dosing changes planned or anticipated during the study, and doesn’t require any excluded medications per exclusion #8
22. 13. Has any of the following cardiovascular health-related issues: a. any major cardiovascular events (e.g., myocardial infarct, unstable angina, acute coronary syndrome, coronary revascularization, stroke) within 3 months prior to screening. b. Congestive heart failure; New York Heart Association [NYHA] Class ≥ 2 c. Angina pectoris; Canadian Cardiovascular Society [CCS] Grade > 2 d. History of symptomatic ventricular tachycardia or torsade de pointes, personal or family history of sudden death or long QT syndrome or arrhythmias requiring antiarrhythmic therapy e. Mean QTcF Interval >450 msec at Screening or Baseline Day 1; if the QRS interval is >110msec, then the adjusted QTcF > 450 msec f. PR interval > 250 ms g. Second or third degree atrioventricular (AV) block
23. 14. Based on ophthalmological examination performed during Screening, patient must not have, in the opinion of the ophthalmologist, any clinically significant lens opacity or ocular condition that may require medical or surgical intervention during the course of the trial
24. 15. Has any psychiatric disorder where changes in pharmacotherapy are needed or anticipated during the study
25. 16. Reports having experienced suicidal ideation (Type 4 or 5 on the C SSRS) within 6 months prior to Screening, any suicidal behavior within 2 years prior to Screening (any “Yes” answers on Suicidal Behavior section of C SSRS), more than 1 lifetime suicide attempt, and/or the Investigator assesses the patient to be a safety risk to him/herself or others
26. 17. Has history or evidence of moderate or severe Substance Use Disorder as defined by the Diagnostic and Statistical Manual of Mental Disorders (5th Edition)
27. 26. Has known or suspected hypersensitivity to ENX-101 or any inactive ingredients used in its formulation or in placebo

Endpoints

Primary and secondary outcome measures (English text)

Primary endpoints 1

1. The responder rate defined as the percent of patients who experience a 50% or greater reduction from baseline in seizure frequency in the Treatment Period compared to placebo

Secondary endpoints 3

1. The median percent change from baseline in 28-day focal seizure frequency (focal aware motor with observable component, focal impaired awareness, or focal to bilateral tonic-clonic seizures) compared to placebo
2. The percent of patients who are seizure free during the last 28 days of the Treatment Period
3. The percent of patients who are seizure free during the entire Treatment Period

Investigational products

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

Test 3

Placebo 2

Sponsors and contacts

Sponsor organisations, regulatory contacts, third parties

Engrail Therapeutics Inc.

Sponsor organisation

Engrail Therapeutics Inc.

Address

12750 High Bluff Drive Suite 190

City

San Diego

Postcode

92130-2083

Country

United States

Scientific contact point

Organisation

Engrail Therapeutics Inc.

Contact name

Engrail Therapeutics, Inc.

Public contact point

Organisation

Engrail Therapeutics Inc.

Contact name

Engrail Therapeutics, Inc.

Third parties 1

Locations

4 EU/EEA countries · 12 investigational sites

By country

Investigational sites

Application history

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