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
- Trial ID
- 2022-501028-95-00
- Protocol
- ENX-101-005
- Sponsor
- Engrail Therapeutics Inc.
Trial statistics
Diseases & Conditions
Objectives
The primary objective of the ENACT Trial is to evaluate the **efficacy** of ENX-101 when administered adjunctively with 1 to 4 antiseizure medications for the treatment of focal (partial onset) seizures. This is clinically relevant as focal seizures are a common form of epilepsy, and effective management is crucial for improving patient outcomes and quality of life.
Secondary objectives include:
- Evaluating the efficacy of ENX-101 administered adjunctively with 1 to 4 antiseizure medications for the treatment of focal seizures from Day 1 to the end of the Treatment Period (Day 56) compared to placebo.
- Assessing the efficacy of ENX-101 during the Treatment Period from Day 29 to Day 56 compared to placebo.
- Evaluating the efficacy of ENX-101 throughout the entire Treatment Period from Day 1 to Day 56 compared to placebo.
Participants
The clinical trial involves a total of **108 participants** diagnosed with **focal (partial onset) epilepsy**. The study population includes both male and female subjects, aged between 18 to 75 years. Participants were selected based on their diagnosis of focal epilepsy, as confirmed by the International League Against Epilepsy (ILAE) 2017 classification, and their experience of poorly controlled focal onset seizures despite adequate trials of effective medications. All participants have been treated with approved antiseizure medications for at least two years and are currently on stable doses of one to four such medications. The trial allows the use of benzodiazepines as rescue medication if used, on average, no more than once per week. Participants are required to have a body mass index between 18 to 40 kg/m² and must be capable of maintaining an accurate seizure eDiary throughout the study. The trial includes individuals who are able to provide informed consent and are willing to have their data entered into a study participant database. The study population is characterized by a diverse range of lifestyle considerations, including the use of contraception or abstinence for those of childbearing potential, and the ability to provide imaging studies to rule out progressive causes of epilepsy. The trial does not specify any particular dietary or physical activity requirements for participants.
Plans and Procedures
The clinical trial is designed as a **randomized**, **double-blind**, **placebo-controlled** study to evaluate the efficacy and safety of ENX-101 as an adjunctive treatment in patients with **focal (partial onset) epilepsy**. The trial will involve the administration of ENX-101 in both tablet and capsule forms, alongside a placebo, to assess its impact on seizure frequency. The study is set to span a treatment period of 56 days, with the overall trial expected to conclude by December 2024.
Participants will undergo a series of study visits, beginning with an inclusion (screening) visit to confirm eligibility based on criteria such as age, seizure history, and current treatment regimen. Following successful screening, participants will enter an 8-week baseline period to establish seizure frequency. The treatment phase will commence on Day 1, during which participants will receive either ENX-101 or a placebo, with doses administered orally. Follow-up visits will be scheduled throughout the treatment period to monitor safety, efficacy, and adherence to the study protocol. The end-of-study visit will occur after the treatment period, where final assessments will be conducted to evaluate the primary and secondary endpoints.
The expected length of participant involvement is approximately 16 weeks, including the baseline, treatment, and follow-up periods. Conditions that may lead to early termination from the study include significant adverse events, non-compliance with the study protocol, or withdrawal of consent by the participant. The primary endpoint is the responder rate, defined as the percentage of patients experiencing a 50% or greater reduction in seizure frequency compared to baseline. Secondary endpoints include the median percent change in seizure frequency and the percentage of patients who are seizure-free during the treatment period.
Treatment
The clinical trial involves the administration of **ENX-101**, a chemical compound developed by Engrail Therapeutics Inc. **ENX-101** is provided in two pharmaceutical forms: **tablet** and **capsule**. The **tablet** form is administered orally with a maximum daily dose of 30 mg and a total dose of 1680 mg over a maximum treatment period of 8 weeks. The **capsule** form is also administered orally, with a maximum daily dose of 10 mg and a total dose of 140 mg over a maximum treatment period of 2 weeks. The dosing schedule is designed to ensure participant compliance, with regular monitoring throughout the trial period.
In addition to the experimental medication, the trial includes the use of a **placebo** to maintain the double-blind nature of the study. The **ENX-101 Placebo** is available in both **capsule** and **tablet** forms, mirroring the administration routes of the active medication. The placebo is administered with the same frequency and schedule as the active treatment to ensure blinding is maintained.
Participants in the trial will receive either the active treatment or the placebo, in conjunction with 1 to 4 standard antiseizure medications, as part of the adjunctive treatment for focal seizures. Compliance with the dosing regimen will be closely monitored to ensure the integrity of the trial data and participant safety. The trial aims to evaluate the efficacy and safety of **ENX-101** in comparison to the placebo over the designated treatment period.
Efficacy
The efficacy of ENX-101 in the treatment of focal (partial onset) seizures will be assessed through a randomized, double-blind, placebo-controlled trial. The primary endpoint for evaluating efficacy is the **responder rate**, defined as the percentage of patients experiencing a 50% or greater reduction in seizure frequency from baseline during the treatment period compared to placebo. Secondary endpoints include the median percent change from baseline in 28-day focal seizure frequency, the percentage of patients who are seizure-free during the last 28 days of the treatment period, and the percentage of patients who are seizure-free throughout the entire treatment period.
Data collection will occur over a treatment period from Day 1 to Day 56. Efficacy parameters will be measured using patient-reported outcomes, specifically through the maintenance of a seizure eDiary by participants. This diary will document the frequency and type of seizures experienced, allowing for accurate assessment of changes in seizure activity. The analysis will compare the treatment group receiving ENX-101 with the placebo group to determine the efficacy of the adjunctive treatment. The trial is designed to ensure that any observed effects are attributable to the intervention, with the use of a placebo control to account for potential placebo effects.
Inclusion and Exclusion Criteria
Inclusion Criteria
- Male or female aged 18 to 75 years, inclusive, at Screening
- Body mass index of 18 to 40 kg/m2 at Screening
- Capable of giving written informed consent
- Is willing to give written consent to have data entered into a study participant database
- Patient is able to keep accurate seizure eDiary for duration of study
- 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
- 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
- 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
- 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
- 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
- Use of benzodiazepines as rescue medication is allowed if such use is, on average, ≤ 1 time per week
- 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
- 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
- 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
- EEG shows any pattern not consistent with focal etiology of seizures (e.g., generalized spike-wave)
- 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
- Has evidence of renal impairment defined as estimated glomerular filtration rate (eGFR) <60 mL/min/1.73m2
- 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
- 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
- Has clinically significant, abnormal findings in vital sign assessments, at Screening or Day 1 (pre-dose)
- Has history of hepatitis B or hepatitis C or demonstration of hepatitis B surface antigen or hepatitis C antibody at Screening
- Has history of HIV infection or demonstration of HIV antibodies at Screening
- Has a positive test for COVID-19 at Screening or Day 1 (pre-dose)
- 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
- Has genetic/idiopathic generalized epilepsies or combined generalized and focal epilepsies, including a history of Lennox-Gastaut syndrome
- 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
- 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
- Has history of psychogenic non-epileptic seizures
- Has history of status epilepticus within two years prior to Screening
- Treatment of epilepsy with ASM was initiated < 2 years prior to Screening
- 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))
- Had epilepsy surgery for tissue resection < 1 year prior to Screening or radiosurgery < 2 years prior to Screening
- Unable to comply with the requirements of the study or, in the opinion of the Investigator, is unsuitable for the study
- Initiated dietary therapy for epilepsy (e.g., ketogenic diet) < 3 months prior to Screening
- 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
- 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
- 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
- Has any psychiatric disorder where changes in pharmacotherapy are needed or anticipated during the study
- 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
- Has history or evidence of moderate or severe Substance Use Disorder as defined by the Diagnostic and Statistical Manual of Mental Disorders (5th Edition)
- Has known or suspected hypersensitivity to ENX-101 or any inactive ingredients used in its formulation or in placebo
Trial Status by Country
| Country | Status | Start of Recruitment | Planned Patients |
|---|---|---|---|
 Belgium | Not Recruiting | 14 Oct 2022 | 12 |
 Germany | Not Recruiting | 14 Oct 2022 | 30 |
 The Netherlands | Not Recruiting | 14 Oct 2022 | — |
 Spain | Not Recruiting | 14 Oct 2022 | 15 |
| Netherlands | — | — | 15 |
Sites & Investigators
Investigational Products
Details about the medicinal products being studied in this clinical trial.
| Product Name | Role in Trial | Formulation | Administration | Max Daily Dose | Treatment Duration | EU MP Number |
|---|---|---|---|---|---|---|
ENX-101 Placebo Capsule | Placebo | N/A | — | — | — | N/A |
ENX-101 | Test | TABLET | ORAL | 20 | 1 | PRD9831878 |
ENX-101 | Test | CAPSULE | ORAL USE | 10 | 2 | PRD9831877 |
ENX-101 | Test | TABLET | ORAL USE | 30 | 8 | PRD9831879 |
ENX-101 Placebo tablet | Placebo | N/A | — | — | — | N/A |