| E.1 Medical condition or disease under investigation |
| E.1.1 | Medical condition(s) being investigated |
| highly drug-resistant focal epilepsy |
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| E.1.1.1 | Medical condition in easily understood language |
| highly drug-resistant focal epilepsy |
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| E.1.1.2 | Therapeutic area | Diseases [C] - Nervous System Diseases [C10] |
| MedDRA Classification |
| E.1.2 Medical condition or disease under investigation |
| E.1.2 | Version | 18.1 |
| E.1.2 | Level | LLT |
| E.1.2 | Classification code | 10065337 |
| E.1.2 | Term | Focal epilepsy |
| E.1.2 | System Organ Class | 100000004852 |
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| E.1.3 | Condition being studied is a rare disease | No |
| E.2 Objective of the trial |
| E.2.1 | Main objective of the trial |
To evaluate the efficacy of UCB0942 administered concomitantly with each subject’s current, stable AED regimen in subjects who have 4 or more focal seizures with or without secondary generalization per week and who have failed to achieve seizure control with ≥4 AED regimens of adequate dose and duration.
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| E.2.2 | Secondary objectives of the trial |
• Evaluate the safety and tolerability of UCB0942
• Evaluate the PK of UCB0942 and its metabolites
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| E.2.3 | Trial contains a sub-study | No |
| E.3 | Principal inclusion criteria |
• Subject is an adult (18 years of age or more).
• Subjects with known mental retardation (defined as IQ below 70) are not eligible to participate.
• Subject and/or caregiver is considered reliable and capable of adhering to the protocol (eg, able to understand and complete diaries), visit schedule, and take the medication as instructed according to the judgment of the Investigator.
• Subject is of normal weight as determined by a body mass index (BMI) between 18.0 and 35.0kg/m2 (exclusive), with a body weight of at least 50kg (males) or 45kg (females).
• Subject fulfills ILAE (1989) criteria for focal epilepsy.
• Subject has failed to achieve seizure control with ≥4 appropriately-chosen AED regimens of adequate dose and duration, including the current treatment, as documented in medical records and per Investigator assessment of patient report.
• Subject is currently treated with a stable dose of at least 1 AED for the 4 weeks prior to the Screening Visit (Visit 1) and throughout the duration of the Treatment Period with or without additional concurrent VNS or other neurostimulation treatments. The VNS must have been in place for at least 12 months with constant settings for at least 3 months.
• During the 4 weeks prior to Screening, subject must have reported to have had an average of at least 4 spontaneous and observable focal seizures per week, and cannot have had any seizure-free period longer than 3 days. The cut-off seizure frequency (4 seizures per week) and maximum seizure-free interval (3 days) must be maintained during the 2-week prospective Baseline Period.
• Subject has clinical laboratory test results within the reference ranges of the laboratory or isolated test results that are outside the specified ranges and that are deemed as not clinically significant by the Investigator.
• Subject has blood pressure and heart rate within normal range in the supine position after 5 minutes rest, or the subject has hypertension that is under partial control with a stable antihypertensive medication regimen but that the Investigator deems as clinically not significant.
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| E.4 | Principal exclusion criteria |
• Subject has participated in another study of an investigational medication (or medical device) within the last 30 days or is currently participating in another study of an investigational medication (or a medical device).
• Subject has a history of liver disease, including but not limited to, stable (on repeat testing) elevation of liver enzymes (alanine aminotransferase [ALT] or aspartate aminotransferase [AST], >1.5 times the upper limit of laboratory reference ranges or alkaline phosphatase [ALP] >2 times the upper limit of laboratory reference range).
• Subject has a known hypersensitivity to any components of UCB0942 formulation or to similar drugs (LEV, BRV, or benzodiazepines), or a history of drug or other allergy that, in the opinion of the Investigator or UCB Study Physician, contraindicates her/his participation.
• Subject has had significant blood loss or has donated or received 1 or more units (450mL) of blood within 30 days prior to UCB0942 administration, or has donated plasma or platelets within 14 days prior to UCB0942 administration for this study.
• Subject tests positive for human immunodeficiency virus-1/2 antibody (HIV-1/2Ab), hepatitis B surface antigen (HBsAg), or hepatitis C antibody (HCV-Ab).
• Subject has a medical condition that, in the opinion of the Investigator, could jeopardize or would compromise the subject’s safety or his/her ability to participate in this study.
• Subject has current or past psychiatric condition that, in the opinion of the Investigator, could compromise his/her safety or ability to participate in this study including a history of schizophrenia, schizoaffective disorder, bipolar disorder, or severe unipolar depression.
The presence of potential psychiatric exclusion criteria will be determined based on screening with the BPRS and MINI.
• Subject has a history of status epilepticus or has been hospitalized for status epilepticus within the 6-month period prior to Screening Visit.
• Subject has had EEGs showing a pattern not consistent with a diagnosis of focal epilepsy (eg, generalized spike-wave).
• Subject only has seizures that are uncountable due to clustering.
• Subject has had pseudoseizures, conversion disorder, or other nonepileptic ictal events that in the opinion of the Investigator could be confused with seizures.
• Subject had epilepsy surgery <1 year or an epilepsy dietary therapy initiated < 3 months prior to Screening.
• Subject has taken other (non-AED) prescription, nonprescription, dietary (eg, grapefruit or passion fruit), or herbal products that are potent inducers or inhibitors of the CYP3A4 pathway for 2 weeks (or 5 half-lives whichever is longer) prior to the Baseline Visit.
• Subject is currently treated with carbamazepine, phenytoin, primidone, or phenobarbital or any other drug known to induce CYP3A4 liver enzymes.
• Subject is taking tiagabine, felbamate, or vigabatrin.
• Subject is taking benzodiazepines, zolpidem, zaleplon, or zopiclone >3 times per week for any indication.
• Subject had intolerable or serious psychiatric side effects with a previous exposure to LEV or BRV.
• Subject has past or present substance abuse/dependence that in the opinion of the Investigator could threaten the subject's safety within the study, affect the subject's ability to fully participate in the study, or confound study interpretation
• Subject has a history in the last 5 years of drug or alcohol dependency or tests positive for drugs of abuse or alcohol during screening.
• Subject has a lifetime history of suicide attempt (including an actual attempt, interrupted attempt, or aborted attempt), or has suicidal ideation in the past 6 months as indicated by a positive response (Yes) to either Question 4 or Question 5 of the C-SSRS at Screening.
• Subject has a clinically significant abnormality on ECG that, in the opinion of the Investigator, increases the risks associated with participating in the study.
• QT corrected for heart rate using Bazett’s formula (QTcB) or QT corrected for heart rate using Fridericia’s formula (QTcF) interval >450ms
• Bundle branch blocks and other conduction abnormalities that are clinically significant according to the Investigator and/or with a PR interval ≥220ms
• Irregular rhythms other than sinus arrhythmia or occasional, rare supraventricular or rare ventricular ectopic beats
• In the judgment of the Investigator, T-wave configurations are not of sufficient quality for assessing QT interval duration
• Subject has a history of unexplained syncope or a family history of sudden death due to long QT syndrome.
• Subject has a clinically-significant abnormality on echocardiography at screening or a history of rheumatic heart disease or other known valvular abnormalities.
• Subjects with a history of hypersensitivity reactions or autoimmune disease.
• Female subject who is pregnant or breastfeeding.
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| E.5 End points |
| E.5.1 | Primary end point(s) |
| 75 % responder rate (75 % RR, proportion of subjects who achieve ≥75 % reduction in focal seizure frequency) |
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| E.5.1.1 | Timepoint(s) of evaluation of this end point |
| During 2 weeks of the Inpatient Period |
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| E.5.2 | Secondary end point(s) |
• Median percent reduction in weekly focal seizure frequency , during 2-weeks of the Inpatient Period
• Median percent reduction in weekly focal seizure frequency , during the UCB0942 overall period (approximately 11 weeks)
• 75 % responder rate (75 % RR, proportion of subjects who achieve ≥75 % reduction in focal seizure frequency) during the last 4 weeks of the Outpatient Maintenance Period
• Seizure-free rate during the 2-week Inpatient Period, during 2 weeks of the Inpatient Period
• Seizure-free rate during the last 4 weeks of the Outpatient Maintenance Period
• Seizure-free rate during the UCB0942 Overall period during UCB0942 Overall period (approximately 11 weeks)
• Percentage of seizure free days during the 2-week Inpatient Period, 2 weeks of the Inpatient Period
• Percentage of seizure free days during the Outpatient Maintenance Period, during the Outpatient Maintenance Period (approximately 8 weeks)
• Number of patients reporting at least one Adverse Event (AE) during the course of the study, all study duration (approximately 19 to 20 weeks)
• Number of patients reporting at least one at least one Serious Adverse Event (SAE) during the course of the study, all study duration (approximately 19 to 20 weeks)
• Number of subject withdrawals due to Adverse Events (AEs) during the course of the study, all study duration (approximately 19 to 20 weeks)
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| E.5.2.1 | Timepoint(s) of evaluation of this end point |
| During the complete study at different time points as defined in field Secondary End Point. |
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| E.6 and E.7 Scope of the trial |
| E.6 | Scope of the trial |
| E.6.1 | Diagnosis | No |
| E.6.2 | Prophylaxis | No |
| E.6.3 | Therapy | Yes |
| E.6.4 | Safety | Yes |
| E.6.5 | Efficacy | Yes |
| E.6.6 | Pharmacokinetic | Yes |
| E.6.7 | Pharmacodynamic | No |
| E.6.8 | Bioequivalence | No |
| E.6.9 | Dose response | No |
| E.6.10 | Pharmacogenetic | No |
| E.6.11 | Pharmacogenomic | Yes |
| E.6.12 | Pharmacoeconomic | No |
| E.6.13 | Others | No |
| E.7 | Trial type and phase |
| E.7.1 | Human pharmacology (Phase I) | No |
| E.7.1.1 | First administration to humans | No |
| E.7.1.2 | Bioequivalence study | No |
| E.7.1.3 | Other | No |
| E.7.1.3.1 | Other trial type description | |
| E.7.2 | Therapeutic exploratory (Phase II) | Yes |
| E.7.3 | Therapeutic confirmatory (Phase III) | No |
| E.7.4 | Therapeutic use (Phase IV) | No |
| E.8 Design of the trial |
| E.8.1 | Controlled | Yes |
| E.8.1.1 | Randomised | Yes |
| E.8.1.2 | Open | No |
| E.8.1.3 | Single blind | No |
| E.8.1.4 | Double blind | Yes |
| E.8.1.5 | Parallel group | Yes |
| E.8.1.6 | Cross over | No |
| E.8.1.7 | Other | No |
| E.8.2 | Comparator of controlled trial |
| E.8.2.1 | Other medicinal product(s) | No |
| E.8.2.2 | Placebo | Yes |
| E.8.2.3 | Other | No |
| E.8.2.4 | Number of treatment arms in the trial | 2 |
| E.8.3 |
The trial involves single site in the Member State concerned
| No |
| E.8.4 | The trial involves multiple sites in the Member State concerned | No |
| E.8.4.1 | Number of sites anticipated in Member State concerned | 2 |
| E.8.5 | The trial involves multiple Member States | Yes |
| E.8.5.1 | Number of sites anticipated in the EEA | 27 |
| E.8.6 Trial involving sites outside the EEA |
| E.8.6.1 | Trial being conducted both within and outside the EEA | No |
| E.8.6.2 | Trial being conducted completely outside of the EEA | No |
| E.8.7 | Trial has a data monitoring committee | No |
| E.8.8 |
Definition of the end of the trial and justification where it is not the last
visit of the last subject undergoing the trial
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| E.8.9 Initial estimate of the duration of the trial |
| E.8.9.1 | In the Member State concerned years | 2 |
| E.8.9.1 | In the Member State concerned months | 5 |
| E.8.9.1 | In the Member State concerned days | 0 |
| E.8.9.2 | In all countries concerned by the trial years | 1 |
| E.8.9.2 | In all countries concerned by the trial months | 9 |
| E.8.9.2 | In all countries concerned by the trial days | 0 |
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