E.1 Medical condition or disease under investigation |
E.1.1 | Medical condition(s) being investigated |
refractory epilepsy with partial-onset seizures in children aged from 1 month to < 2 years |
|
E.1.1.1 | Medical condition in easily understood language |
|
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 | 21.1 |
E.1.2 | Level | LLT |
E.1.2 | Classification code | 10065336 |
E.1.2 | Term | Partial epilepsy |
E.1.2 | System Organ Class | 100000004852 |
|
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 steady state PK profile of ESL. |
|
E.2.2 | Secondary objectives of the trial |
To assess the safety and tolerability of ESL in the defined patient population at the doses used and to perform exploratory analyses of efficacy. |
|
E.2.3 | Trial contains a sub-study | No |
E.3 | Principal inclusion criteria |
1. Have an informed consent signed by their parent(s) or guardian(s) before undergoing any study-related activities. 2. Male or female ≥1 month (i.e. at least 28 days) but <2 years of age. 3. Weigh a minimum of 4 kg at Visit 1. 4. Epilepsy refractory to treatment with 1 to 2 AEDs and with clinical or electroencephalogram (EEG) evidence of partial onset seizures for at least 1 month in infants ≥6 months of age, or for at least 2 weeks in infants <6 months of age, as defined by the International League Against Epilepsy. In case a child has a significant birth defect, hydrocephalus, or tetraparesis, EEG confirmation must be available. 5. Current treatment with 1 to 2 AEDs (except OXC; vagus nerve stimulation if present and functioning will not be counted as an AED). 6. Ability to come to the study site every day during the Titration/Evaluation Periods.
|
|
E.4 | Principal exclusion criteria |
1. A neonate who is a preterm baby (i.e. born before 36 weeks of gestation). 2. Diagnosis of treatable seizure aetiology such as metabolic, toxic, and infectious disorders. 3. Primarily generalised seizures. 4. Known rapidly progressive neurological disorders (e.g. rapidly progressive brain disease, epilepsy secondary to rapidly progressive cerebral lesion). 5. History of status epilepticus or cluster seizures (i.e. 3 or more seizures within 30 minutes) within the month prior to screening. 6. Seizures of non-epileptic origin. Ohtahara syndrome, West syndrome [current], Dravet’s syndrome, or Lennox-Gastaut syndrome). 8. Difficult venous access. 9. Ketogenic diet. 10. Currently treated with OXC (at Screening or for at least 2 weeks before). 11. Previous use of ESL. 12. An AED that started or was discontinued in the 3 weeks before Visit 1. 13. Diseases that can have an impact on drug absorption (e.g. any disease leading to diarrhoea or vomiting). 14. Treatments that can have an impact on blood volume (e.g. transfusions or intravenous infusions). 15. Hypersensitivity to the active substance, to other carboxamide derivatives (e.g. carbamazepine, OXC), or to any of the excipients, in particular methyl parahydroxybenzoate (E218) or sulphites. 16. Uncontrolled cardiac (including atrioventricular block and other clinically significant electrocardiographic abnormalities), renal, hepatic, endocrine, gastrointestinal, metabolic, haematological, or oncology disorders. 17. Relevant clinical laboratory abnormalities (e.g. sodium <130 mmol/L, alanine or aspartate transaminases >2 x the upper limit of normal, white blood cell count <3000 cells/mm3) (measured at Visit 1). 18. Estimated glomerular filtration rate below the lower limit of the normal range (measured at Visit 1). 19. Participation in other drug clinical trial within the last 2 months or having received an IMP within 5 half-lives of that IMP, whichever is longer. 20. Any other condition or circumstance that, in the opinion of the investigator, could compromise the subject’s ability to comply with the study protocol.
|
|
E.5 End points |
E.5.1 | Primary end point(s) |
• Minimum (i.e. pre-dose) plasma concentration (Cmin). • Maximum observed plasma concentration (Cmax). • Time of occurrence of Cmax (tmax). • Area under the plasma concentration-time curve (AUC) from time zero to the last sampling time at which concentrations were at or above the limit of quantification (AUC0-t), calculated by the linear trapezoidal rule. • AUC from time zero to 24 hours post-dose (AUC0-τ). • Apparent terminal rate constant (λz) calculated by log-linear regression of the terminal segment of the drug plasma concentration versus time curve. • Apparent half-life (t1/2), calculated from ln 2/λz. • Apparent plasma clearance (CL/F), calculated from Dose/AUC0-τ. Additional PK parameters may also be calculated if considered appropriate.
|
|
E.5.1.1 | Timepoint(s) of evaluation of this end point |
• An interim analysis of the PK data will be performed after at least 8 subjects in Group 1 (4 in each age group) have completed their 24-hour PK profile. • At the end of the trial |
|
E.5.2 | Secondary end point(s) |
Efficacy: • Seizures (date, time, type, and duration) recorded by the investigator at each visit.
Safety: • Treatment-emergent adverse events (TEAEs) defined as all AEs with onset or worsening after first intake of study treatment until 4 weeks after last intake of study treatment. • Clinical laboratory safety tests: - Biochemistry: sodium, potassium, calcium, creatinine, blood urea nitrogen, aspartate transaminase, alanine transaminase, gamma-glutamyl transferase, albumin, total protein, total bilirubin, and glucose. - Haematology: haemoglobin, haematocrit, erythrocyte count, leucocyte count with differential, and platelet count. • Urinalysis: local dipstick test of pH, specific gravity, protein, blood, glucose, ketones, bilirubin, and urobilinogen. If dipstick results indicate a significant abnormality, microscopy and other appropriate tests (as needed) will be performed by the central laboratory. • Physical examination, vital signs, neurological examination, and electrocardiogram.
|
|
E.5.2.1 | Timepoint(s) of evaluation of this end point |
|
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 | No |
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 | No |
E.8.1.1 | Randomised | No |
E.8.1.2 | Open | Yes |
E.8.1.3 | Single blind | No |
E.8.1.4 | Double blind | No |
E.8.1.5 | Parallel group | No |
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) | Information not present in EudraCT |
E.8.2.2 | Placebo | Information not present in EudraCT |
E.8.2.3 | Other | Information not present in EudraCT |
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 | Yes |
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 | 12 |
E.8.6 Trial involving sites outside the EEA |
E.8.6.1 | Trial being conducted both within and outside the EEA | Yes |
E.8.6.2 | Trial being conducted completely outside of the EEA | No |
E.8.6.3 | If E.8.6.1 or E.8.6.2 are Yes, specify the regions in which trial sites are planned |
Croatia |
Czechia |
Italy |
Portugal |
Romania |
Russian Federation |
Serbia |
Ukraine |
|
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
|
|
E.8.9 Initial estimate of the duration of the trial |
E.8.9.1 | In the Member State concerned years | 0 |
E.8.9.1 | In the Member State concerned months | 4 |
E.8.9.1 | In the Member State concerned days | 0 |
E.8.9.2 | In all countries concerned by the trial years | 0 |
E.8.9.2 | In all countries concerned by the trial months | 4 |
E.8.9.2 | In all countries concerned by the trial days | 0 |