| E.1 Medical condition or disease under investigation |
| E.1.1 | Medical condition(s) being investigated |
| Adult patients with newly diagnosed partial-onset seizures |
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| E.1.1.1 | Medical condition in easily understood language |
| Adult patients with newly diagnosed partial 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 | 18.0 |
| E.1.2 | Level | LLT |
| E.1.2 | Classification code | 10065336 |
| E.1.2 | Term | Partial 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 demonstrate that monotherapy with Eslicarbazepine Acetate (ESL; 800 to 1600 mg once daily) is not inferior to monotherapy with controlled-release carbamazepine (CBZ-CR; 200 to 600 mg twice daily) in adults (≥18 years) with newly diagnosed epilepsy experiencing partial-onset seizures. |
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| E.2.2 | Secondary objectives of the trial |
| To further demonstrate the efficacy, safety, and pharmacokinetics of ESL in this patient population at the doses used. |
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| E.2.3 | Trial contains a sub-study | No |
| E.3 | Principal inclusion criteria |
Visit 1 (Days –1 to –7; Screening)
1. Have signed an informed consent before undergoing any study-related activities. Subjects of Asian ancestry (subjects with a direct ancestor of Asian origin, irrespective of the generational difference) are required to give written informed consent for genotyping.
2. Male or female ≥18 years of age.
3. Newly diagnosed epilepsy with at least 2 well documented, unprovoked, clinically evaluated and classified partial seizures (with or without secondary generalization) with clear focal origin, documented clinically OR by electroencephalogram (EEG) OR imaging studies, within 12 months of Visit 1. In this context, seizures that occur within a period of 48 hours are counted as 1 seizure.
4. At least 1 seizure during the previous 3 months.
5. Demonstrated cooperation and willingness to complete all aspects of the study.
6. Female subjects without childbearing potential (2 years postmenopausal, bilateral oophorectomy or tubal ligation, or complete hysterectomy) are eligible. Female subjects with childbearing potential must not be pregnant as confirmed by a negative serum beta-human chorionic gonadotropin (hCG) test and sexually active females must be using a medically acceptable effective non-hormonal method of contraception for the duration of the study and until the Post-study visit (PSV).
Visit A1 (Day 1; Randomization and start of double-blind treatment period)
7. Have satisfactorily completed the electronic subject diary (eDiary).
8. Female subjects with childbearing potential must not be pregnant as confirmed by a negative urine pregnancy test and sexually active females must be using a medically acceptable effective non-hormonal method of contraception for the duration of the study and until the PSV.
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| E.4 | Principal exclusion criteria |
Visit 1 (Days –1 to –7; Screening)
1. History of pseudo-seizures.
2. Seizures occurring only in clusters.
3. History of absence, myoclonic, clonic, tonic, or atonic seizures.
4. Documented EEG within 12 months of Visit 1 suggestive of primarily generalized epilepsy.
5. History of status epilepticus within the 3 months prior to Visit 1.
6. Known progressive neurologic disorder (progressive brain disease, epilepsy secondary to progressive cerebral lesion) as assessed by magnetic resonance imaging or computer tomography.
7. Former or current use of any AED, except for the use of a single AED for a maximum duration of 2 weeks before Visit 1.
8. Previous regular use of ESL or CBZ (previous use as acute treatment for seizures in an emergency situation is not an exclusion criterion).
9. Using mono-amine oxidase inhibitors (MAOIs), tricyclic antidepressants, nefazodone, isoniazid, or protease inhibitors or any other anti-retroviral agents (e.g. efavirez) that may raise the levels of CBZ-CR.
10. Known hypersensitivity to carboxamide derivatives or tricyclic antidepressants.
11. History of uncontrolled psychiatric illness or mood disorder requiring electro-convulsive or drug therapy within the previous 6 months, a history of suicide attempt, schizophrenia, chronic treatment with benzodiazepines (except short-acting benzodiazepines) or barbiturates.
12. Judged clinically to have a suicidal risk in the opinion of the investigator based upon a clinical interview and the Columbia Suicide-Severity Rating Scale (C-SSRS).
13. History of alcohol, drug, or medication abuse within the last 2 years.
14. Uncontrolled cardiac (including atrioventricular block and other clinically significant electrocardiographic abnormalities), renal, hepatic, endocrine, gastrointestinal, metabolic, hematological, or oncology disorder.
15. History of bone marrow depression.
16. History of hepatic porphyrias (e.g. acute intermittent porphyria, variegate porphyria, porphyria cutanea tarda).
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 (eGFR) <60 mL/min/1.73 m2 (measured at Visit 1).
19. Subjects of Asian ancestry who test positive for the presence of the HLA-B*1502 allele.
20. Pregnancy or lactating.
21. 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.
22. Any other condition or circumstance that, in the opinion of the investigator, could compromise the subject’s ability to comply with the study protocol.
Visit A1 (Day 1; Randomization and start of double-blind treatment period)
23. Former or current use of any AED *, except for the use of a single AED for a maximum duration of 2 weeks before Visit 1 and with a drug-free period of at least 5 days before Visit A1. Benzodiazepines are allowed for an epileptic indication and as rescue medication during the ≥5-day drug-free period.
24. Using prohibited medication.
25. Pregnancy.
26. Any other condition or circumstance that, in the opinion of the investigator, could compromise the subject’s ability to comply with the study protocol.
*For clarification, an acute treatment for a seizure during the study (e.g. in the emergency room) is allowed and is not considered a deviation. |
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| E.5 End points |
| E.5.1 | Primary end point(s) |
| Proportion of subjects in the per protocol set who are seizure free for the entire 26-week Evaluation Period at the last received dose level. |
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| E.5.1.1 | Timepoint(s) of evaluation of this end point |
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| E.5.2 | Secondary end point(s) |
To further demonstrate the efficacy, safety, and pharmacokinetics of ESL in this patient population at the doses used.
Secondary Outcome Measures:
•Proportion of subjects in the ITT set without a seizure during the 26-week Evaluation Period at the last evaluated dose. [ Time Frame: 26 weeks ] [ Designated as safety issue: No ]
•Proportion of subjects without a seizure during the 26-week Evaluation Period at the last evaluated dose. [ Time Frame: 26 weeks ] [ Designated as safety issue: No ]
•Proportion of seizure-free subjects during 1 year of treatment at the last evaluated dose, where the end of the 1-year period is defined as the same start date as for the 26-week evaluation +365 days. [ Time Frame: 52 weeks ] [ Designated as safety issue: No ]
•Time to first seizure at the last evaluated dose set. [ Time Frame: up to 183 weeks ] [ Designated as safety issue: No ]
•QOLIE-31 and Bond-Lader VAS [ Time Frame: 26 weeks; up to 183 weeks ] [ Designated as safety issue: No ]
Changes in quality of life assessed using the QOLIE-31 (Overall score, subscores covering emotional well-being, social functioning, energy/fatigue, cognitive functioning, seizure worry, medication effects and assessment of overall health).
•Treatment retention time at the last evaluated dose [ Time Frame: 26 weeks ] [ Designated as safety issue: No ]
Treatment retention time at the last evaluated dose, where treatment retention time is defined as the time of the first occurrence of one of the following:
◦Withdrawal of IMP due to AEs.
◦Withdrawal of IMP due to lack of efficacy.
•Time to treatment failure at the first evaluated dose [ Time Frame: 26 weeks ] [ Designated as safety issue: No ]
Time to treatment failure at the first evaluated dose, where time to treatment failure is defined as the time of the first occurrence of 1 of the following:
◦Seizure
◦Withdrawal of IMP due to AEs.
◦Withdrawal of IMP due to lack of efficacy.
•seizure freedom [ Time Frame: 26 weeks ] [ Designated as safety issue: No ]
Dose level at which subjects reached 26-week seizure freedom.
•Adverse Event monitoring [ Time Frame: up to 183 weeks ] [ Designated as safety issue: Yes ]
Incidence of AEs, SAEs, withdrawals, out-of-range laboratory values, abnormal 12-lead ECG and physical examination findings.
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| E.5.2.1 | Timepoint(s) of evaluation of this end point |
| maximum time-frame: up to 183 weeks |
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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 | 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) | No |
| E.7.3 | Therapeutic confirmatory (Phase III) | Yes |
| 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) | Yes |
| E.8.2.2 | Placebo | No |
| 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 | Yes |
| E.8.4.1 | Number of sites anticipated in Member State concerned | 7 |
| E.8.5 | The trial involves multiple Member States | Yes |
| E.8.5.1 | Number of sites anticipated in the EEA | 102 |
| 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 |
| Argentina |
| Australia |
| Austria |
| Belgium |
| Brazil |
| Bulgaria |
| Chile |
| Croatia |
| Czech Republic |
| Estonia |
| Finland |
| France |
| Germany |
| Hungary |
| India |
| Ireland |
| Israel |
| Italy |
| Latvia |
| Lithuania |
| Peru |
| Poland |
| Portugal |
| Romania |
| Russian Federation |
| Serbia |
| Slovakia |
| Spain |
| Ukraine |
| United Kingdom |
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| 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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The end of the study is defined as the last subject’s last visit, which is
• PSV for all subjects not participating in the open-label extension study,
• EOT for all subjects who were on treatment with double-blind CBZ-CR and are now participating in the open-label extension study, and
• last EPV for all subjects on treatment with double-blind ESL who plan on participating in the open-label extension study.
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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 | 5 |
| E.8.9.1 | In the Member State concerned months | 10 |
| E.8.9.1 | In the Member State concerned days | 0 |
| E.8.9.2 | In all countries concerned by the trial years | 5 |
| E.8.9.2 | In all countries concerned by the trial months | 10 |
| E.8.9.2 | In all countries concerned by the trial days | 0 |
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