| E.1 Medical condition or disease under investigation |
| E.1.1 | Medical condition(s) being investigated |
| simple partial seizures with no motor symptomatology Epilepsy |
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| E.1.1.1 | Medical condition in easily understood language |
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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 | 17.0 |
| 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 evaluate the efficacy of Eslicarbazepine acetate administered QD at doses of 800 mg and 1200 mg compared with placebo as adjunctive therapy in patients with refractory partial epilepsy over a 12-week maintenance period. |
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| E.2.2 | Secondary objectives of the trial |
(1)To evaluate the safety and tolerability of Eslicarbazepine acetate at QD doses of 800 mg and 1200 mg in comparison with placebo, over a 12-week maintenance period preceded by a 2 week titration period.
(2)To evaluate the safety and tolerability of Eslicarbazepine acetate at doses titrated to an efficacy or safety endpoint over a 1-year open-label period.
(3)To assess the maintenance of therapeutic effects of Eslicarbazepine acetate over a 12 week maintenance period preceded by a 2-week titration period, and over a 1-year open label period.
(4)To assess the drug-drug (PK) interactions between Eslicarbazepine acetate and concomitant anti-epileptic drugs (AEDs) over the double-blind and Part II of the study.
(5)To assess the health-related quality-of-life and depressive symptoms over the double blind and Part II of the study.
(6) To study the effects of long-term use of eslicarbazepine acetate in Part III of the study.
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| E.2.3 | Trial contains a sub-study | No |
| E.3 | Principal inclusion criteria |
At V1 (screening), patient must be/have:
1. Written informed consent signed by patient.
2. Aged 16 years or more (patients under 18 years of age require parental/legal representative consent). In North America as well as in other participating countries, when appropriate and/or required by state or local law, minor patients must give written informed assent prior to participation in the study.
3. A documented diagnosis of epilepsy since at least 12 months prior to screening.
4. At least 4 partial-onset seizures (including subtypes of simple partial, complex partial and partial seizures evolving to secondarily generalised) on the 4 weeks prior to screening.
5. Currently treated with 1 or 2 AEDs (any except OXC), in a stable dose regimen during at least 1 month prior to screening. Patients using vigabatrin should have been on this medication for at least 1 year with no deficit in visual field identified (a confirmatory test should be available within 1 month before study entry). The device for VNS should be implanted at least 6 months before screening; parameters need to be stable for at least 1 month prior to screening (VNS will not be counted as concomitant AED).
6. Excepting epilepsy, patient is judged to be in general good health based on medical history, physical examination findings, and clinical laboratory test results.
7. Post-menopausal or otherwise incapable of becoming pregnant by reason of surgery or tubal ligation. In case of women of childbearing potential (WOCBP), patient must present a serum beta-human chorionic gonadotropin (β-hCG) test consistent with a non gravid state and agree to remain abstinent or use reliable contraception (hormonal contraception should be combined with a barrier method) beginning at screening and continuing at least to the PSV or at least until 30 days after last dose of study drug.
At V2 (randomisation), patient must have:
8. At least 8 partial-onset seizures during baseline with at least 3 partial-onset seizures in each 4-week section of the 8-week baseline period prior to randomisation (documented in a diary) and no seizure-free interval exceeding 28 consecutive days.
9. In case of WOCBP, patient must present a urine β-hCG test consistent with a non gravid state.
10. Diaries satisfactorily completed by the patient or his/her caregiver.
11. Satisfactorily complied with the study requirements during the baseline period (including no changes in concomitant AED therapy should have occurred in the baseline period).
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| E.4 | Principal exclusion criteria |
At V1 (screening), patients must not be/have:
1. Only simple partial seizures with no motor symptomatology (classified as A2 4 according to the International Classification of Epileptic Seizures).
2. Primarily generalised seizures.
3. Known progressive neurological disorders (progressive brain disease; epilepsy secondary to progressive cerebral lesion).
4. Occurrence of seizures too close to count accurately.
5. History of status epilepticus or cluster seizures (i.e., 3 or more seizures within 30 minutes) within the 3 months prior to screening.
6. Seizures of non-epileptic origin.
7. Seizures of psychogenic origin within the last 2 years.
8. Major psychiatric disorders.
9. Documented diagnosis of schizophrenia with accompanying documented history of at least 1 acute psychosis episode within the last 2 years) or history of suicide attempt.
10. Currently treated with OXC.
11. Using benzodiazepines on more than an occasional basis (defined as more than 2 times per week), except when used chronically as AED.
12. Known exposure to Eslicarbazepine acetate from previous study.
Previous use of Eslicarbazepine acetate or participation in a clinical study with Eslicarbazepine acetate (patients not exposed to Eslicarbazepine acetate - e.g., screen failed are allowed)
13. Known hypersensitivity to carboxamide derivatives.
14. History of abuse of alcohol, drugs or medications within the last 2 years.
15. Uncontrolled cardiac, renal, hepatic, endocrine, gastrointestinal, metabolic, haematological or oncology disorder.
16. Second or third-degree atrioventricular blockade not corrected with a pacemaker.
17. Relevant clinical laboratory abnormalities (e.g., sodium <130 mmol/L, alanine or aspartate transaminases >2.0 times the upper limit of the normal, white blood cell [WBC] count <3,000 cells/mm3) or for patients of Asian ancestry, positive HLA B*1502 test.
18. Estimated creatinine clearance <60 mL/min [men: (140-age) x weight/serum creatinine x 72; women: (0.85) (140-age) x weight/serum creatinine x 72. Age in years, weight in kg, and serum creatinine in mg/dL].
19. Pregnant or nursing.
20. Participation in other drug clinical trial within the last 2 months or received an investigational drug within 5 half-lives of this other product, whichever is longer. Patient(s) who are known to have not taken any doses of study drug(s) in earlier study(ies) (e.g. screen-failures) are allowed without any time limitation.
21. Not ensured capability to perform the trial.
22. Any other condition or circumstance that, in the opinion of the Investigator, may compromise the patient’s ability to comply with the study protocol.
23. Currently treated with VNS, but implanted < 6 months before screening or parameters not stable for at least 1 month prior to screening.
At V2 (randomisation), patients must not be/have:
24. Inadequate compliance to concomitant AEDs during the 8-week baseline period or to screening exclusion criteria.
25. Inadequate completion of the study diary.
26. Any other condition or circumstance that, in the opinion of the Investigator, may compromise the patient’s ability to comply with the study protocol.
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| E.5 End points |
| E.5.1 | Primary end point(s) |
| Standardised seizure frequency over the 12-week maintenance period. Seizure frequency for all the periods considered during Part I of the study, including the baseline, titration and maintenance periods, will be standardised on a “frequency per 4 weeks” basis. This is referred to as ‘standardised seizure frequency’ in this protocol. |
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| E.5.1.1 | Timepoint(s) of evaluation of this end point |
| V5, Standardised seizure frequency over the 12-week maintenance period. |
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| E.5.2 | Secondary end point(s) |
Secondary Efficacy Endpoints
Proportion of patients with a 50% or greater reduction in seizure frequency from the baseline period to the 12-week maintenance period (responders).
Relative change from baseline (percent) in standardised seizure frequency over the 12-week maintenance period compared to the 8-week baseline period.
Seizure frequency for the titration period and every 4-weeks during the maintenance periods.
Distribution of seizure reduction over the 12-week maintenance period as compared to baseline (seizure reduction <50%, from 50% to 75% and >75%).
Proportion of seizure-free patients over the 12-week maintenance period (100% seizure reduction from baseline in patients who completed Part I of the study).
Proportion of patients with a 25% or greater exacerbation in seizure frequency over the 12-week maintenance period as compared to baseline.
Standardised seizure frequency and relative change from baseline (percent) in seizure frequency over the 12-week maintenance period by seizure type.
Proportion of patients remaining on treatment for the duration of Part I of the study.
Clinical Global Impressions (CGI).
Seizure severity (SSQ) assessments.
Quality of Life in Epilepsy Inventory - 31 (QOLIE-31) assessments.
Symptoms of depression assessed by the Montgomery Asberg Depression Rating Scale (MADRS).
CGI severity of illness during Part III of the study.
Secondary Safety Endpoints
Adverse events.
Clinical laboratory test results (haematology, biochemistry, thyroid function, bone turnover markers, and urinalysis).
Vital sign measurements and body weight.
Physical and neurological examination.
12-lead electrocardiogram (ECG) readings.
Medical Outcomes Sleep (MOS) assessments.
Blood levels of eslicarbazepine and concomitant AEDs.
Columbia Suicide Severity Rating Scale (CSSRS). |
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| E.5.2.1 | Timepoint(s) of evaluation of this end point |
Efficacy:End of part I, ie V5 for-Proportion of patients remaining on treatment for the duration of Part I of the study;V2,V5,DISCONT,V16 or EDV FOR-CGI;V2,V4-10,DISCONT, for-SSQ;V1,V2,V5,V8,V10,DISC for-Quality of Life in Epilepsy Inventory-31(QOLIE-31)assessments;V1,V2,V5,V8,V10,DISC for-Symptoms of depression assessed by the MADRS;Other efficacy endpoints-V5
Safety:AT EVERY VISIT-AEDs, vital sign measurements and body weight;EVERY VISIT EXCEPT V3,V7,V9 Clinical laboratory test results;V1-2,V5,V10,DISCONT-Physical and neurological examination;V1-2,V5-6,V8,V10, DISC, THEN ONCE A YEAR IN PART III-12-lead ECG readings;V2,V5-MOS assessments;V4,v6,v8,v10, discount-Blood levels of eslicarbazepine and concomitant AEDs;V1-8,V10,DISCONT.,PSV V12,V14,V16-CSSRS
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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 | No |
| E.6.4 | Safety | Yes |
| E.6.5 | Efficacy | Yes |
| E.6.6 | Pharmacokinetic | No |
| 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) | No |
| E.8.2.2 | Placebo | Yes |
| E.8.2.3 | Other | No |
| E.8.2.4 | Number of treatment arms in the trial | 3 |
| 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 | 4 |
| E.8.5 | The trial involves multiple Member States | Yes |
| E.8.5.1 | Number of sites anticipated in the EEA | 38 |
| 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 |
| Belgium |
| Brazil |
| Cyprus |
| France |
| Greece |
| Hungary |
| India |
| Italy |
| Korea, Democratic People's Republic of |
| Poland |
| Romania |
| Russian Federation |
| South Africa |
| Turkey |
| Ukraine |
| United States |
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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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| E.8.9 Initial estimate of the duration of the trial |
| E.8.9.1 | In the Member State concerned years | 6 |
| E.8.9.1 | In the Member State concerned months | 2 |
| E.8.9.1 | In the Member State concerned days | 0 |
| E.8.9.2 | In all countries concerned by the trial years | 6 |
| E.8.9.2 | In all countries concerned by the trial months | 2 |
| E.8.9.2 | In all countries concerned by the trial days | 0 |
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