| E.1 Medical condition or disease under investigation |
| E.1.1 | Medical condition(s) being investigated |
| Epilepsy, partial onset or generalised tonic-clonic seizures. |
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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 | 17.1 |
| E.1.2 | Level | PT |
| E.1.2 | Classification code | 10015037 |
| E.1.2 | Term | Epilepsy |
| E.1.2 | System Organ Class | 10029205 - Nervous system disorders |
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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 |
| The objective of this study is to compare the efficacy and safety of Lacosamide (LCM) (200 to 600mg/day) to Carbamazepine Controlled release CBZ CR (400 to 1200mg/day) used as monotherapy for at least 1 year, efficacy being measured as a primary endpoint by 6 month seizure freedom, in newly or recently diagnosed epilepsy subjects. The study will employ a noninferiority design to show at least a similar benefit risk balance for LCM compared with CBZ CR, using 6-month seizure freedom as primary endpoint. |
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| E.2.2 | Secondary objectives of the trial |
| See protocol sections 4.1.2 and 4.2.2 |
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| E.2.3 | Trial contains a sub-study | No |
| E.3 | Principal inclusion criteria |
Subjects must fulfill the following inclusion criteria to be eligible to participate in this study:
1. An Institutional Review Board (IRB)/Independent Ethics Committee (IEC) approved written Informed Consent form is signed and dated by the subject or by the parent(s) or legal representative. The Consent form or a specific Assent form, where required, will be signed and dated by minors.
2. Subject is willing and able to comply with all study requirements.
3. Subject is male or female and ≥16 years of age. Minors will be included in some countries only if legally permitted.
4. Subject has newly or recently diagnosed epilepsy having experienced unprovoked POS (IA, IB, IC with clear focal origin) or generalized tonic-clonic seizures (without clear focal origin) that are classifiable according to the ILAE Classification of Epileptic Seizures, 1981. The discrimination between IC and IIE is not requested for inclusion.
5. Subject has experienced at least 2 unprovoked seizures (separated by a minimum of 48 hours) in the 12 months preceding randomization out of which at least 1 unprovoked seizure occurred in the 3 months preceding Visit 1.
6. Subject has had an electroencephalogram (EEG) and a brain computed tomography (CT) scan or magnetic resonance imaging (MRI) exam of the brain within the past 12 months. If the EEG and brain CT scan or MRI exam were not performed prior to Visit 1, they need to be completed and results must be available prior to randomization at Visit 2.
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| E.4 | Principal exclusion criteria |
Subjects are not permitted to enroll in the study if any of the following criteria are met:
1. Subject has previously been assigned to treatment in this study or in a study of the drugs under investigation in this study.
2. Subject is currently participating or has participated within the last 2 months in any other study of an investigational drug or experimental device.
3. Subject has a history or presence of seizures of other types than partial-onset (IA, IB, IC with clear focal origin) and generalized tonic-clonic (without clear focal origin) seizures (eg, myoclonic, absence).
4. Subject has a history or presence of seizures occurring in clustered patterns, defined as repeated seizures occurring over a short period of time (ie, <20 minutes) with or without function regained between 2 ictal events.
5. Subject has a history, clinical, or EEG finding suggestive of idiopathic generalized epilepsy (IGE) at randomization.
6. Subject has current or previous diagnosis of pseudoseizures, conversion disorders, or other nonepileptic ictal events that could be confused with seizures based on expert opinion and/or EEG evidence
7. Subject has any medical or psychiatric condition, which in the opinion of the investigator, could jeopardize the subject’s health or would compromise the subject’s ability to participate in this study.
8. Deleted and no longer applicable with Protocol Amendment 2 (see protocol amendment details in Section 17.6)
9. Subject has a known hypersensitivity to any components of the investigational product(s).
10. Subject has ever been treated (for any indication) with LCM or CBZ in the past.
11. Subject has been treated for epilepsy with any AED (including benzodiazepines) in the last 6 months before Visit 1.
• However, acute and subacute seizure treatment is accepted with a maximum of 2 weeks duration and if treatment was stopped at least 3 days prior to randomization .
• Prior use of felbamate or vigabatrin is not allowed.
• Benzodiazepines as rescue therapy for epilepsy may have been used as needed in this time period, but not more frequently than once per week.
12. Subject has received treatment with phenobarbital or primidone within 28 days prior to Visit 1.
13. Subject is taking benzodiazepines for a nonepilepsy indication.
14. The use of monoamine oxidase inhibitors (MAOIs) is not allowed within 14 days of Visit 1.
15. Subject has experienced seizure(s) while treated with any AED for an indication other than epilepsy.
16. Subject is taking any drug or product (eg, grapefruit) that may influence CBZ metabolism (see Section 7.8.3).
17. Subject has a known history of severe anaphylactic reaction, serious blood dyscrasias, or hepatic porphyrias.
18. Subject has an acute or sub-acutely progressive central nervous system disease.
19. Subject has alanine aminotransferase (ALT), aspartate aminotransferase (AST), or total bilirubin levels ≥2× the upper limit of normal (ULN) or has alkaline phosphatase levels ≥3× the ULN.
20. Subject has a medical condition that could reasonably be expected to interfere with drug absorption, distribution, metabolism, or excretion.
21. Subject has a history of alcohol or drug abuse within the previous 2 years.
22. Subject is of Asian ancestry and tests positive for human leukocyte antigen HLA-B*1502 allele.
23. Subject has impaired renal function, ie, creatinine clearance (CLcr) is lower than 30mL/min at Visit 1. Creatinine clearance will be estimated as follows:
Adult males: CLcr=(140-age)×weight in kg/(72×serum creatinine in mg/dL)
Adult females: CLcr=[(140-age)×weight in kg/(72×serum creatinine in mg/dL)]×0.85
24. Subject has sick sinus syndrome without a pacemaker, or second- or third-degree atrioventricular (AV) block, or subject has any other clinically significant ECG abnormalities.
25. Subject has experienced a myocardial infarction in the last 3 months.
26. Subject has New York Heart Association Class III or Class IV heart failure.
27. Female subject who is pregnant or nursing and/or a woman of childbearing potential who is not surgically sterile, not at least 2 years postmenopausal, or does not practice 1 highly effective method of contraception according to the WHO recommendation with administration of enzyme-inducing AEDs or does not practice 2 combined methods of contraception (ie, combined hormonal contraception plus barrier method with spermicidal agent), unless sexually abstinent, for the duration of the study.
28. Subject has a history of status epilepticus.
29. Subject has a known sodium channelopathy, such as Brugada syndrome.
30. Deleted
32. 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 to either Question 4 or Question 5 of the (C-SSRS) at Screening.
33. Subject is of Asian ancestry and tests positive for HLA-A*3101 allele. |
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| E.5 End points |
| E.5.1 | Primary end point(s) |
1. Primary efficacy variable
The primary efficacy variable is as follows:
•Proportion of subjects remaining seizure free for 6 consecutive months (26 consecutive weeks) of treatment following stabilization at the last evaluated dose for each subject
2.The primary safety variables are as follows:
• AEs reported spontaneously by the subject and/or caregiver or observed by the investigator
• Subject withdrawal due to AEs
• Serious AEs (SAEs)
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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) |
Proportion of subjects remaining seizure free for 12 consecutive months (52 consecutive weeks) of treatment following stabilization at the last evaluated dose for each subject
•Time to first seizure or discontinuation due to AE or lack of efficacy (LOE) during 12 months of treatment following stabilization at the last evaluated dose for each subject
•Time to first seizure or discontinuation during 12 months of treatment following stabilization at the last evaluated dose for each subject
•Time to first seizure during 12 months of treatment from the first dose of study medication
•Time to first seizure or discontinuation due to AE or LOE during 12 months of treatment from the first dose of study medication
•Time to first seizure or discontinuation during 12 months of treatment from the first dose of study medication
•Time to discontinuation due to AE or LOE during 12 months of treatment from the first dose of study medication
Safety variables are as follows:
• Changes in hematology, chemistry, and urinalysis parameters
Changes in 12-lead electrocardiograms (ECGs)
• Changes in vital sign measurements (ie, blood pressure [BP] and pulse rate)
• Changes in physical or neurological examination findings
• Changes in body weight
• Changes in fasting serum lipid levels, and thyroid and sex hormone concentrations |
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| E.5.2.1 | Timepoint(s) of evaluation of this 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 | Yes |
| 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 | Yes |
| 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 | Yes |
| E.8.1.7.1 | Other trial design description |
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| 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
| Yes |
| E.8.4 | The trial involves multiple sites in the Member State concerned | No |
| E.8.5 | The trial involves multiple Member States | Yes |
| E.8.5.1 | Number of sites anticipated in the EEA | 115 |
| 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 |
| Australia |
| Canada |
| European Union |
| Mexico |
| Philippines |
| Russian Federation |
| Thailand |
| Ukraine |
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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 | 4 |
| E.8.9.1 | In the Member State concerned months | 0 |
| E.8.9.1 | In the Member State concerned days | 0 |
| E.8.9.2 | In all countries concerned by the trial years | 4 |
| E.8.9.2 | In all countries concerned by the trial months | 0 |
| E.8.9.2 | In all countries concerned by the trial days | 0 |
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