E.1 Medical condition or disease under investigation |
E.1.1 | Medical condition(s) being investigated |
Epilepsy (partial-onset seizures with or without secondary generalisation) |
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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 | 14.1 |
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 trial is to demonstrate the efficacy and safety of conversion to Lacosamide (LCM) 400mg/day monotherapy for partial-onset seizures (with or without secondary generalization) in subjects 16 to 70 years of age who are withdrawn from 1 to 2 marketed AEDs. |
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E.2.2 | Secondary objectives of the trial |
There are no secondary objectives. |
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E.2.3 | Trial contains a sub-study | No |
E.3 | Principal inclusion criteria |
1. Subject is informed and given ample time and opportunity to think about her/his participation and has given her/his written informed consent.
2. Subject is willing and able to comply with all trial requirements.
3. Subject is male or female between the age of 16 and 70 years of age, inclusive.
4. Subject has a diagnosis of epilepsy with simple partial seizures (motor component) and/or complex partial seizures (with or without secondary generalization) according to the International Classification of Epileptic Seizures, 1981.
5. Subject has been maintained on a stable dose of 1 or 2 marketed AEDs for at least 28 days prior to Visit 1 and during Baseline.
6. If a subject is on 2 AEDs, the second AED must be ≤50% of the minimum recommended maintenance dose per USA product label at Visit 1 and during Baseline when used as an adjunctive therapy.
7. The minimum required seizure frequency during the 8-week Baseline Phase is 2 partial onset seizures (IA, IB, or IC) per 28 days. In the case of simple partial seizures, only those with motor signs (IA1) will be counted towards meeting this inclusion criterion. (See Section 15.2, International Classification of Epileptic Seizures, 1981.)
8. Subject has ≤ 40 partial seizures (ie, IA1, IA2, IA3, IA4, IB, IC) per 28 days during the 8 week Baseline Phase. (See Section 15.2, International Classification of Epileptic Seizures, 1981.)
9. Subject has had an electroencephalogram and a brain computerized tomography scan or magnetic resonance imaging exam of the brain consistent with the diagnosis of partial-onset epilepsy. If the electroencephalogram and brain computerized tomography scan or magnetic resonance imaging exam were not performed prior to Visit 1, it needs to be completed and results must be available prior to randomization at Visit 3.
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E.4 | Principal exclusion criteria |
1. Subject has previously participated in this trial, or subject has previously been assigned to treatment in a trial of the drug under investigation in this trial. Subjects who have previously received commercial LCM may be considered for participation if the treatment period was limited to a single iv administration for acute treatment. If the subject received a single iv administration of commercial LCM, it must have occurred earlier than 28 days prior to Visit 1. These cases must be discussed with the medical monitor prior to screening.
2. Subject is currently participating or has participated within the last 2 months in any trial of an investigational drug or experimental device.
3. Subject has a seizure disorder characterized primarily by isolated auras (ie, simple partial seizures without observable motor signs).
4. Subject has a history of primary generalized or unclassified seizures.
5. Subject has a history of status epilepticus within the 12-month period prior to Vis 1
6. Subject has a history of cluster seizures, defined as bouts of increased seizures which cannot be reliably counted (but which do not represent status epilepticus) during the 8-week period prior to Visit 1 and during the 8-week Baseline Phase.
7. Subject has a seizure-free period ≥28 consecutive days during the 8-week Baseline Phase.
8. Subject has >5 seizures of any type, including isolated auras, on any day during the 8-week Baseline Phase.
9. Subject has a current or previous diagnosis of pseudoseizures, conversion disorders, or other non-epileptic ictal events which could be confused with seizures.
10. Subject has an implanted VNS.
11. Subject has received treatment with benzodiazepines, phenobarbital, or primidone within 28 days prior to Visit 1 or during Baseline.
12. Subject is taking 1 or more of the following medications on a regular basis within 28 days prior to Visit 1 or during Baseline: neuroleptics, monoamine oxidase (MAO) inhibitors, barbiturates, or narcotic analgesics.
13. 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 trial.
14. Subject has a history of suicide attempt, has received professional counseling for suicidal ideation, or is currently experiencing active suicidal ideation.
15. Subject has a known hypersensitivity to any components of the investigational product(s) as stated in Section 4.4.2.
16. Subject has a medical condition that could reasonably be expected to interfere with drug absorption, distribution, metabolism or excretion.
17. Subject has any history of alcohol or drug abuse within the previous 2 years.
18. Subject has an acute or sub-acutely progressive central nervous system disease.
19. Subject with a known history of severe anaphylactic reaction or serious blood dyscrasias.
20. Subject weighs <40kg.
21. Subject has alanine aminotransferase (ALT), aspartate aminotransferase (AST), or total bilirubin levels ≥2 times the upper limit of normal (ULN) or has alkaline phosphatase levels ≥3 times the ULN at Visit 1.
22. Subject has impaired renal function, ie, creatinine clearance (CLCR) is lower than 50 mL/minute, at Visit 1. Creatinine clearance will be estimated by the central laboratory as follows:
Adult males: CLCR = (140-age) x weight in kg/(72 x serum creatinine in mg/dL)
Adult females: CLCR = [(140-age) x weight in kg/(72 x serum creatinine in mg/dL)] x 0.85.
23. Deleted and no longer applicable beginning with protocol amendment 3
4. (Deleted and no longer applicable beginning with protocol amendment 3
25. Subject has sick sinus syndrome without a pacemaker, or second- or third-degree atrioventricular (AV) block.
26. Subject has experienced a myocardial infarction in the last 3 months.
27. Subject has New York Heart Association Class III or Class IV heart failure.
28. (Deleted and no longer applicable beginning with protocol amendment 3
29. (Deleted and no longer applicable beginning with protocol amendment 3
30. Subject is a pregnant female, nursing woman and/or a female of childbearing potential who is not surgically sterile, 2 years postmenopausal, or does not practice 2 combined methods of contraception (unless sexually abstinent) for the duration of the trial.
31. Subject has ever received treatment with ethosuximide.
32. Subject is on a ketogenic diet.
33. Subject has been on felbamate after 1994.
34. Subject has been on vigabatrin after 1997, or subject has been on vigabatrin before 1997 and no visual fields examination report is available, including standard static (Humphrey or Octopus) or cinetic perimetry (Goldman), or if results of these examinations are abnormal. The visual fields examination report must be available no later than Visit 3 prior to randomization.
35. Subject has a known sodium channelopathy, such as Brugada syndrome.
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E.5 End points |
E.5.1 | Primary end point(s) |
The percentage of subjects who are identified as meeting at least 1 of the following exit criteria by Day 112 relative to the start of the withdrawal of background AEDs is considered the primary efficacy variable.
1. A 2-fold or greater increase in average monthly (28-day) partial seizure frequency (motor and non-motor) compared to average monthly partial seizure frequency (motor and non motor) during the Baseline Phase.
2. A 2-fold or greater increase in consecutive 2-day partial seizure frequency (motor and non motor) versus the highest consecutive 2-day partial seizure frequency (motor and non motor) that occurred during the Baseline Phase.
Note: if the highest consecutive 2-day partial seizure frequency during the Baseline Phase is 1, a 2-day partial seizure frequency of ≥3 is required to meet this exit criterion.
3. Occurrence of a single generalized tonic-clonic seizure if none had occurred in the 6 months prior to randomization.
4. A prolongation or worsening of overall seizure duration, frequency, type or pattern considered by the investigator as serious enough to warrant trial discontinuation.
5. Status epilepticus, or new onset of serial/cluster seizures.
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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) |
There are no secondary endpoints |
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E.5.2.1 | Timepoint(s) of evaluation of this end point |
There are no secondary endpoints |
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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 | 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 | 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) | No |
E.8.2.2 | Placebo | No |
E.8.2.3 | Other | Yes |
E.8.2.3.1 | Comparator description |
same IMP different dose (LCM 300mg/day) |
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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 | 6 |
E.8.5 | The trial involves multiple Member States | Yes |
E.8.5.1 | Number of sites anticipated in the EEA | 45 |
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 |
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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Last visit of the last subject |
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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 | 4 |
E.8.9.1 | In the Member State concerned days | 0 |
E.8.9.2 | In all countries concerned by the trial years | 3 |
E.8.9.2 | In all countries concerned by the trial months | 5 |
E.8.9.2 | In all countries concerned by the trial days | 0 |