| E.1 Medical condition or disease under investigation |
| E.1.1 | Medical condition(s) being investigated |
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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 | 21.0 |
| 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 |
• To evaluate the safety and tolerability of LCM when added to 1 to 3 concomitant AEDs in pediatric subjects with epilepsy syndromes associated with generalized seizures
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| E.2.2 | Secondary objectives of the trial |
• To obtain preliminary efficacy data of LCM on seizure frequency in pediatric epilepsy syndromes associated with generalized seizures
• To evaluate the PK of LCM in subjects ≥1 month to <18 years of age. |
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| E.2.3 | Trial contains a sub-study | No |
| E.3 | Principal inclusion criteria |
1. A signed informed consent has been obtained from the parent/legal representative and assent has been obtained from the subject (when possible or as required according to local Institutional Review Boards [IRBs]/Independent Ethics Committees [IECs]).
2. Subject and/ or caregiver (which may be a parent, a legal representative, or other caregiver) are willing and able to comply with all study requirements including maintaining a daily seizure diary.
3. Subject is male or female, ≥1 month to <18 years of age. For preterm infants <1 year old, the corrected gestational age should be used when determining eligibility. The generally accepted definition of corrected gestational age, which is calculated by subtracting the number of weeks born before 37 weeks of gestation from the chronological age, will be used for this study.
4. Subject has a diagnosis of uncontrolled epilepsy with generalized seizures (Type II) according to the International Classification of Epileptic Seizures (1981). The underlying epilepsy syndrome should be documented. Diagnosis should have been established by clinical history and an EEG with generalized spike-wave discharges. Documentation of the EEG finding of generalized spike waves (EEG recording or a report) is required. The EEG should have been performed no more than 18 months prior to Visit 1 (with no change to diagnosis or seizures during this time).
5. Subject must have experienced 2 or more events (typical generalized seizures associated with diagnosed epilepsy syndrome) within the 6 week prospective Baseline Period.
6. Subject is on a stable dosage regimen of 1 to 3 AEDs. The daily dosage regimen of
concomitant AED therapy must be kept constant for a period of at least 4 weeks
prior to the Baseline Period.
7. Vagal nerve stimulation is allowed and will not be counted as a concomitant AED.
The VNS device must be implanted for at least 6 months before Visit 1, and the device settings must be stable for at least 4 weeks before Visit 1 and be kept stable during the Baseline Period and the Treatment Period. Use of the VNS device magnet is allowed.
8. Body weight at Visit 1 is at least 4kg for infants.
9. Females of childbearing potential must have a negative pregnancy test at Visit 1.
10. Subjects with West Syndrome are eligible if Baseline EEG demonstrates hypsarrhythmia despite treatment with at least 2 AEDs appropriate for the treatment of this syndrome. |
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| E.4 | Principal exclusion criteria |
1. Subject has previously participated in this study, subject has been assigned
to LCM in a previous LCM study, or subject has ever received LCM.
2. Subject is currently participating or has participated within the last 2 months in any study of an investigational drug or experimental device.
3. Subject has a history of convulsive status epilepticus within 1 month prior to Visit 1.
4. Subject has a current or previous diagnosis of pseudoseizures, conversion disorders, or
other nonepileptic ictal events that could be confused with seizures.
5. Subject has exclusively typical absence (Type IIA1) or atypical absence (Type IIA2)
seizures (no other generalized seizure types are reported), or has only partial onset seizures (Type I).
6. Subject has primary generalized tonic-clonic seizures with a diagnosis of idiopathic
generalized epilepsy.
7. Subject has any medical or psychiatric condition that 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. Subject ≥6 years of age 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 (“Yes”) to either Question 4 or Question 5 of the Columbia Suicide Severity Rating Scale (C-SSRS) at Screening.
9. Subject has a known hypersensitivity to any components of the investigational medicinal product (IMP).
10. Subject has a medical condition that could reasonably be expected to interfere with drug
absorption, distribution, metabolism, or excretion.
11. Subject has a known history of severe anaphylactic reaction or serious blood dyscrasias.
12. Subject has any history of alcohol or drug abuse within the previous 2 years.
13. Subject has an acute or sub-acutely progressive central nervous system disease. Subject has epilepsy secondary to a progressing cerebral disease or any other progressively neurodegenerative disease (malignant brain tumor or Rasmussen Syndrome).
14. Subject has alanine aminotransferase (ALT), aspartate aminotransferase (AST), or total bilirubin levels ≥2x the upper limit of normal (ULN) or has alkaline phosphatase levels ≥3x ULN.
15. Subject has impaired renal function (ie, creatinine clearance is lower than 30mL/min) at
Visit 1.
16. Subject has sick sinus syndrome without a pacemaker, or second or third degree
atrioventricular (AV) block.
17. Subject has a clinically relevant ECG abnormality, in the opinion of the principal
investigator (ie, second or third degree heart block or a corrected QT interval [QTc] greater than 450ms).
18. Subject has hemodynamically significant heart disease (eg, heart failure).
19. Subject has an arrhythmic heart condition requiring medical therapy.
20. Subject has a known cardiac sodium channelopathy, such as Brugada syndrome.
21.Female subject who is pregnant or nursing, and/or a female subject of childbearing potential who is not surgically sterile or does not practice 1 highly effective method of contraception (according to International Conference on Harmonisation [ICH] guidance defined as those that result in a failure rate of less than 1% per year when used consistently and correctly), unless sexually abstinent, for the duration of the study. Female subject of childbearing potential taking enzyme inducing antiepileptic drugs (EI AEDs): (carbamazepine, phenytoin, barbiturates, primidone, topiramate, oxcarbazepine) who is not surgically sterile or does not practice 1 highly effective method of contraception according to the World Health Organization recommendation (ie, depot medroxyprogesterone acetate, norethisterone enantate, intrauterine devices, combined injectables, and progestogen implants) with administration of EI 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.
22. Subject has been treated with vigabatrin and experienced any vision loss. Subjects who
have received vigabatrin in the past must have documentation of an assessment for vision loss prior to study entry or documentation of why visual field testing cannot be performed.
23. Subject has been treated with felbamate and has experienced any serious toxicity issues (defined as liver failure, aplastic anemia) with this treatment. Subjects treated with felbamate for less than 12 months are excluded. Note: any subject who has been treated with felbamate for at least 12 months and has not experienced serious toxicity issues is eligible.
24. Subject is taking monoamine oxidase (MAO) inhibitors or narcotic analgesics.
25. Subject is on a ketogenic or other specialized diet. If he/she was on a specialized diet in the past, he/she must be off the diet for at least 2 months prior to the Screening Visit (Visit 1). |
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| E.5 End points |
| E.5.1 | Primary end point(s) |
1) Changes in count of generalized spike-wave discharges on 24-hour ambulatory electroencephalogram (EEG) from Visit 2 to Visit 6
2) Change in days with any generalized seizures (absence, myoclonic, clonic, tonic, tonic-clonic, atonic, partial evolving to secondarily generalized) per 28 days from the Baseline Period to the Maintenance Period
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| E.5.1.1 | Timepoint(s) of evaluation of this end point |
1) Visit 2; Visit 6
2) Baseline Period to the Maintenance Period (approximately 24 weeks)
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| E.5.2 | Secondary end point(s) |
1) Changes in count of 3Hz spike-wave discharges (during waking hours) on 24-hour ambulatory EEG from Visit 2 to Visit 6
2) AEs as reported spontaneously by the subject and/or caregiver, or observed by the investigator
3) Subject withdrawals due to AEs
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| E.5.2.1 | Timepoint(s) of evaluation of this end point |
1) Visit 2; Visit 6
2) From baseline to end of study
3) From baseline to end of study |
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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) | 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) | No |
| E.8.2.2 | Placebo | No |
| E.8.2.3 | Other | No |
| E.8.2.4 | Number of treatment arms in the trial | 1 |
| E.8.3 |
Will this trial be conducted at a single site globally?
| No |
| E.8.4 | Will this trial be conducted at multiple sites globally? | Yes |
| E.8.6 Trial involving sites outside the EEA |
| E.8.6.2 | Trial being conducted completely outside of the EEA | No |
| E.8.6.3 | Specify the countries outside of the EEA in which trial sites are planned |
| United States |
| European Union |
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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.8.9.2 | In all countries concerned by the trial years | 2 |
| E.8.9.2 | In all countries concerned by the trial months | 9 |
| E.8.9.2 | In all countries concerned by the trial days | 0 |
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