Epilepsy, Partial-onset Seizures
Conditions
Keywords
Lacosamide, Epilepsy, Focal, Partial-Onset Seizures with or without secondary generalization, Monotherapy
Brief summary
This study is to evaluate the long-term safety and tolerability of Lacosamide (LCM) 200 mg/day to LCM 600 mg/day taken in monotherapy in Japanese subjects who currently have partial-onset seizures with or without secondary generalization and who are treated with a single Anti-Epileptic Drug (AED) with marketing approval in Japan.
Interventions
DRUGLacosamide
Lacosamide (LCM) immediate-release, film-coated tablets at a strength of 50 mg orally administered twice daily in two equally divided doses. * 4-week Titration Period: Starting on LCM 100 mg/day increased by 100 mg/day each week until 400 mg/day dose reached at the beginning of Week 4 . * The AED Withdrawal Period and Monotherapy Period (52- week Evaluation Period plus a Follow Up Period): During the AED Withdrawal and Monotherapy Period, the investigator may increase or decrease the dose of LCM to optimize tolerability and seizure control. The LCM dose may be decreased no lower than 200 mg/day or increased, no faster than 100 mg/day per week, up to 600 mg/day.
Sponsors
UCB Japan Co. Ltd.
Study design
Allocation
NA
Intervention model
SINGLE_GROUP
Primary purpose
TREATMENT
Masking
NONE
Eligibility
Sex/Gender
ALL
Age
16 Years to No maximum
Healthy volunteers
No
Inclusion criteria
* Subject is male or female and ≥16 years of age * Subject has a diagnosis of epilepsy, having experienced unprovoked partial-onset seizures (IA, IB, or IC with clear focal origin) that are classifiable according to the International League Against Epilepsy (ILAE) Classification of Epileptic Seizures, 1981 * Subject experiences partial-onset seizures despite appropriately chosen and adequately tried treatment with 1 antiepileptic drug (AED) * Subject has been treated for epilepsy with a stable dose of 1 marketed AED The use of benzodiazepines is permitted as rescue therapy for epilepsy. Benzodiazepines may have been used as needed but not more frequently than once per week.
Exclusion criteria
* Subject has a history or presence of seizures of other types than partial onset (IA, IB, or IC with clear focal origin) * Subject is taking benzodiazepines for a nonepilepsy indication (Exception: Concomitant use of benzodiazepines is allowed if the subject is taking them on a regular basis, has been on a stable dose for at least 1 month prior to Visit 1, and does not require changes in the dosage and administration throughout the study period. However, concomitant use of benzodiazepines on an as needed basis is not permitted.) * Female subject who is pregnant or nursing, and/or a woman of childbearing potential who is not surgically sterile, 2 years postmenopausal or does not practice 1 highly effective method of contraception, unless sexually abstinent, for the duration of the study * Female subject of childbearing potential taking enzyme-inducing antiepileptic drugs (EI-AEDs: CBZ, phenytoin, barbiturates, primidone, topiramate) who is not surgically sterile, 2 years postmenopausal or does not practice 1 highly effective method of contraception according to the World Health Organization (WHO) 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 * Subject has sick sinus syndrome without a pacemaker, or a second or third degree atrioventricular (AV) block, or subject has any other clinically relevant electrocardiogram (ECG) abnormalities * Subject has a history of convulsive status epilepticus within the last 12 months prior to Visit 1
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Number of Subjects With at Least One Incidence of Treatment-Emergent Adverse Events (TEAEs) During the Study | From the Titration Period (investigational product is taken) to the End of Study Visit (up to 3.5 years) | An Adverse Event (AE) is any untoward medical occurrence in a patient or clinical investigation subject administered a pharmaceutical product, which does not necessarily have a causal relationship with this treatment. An AE could therefore be any unfavorable and unintended sign, symptom, or disease temporally associated with the use of a medicinal (investigational) product, whether or not related to the medicinal (investigational) product. |
| Number of Subjects Who Withdraw Due to Adverse Events (AEs) During the Study | From the Titration Period (investigational product is taken) to the End of Study Visit (up to 3.5 years) | An Adverse Event (AE) is any untoward medical occurrence in a patient or clinical investigation subject administered a pharmaceutical product, which does not necessarily have a causal relationship with this treatment. An AE could therefore be any unfavorable and unintended sign, symptom, or disease temporally associated with the use of a medicinal (investigational) product, whether or not related to the medicinal (investigational) product. |
| Number of Subjects With at Least One Incidence of Serious Adverse Events (SAEs) During the Study | From the Titration Period (investigational product is taken) to the End of Study Visit (up to 3.5 years) | A Serious Adverse Event (SAE) is any untoward medical occurrence that at any dose: * Results in death * Is life-threatening * Requires in patient hospitalization or prolongation of existing hospitalization * Is a congenital anomaly or birth defect * Is as infection that requires treatment parenteral antibiotics * Other important medical events which based on medical or scientific judgement may jeopardize the patients, or may require medical or surgical intervention to prevent any of the above |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Number of Subjects Remaining Seizure Free for 6 Consecutive Months During the Monotherapy Period | From the beginning of the Monotherapy Period to the end of the Follow-Up Period (up to 3.1 years until the time of approval granted) | Subjects were considered seizure free if their seizure counts for every day over the entire Treatment Period was zero and if they completed the Treatment Period. A subject was considered seizure free, if no seizure occurred during the 6 consecutive months in the Evaluation Period. If one of the following occurred, the subject was not considered seizure free: * A documented seizure during 6 consecutive months of the Evaluation Analysis Period * Subject discontinued the study prematurely during the Evaluation Analysis Period * Missing Seizure Count Case Report Forms (CRFs) prior to completing the Evaluation Analysis Period |
| Plasma Concentrations of Lacosamide Versus Time Postdose | From Titration Period up to Week 94 | Dose-normalized lacosamide Plasma Concentration (µg/mL) by Visit and Dose during the Evaluation Period. |
| Number of Subjects Remaining Seizure Free for 12 Consecutive Months During the Monotherapy Period | From the beginning of the Monotherapy Period to the end of the Follow-Up Period (up to 3.1 years until the time of approval granted) | Subjects were considered seizure free if their seizure counts for every day over the entire Treatment Period was zero and if they completed the Treatment Period. A subject was considered seizure free, if no seizure occurred during the 12 consecutive months in the Evaluation Period. If one of the following occurred, the subject was not considered seizure free: * A documented seizure during 6 consecutive months of the Evaluation Analysis Period * Subject discontinued the study prematurely during the Evaluation Analysis Period * Missing Seizure Count Case Report Forms (CRFs) prior to completing the Evaluation Analysis Period. Subjects who discontinued before the end date of 6 consecutive months were included in this analysis. |
| Percentage of Participants in the Monotherapy Period Without Discontinuation Due to Adverse Events (AE) or Lack of Efficacy (LOE) | From the beginning of the Monotherapy Period to the end of the Follow-Up Period (up to 3.1 years until the time of approval granted) | For Time to discontinuation (event), Retention rate and 95% CI was calculated using the Kaplan-Meier method. Retention rate is indicated in Percent and 95% confidence intervals (CI) with respect to the Time to discontinuation. |
Countries
Japan
Participant flow
Recruitment details
The study started to enroll patients in April 2014 and concluded in November 2017.
Pre-assignment details
Participant flow refers to Safety Set including all subjects which took at least one dose of study medication.
Participants by arm
| Arm | Count |
|---|---|
| Lacosamide Subjects randomized in this arm received lacosamide from 200 mg/day to 600 mg/day, from the Titration to the End of Study Visit (up to 3.5 years). | 19 |
| Total | 19 |
Withdrawals & dropouts
| Period | Reason | FG000 |
|---|---|---|
| Treatment Period | Adverse Event | 2 |
| Treatment Period | Lack of Efficacy | 3 |
| Treatment Period | Withdrawal by Subject | 2 |
Baseline characteristics
| Characteristic | Lacosamide |
|---|---|
| Age, Categorical <=18 years | 0 Participants |
| Age, Categorical >=65 years | 2 Participants |
| Age, Categorical Between 18 and 65 years | 17 Participants |
| Age, Continuous | 39.2 years STANDARD_DEVIATION 15.8 |
| Race/Ethnicity, Customized Asian (Japanese) | 19 Participants |
| Race/Ethnicity, Customized Other | 0 Participants |
| Sex: Female, Male Female | 8 Participants |
| Sex: Female, Male Male | 11 Participants |
Adverse events
| Event type | EG000 affected / at risk |
|---|---|
| deaths Total, all-cause mortality | 0 / 19 |
| other Total, other adverse events | 19 / 19 |
| serious Total, serious adverse events | 2 / 19 |
Outcome results
Primary
Number of Subjects Who Withdraw Due to Adverse Events (AEs) During the Study
An Adverse Event (AE) is any untoward medical occurrence in a patient or clinical investigation subject administered a pharmaceutical product, which does not necessarily have a causal relationship with this treatment. An AE could therefore be any unfavorable and unintended sign, symptom, or disease temporally associated with the use of a medicinal (investigational) product, whether or not related to the medicinal (investigational) product.
Time frame: From the Titration Period (investigational product is taken) to the End of Study Visit (up to 3.5 years)
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Lacosamide (Safety Set) | Number of Subjects Who Withdraw Due to Adverse Events (AEs) During the Study | 2 Participants |
Primary
Number of Subjects With at Least One Incidence of Serious Adverse Events (SAEs) During the Study
A Serious Adverse Event (SAE) is any untoward medical occurrence that at any dose: * Results in death * Is life-threatening * Requires in patient hospitalization or prolongation of existing hospitalization * Is a congenital anomaly or birth defect * Is as infection that requires treatment parenteral antibiotics * Other important medical events which based on medical or scientific judgement may jeopardize the patients, or may require medical or surgical intervention to prevent any of the above
Time frame: From the Titration Period (investigational product is taken) to the End of Study Visit (up to 3.5 years)
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Lacosamide (Safety Set) | Number of Subjects With at Least One Incidence of Serious Adverse Events (SAEs) During the Study | 2 Participants |
Primary
Number of Subjects With at Least One Incidence of Treatment-Emergent Adverse Events (TEAEs) During the Study
An Adverse Event (AE) is any untoward medical occurrence in a patient or clinical investigation subject administered a pharmaceutical product, which does not necessarily have a causal relationship with this treatment. An AE could therefore be any unfavorable and unintended sign, symptom, or disease temporally associated with the use of a medicinal (investigational) product, whether or not related to the medicinal (investigational) product.
Time frame: From the Titration Period (investigational product is taken) to the End of Study Visit (up to 3.5 years)
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Lacosamide (Safety Set) | Number of Subjects With at Least One Incidence of Treatment-Emergent Adverse Events (TEAEs) During the Study | 19 Participants |
Secondary
Number of Subjects Remaining Seizure Free for 12 Consecutive Months During the Monotherapy Period
Subjects were considered seizure free if their seizure counts for every day over the entire Treatment Period was zero and if they completed the Treatment Period. A subject was considered seizure free, if no seizure occurred during the 12 consecutive months in the Evaluation Period. If one of the following occurred, the subject was not considered seizure free: * A documented seizure during 6 consecutive months of the Evaluation Analysis Period * Subject discontinued the study prematurely during the Evaluation Analysis Period * Missing Seizure Count Case Report Forms (CRFs) prior to completing the Evaluation Analysis Period. Subjects who discontinued before the end date of 6 consecutive months were included in this analysis.
Time frame: From the beginning of the Monotherapy Period to the end of the Follow-Up Period (up to 3.1 years until the time of approval granted)
Population: The Full Analysis Set (FAS) consisted of subjects in the SS who had at least 1 seizure diary assessment. Subjects who discontinued before the end date of 12 consecutive months were included in this Analysis.
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Lacosamide (Safety Set) | Number of Subjects Remaining Seizure Free for 12 Consecutive Months During the Monotherapy Period | 6 Participants |
Secondary
Number of Subjects Remaining Seizure Free for 6 Consecutive Months During the Monotherapy Period
Subjects were considered seizure free if their seizure counts for every day over the entire Treatment Period was zero and if they completed the Treatment Period. A subject was considered seizure free, if no seizure occurred during the 6 consecutive months in the Evaluation Period. If one of the following occurred, the subject was not considered seizure free: * A documented seizure during 6 consecutive months of the Evaluation Analysis Period * Subject discontinued the study prematurely during the Evaluation Analysis Period * Missing Seizure Count Case Report Forms (CRFs) prior to completing the Evaluation Analysis Period
Time frame: From the beginning of the Monotherapy Period to the end of the Follow-Up Period (up to 3.1 years until the time of approval granted)
Population: The Full Analysis Set (FAS) consisted of subjects in the Safety Set (SS) who had at least 1 seizure diary assessment. Subjects who discontinued before the end date of 6 consecutive months were included in this analysis.
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Lacosamide (Safety Set) | Number of Subjects Remaining Seizure Free for 6 Consecutive Months During the Monotherapy Period | 6 Participants |
Secondary
Percentage of Participants in the Monotherapy Period Without Discontinuation Due to Adverse Events (AE) or Lack of Efficacy (LOE)
For Time to discontinuation (event), Retention rate and 95% CI was calculated using the Kaplan-Meier method. Retention rate is indicated in Percent and 95% confidence intervals (CI) with respect to the Time to discontinuation.
Time frame: From the beginning of the Monotherapy Period to the end of the Follow-Up Period (up to 3.1 years until the time of approval granted)
Population: The Full Analysis Set (FAS) consisted of subjects in the Safety Set (SS) who had at least 1 seizure diary assessment. Subjects who discontinued before Monotherapy Period were not included in this Analysis.
| Arm | Measure | Group | Value (MEDIAN) |
|---|---|---|---|
| Lacosamide (Safety Set) | Percentage of Participants in the Monotherapy Period Without Discontinuation Due to Adverse Events (AE) or Lack of Efficacy (LOE) | Retention Rate after 6-months | 81.3 Percentage of participant |
| Lacosamide (Safety Set) | Percentage of Participants in the Monotherapy Period Without Discontinuation Due to Adverse Events (AE) or Lack of Efficacy (LOE) | Retention Rate after 12-months | 81.3 Percentage of participant |
| Lacosamide (Safety Set) | Percentage of Participants in the Monotherapy Period Without Discontinuation Due to Adverse Events (AE) or Lack of Efficacy (LOE) | Retention Rate after 18-months | 81.3 Percentage of participant |
| Lacosamide (Safety Set) | Percentage of Participants in the Monotherapy Period Without Discontinuation Due to Adverse Events (AE) or Lack of Efficacy (LOE) | Retention Rate after 24-months | 81.3 Percentage of participant |
Secondary
Plasma Concentrations of Lacosamide Versus Time Postdose
Dose-normalized lacosamide Plasma Concentration (µg/mL) by Visit and Dose during the Evaluation Period.
Time frame: From Titration Period up to Week 94
Population: Two Subjects withdrew during the AED Withdrawal Period (prior to the Evaluation Period).
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Lacosamide (Safety Set) | Plasma Concentrations of Lacosamide Versus Time Postdose | Concentration at First Visit | 0.028 µg/mL | Standard Deviation 0.016 |
| Lacosamide (Safety Set) | Plasma Concentrations of Lacosamide Versus Time Postdose | Concentration at Last Visit | 0.034 µg/mL | Standard Deviation 0.01 |