Epilepsy, Partial Onset Seizures
Conditions
Keywords
Lacosamide, Epilepsy, Partial Onset Seizures
Brief summary
The purpose of this study is to evaluate the efficacy and safety of 200 and 400 mg/day of orally administered Lacosamide as adjunctive therapy compared with placebo in Japanese and Chinese adults with uncontrolled Partial-Onset Seizures with or without secondary generalization.
Interventions
DRUGLacosamide 50 mg
* Active Substance: Lacosamide * Pharmaceutical Form: Film-coated tablet * Concentration: 50 mg * Route of Administration: Oral use
* Active Substance: Lacosamide * Pharmaceutical Form: Film-coated tablet * Concentration: 100 mg * Route of Administration: Oral use
DRUGPlacebo
Matching oral Placebo tablets twice daily for 16 weeks.
Sponsors
UCB Japan Co. Ltd.
UCB Pharma SA
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
TRIPLE (Subject, Investigator, Outcomes Assessor)
Eligibility
Sex/Gender
ALL
Age
16 Years to 70 Years
Healthy volunteers
No
Inclusion criteria
* Subject has had an Electroencephalogram (EEG) and a brain Computerized Tomography (CT) scan or Magnetic Resonance Imaging (MRI) exam consistent with a Diagnosis of Epilepsy with Partial-Onset Seizures according to the International Classification of Epileptic Seizures (1981) * Subject must have been observed to have Partial-Onset Seizures for at least the previous 2 years despite prior therapy with at least 2 Anti-Epileptic Drugs (AEDs)(concurrently or sequentially) and must have been observed to have on average at least 4 Partial-Onset Seizures per 28 days with a seizure-free phase no longer than 21 days in the 8-Week Period prior to entry into the Baseline Period. In the case of Simple Partial Seizures, only those with motor signs will be counted towards meeting the inclusion criterion * Subjects must be on a stable dose regimen of at least 1, but no more than 3 AEDs (concurrent stable Vagus Nerve Stimulation (VNS) is not counted as an AED). The VNS must have been in place for at least 6 months prior to study entry. The dosage of concomitant AED therapy and the settings of the VNS must be kept constant for a period of at least 4 weeks prior to entry into the Baseline Period * Minimum Body Weight of 40 kg
Exclusion criteria
* Subject has a lifetime history of suicide attempt (including an active attempt, interrupted attempt, or aborted attempt) or has a 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 * Subject has a current or previous diagnosis of Pseudo-Seizures, Conversion Disorders, or other non-epileptical events that could be confused with Seizures * Subject has Seizures that are uncountable due to Clustering (ie, an episode lasting less than 30 minutes in which several Seizures occur with such frequency that the initiation and completion of each individual Seizure cannot be distinguished) during the 8-Week Period prior to Visit 1 * Subject has a history of Primary Generalized Seizures * Subject with a history of Status Epilepticus within the 12-Months Period prior to Visit 1 * Subject who underwent surgery for Epilepsy within the 2 Years Period prior to Visit 1 * Subjects with cardiac, renal, hepatic, endocrinological dysfunction or psychiatric illness that may impair reliable participation in the study or necessitate the use of medication not allowed by the protocol
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Change in Partial-Onset Seizure Frequency Per 28 Days From Baseline to the Maintenance Period | 8-week Baseline Period (Visit 1 to 3) and 12-week Maintenance Period (Visit 5 to 8) | Partial-onset seizure (POS) frequency per 28 days was calculated as: POS frequency = (Number of POS over the specified time interval) / (Number of days in the interval with available diary data) x 28. A negative value in Change in Partial-onset seizure frequency indicates a reduction of Partial-onset seizure frequency from Baseline to the Maintenance Period. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| The Proportion of Individual Patients Who Experience a 50 % or Greater Reduction in Seizure Frequency From Baseline to the Maintenance Period (50 % Responder Rate) | 8-week Baseline Period (Visit 1 to 3) to the 12-week Maintenance Period (Visit 5 to 8) | — |
| Percent Change in Partial-Onset Seizure Frequency Per 28 Days From Baseline to the Maintenance Period | 8-week Baseline Period (Visit 1 to 3) to the 12-week Maintenance Period (Visit 5 to 8) | Calculates as 28-day seizure frequency during the Maintenance Period - 28-day seizure frequency during the Baseline Period, divided by the 28-day seizure frequency during the Baseline Period with this quantity multiplied by 100. A negative value in percent change from Baseline indicates a decrease in Partial-Onset Seizure frequency from Baseline to the Maintenance Period. |
| Change in Partial-Onset Seizure Frequency Per 28 Days From Baseline to the Treatment Period (i.e., Titration + Maintenance Period) | 8-week Baseline Period (Visit 1 to 3) to the 16-week Treatment Period (Visit 3 to 8) | Partial-onset seizure (POS) frequency per 28 days was calculated as: POS frequency = (Number of POS over the specified time interval) / (Number of days in the interval with available diary data) x 28. A negative value in Change in Partial-onset seizure frequency indicates a reduction of Partial-onset seizure frequency from Baseline to the Treatment Period. |
Countries
China, Japan
Participant flow
Recruitment details
A total of 676 subjects with uncontrolled partial-onset seizures (of the 676 subjects, the number of Chinese subjects and Japanese subjects was planned to be 507 and 169, respectively) was planned to be screened and 540 subjects were planned to be enrolled in all regions of Japan and China.
Pre-assignment details
Overall, 692 subjects were screened and 548 subjects were enrolled. The Participant Flow refers to the Safety Set (SS) which was defined as all enrolled subjects who took at least 1 dose of Lacosamide. Reasons for discontinuation were only calculated for the SS. 547 subjects were included in the Safety Set.
Participants by arm
| Arm | Count |
|---|---|
| Placebo Matching Placebo for 16 weeks.
Placebo: Matching oral Placebo tablets twice daily for 16 weeks. | 184 |
| Lacosamide 200 mg/Day Lacosamide Treatment of 200 mg/day (100 mg bid) for 16 weeks.
Lacosamide 50 mg: - Active Substance: Lacosamide
* Pharmaceutical Form: Film-coated tablet
* Concentration: 50 mg
* Route of Administration: Oral use
Lacosamide 100 mg: - Active Substance: Lacosamide
* Pharmaceutical Form: Film-coated tablet
* Concentration: 100 mg
* Route of Administration: Oral use | 183 |
| Lacosamide 400 mg/Day Lacosamide Treatment of 400 mg/day (200 mg bid) for 16 weeks.
Lacosamide 50 mg: - Active Substance: Lacosamide
* Pharmaceutical Form: Film-coated tablet
* Concentration: 50 mg
* Route of Administration: Oral use
Lacosamide 100 mg: - Active Substance: Lacosamide
* Pharmaceutical Form: Film-coated tablet
* Concentration: 100 mg
* Route of Administration: Oral use | 180 |
| Total | 547 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 | FG002 |
|---|---|---|---|---|
| Overall Study | Adverse Event | 14 | 8 | 28 |
| Overall Study | Lack of Efficacy | 0 | 1 | 1 |
| Overall Study | Lost to Follow-up | 2 | 0 | 1 |
| Overall Study | Protocol Violation | 2 | 2 | 0 |
| Overall Study | Withdrawal by Subject | 0 | 1 | 2 |
Baseline characteristics
| Characteristic | Placebo | Lacosamide 200 mg/Day | Lacosamide 400 mg/Day | Total |
|---|---|---|---|---|
| Age, Categorical <=18 years | 20 Participants | 18 Participants | 15 Participants | 53 Participants |
| Age, Categorical >=65 years | 0 Participants | 2 Participants | 1 Participants | 3 Participants |
| Age, Categorical Between 18 and 65 years | 164 Participants | 163 Participants | 164 Participants | 491 Participants |
| Age, Continuous | 31.8 years STANDARD_DEVIATION 12 | 33.2 years STANDARD_DEVIATION 12.2 | 32.3 years STANDARD_DEVIATION 11.9 | 32.4 years STANDARD_DEVIATION 12 |
| Race/Ethnicity, Customized Chinese | 136 participants | 136 participants | 133 participants | 405 participants |
| Race/Ethnicity, Customized Japanese | 48 participants | 47 participants | 47 participants | 142 participants |
| Race (NIH/OMB) American Indian or Alaska Native | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Asian | 184 Participants | 183 Participants | 180 Participants | 547 Participants |
| Race (NIH/OMB) Black or African American | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) More than one race | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Native Hawaiian or Other Pacific Islander | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Unknown or Not Reported | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) White | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Sex: Female, Male Female | 82 Participants | 89 Participants | 76 Participants | 247 Participants |
| Sex: Female, Male Male | 102 Participants | 94 Participants | 104 Participants | 300 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk | EG002 affected / at risk |
|---|---|---|---|
| deaths Total, all-cause mortality | — / — | — / — | — / — |
| other Total, other adverse events | 77 / 184 | 87 / 183 | 112 / 180 |
| serious Total, serious adverse events | 4 / 184 | 2 / 183 | 9 / 180 |
Outcome results
Primary
Change in Partial-Onset Seizure Frequency Per 28 Days From Baseline to the Maintenance Period
Partial-onset seizure (POS) frequency per 28 days was calculated as: POS frequency = (Number of POS over the specified time interval) / (Number of days in the interval with available diary data) x 28. A negative value in Change in Partial-onset seizure frequency indicates a reduction of Partial-onset seizure frequency from Baseline to the Maintenance Period.
Time frame: 8-week Baseline Period (Visit 1 to 3) and 12-week Maintenance Period (Visit 5 to 8)
Population: The Full Analysis Set consists of all subjects who were randomized, received at least 1 dose of study drug, and had at least 1 post-baseline efficacy assessment.
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Placebo | Change in Partial-Onset Seizure Frequency Per 28 Days From Baseline to the Maintenance Period | -1.22 Seizures per 28 days |
| Lacosamide 200 mg/Day | Change in Partial-Onset Seizure Frequency Per 28 Days From Baseline to the Maintenance Period | -3.33 Seizures per 28 days |
| Lacosamide 400 mg/Day | Change in Partial-Onset Seizure Frequency Per 28 Days From Baseline to the Maintenance Period | -4.50 Seizures per 28 days |
Comparison: To avoid inflation of Type I error, hypothesis testing followed predefined hierarchical procedure starting LCM 400 mg/day treatment group versus the placebo group.~If the test was not statistically significant, the procedure stopped and no Groups were declared different from placebo. If the test was statistically significant, the treatment group was considered different from placebo and the procedure continued with the LCM 200 mg/day treatment group.p-value: <0.00195% CI: [30.5, 47.6]ANCOVA
Comparison: To avoid inflation of Type I error, hypothesis testing followed predefined hierarchical procedure starting LCM 400 mg/day treatment group versus the placebo group.~If the test was not statistically significant, the procedure stopped and no Groups were declared different from placebo. If the test was statistically significant, the treatment group was considered different from placebo and the procedure continued with the LCM 200 mg/day treatment group.p-value: <0.00195% CI: [18.7, 38.7]ANCOVA
Secondary
Change in Partial-Onset Seizure Frequency Per 28 Days From Baseline to the Treatment Period (i.e., Titration + Maintenance Period)
Partial-onset seizure (POS) frequency per 28 days was calculated as: POS frequency = (Number of POS over the specified time interval) / (Number of days in the interval with available diary data) x 28. A negative value in Change in Partial-onset seizure frequency indicates a reduction of Partial-onset seizure frequency from Baseline to the Treatment Period.
Time frame: 8-week Baseline Period (Visit 1 to 3) to the 16-week Treatment Period (Visit 3 to 8)
Population: The Full Analysis Set consists of all subjects who were randomized, received at least 1 dose of study drug, and had at least 1 post-baseline efficacy assessment.
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Placebo | Change in Partial-Onset Seizure Frequency Per 28 Days From Baseline to the Treatment Period (i.e., Titration + Maintenance Period) | -1.10 Seizures per 28 days |
| Lacosamide 200 mg/Day | Change in Partial-Onset Seizure Frequency Per 28 Days From Baseline to the Treatment Period (i.e., Titration + Maintenance Period) | -3.39 Seizures per 28 days |
| Lacosamide 400 mg/Day | Change in Partial-Onset Seizure Frequency Per 28 Days From Baseline to the Treatment Period (i.e., Titration + Maintenance Period) | -4.00 Seizures per 28 days |
Secondary
Percent Change in Partial-Onset Seizure Frequency Per 28 Days From Baseline to the Maintenance Period
Calculates as 28-day seizure frequency during the Maintenance Period - 28-day seizure frequency during the Baseline Period, divided by the 28-day seizure frequency during the Baseline Period with this quantity multiplied by 100. A negative value in percent change from Baseline indicates a decrease in Partial-Onset Seizure frequency from Baseline to the Maintenance Period.
Time frame: 8-week Baseline Period (Visit 1 to 3) to the 12-week Maintenance Period (Visit 5 to 8)
Population: The Full Analysis Set consists of all subjects who were randomized, received at least 1 dose of study drug, and had at least 1 post-baseline efficacy assessment.
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Placebo | Percent Change in Partial-Onset Seizure Frequency Per 28 Days From Baseline to the Maintenance Period | -10.10 percentage change |
| Lacosamide 200 mg/Day | Percent Change in Partial-Onset Seizure Frequency Per 28 Days From Baseline to the Maintenance Period | -36.75 percentage change |
| Lacosamide 400 mg/Day | Percent Change in Partial-Onset Seizure Frequency Per 28 Days From Baseline to the Maintenance Period | -48.78 percentage change |
Secondary
The Proportion of Individual Patients Who Experience a 50 % or Greater Reduction in Seizure Frequency From Baseline to the Maintenance Period (50 % Responder Rate)
Time frame: 8-week Baseline Period (Visit 1 to 3) to the 12-week Maintenance Period (Visit 5 to 8)
Population: The Full Analysis Set consists of all subjects who were randomized, received at least 1 dose of study drug, and had at least 1 post-baseline efficacy assessment.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Placebo | The Proportion of Individual Patients Who Experience a 50 % or Greater Reduction in Seizure Frequency From Baseline to the Maintenance Period (50 % Responder Rate) | 36 participants |
| Lacosamide 200 mg/Day | The Proportion of Individual Patients Who Experience a 50 % or Greater Reduction in Seizure Frequency From Baseline to the Maintenance Period (50 % Responder Rate) | 70 participants |
| Lacosamide 400 mg/Day | The Proportion of Individual Patients Who Experience a 50 % or Greater Reduction in Seizure Frequency From Baseline to the Maintenance Period (50 % Responder Rate) | 88 participants |