Epilepsy
Conditions
Keywords
Brivaracetam, Epilepsy, Child, Infant, Adolescents, Partial onset seizures
Brief summary
This study will evaluate the safety and tolerability of brivaracetam in pediatric subjects with epilepsy.
Detailed description
This is a Phase 3, open-label, single-arm, multicenter, long-term study to evaluate the safety and efficacy of brivaracetam (BRV) in children with epilepsy. This study was initially designed for pediatric subjects who had completed a previous BRV study. With protocol amendment 4, enrollment for directly enrolled subjects was modified from 'up to' an additional 100 subjects to at least 100 subjects, keeping the planned total enrollment of approximately 600 subjects to allow flexibility in the number of patients reaching 1 year of exposure. With protocol amendment 5, entry criteria for subjects coming for other pediatric core studies in development were included. Additional clarity was provided for subjects enrolled in N01266 that temporary roll over to one of those studies and resume participation in N01266. With protocol amendment 6, central EEG reading and entry visit EEG were removed. Some clarifications on study assessments (questionnaires, EEGs) was provided and inclusion criteria were aligned from an earlier local amendment. With protocol amendment 7, the pregnancy section was updated to clarify that Pregnancy Report and Outcome Form has to be completed in all pregnancies. With protocol amendment 8, re-categorization of study variables in compliance with reporting registries was performed. Modifications due to COVID19 pandemic were implemented and clarification provided that participants may transition to another BRV study. The primary objective is to evaluate the long-term safety and tolerability of BRV. The secondary objective is to assess the efficacy of BRV during long-term exposure.
Interventions
DRUGBrivaracetam (BRV)
The max BRV dose will be 5.0 mg/kg/day, not to exceed a dose of 200 mg/day for subjects with body weight \>40kg. Subjects may receive oral solution or oral tablets. The LTFU subjects will start dosing in N01266 on the individualized BRV dose they were receiving at the completion of the core study. Subjects must be able to tolerate the min BRV dose specified in the core study to be eligible for entry into the Evaluation Period of N01266. Dose can be adjusted as considered necessary by the Investigator and required by the subject's medical condition. All subjects who prematurely discontinue the study should complete an EDV and have their BRV dose down titrated by a maximum of half the dose every week for a maximum of 4 weeks until a dose of 1 mg/kg/day (50 mg/day for subjects with body weights \>50kg) is reached.
Sponsors
UCB Pharma SA
Study design
Allocation
NA
Intervention model
SINGLE_GROUP
Primary purpose
TREATMENT
Masking
NONE
Eligibility
Sex/Gender
ALL
Age
28 Days to 17 Years
Healthy volunteers
No
Inclusion criteria
All Subjects: * Informed Consent form (ICF) is signed and dated by the parent(s) or legal representative(s) * Subject/legal representative is considered reliable and capable of adhering to the protocol * For female subjects: * Subject is not of childbearing potential OR if women of childbearing potential, and sexually active only if: * Adequate Contraceptive method * Negative pregnancy test * Understands the consequences and potential risks of inadequately protected sexual activity, understands and properly uses contraceptive methods, and is willing to inform the Investigator of any contraception changes Long Term Follow-up Subjects: \- Male or female subjects having participated in a core study with a confirmed diagnosis of epilepsy and for whom a reasonable benefit from long-term administration of BRV is expected Directly Enrolled Subjects: * Subject is a male or female ≥4 years to \<17 years of age * Subject has a clinical diagnosis of partial-onset seizures (POS) according to the International League Against Epilepsy (ILAE) classification * Subject has an EEG compatible with the clinical diagnosis of POS * Subject has been observed to have uncontrolled POS after an adequate course of treatment (in the opinion of the Investigator) with at least 1 antiepileptic drug (AED; concurrently or sequentially) * Subject had at least 1 seizure (POS) during the 3 weeks before the Screening Visit (ScrV) * Subject is taking at least 1 AED. All AEDs need to be at a stable dose for at least 7 days before the ScrV. Vagal nerve stimulator stable for at least 2 weeks before the ScrV is allowed and will be counted as a concomitant AED. Benzodiazepines taken more than once a week (for any indication) will be considered as a concomitant AED
Exclusion criteria
All Subjects: * Subject is a pregnant or nursing female * Subject has severe medical, neurological, or psychiatric disorders or laboratory values, which may have an impact on the safety of the subject. * Subject has planned participation in any clinical study of another investigational drug or device. * Subject has \>1.5x upper limit of normal (ULN) of any of the following: alanine aminotransferase (ALT), aspartate aminotransferase (AST), alkaline phosphatase (ALP), or \>1.0xULN total bilirubin (≥1.5xULN total bilirubin if known Gilbert's syndrome). If subject has elevations only in total bilirubin that are \>ULN and \<1.5xULN, fractionate bilirubin to identify possible undiagnosed Gilbert's syndrome (ie, direct bilirubin \<35%). N01349 subjects with a total bilirubin \> ULN may be considered for the study if benign unconjugated hyperbilirubinemia is suspected in the context of prolonged neonatal jaundice, after discussion with the medical monitor. For randomized subjects with a baseline result \>ULN for ALT, AST, ALP, or total bilirubin, a baseline diagnosis and/or the cause of any clinically meaningful elevation must be understood and recorded in the eCRF. If subject has \>ULN ALT, AST, or ALP that does not meet the exclusion limit at the baseline referenced in Table 5-1 for LTFU subjects and at the Screening Visit for directly enrolled subjects, repeat the tests, if possible, prior to dosing to ensure there is no further ongoing clinically relevant increase. In case of a clinically relevant increase, inclusion of the subject must be discussed with the Medical Monitor. Tests that result in ALT, AST, or ALP up to 25% above the exclusion limit may be repeated once for confirmation. This includes re-screening. * Subject has chronic liver disease. Long Term Follow-up Subjects: * Subject had hypersensitivity to BRV or excipients or comparative drugs as stated in this protocol during the course of the core study. * Subject had poor compliance with the visit schedule or medication intake in the core study. * Subject ≥6 years of age has a lifetime history of suicide attempt (including actual attempt, interrupted attempt, or aborted attempt), or has suicidal ideation in the past 6 months as indicated by a positive response (Yes) to Question 5 of the Columbia-Suicide Severity Rating Scale (C-SSRS) at the EV. If a subject has active suicidal ideation without a specific plan as indicated by a positive response (Yes) to Question 4 of Columbia-Suicide Severity Rating Scale (C SSRS) at the EV, the subject should be referred immediately to a Mental Healthcare Professional and may be excluded from the study based upon the Investigator's judgment of benefit/risk of continuing the subject in the study/on study medication. Directly Enrolled Subjects: * Subject has previously received BRV. * Subject had concomitant use of LEV at the ScrV. In addition, the use of LEV is prohibited for at least 4 weeks prior to the ScrV. * Subject has epilepsy secondary to a progressive cerebral disease or tumor, or any other progressively neurodegenerative disease. Stable arteriovenous malformations, meningiomas or other benign tumors may be acceptable according to Investigator's opinion. * Subject has a history of primary generalized epilepsy. * Subject has a history of status epilepticus in the month immediately prior to the ScrV or during the Up Titration Period. * Subject has a history or presence of pseudoseizures. * Subject is suffering only from febrile seizures. * Subject is on felbamate with less than 18 months continuous exposure. Subject who has taken felbamate for a combined duration of treatment and wash out of \<18 months before the ScrV. * Subjects treated with vigabatrin who have visual field defects. * Subject has an allergy to pyrrolidone derivatives or investigational product excipients or a history of multiple drug allergies. * Subject has any clinically significant acute or chronic illness as determined during the physical examination or from other information available to the Investigator (eg, bone marrow depression, chronic hepatic disease, severe renal impairment, psychiatric disorder). * Subject has an underlying disease or is receiving a treatment that may interfere with the absorption, distribution, metabolism, and elimination of the study drug. * Subject has any medical condition that might interfere with his/her study participation (eg, serious infection or scheduled elective surgery). * Subject has a terminal illness. * Subject has any clinically significant deviations from reference range values for laboratory parameters as determined by the Investigator. * Subject has a clinically relevant ECG abnormality according to the Investigator. * Subject had major surgery within 6 months prior to the ScrV. * Subject received any investigational drug or device within the 30 days prior to the ScrV.
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Percentage of Participants With Treatment-emergent Adverse Events (TEAEs) During the Study | From Baseline to end of study (up to 10 years) | TEAEs are defined as AEs that had onset on or after the day of first BRV dose. |
| Percentage of Participants With Treatment-emergent Serious Adverse Events (SAEs) During the Study | From Baseline to end of study (up to 10 years) | TEAEs are defined as AEs that had onset on or after the day of first BRV dose. A SAE was defined as an event that met 1 or more of the below criteria: a) Death, b) Life-threatening, (Life-threatening did not include a reaction that might have caused death had it occurred in a more severe form.) c) Significant or persistent disability/incapacity, d) Congenital anomaly/birth defect (including that occurring in a fetus), e) Important medical event that, based upon appropriate medical judgment, may have jeopardized participant and may have required medical or surgical intervention to prevent 1 of the other outcomes listed in the definition of serious, (Important medical events may have included allergic bronchospasm requiring intensive treatment in an emergency room \[ER\] or at home) f) Initial inpatient hospitalization or prolongation of hospitalization. (A participant admitted to a hospital, even if released on the same day, met the criteria for the initial inpatient hospitalization). |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| 50% Responder Rate for Participants ≥2 Years of Age for Total Seizures (All Types) (Based on DRC Data) | From Baseline (LTFU participants: Baseline of previous studies N01263 [NCT00422422]; and DE participants: Baseline of current study) to the end of the evaluation period (up to 10 years) | A responder is defined as a participant with a ≥50% reduction in seizure frequency from the baseline period of the previous study for LTFU participants or during this study for DE participants. This OM was analyzed in participants ≥2 years (per DRC data) only. |
| Absolute Change in Average Daily Frequency (ADF) of Partial-onset-seizures (POS) in Participants <2 Years of Age With POS Only (Based on EEG Data) | From Baseline (LTFU participants: Baseline of previous studies N01263 [NCT00422422] or N01349 [NCT03325439]) to the end of the evaluation period (up to 10 years) | Absolute change in ADF is calculated as the baseline ADF minus post-baseline ADF. ADF is calculated as (number of seizures from central reader divided by stop date and time of EEG minus start date and time of EEG) multiplied to 60, multiplied to 24. This OM was analyzed in participants \<2 years (per EEG data) only. |
| Percent Change in Average Daily Frequency (ADF) of Partial-onset-seizures (POS) in Participants <2 Years of Age With POS Only (Based on EEG Data) | From Baseline (LTFU participants: Baseline of previous studies N01263 [NCT00422422] or N01349 [NCT03325439]) to the end of the evaluation period (up to 10 years) | Percent change in average daily frequency (ADF) is calculated as absolute change in ADF divided by baseline ADF multiplied to 100. ADF is calculated as (number of seizures from central reader divided by stop date and time of EEG minus start date and time of EEG) multiplied to 60, multiplied to 24. This OM was analyzed in participants \<2 years (per EEG data) only. |
| Absolute Change in 28-days Adjusted Partial-onset-seizure (POS) Frequency for Participants Aged ≥2 Years From Baseline to the End of the Evaluation Period in Participants With POS Only (Based on Daily Record Card [DRC]) | From Baseline (LTFU participants: Baseline of previous studies N01263 [NCT00422422]; and DE participants: Baseline of current study) to the end of the evaluation period (up to 10 years) | Absolute change in seizure frequency per 28 days based on the daily record card (DRC) data, is calculated as baseline seizure frequency per 28 days minus post-Baseline seizure frequency per 28 days. The 28 day adjusted seizure frequency was calculated by dividing the number of partial seizures by the number of days for which the diary was completed, and multiplying the resulting value by 28. This OM was analyzed in participants ≥2 years (per DRC data) only. Here in the study FAS indicates Full Analysis Set, EEG indicates electroencephalogram, OM indicates Outcome measure |
| Absolute Change in Average Daily Frequency of POS in Participants <2 Years of Age With Typical Absence Seizures (Based on EEG Data) | From Baseline (LTFU participants: Baseline of previous studies N01263 [NCT00422422] or N01349 [NCT03325439]) to the end of the evaluation period (up to 10 years) | Absolute change in ADF is calculated as the baseline ADF minus post-baseline ADF. ADF is calculated as (number of seizures from central reader divided by stop date and time of EEG minus start date and time of EEG) multiplied to 60, multiplied to 24. |
| Percent Change in Average Daily Frequency of POS in Participants <2 Years of Age With Typical Absence Seizures (Based on EEG Data) | From Baseline (LTFU participants: Baseline of previous studies N01263 [NCT00422422] or N01349 [NCT03325439]) to the end of the evaluation period (up to 10 years) | Percent change in average daily frequency (ADF) is calculated as absolute change in ADF divided by baseline ADF multiplied to 100. ADF is calculated as (number of seizures from central reader divided by stop date and time of EEG minus start date and time of EEG) multiplied to 60, multiplied to 24. |
| 50% Responder Rate for Total Seizures (All Types) in Participants <2 Years of Age With Typical Absence Seizures (Based on EEG Data) | From Baseline (LTFU participants: Baseline of previous studies N01263 [NCT00422422] or N01349 [NCT03325439]) to the end of the evaluation period (up to 10 years) | A responder is defined as a participant with a ≥50% reduction in seizure frequency from the baseline period of the previous study for LTFU participants. |
| 50% Responder Rate for Participants <2 Years of Age for Total Seizures (All Types) (Based on EEG Data) | From Baseline (LTFU participants: Baseline of previous studies N01263 [NCT00422422] or N01349 [NCT03325439]) to the end of the evaluation period (up to 10 years) | A responder is defined as a participant with a ≥50% reduction in seizure frequency from the baseline period of the previous study for LTFU participants. This OM was analyzed in participants \<2 years (per EEG data) only. |
| Percent Change in 28-days Adjusted Partial-onset-seizure (POS) Frequency for Participants Aged ≥2 Years From Baseline to the End of the Evaluation Period in Participants With POS Only (Based on DRC Data) | From Baseline (LTFU participants: Baseline of previous studies N01263 [NCT00422422]; and DE participants: Baseline of current study) to the end of the evaluation period (up to 10 years) | Percent change is calculated as absolute change in seizure frequency per 28 days divided by baseline seizure frequency per 28 Days multiplied to 100. The 28 day adjusted seizure frequency was calculated by dividing the number of partial seizures by the number of days for which the diary was completed, and multiplying the resulting value by 28. This OM was analyzed in participants ≥2 years (per DRC data) only. |
Countries
Belgium, Czechia, France, Germany, Hungary, Ireland, Italy, Mexico, Poland, Spain, United Kingdom, United States
Participant flow
Recruitment details
The study started to enroll participants in August 2011 and concluded in February 2022.
Pre-assignment details
The Participant Flow refers to the Enrolled Set.
Participants by arm
| Arm | Count |
|---|---|
| Age Cohort: ≥1 Month to <2 Years Participants from core study (LTFU \[Long term follow-up\] participants from N01263 \[NCT00422422\], EP0065 \[NCT03405714\] or N01349 \[NCT03325439\]) aged greater than or equal to (≥) 1 month to less than (\<) 2 years entered evaluation period (EP) and received individualized Brivaracetam (BRV) dose as they were receiving at completion of core study. For all participants, the approximate BRV doses to be administered are 1 to 5 milligrams per kilogram per day (mg/kg/day) (0.5, 1, 2, and 2.5 mg/kg twice daily\[bid\]), tablet or oral solution and can be up-titrated or down-titrated based on investigator decision with a maximum allowable BRV dose of 5.0 mg/kg/day (2.5 mg/kg bid), not to exceed a dose of 200 mg/day. The duration of the treatment for each participant was planned to be at least 3 years, until BRV received approval for pediatric participants in their age range or until the investigational medicinal product (IMP) development was stopped by the Sponsor. | 36 |
| Age Cohort: ≥2 to <4 Years Participants from core study (LTFU participants from N01263 \[NCT00422422\] and EP0065 \[NCT03405714\]) aged ≥2 Years to \<4 years entered EP and received individualized BRV dose as they were receiving at completion of core study. For all participants, the approximate BRV doses to be administered are 1 to 5 mg/kg/day (0.5, 1, 2, and 2.5mg/kg bid), tablet or oral solution and can be up-titrated or down-titrated based on investigator decision with a maximum allowable BRV dose of 5.0 mg/kg/day (2.5mg/kg bid), not to exceed a dose of 200mg/day. The duration of the treatment for each participant was planned to be at least 3 years, until BRV received approval for pediatric participants in their age range or until the IMP development was stopped by the Sponsor. | 15 |
| Age Cohort: ≥4 to <12 Years Participants from core study (LTFU participants from N01263 \[NCT00422422\] and EP0065 \[NCT03405714\]) aged ≥4 Years to \<12 years entered EP and received individualized BRV dose as they were receiving at completion of core study and Directly Enrolled (DE) participants in this study aged ≥4 years to \<12 years of age received BRV dose based on tolerability confirmed during screening period. For all participants, the approximate BRV doses to be administered are 1 to 5 mg/kg/day (0.5, 1, 2, and 2.5mg/kg bid), tablet or oral solution and can be up-titrated or down-titrated based on investigator decision with a maximum allowable BRV dose of 5.0 mg/kg/day (2.5 mg/kg bid), not to exceed a dose of 200 mg/day. The duration of the treatment for each participant was planned to be at least 3 years, until BRV received approval for pediatric participants in their age range or until the IMP development was stopped by the Sponsor. | 141 |
| Age Cohort: ≥12 to <17 Years Participants from core study (LTFU participants from N01263 \[NCT00422422\] and EP0065 \[NCT03405714\]) aged ≥12 Years to \<17 years entered EP and received individualized BRV dose as they were receiving at completion of core study and DE participants in this study aged ≥12 years to \<17 years of age received BRV dose based on tolerability confirmed during screening period. For all participants, the approximate BRV doses to be administered are 1 to 5 mg/kg/day (0.5, 1, 2, and 2.5 mg/kg bid), tablet or oral solution and can be up-titrated or down-titrated based on investigator decision with a maximum allowable BRV dose of 5.0 mg/kg/day (2.5 mg/kg bid), not to exceed a dose of 200 mg/day. The duration of the treatment for each participant was planned to be at least 3 years, until BRV received approval for pediatric participants in their age range or until the IMP development was stopped by the Sponsor. | 65 |
| Total | 257 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 | FG002 | FG003 |
|---|---|---|---|---|---|
| Overall Study | 5 year without seizures. Treatment is finish | 0 | 0 | 1 | 0 |
| Overall Study | Adverse Event | 4 | 5 | 16 | 7 |
| Overall Study | BRV administration dropout | 0 | 0 | 1 | 0 |
| Overall Study | BRV discontinued as no seizures during 2 years | 0 | 0 | 1 | 0 |
| Overall Study | Cure | 1 | 0 | 0 | 0 |
| Overall Study | Dropout | 0 | 0 | 3 | 1 |
| Overall Study | End of treatment epilepsy | 1 | 0 | 0 | 0 |
| Overall Study | Investigator decision | 0 | 0 | 1 | 0 |
| Overall Study | Lack of compliance | 1 | 0 | 0 | 0 |
| Overall Study | Lack of Efficacy | 4 | 4 | 23 | 8 |
| Overall Study | Lack of reliability from the subject's caregiver | 1 | 0 | 0 | 0 |
| Overall Study | Lost to Follow-up | 0 | 0 | 5 | 3 |
| Overall Study | Non compliance | 1 | 0 | 1 | 0 |
| Overall Study | No Seizures | 1 | 0 | 0 | 0 |
| Overall Study | Other | 0 | 0 | 0 | 1 |
| Overall Study | Parents went abroad with the patient | 0 | 0 | 1 | 0 |
| Overall Study | Patient became seizure-free after surgery | 0 | 0 | 1 | 0 |
| Overall Study | Patient cured from Epilepsy | 0 | 0 | 1 | 0 |
| Overall Study | Patient was moving | 0 | 1 | 0 | 0 |
| Overall Study | Protocol Violation | 0 | 0 | 2 | 0 |
| Overall Study | Seizures resolved | 0 | 0 | 1 | 0 |
| Overall Study | Sponsor recommended discontinuation | 0 | 0 | 0 | 1 |
| Overall Study | Unreliable subject | 0 | 0 | 0 | 1 |
| Overall Study | Withdrawal by Subject | 4 | 1 | 18 | 6 |
Baseline characteristics
| Characteristic | Age Cohort: ≥2 to <4 Years | Age Cohort: ≥1 Month to <2 Years | Age Cohort: ≥4 to <12 Years | Age Cohort: ≥12 to <17 Years | Total |
|---|---|---|---|---|---|
| Age, Categorical <=18 years | 15 Participants | 36 Participants | 141 Participants | 65 Participants | 257 Participants |
| Age, Categorical >=65 years | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Age, Categorical Between 18 and 65 years | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Age, Continuous | 2.761 years STANDARD_DEVIATION 0.582 | 1.122 years STANDARD_DEVIATION 0.504 | 7.699 years STANDARD_DEVIATION 2.394 | 13.824 years STANDARD_DEVIATION 1.274 | 8.039 years STANDARD_DEVIATION 4.529 |
| Race/Ethnicity, Customized American Indian/ Alaskan native | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Race/Ethnicity, Customized Asian | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Race/Ethnicity, Customized Black | 0 Participants | 0 Participants | 2 Participants | 2 Participants | 4 Participants |
| Race/Ethnicity, Customized Hispanic or Latino | 1 Participants | 11 Participants | 38 Participants | 19 Participants | 69 Participants |
| Race/Ethnicity, Customized Missing | 0 Participants | 1 Participants | 0 Participants | 0 Participants | 1 Participants |
| Race/Ethnicity, Customized Native Hawaiian or other Pacific Islander | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Race/Ethnicity, Customized Not Hispanic or Latino | 14 Participants | 24 Participants | 103 Participants | 46 Participants | 187 Participants |
| Race/Ethnicity, Customized Other/Mixed | 1 Participants | 8 Participants | 32 Participants | 15 Participants | 56 Participants |
| Race/Ethnicity, Customized White | 14 Participants | 28 Participants | 107 Participants | 48 Participants | 197 Participants |
| Sex: Female, Male Female | 5 Participants | 19 Participants | 62 Participants | 30 Participants | 116 Participants |
| Sex: Female, Male Male | 10 Participants | 17 Participants | 79 Participants | 35 Participants | 141 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk | EG002 affected / at risk | EG003 affected / at risk |
|---|---|---|---|---|
| deaths Total, all-cause mortality | 2 / 36 | 2 / 15 | 2 / 141 | 1 / 65 |
| other Total, other adverse events | 30 / 36 | 13 / 15 | 120 / 141 | 51 / 65 |
| serious Total, serious adverse events | 14 / 36 | 8 / 15 | 42 / 141 | 19 / 65 |
Outcome results
Primary
Percentage of Participants With Treatment-emergent Adverse Events (TEAEs) During the Study
TEAEs are defined as AEs that had onset on or after the day of first BRV dose.
Time frame: From Baseline to end of study (up to 10 years)
Population: The Safety Set (SS) consisted of all enrolled participants who took at least 1 dose of study medication.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Age Cohort: ≥1 Month to <2 Years | Percentage of Participants With Treatment-emergent Adverse Events (TEAEs) During the Study | 94.4 percentage of participants |
| Age Cohort: ≥2 to <4 Years | Percentage of Participants With Treatment-emergent Adverse Events (TEAEs) During the Study | 93.3 percentage of participants |
| Age Cohort: ≥4 to <12 Years | Percentage of Participants With Treatment-emergent Adverse Events (TEAEs) During the Study | 93.6 percentage of participants |
| Age Cohort: ≥12 to <17 Years | Percentage of Participants With Treatment-emergent Adverse Events (TEAEs) During the Study | 92.3 percentage of participants |
Primary
Percentage of Participants With Treatment-emergent Serious Adverse Events (SAEs) During the Study
TEAEs are defined as AEs that had onset on or after the day of first BRV dose. A SAE was defined as an event that met 1 or more of the below criteria: a) Death, b) Life-threatening, (Life-threatening did not include a reaction that might have caused death had it occurred in a more severe form.) c) Significant or persistent disability/incapacity, d) Congenital anomaly/birth defect (including that occurring in a fetus), e) Important medical event that, based upon appropriate medical judgment, may have jeopardized participant and may have required medical or surgical intervention to prevent 1 of the other outcomes listed in the definition of serious, (Important medical events may have included allergic bronchospasm requiring intensive treatment in an emergency room \[ER\] or at home) f) Initial inpatient hospitalization or prolongation of hospitalization. (A participant admitted to a hospital, even if released on the same day, met the criteria for the initial inpatient hospitalization).
Time frame: From Baseline to end of study (up to 10 years)
Population: The Safety Set (SS) consisted of all enrolled participants who took at least 1 dose of study medication.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Age Cohort: ≥1 Month to <2 Years | Percentage of Participants With Treatment-emergent Serious Adverse Events (SAEs) During the Study | 38.9 percentage of participants |
| Age Cohort: ≥2 to <4 Years | Percentage of Participants With Treatment-emergent Serious Adverse Events (SAEs) During the Study | 53.3 percentage of participants |
| Age Cohort: ≥4 to <12 Years | Percentage of Participants With Treatment-emergent Serious Adverse Events (SAEs) During the Study | 29.8 percentage of participants |
| Age Cohort: ≥12 to <17 Years | Percentage of Participants With Treatment-emergent Serious Adverse Events (SAEs) During the Study | 29.2 percentage of participants |
Secondary
50% Responder Rate for Participants ≥2 Years of Age for Total Seizures (All Types) (Based on DRC Data)
A responder is defined as a participant with a ≥50% reduction in seizure frequency from the baseline period of the previous study for LTFU participants or during this study for DE participants. This OM was analyzed in participants ≥2 years (per DRC data) only.
Time frame: From Baseline (LTFU participants: Baseline of previous studies N01263 [NCT00422422]; and DE participants: Baseline of current study) to the end of the evaluation period (up to 10 years)
Population: FAS: all enrolled participants who took at least 1 dose of study drug in this Long-term study and had at least 1 completed post-baseline DRC or EEG. Overall number of participants analyzed included all participants evaluable for this OM. Per planned analysis, participants were grouped as per cohort linked to source (DRC for ≥2 years /EEG for \<2 years) from which their seizure data is recorded. This OM was analyzed in participants ≥2 years of age (per DRC data) only.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Age Cohort: ≥1 Month to <2 Years | 50% Responder Rate for Participants ≥2 Years of Age for Total Seizures (All Types) (Based on DRC Data) | 50.9 percentage of participants |
Secondary
50% Responder Rate for Participants <2 Years of Age for Total Seizures (All Types) (Based on EEG Data)
A responder is defined as a participant with a ≥50% reduction in seizure frequency from the baseline period of the previous study for LTFU participants. This OM was analyzed in participants \<2 years (per EEG data) only.
Time frame: From Baseline (LTFU participants: Baseline of previous studies N01263 [NCT00422422] or N01349 [NCT03325439]) to the end of the evaluation period (up to 10 years)
Population: FAS: enrolled participants who had at least 1 dose of study drug in the study and had at least 1 completed post-baseline DRC or EEG. Overall number of participants analyzed consist of all participants (\<2 years only \[per EEG data\]) evaluable for this OM. Per plan, participants were grouped per cohort linked to source (DRC for ≥2 years/EEG for \<2 years) from which their seizure data is recorded.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Age Cohort: ≥1 Month to <2 Years | 50% Responder Rate for Participants <2 Years of Age for Total Seizures (All Types) (Based on EEG Data) | 75.0 percentage of participants |
Secondary
50% Responder Rate for Total Seizures (All Types) in Participants <2 Years of Age With Typical Absence Seizures (Based on EEG Data)
A responder is defined as a participant with a ≥50% reduction in seizure frequency from the baseline period of the previous study for LTFU participants.
Time frame: From Baseline (LTFU participants: Baseline of previous studies N01263 [NCT00422422] or N01349 [NCT03325439]) to the end of the evaluation period (up to 10 years)
Population: Typical absence seizures data was not collected and analyzed.
Secondary
Absolute Change in 28-days Adjusted Partial-onset-seizure (POS) Frequency for Participants Aged ≥2 Years From Baseline to the End of the Evaluation Period in Participants With POS Only (Based on Daily Record Card [DRC])
Absolute change in seizure frequency per 28 days based on the daily record card (DRC) data, is calculated as baseline seizure frequency per 28 days minus post-Baseline seizure frequency per 28 days. The 28 day adjusted seizure frequency was calculated by dividing the number of partial seizures by the number of days for which the diary was completed, and multiplying the resulting value by 28. This OM was analyzed in participants ≥2 years (per DRC data) only. Here in the study FAS indicates Full Analysis Set, EEG indicates electroencephalogram, OM indicates Outcome measure
Time frame: From Baseline (LTFU participants: Baseline of previous studies N01263 [NCT00422422]; and DE participants: Baseline of current study) to the end of the evaluation period (up to 10 years)
Population: FAS: enrolled participants who had at least 1 dose of study drug in the study and had at least 1 completed post-baseline DRC or EEG. Overall number of participants analyzed consist of all participants (≥2 years only \[per DRC data\]) evaluable for this OM and it differs in absolute and percent change OMs as later cannot be analyzed with 0 baseline ADF. Per plan, participants were grouped per cohort linked to source (DRC for ≥2 years/EEG for \<2 years) from which their seizure data is recorded.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Age Cohort: ≥1 Month to <2 Years | Absolute Change in 28-days Adjusted Partial-onset-seizure (POS) Frequency for Participants Aged ≥2 Years From Baseline to the End of the Evaluation Period in Participants With POS Only (Based on Daily Record Card [DRC]) | -37.48 seizure frequency per 28-days | Standard Deviation 628.34 |
Secondary
Absolute Change in Average Daily Frequency (ADF) of Partial-onset-seizures (POS) in Participants <2 Years of Age With POS Only (Based on EEG Data)
Absolute change in ADF is calculated as the baseline ADF minus post-baseline ADF. ADF is calculated as (number of seizures from central reader divided by stop date and time of EEG minus start date and time of EEG) multiplied to 60, multiplied to 24. This OM was analyzed in participants \<2 years (per EEG data) only.
Time frame: From Baseline (LTFU participants: Baseline of previous studies N01263 [NCT00422422] or N01349 [NCT03325439]) to the end of the evaluation period (up to 10 years)
Population: FAS: enrolled participants who had at least 1 dose of study drug in the study and had at least 1 completed post-baseline DRC or EEG. Overall number of participants analyzed consist of all participants (\<2 years only \[per EEG data\]) evaluable for this OM and it differs in absolute and percent change OMs as later cannot be analyzed with 0 baseline ADF. Per plan, participants were grouped per cohort linked to source (DRC for ≥2 years/EEG for \<2 years) from which their seizure data is recorded.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Age Cohort: ≥1 Month to <2 Years | Absolute Change in Average Daily Frequency (ADF) of Partial-onset-seizures (POS) in Participants <2 Years of Age With POS Only (Based on EEG Data) | 2.56 seizures per day | Standard Deviation 4.44 |
Secondary
Absolute Change in Average Daily Frequency of POS in Participants <2 Years of Age With Typical Absence Seizures (Based on EEG Data)
Absolute change in ADF is calculated as the baseline ADF minus post-baseline ADF. ADF is calculated as (number of seizures from central reader divided by stop date and time of EEG minus start date and time of EEG) multiplied to 60, multiplied to 24.
Time frame: From Baseline (LTFU participants: Baseline of previous studies N01263 [NCT00422422] or N01349 [NCT03325439]) to the end of the evaluation period (up to 10 years)
Population: Typical absence seizures data was not collected and analyzed.
Secondary
Percent Change in 28-days Adjusted Partial-onset-seizure (POS) Frequency for Participants Aged ≥2 Years From Baseline to the End of the Evaluation Period in Participants With POS Only (Based on DRC Data)
Percent change is calculated as absolute change in seizure frequency per 28 days divided by baseline seizure frequency per 28 Days multiplied to 100. The 28 day adjusted seizure frequency was calculated by dividing the number of partial seizures by the number of days for which the diary was completed, and multiplying the resulting value by 28. This OM was analyzed in participants ≥2 years (per DRC data) only.
Time frame: From Baseline (LTFU participants: Baseline of previous studies N01263 [NCT00422422]; and DE participants: Baseline of current study) to the end of the evaluation period (up to 10 years)
Population: FAS: enrolled participants who had at least 1 dose of study drug in the study and had at least 1 completed post-baseline DRC or EEG. Overall number of participants analyzed consist of all participants (≥2 years only \[per DRC data\]) evaluable for this OM and it differs in absolute and percent change OMs as later cannot be analyzed with 0 baseline ADF. Per plan, participants were grouped per cohort linked to source (DRC for ≥2 years/EEG for \<2 years) from which their seizure data is recorded.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Age Cohort: ≥1 Month to <2 Years | Percent Change in 28-days Adjusted Partial-onset-seizure (POS) Frequency for Participants Aged ≥2 Years From Baseline to the End of the Evaluation Period in Participants With POS Only (Based on DRC Data) | 26.57 percent change | Standard Deviation 123.06 |
Secondary
Percent Change in Average Daily Frequency (ADF) of Partial-onset-seizures (POS) in Participants <2 Years of Age With POS Only (Based on EEG Data)
Percent change in average daily frequency (ADF) is calculated as absolute change in ADF divided by baseline ADF multiplied to 100. ADF is calculated as (number of seizures from central reader divided by stop date and time of EEG minus start date and time of EEG) multiplied to 60, multiplied to 24. This OM was analyzed in participants \<2 years (per EEG data) only.
Time frame: From Baseline (LTFU participants: Baseline of previous studies N01263 [NCT00422422] or N01349 [NCT03325439]) to the end of the evaluation period (up to 10 years)
Population: FAS: enrolled participants who had at least 1 dose of study drug in the study and had at least 1 completed post-baseline DRC or EEG. Overall number of participants analyzed consist of all participants (\<2 years only \[per EEG data\]) evaluable for this OM and it differs in absolute and percent change OMs as later cannot be analyzed with 0 baseline ADF. Per plan, participants were grouped per cohort linked to source (DRC for ≥2 years/EEG for \<2 years) from which their seizure data is recorded.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Age Cohort: ≥1 Month to <2 Years | Percent Change in Average Daily Frequency (ADF) of Partial-onset-seizures (POS) in Participants <2 Years of Age With POS Only (Based on EEG Data) | 98.72 percent change | Standard Deviation 2.22 |
Secondary
Percent Change in Average Daily Frequency of POS in Participants <2 Years of Age With Typical Absence Seizures (Based on EEG Data)
Percent change in average daily frequency (ADF) is calculated as absolute change in ADF divided by baseline ADF multiplied to 100. ADF is calculated as (number of seizures from central reader divided by stop date and time of EEG minus start date and time of EEG) multiplied to 60, multiplied to 24.
Time frame: From Baseline (LTFU participants: Baseline of previous studies N01263 [NCT00422422] or N01349 [NCT03325439]) to the end of the evaluation period (up to 10 years)
Population: Typical absence seizures data was not collected and analyzed.