Epilepsy
Conditions
Keywords
Epilepsy, Brivaracetam, Partial Onset Seizures, Adjunctive treatment
Brief summary
This is a Phase 3, open label, long term follow-up (LTFU), multicenter, noncomparative, and single arm study of brivaracetam (BRV).
Detailed description
The primary objective is to evaluate the long term safety and tolerability of BRV at individualized doses up to a maximum of 200 mg/day in epilepsy subjects.
Interventions
DRUGBrivaracetam
Tablet, Flexible dosing up to 200 mg/day, twice daily. The study will continue until either regulatory approval of brivaracetam has been granted by any Health Authority in an indication of adjunctive treatment of partial onset seizures or until the Sponsor decides to close the study, or until the investigational product development is stopped by the Sponsor.
Sponsors
UCB BIOSCIENCES, Inc.
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 completed the Treatment Period of N01358 or the evaluation period of N01258 * Male/female subject from 16 years or older. Subject under 18 years may only be included where legally permitted and ethically accepted * Subject for whom the Investigator believes a reasonable benefit from the long term administration of BRV may be expected * Female subject without childbearing potential (premenarcheal, postmenopausal for at least 2 years, bilateral oophorectomy or tubal ligation, complete hysterectomy) are eligible
Exclusion criteria
* Subject has developed hypersensitivity to any components of the investigational medicinal product (IMP) or comparative drugs as stated in this protocol during the course of the core studies * Severe medical, neurological, or psychiatric disorders, or laboratory values which may have an impact on the safety of the subject * Poor compliance with the visit schedule or medication intake in the previous BRV study * Planned participation in any other clinical study of another investigational drug or device during this study * Pregnant or lactating woman * Any medical condition which, in the Investigator's opinion, warrants exclusion * Subject has a lifetime history of suicide attempt or has suicidal ideation in the past 6 months
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Percentage of Participants With at Least One Treatment-Emergent Adverse Event (TEAE) | From Entry Visit (Month 0) until the Last Visit (up to 84 months) | Treatment-emergent Adverse Events (TEAEs) were defined as those events which started on or after the date of first dose of investigational medicinal product (IMP), or events in which severity worsened on or after the date of first dose of study medication. The event does not necessarily have a causal relationship with that treatment or usage. |
| Percentage of Participants Who Withdrew Due to Adverse Events (AEs) | From Entry Visit (Month 0) until the Last Visit (up to 84 months) | An AE is any untoward medical occurrence in a participant or trial subject that is administered a drug or biologic (medicinal product) or that is using a medical device. The event does not necessarily have a causal relationship with that treatment or usage. |
| Percentage of Participants With at Least One Serious Adverse Event (SAE) | From Entry Visit (Month 0) until the Last Visit (up to 84 months) | 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 |
|---|---|---|
| Partial Onset Seizure (POS) (Type I) Frequency Per 28 Days During the Evaluation Period | From Baseline of the previous study until the Last Visit (up to 84 months) | 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. |
| Percent Change in Partial Onset Seizure (POS) (Type I) Frequency Per 28 Days From Baseline of the Previous Study to the Evaluation Period | From Baseline of the previous study until the Last Visit (up to 84 months) | The percent change from the previous study baselines, in Partial Onset Seizure (POS) (Type I) frequency per 28 days is defined as: (the value at the previous study baselines) minus (the value at each time-points during the evaluation period) divided by the value at the previous study baselines. Note: Since N01258 was a safety study, participants were not required to meet seizure frequency requirements during the Baseline Period, and the Baseline Period was short (ie, 7 days). Therefore, participants from N01258 were excluded from efficacy summaries in the variable of percent change in POS frequency. |
| Responder Rate in POS (Type I) Frequency Over the Evaluation Period | From Baseline of the previous study until the Last Visit (up to 84 months) | A responder is defined as a subject with a ≥ 50% reduction in seizure frequency from the Baseline Period of the previous study. Note: Since N01258 was a safety study, participants were not required to meet seizure frequency requirements during the Baseline Period, and the Baseline Period was short (ie, 7 days). Therefore, participants from N01258 were excluded from efficacy summaries in the variable of responder rates in POS frequency. |
Countries
Austria, Belgium, Brazil, Bulgaria, Canada, Czechia, Estonia, Finland, France, Germany, Hong Kong, Hungary, India, Italy, Japan, Latvia, Lithuania, Mexico, Netherlands, Poland, Puerto Rico, Russia, South Korea, Spain, Sweden, Taiwan, United Kingdom, United States
Participant flow
Recruitment details
The study started to enroll patients in May 2011 and concluded in April 2019. 767 participants were included in the Enrolled Set but 1 participant from the United States of America was lost to follow-up and was excluded from the Safety Analysis Set.
Pre-assignment details
Participants Flow refers to the Safety Set (SS).
Participants by arm
| Arm | Count |
|---|---|
| Brivaracetam Brivaracetam (BRV) was administered with a maximum of 200 mg/day, twice, daily, incremented by 50 mg/day on a weekly basis, during the Up-Titration. During the Down-Titration Period, the BRV dose was decreased in steps of a maximum of 50 mg/day on a weekly basis. A last down-titration step at 20 mg/day for 1 week was included prior to the Post-Treatment Period. | 766 |
| Total | 766 |
Withdrawals & dropouts
| Period | Reason | FG000 |
|---|---|---|
| Overall Study | Adverse Event | 92 |
| Overall Study | Death | 5 |
| Overall Study | Epilepsy surgery | 1 |
| Overall Study | Incarcerated | 2 |
| Overall Study | Investigator decision | 2 |
| Overall Study | Lack of Efficacy | 164 |
| Overall Study | Left the country | 1 |
| Overall Study | Lost to Follow-up | 22 |
| Overall Study | Patient didn't wish to continue | 1 |
| Overall Study | PI decision | 1 |
| Overall Study | Pregnancy planned | 2 |
| Overall Study | Protocol Violation | 15 |
| Overall Study | Study closure at site | 1 |
| Overall Study | Subject choice | 89 |
Baseline characteristics
| Characteristic | Brivaracetam |
|---|---|
| Age, Categorical <=18 years | 19 Participants |
| Age, Categorical >=65 years | 25 Participants |
| Age, Categorical Between 18 and 65 years | 722 Participants |
| Age, Continuous | 40.0 years STANDARD_DEVIATION 12.9 |
| Race/Ethnicity, Customized African-American | 37 Participants |
| Race/Ethnicity, Customized Asian | 85 Participants |
| Race/Ethnicity, Customized Missing | 6 Participants |
| Race/Ethnicity, Customized Other | 77 Participants |
| Race/Ethnicity, Customized White | 561 Participants |
| Sex: Female, Male Female | 396 Participants |
| Sex: Female, Male Male | 370 Participants |
Adverse events
| Event type | EG000 affected / at risk |
|---|---|
| deaths Total, all-cause mortality | 5 / 766 |
| other Total, other adverse events | 421 / 766 |
| serious Total, serious adverse events | 140 / 766 |
Outcome results
Primary
Percentage of Participants Who Withdrew Due to Adverse Events (AEs)
An AE is any untoward medical occurrence in a participant or trial subject that is administered a drug or biologic (medicinal product) or that is using a medical device. The event does not necessarily have a causal relationship with that treatment or usage.
Time frame: From Entry Visit (Month 0) until the Last Visit (up to 84 months)
Population: The Safety Set (SS) consisted of all participants who took at least 1 dose of study drug.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Brivaracetam (SS) | Percentage of Participants Who Withdrew Due to Adverse Events (AEs) | 11.9 Percentage of participants |
Primary
Percentage of Participants With at Least One Serious Adverse Event (SAE)
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 Entry Visit (Month 0) until the Last Visit (up to 84 months)
Population: The Safety Set (SS) consisted of all participants who took at least 1 dose of study drug.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Brivaracetam (SS) | Percentage of Participants With at Least One Serious Adverse Event (SAE) | 18.4 Percentage of participants |
Primary
Percentage of Participants With at Least One Treatment-Emergent Adverse Event (TEAE)
Treatment-emergent Adverse Events (TEAEs) were defined as those events which started on or after the date of first dose of investigational medicinal product (IMP), or events in which severity worsened on or after the date of first dose of study medication. The event does not necessarily have a causal relationship with that treatment or usage.
Time frame: From Entry Visit (Month 0) until the Last Visit (up to 84 months)
Population: The Safety Set (SS) consisted of all participants who took at least 1 dose of study drug.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Brivaracetam (SS) | Percentage of Participants With at Least One Treatment-Emergent Adverse Event (TEAE) | 83.9 Percentage of participants |
Secondary
Partial Onset Seizure (POS) (Type I) Frequency Per 28 Days During the Evaluation Period
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.
Time frame: From Baseline of the previous study until the Last Visit (up to 84 months)
Population: The Partial Onset Seizure (POS) Efficacy Analysis Set consisted of all subjects with POS who took at least 1 dose of study drug and had at least 1 seizure diary day during the Evaluation Period.
| Arm | Measure | Group | Value (MEDIAN) |
|---|---|---|---|
| Brivaracetam (SS) | Partial Onset Seizure (POS) (Type I) Frequency Per 28 Days During the Evaluation Period | Baseline | 9.7 Seizures per 28 days |
| Brivaracetam (SS) | Partial Onset Seizure (POS) (Type I) Frequency Per 28 Days During the Evaluation Period | On Treatment | 4.2 Seizures per 28 days |
Secondary
Percent Change in Partial Onset Seizure (POS) (Type I) Frequency Per 28 Days From Baseline of the Previous Study to the Evaluation Period
The percent change from the previous study baselines, in Partial Onset Seizure (POS) (Type I) frequency per 28 days is defined as: (the value at the previous study baselines) minus (the value at each time-points during the evaluation period) divided by the value at the previous study baselines. Note: Since N01258 was a safety study, participants were not required to meet seizure frequency requirements during the Baseline Period, and the Baseline Period was short (ie, 7 days). Therefore, participants from N01258 were excluded from efficacy summaries in the variable of percent change in POS frequency.
Time frame: From Baseline of the previous study until the Last Visit (up to 84 months)
Population: The Partial Onset Seizure (POS) Efficacy Analysis Set consisted of all subjects with POS who took at least 1 dose of study drug and had at least 1 seizure diary day during the Evaluation Period.~Participants from N01258 were excluded from this analysis.
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Brivaracetam (SS) | Percent Change in Partial Onset Seizure (POS) (Type I) Frequency Per 28 Days From Baseline of the Previous Study to the Evaluation Period | 52.0 Percent change |
Secondary
Responder Rate in POS (Type I) Frequency Over the Evaluation Period
A responder is defined as a subject with a ≥ 50% reduction in seizure frequency from the Baseline Period of the previous study. Note: Since N01258 was a safety study, participants were not required to meet seizure frequency requirements during the Baseline Period, and the Baseline Period was short (ie, 7 days). Therefore, participants from N01258 were excluded from efficacy summaries in the variable of responder rates in POS frequency.
Time frame: From Baseline of the previous study until the Last Visit (up to 84 months)
Population: The Partial Onset Seizure (POS) Efficacy Analysis Set consisted of all subjects with POS who took at least 1 dose of study drug and had at least 1 seizure diary day during the Evaluation Period.~Participants from N01258 were excluded from this analysis.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Brivaracetam (SS) | Responder Rate in POS (Type I) Frequency Over the Evaluation Period | 51.7 Percentage of participants |