Epilepsy
Conditions
Keywords
Brivaracetam, Levetiracetam, Epilepsy, Nonpsychotic behavior
Brief summary
Trial N01395 is to evaluate the reduction of nonpsychotic behavioral side effects in subjects with Epilepsy who switched to BRV 200 mg/day after discontinuing LEV due to such side effects; as well as the efficacy, safety and tolerability of BRV. No statistical hypothesis testing will be performed.
Interventions
DRUGBrivaracetam
Sponsors
UCB Pharma SA
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 with well-characterized Epilepsy according to the 1989 International League Against Epilepsy (ILAE) classification * Subject with Epilepsy who the investigator expects will benefit from Levetiracetam (LEV) but for whom the investigator has decided to discontinue due to nonpsychotic behavioral side effects following the introduction of LEV * Subject is currently receiving LEV at the recommended therapeutic dose (dose ranging from 1 g/day to 3 g/day) * Subject currently treated with minimum 2 and maximum 3 Anti-Epileptic Drugs (AEDs) including LEV. Vagal Nerve Stimulation (VNS) is allowed and will be counted as a concomitant AED * Female subjects without childbearing potential (postmenopausal for at least 2 years, bilateral oophorectomy or tubal ligation, complete hysterectomy) are eligible. Female subjects with childbearing potential are eligible if they use a medically accepted contraceptive method
Exclusion criteria
* Subject has a lifetime history of suicide attempt (including an actual, interrupted or aborted attempt), or has had 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 Visit 1 * Subject whose seizures could not be reliably counted on a regular basis due to their fast and repetitive occurrence (clusters or flurries) * Subject has history or presence of status epilepticus during the year preceding Visit 1 or during Baseline * Subject has history or presence of known psychogenic nonepileptic seizures * Subject has any clinical conditions (eg, bone marrow depression, chronic hepatic disease, and/or severe renal impairment) which impair reliable participation in the study or necessitate the use of medication not allowed by protocol * Subject is pregnant or lactating
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Percentage of Subjects Who Achieved a Clinically Meaningful Reduction of Nonpsychotic Behavioral Side Effects Based on the Investigator's Overall Assessment From Study Entry to the End of the Treatment Period | From Study Entry (Visit1, Week -1) to the end of the Treatment Period (Visit 6, Week 12) or Early Discontinuation Visit | Nonpsychotic behavioral side effects include (but are not limited to) such symptoms as aggression, agitation, anger, anxiety, apathy, depersonalization, depression, emotional lability, hostility, irritability, etc. The Investigator completed the assessment by answering the following: Has there been a clinically meaningful reduction of nonpsychotic behavioral side effects since the start of BRV? \- Yes/No |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Change From Study Entry in Nonpsychotic Behavioral Side Effects to the End of the Treatment Period/Early Discontinuation Visit, Measured by Means of the Investigator Global Evaluation of Nonpsychotic Behavioral Side Effects (I-GEBSE) Scale | From Study Entry (Visit1, Week -1) to the end of the Treatment Period (Visit 6, Week 12) or Early Discontinuation Visit | There are seven levels for the I-GEBSE: * Marked improvement * Moderate improvement * Slight improvement * No change * Slight worsening * Moderate worsening * Marked worsening |
| Number of Subjects Who Have a Complete Abatement of Nonpsychotic Behavioral Side Effects for the Last Assessment During the Treatment Period, Based on the Investigator's Overall Assessment | From Baseline (maximum of 12 weeks prior to Study Entry at Week -1) to the end of the Treatment Period (Visit 6, Week 12) or Early Discontinuation Visit | Nonpsychotic behavioral side effects include (but are not limited to) such symptoms as aggression, agitation, anger, anxiety, apathy, depersonalization, depression, emotional lability, hostility, irritability, etc. |
| Number of Subjects Who Are Free From Nonpsychotic Behavioral Side Effects Over the Entire Treatment Period | From Visit 2 (Week 0) to Visit 6 (Week 12) | Nonpsychotic behavioral side effects (NBSE) include (but are not limited to) such symptoms as aggression, agitation, anger, anxiety, apathy, depersonalization, depression, emotional lability, hostility, irritability, etc. |
| Incidence of Treatment Emergent Adverse Events During the Study Period | From Study Entry (Visit1, Week -1) to the end of the Treatment Period (Visit 6, Week 12) or Early Discontinuation Visit | An Adverse Event (AE) is any untoward medical occurrence in a patient or clinical investigation subject administered a pharmaceutical product that does not necessarily have a causal relationship with this treatment. A treatment emergent AE is any event that emerges during treatment having been absent pre-treatment, or worsens relative to the pre-treatment state. |
| Shift in the Maximum Intensity From Baseline to the End of the Treatment Period for Side Effects Primarily Associated With Discontinuation of Levetiracetam (LEV) as Determined by the Investigator | From Baseline (maximum of 12 weeks prior to Study Entry at Week -1) to the end of the Treatment Period (Visit 6, Week 12) or Early Discontinuation Visit | Nonpsychotic behavioral side effects include (but are not limited to) such symptoms as aggression, agitation, anger, anxiety, apathy, depersonalization, depression, emotional lability, hostility, irritability, etc. |
| Occurrence of Serious Adverse Events During the Study Period | From Study Entry (Visit1, Week -1) to the end of the Treatment Period (Visit 6, Week 12) or Early Discontinuation Visit | A serious adverse event is any untoward medical occurrences in a subject administered study treatment, whether or not the event is related to treatment, with at least one of the follow outcomes: death, life-threatening, initial inpatient hospitalization or prolongation of hospitalization, significant or persistent disability/incapacity, congenital anomaly/birth defect, or an important medical event that may jeopardize the subject and require a medical/surgical intervention. |
| Partial Onset Seizure (POS) Frequency Over the Treatment Period for Subjects With Focal Epilepsy | From 4 weeks prior to Visit 2 (Week 0) to the end of the Treatment Period (Visit 6, Week 12) or Early Discontinuation Visit | The POS frequency is standardized to a 28-day duration and changes in POS frequency are measured relative to the reported seizure counts for the 4 weeks prior to Visit 2 (Week 0). Partial seizures can be classified into one of the following three groups: * Simple partial seizures (IA) * Complex partial seizures (IB) * Partial seizures evolving to secondarily generalized seizures (IC) |
| Generalized Seizure Days Over the Treatment Period for Subjects With Idiopathic Generalized Epilepsy | From 4 weeks prior to Visit 2 (Week 0) to the end of the Treatment Period (Visit 6, Week 12) or Early Discontinuation Visit | Generalized seizure days are standardized to a 28-day duration and changes in generalized seizure days are measured relative to the reported seizure counts for the 4 weeks prior to Visit 2 (Week 0). Generalized seizures (Type II) include the following seizure types: * Absence (IIA1) * Atypical absence (IIA2) * Myoclonic (IIB) * Clonic (IIC) * Tonic (IID) * Tonic-clonic (IIE) * Atonic (IIF) A specific effect of BRV on the occurrence of generalized seizures was not assessed. |
| Withdrawal Due to an Adverse Event (AE) During the Study Period | From Study Entry (Visit1, Week -1) to the end of the Treatment Period (Visit 6, Week 12) or Early Discontinuation Visit | An Adverse Event (AE) is any untoward medical occurrence in a patient or clinical investigation subject administered a pharmaceutical product that does not necessarily have a causal relationship with this treatment. |
Countries
France, Germany, Spain, United Kingdom, United States
Participant flow
Recruitment details
This study started to enroll subjects in July 2012. In Oct 2013, the Sponsor evaluated the study in light of the recruitment rate. Given the unanticipated lack of recruitment during the prior 8 weeks, a decision was made to stop recruitment as of 16 Oct 2013.
Pre-assignment details
Participant Flow refers to the Enrolled Set. In total, 32 subjects were screened and 29 subjects were enrolled instead of 30 subjects as per protocol amendment 2. This difference was considered as insignificant and not affecting the planned analysis.
Participants by arm
| Arm | Count |
|---|---|
| Brivaracetam The subjects will be treated with Brivaracetam (BRV) tablets 200 mg/day during 12 weeks: four 25 mg tablets, twice daily.
Based on the Investigator's judgement, at any time, the dose can be decreased to BRV 150 mg/day, 100 mg/day, or 50 mg/day. Flexible dosing, can be up- and down-titrated as needed.
At the end of the Treatment Period, the subject will either enter the N01372 long-term follow-up study or down-titrate during 4 weeks. | 29 |
| Total | 29 |
Withdrawals & dropouts
| Period | Reason | FG000 |
|---|---|---|
| Overall Study | AE, non-serious non-fatal | 1 |
| Overall Study | Lack of Efficacy | 1 |
| Overall Study | SAE, non-fatal | 1 |
Baseline characteristics
| Characteristic | Brivaracetam |
|---|---|
| Age, Categorical <=18 years | 0 Participants |
| Age, Categorical >=65 years | 0 Participants |
| Age, Categorical Between 18 and 65 years | 29 Participants |
| Age, Continuous | 35.8 years STANDARD_DEVIATION 11.8 |
| Sex: Female, Male Female | 14 Participants |
| Sex: Female, Male Male | 15 Participants |
Adverse events
| Event type | EG000 affected / at risk |
|---|---|
| deaths Total, all-cause mortality | — / — |
| other Total, other adverse events | 13 / 29 |
| serious Total, serious adverse events | 1 / 29 |
Outcome results
Primary
Percentage of Subjects Who Achieved a Clinically Meaningful Reduction of Nonpsychotic Behavioral Side Effects Based on the Investigator's Overall Assessment From Study Entry to the End of the Treatment Period
Nonpsychotic behavioral side effects include (but are not limited to) such symptoms as aggression, agitation, anger, anxiety, apathy, depersonalization, depression, emotional lability, hostility, irritability, etc. The Investigator completed the assessment by answering the following: Has there been a clinically meaningful reduction of nonpsychotic behavioral side effects since the start of BRV? \- Yes/No
Time frame: From Study Entry (Visit1, Week -1) to the end of the Treatment Period (Visit 6, Week 12) or Early Discontinuation Visit
Population: The Full Analysis Set (FAS) consisted of all subjects who received at least 1 dose of Brivaracetam and had at least 1 post-Baseline evaluation of behavioral side effects.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Brivaracetam | Percentage of Subjects Who Achieved a Clinically Meaningful Reduction of Nonpsychotic Behavioral Side Effects Based on the Investigator's Overall Assessment From Study Entry to the End of the Treatment Period | 93.1 percentage of subjects |
Secondary
Change From Study Entry in Nonpsychotic Behavioral Side Effects to the End of the Treatment Period/Early Discontinuation Visit, Measured by Means of the Investigator Global Evaluation of Nonpsychotic Behavioral Side Effects (I-GEBSE) Scale
There are seven levels for the I-GEBSE: * Marked improvement * Moderate improvement * Slight improvement * No change * Slight worsening * Moderate worsening * Marked worsening
Time frame: From Study Entry (Visit1, Week -1) to the end of the Treatment Period (Visit 6, Week 12) or Early Discontinuation Visit
Population: The Full Analysis Set (FAS) consisted of all subjects who received at least 1 dose of Brivaracetam and had at least 1 post-Baseline evaluation of behavioral side effects.
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| Brivaracetam | Change From Study Entry in Nonpsychotic Behavioral Side Effects to the End of the Treatment Period/Early Discontinuation Visit, Measured by Means of the Investigator Global Evaluation of Nonpsychotic Behavioral Side Effects (I-GEBSE) Scale | No change | 2 subjects |
| Brivaracetam | Change From Study Entry in Nonpsychotic Behavioral Side Effects to the End of the Treatment Period/Early Discontinuation Visit, Measured by Means of the Investigator Global Evaluation of Nonpsychotic Behavioral Side Effects (I-GEBSE) Scale | Marked improvement | 10 subjects |
| Brivaracetam | Change From Study Entry in Nonpsychotic Behavioral Side Effects to the End of the Treatment Period/Early Discontinuation Visit, Measured by Means of the Investigator Global Evaluation of Nonpsychotic Behavioral Side Effects (I-GEBSE) Scale | Moderate improvement | 10 subjects |
| Brivaracetam | Change From Study Entry in Nonpsychotic Behavioral Side Effects to the End of the Treatment Period/Early Discontinuation Visit, Measured by Means of the Investigator Global Evaluation of Nonpsychotic Behavioral Side Effects (I-GEBSE) Scale | Slight improvement | 4 subjects |
| Brivaracetam | Change From Study Entry in Nonpsychotic Behavioral Side Effects to the End of the Treatment Period/Early Discontinuation Visit, Measured by Means of the Investigator Global Evaluation of Nonpsychotic Behavioral Side Effects (I-GEBSE) Scale | Slight worsening | 1 subjects |
| Brivaracetam | Change From Study Entry in Nonpsychotic Behavioral Side Effects to the End of the Treatment Period/Early Discontinuation Visit, Measured by Means of the Investigator Global Evaluation of Nonpsychotic Behavioral Side Effects (I-GEBSE) Scale | Moderate worsening | 0 subjects |
| Brivaracetam | Change From Study Entry in Nonpsychotic Behavioral Side Effects to the End of the Treatment Period/Early Discontinuation Visit, Measured by Means of the Investigator Global Evaluation of Nonpsychotic Behavioral Side Effects (I-GEBSE) Scale | Marked worsening | 1 subjects |
| Brivaracetam | Change From Study Entry in Nonpsychotic Behavioral Side Effects to the End of the Treatment Period/Early Discontinuation Visit, Measured by Means of the Investigator Global Evaluation of Nonpsychotic Behavioral Side Effects (I-GEBSE) Scale | Missing | 1 subjects |
Secondary
Generalized Seizure Days Over the Treatment Period for Subjects With Idiopathic Generalized Epilepsy
Generalized seizure days are standardized to a 28-day duration and changes in generalized seizure days are measured relative to the reported seizure counts for the 4 weeks prior to Visit 2 (Week 0). Generalized seizures (Type II) include the following seizure types: * Absence (IIA1) * Atypical absence (IIA2) * Myoclonic (IIB) * Clonic (IIC) * Tonic (IID) * Tonic-clonic (IIE) * Atonic (IIF) A specific effect of BRV on the occurrence of generalized seizures was not assessed.
Time frame: From 4 weeks prior to Visit 2 (Week 0) to the end of the Treatment Period (Visit 6, Week 12) or Early Discontinuation Visit
Population: This variable was not analyzed and no results are available.
Secondary
Incidence of Treatment Emergent Adverse Events During the Study Period
An Adverse Event (AE) is any untoward medical occurrence in a patient or clinical investigation subject administered a pharmaceutical product that does not necessarily have a causal relationship with this treatment. A treatment emergent AE is any event that emerges during treatment having been absent pre-treatment, or worsens relative to the pre-treatment state.
Time frame: From Study Entry (Visit1, Week -1) to the end of the Treatment Period (Visit 6, Week 12) or Early Discontinuation Visit
Population: The Safety Set (SS) consisted of all subjects who received at least 1 dose of Brivaracetam.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Brivaracetam | Incidence of Treatment Emergent Adverse Events During the Study Period | 67 events |
Secondary
Number of Subjects Who Are Free From Nonpsychotic Behavioral Side Effects Over the Entire Treatment Period
Nonpsychotic behavioral side effects (NBSE) include (but are not limited to) such symptoms as aggression, agitation, anger, anxiety, apathy, depersonalization, depression, emotional lability, hostility, irritability, etc.
Time frame: From Visit 2 (Week 0) to Visit 6 (Week 12)
Population: The Full Analysis Set (FAS) consisted of all subjects who received at least 1 dose of Brivaracetam and had at least 1 post-Baseline evaluation of behavioral side effects.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Brivaracetam | Number of Subjects Who Are Free From Nonpsychotic Behavioral Side Effects Over the Entire Treatment Period | 3 subjects |
Secondary
Number of Subjects Who Have a Complete Abatement of Nonpsychotic Behavioral Side Effects for the Last Assessment During the Treatment Period, Based on the Investigator's Overall Assessment
Nonpsychotic behavioral side effects include (but are not limited to) such symptoms as aggression, agitation, anger, anxiety, apathy, depersonalization, depression, emotional lability, hostility, irritability, etc.
Time frame: From Baseline (maximum of 12 weeks prior to Study Entry at Week -1) to the end of the Treatment Period (Visit 6, Week 12) or Early Discontinuation Visit
Population: The Full Analysis Set (FAS) consisted of all subjects who received at least 1 dose of Brivaracetam and had at least 1 post-Baseline evaluation of behavioral side effects.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Brivaracetam | Number of Subjects Who Have a Complete Abatement of Nonpsychotic Behavioral Side Effects for the Last Assessment During the Treatment Period, Based on the Investigator's Overall Assessment | 18 subjects |
Secondary
Occurrence of Serious Adverse Events During the Study Period
A serious adverse event is any untoward medical occurrences in a subject administered study treatment, whether or not the event is related to treatment, with at least one of the follow outcomes: death, life-threatening, initial inpatient hospitalization or prolongation of hospitalization, significant or persistent disability/incapacity, congenital anomaly/birth defect, or an important medical event that may jeopardize the subject and require a medical/surgical intervention.
Time frame: From Study Entry (Visit1, Week -1) to the end of the Treatment Period (Visit 6, Week 12) or Early Discontinuation Visit
Population: The Safety Set (SS) consisted of all subjects who received at least 1 dose of Brivaracetam.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Brivaracetam | Occurrence of Serious Adverse Events During the Study Period | 1 events |
Secondary
Partial Onset Seizure (POS) Frequency Over the Treatment Period for Subjects With Focal Epilepsy
The POS frequency is standardized to a 28-day duration and changes in POS frequency are measured relative to the reported seizure counts for the 4 weeks prior to Visit 2 (Week 0). Partial seizures can be classified into one of the following three groups: * Simple partial seizures (IA) * Complex partial seizures (IB) * Partial seizures evolving to secondarily generalized seizures (IC)
Time frame: From 4 weeks prior to Visit 2 (Week 0) to the end of the Treatment Period (Visit 6, Week 12) or Early Discontinuation Visit
Population: The Efficacy Analysis Set (EAS) consisted of all subjects who received at least 1 dose of Brivaracetam and had at least 1 post-Baseline day of seizure daily record card (subject diary card).
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Brivaracetam | Partial Onset Seizure (POS) Frequency Over the Treatment Period for Subjects With Focal Epilepsy | 6.0 partial onset seizures |
Secondary
Shift in the Maximum Intensity From Baseline to the End of the Treatment Period for Side Effects Primarily Associated With Discontinuation of Levetiracetam (LEV) as Determined by the Investigator
Nonpsychotic behavioral side effects include (but are not limited to) such symptoms as aggression, agitation, anger, anxiety, apathy, depersonalization, depression, emotional lability, hostility, irritability, etc.
Time frame: From Baseline (maximum of 12 weeks prior to Study Entry at Week -1) to the end of the Treatment Period (Visit 6, Week 12) or Early Discontinuation Visit
Population: The Full Analysis Set (FAS) consisted of all subjects who received at least 1 dose of Brivaracetam and had at least 1 post-Baseline evaluation of behavioral side effects.
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| Brivaracetam | Shift in the Maximum Intensity From Baseline to the End of the Treatment Period for Side Effects Primarily Associated With Discontinuation of Levetiracetam (LEV) as Determined by the Investigator | Unchanged | 2 subjects |
| Brivaracetam | Shift in the Maximum Intensity From Baseline to the End of the Treatment Period for Side Effects Primarily Associated With Discontinuation of Levetiracetam (LEV) as Determined by the Investigator | Worsening | 0 subjects |
| Brivaracetam | Shift in the Maximum Intensity From Baseline to the End of the Treatment Period for Side Effects Primarily Associated With Discontinuation of Levetiracetam (LEV) as Determined by the Investigator | Improvement | 8 subjects |
| Brivaracetam | Shift in the Maximum Intensity From Baseline to the End of the Treatment Period for Side Effects Primarily Associated With Discontinuation of Levetiracetam (LEV) as Determined by the Investigator | Resolved | 19 subjects |
Secondary
Withdrawal Due to an Adverse Event (AE) During the Study Period
An Adverse Event (AE) is any untoward medical occurrence in a patient or clinical investigation subject administered a pharmaceutical product that does not necessarily have a causal relationship with this treatment.
Time frame: From Study Entry (Visit1, Week -1) to the end of the Treatment Period (Visit 6, Week 12) or Early Discontinuation Visit
Population: The Safety Set (SS) consisted of all subjects who received at least 1 dose of Brivaracetam.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Brivaracetam | Withdrawal Due to an Adverse Event (AE) During the Study Period | 2 subjects |