Clinical Trial Results:
An Open-label, Multicenter, Follow-up Study to Evaluate the Long-term Safety and Efficacy of Brivaracetam Used as Adjunctive Treatment in Subjects Aged 16 Years or Older with Epilepsy
Summary
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EudraCT number |
2012-000827-42 |
Trial protocol |
GB DE ES IT |
Global end of trial date |
09 Aug 2016
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Results information
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Results version number |
v2(current) |
This version publication date |
18 Aug 2017
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First version publication date |
26 Jul 2017
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Other versions |
v1 |
Version creation reason |
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Trial Information
Subject Disposition
Baseline Characteristics
End Points
Adverse Events
More Information
Subject Disposition
Baseline Characteristics
End Points
Adverse Events
More Information
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Trial identification
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Sponsor protocol code |
N01372
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Additional study identifiers
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ISRCTN number |
- | ||
US NCT number |
NCT01728077 | ||
WHO universal trial number (UTN) |
- | ||
Sponsors
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Sponsor organisation name |
UCB Pharma SA
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Sponsor organisation address |
Allée de la Recherche 60, Brussels, Belgium, B-1070
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Public contact |
Clin Trial Reg & Results Disclosure, UCB BIOSCIENCES GmbH, clinicaltrials@ucb.com
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Scientific contact |
Clin Trial Reg & Results Disclosure, UCB BIOSCIENCES GmbH, clinicaltrials@ucb.com
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Paediatric regulatory details
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Is trial part of an agreed paediatric investigation plan (PIP) |
No
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Does article 45 of REGULATION (EC) No 1901/2006 apply to this trial? |
No
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Does article 46 of REGULATION (EC) No 1901/2006 apply to this trial? |
No
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Results analysis stage
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Analysis stage |
Final
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Date of interim/final analysis |
18 Oct 2016
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Is this the analysis of the primary completion data? |
No
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Global end of trial reached? |
Yes
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Global end of trial date |
09 Aug 2016
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Was the trial ended prematurely? |
No
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General information about the trial
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Main objective of the trial |
To evaluate the long-term safety and tolerability of brivaracetam (BRV) at individualized doses up to a maximum of 200 mg/day as adjunctive treatment in adult subjects with epilepsy.
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Protection of trial subjects |
During the course of the study all subjects were closely monitored.
The following safety parameters were assessed at 6 month intervals:
• Vital signs
• Physical Exam
• Neurological Exam
• Psychiatric and mental status
• Electrocardiogram (ECG)
• Seizure assessment
• Laboratory assessment
• Pregnancy
• Review of Adverse Events(AEs)/Medical Procedures
• Suicidality Assessment
• Quality of Life (QOL) Assessment
There are withdrawal criteria specified within the protocol:
• Worsening of seizures
• Lack/Loss of efficacy
• Non-compliance
• Prohibited Concomitant Medication
• Pregnancy
• Significant Liver Function Test (LFT) results
• Illness (interfering with continued study participation)
• Suicidal ideation
• Withdrawal of consent
• Lost to follow-up
• Sponsor/agency request
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Background therapy |
Background antiepileptic drug (AED) therapy was permitted as described in the protocol. | ||
Evidence for comparator |
Not applicable | ||
Actual start date of recruitment |
17 Oct 2012
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Long term follow-up planned |
No
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Independent data monitoring committee (IDMC) involvement? |
No
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Population of trial subjects
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Number of subjects enrolled per country |
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Country: Number of subjects enrolled |
Spain: 2
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Country: Number of subjects enrolled |
United States: 18
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Country: Number of subjects enrolled |
France: 3
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Country: Number of subjects enrolled |
Germany: 3
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Worldwide total number of subjects |
26
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EEA total number of subjects |
8
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Number of subjects enrolled per age group |
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In utero |
0
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Preterm newborn - gestational age < 37 wk |
0
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Newborns (0-27 days) |
0
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Infants and toddlers (28 days-23 months) |
0
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Children (2-11 years) |
0
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Adolescents (12-17 years) |
0
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Adults (18-64 years) |
26
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From 65 to 84 years |
0
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85 years and over |
0
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Recruitment
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Recruitment details |
This study started to enroll subjects in October 2012 and concluded in August 2016. | ||||||||||||||||||||||||||||||
Pre-assignment
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Screening details |
Participant Flow refers to the Safety Set (SS), which consisted of all subjects who took at least 1 dose of study drug. | ||||||||||||||||||||||||||||||
Period 1
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Period 1 title |
Overall Study (overall period)
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Is this the baseline period? |
Yes | ||||||||||||||||||||||||||||||
Allocation method |
Not applicable
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Blinding used |
Not blinded | ||||||||||||||||||||||||||||||
Arms
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Are arms mutually exclusive |
Yes
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Arm title
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Brivaracetam Focal Epilepsy | ||||||||||||||||||||||||||||||
Arm description |
This arm includes subjects with focal epilepsy, who received a flexible dose of Brivaracetam (BRV) tablets, administered twice a day, starting with an individual dose that they had reached at the completion of study N01395 (feeder study). The BRV dose could have been increased or decreased in increments of 50mg/day based on the individual subject’s seizure control and/or tolerability, but was to not exceed 200mg/day. | ||||||||||||||||||||||||||||||
Arm type |
Experimental | ||||||||||||||||||||||||||||||
Investigational medicinal product name |
Brivaracetam
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Investigational medicinal product code |
BRV
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Other name |
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Pharmaceutical forms |
Film-coated tablet
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Routes of administration |
Oral use
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Dosage and administration details |
10 mg, 25 mg and 50 mg BRV tablets were used in this study. Subjects started with an individual dose that they had reached at the completion of study N01395 (feeder study). During the study the BRV dose could have been increased or decreased in increments of 50mg/day based on the individual subject’s seizure control and/or tolerability, but was to not exceed 200mg/day. The BRV 10mg dose (20mg/day) was used only for down-titration.
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Arm title
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Brivaracetam Generalized Epilepsy | ||||||||||||||||||||||||||||||
Arm description |
This arm includes subjects with generalized epilepsy, who received a flexible dose of Brivaracetam (BRV) tablets, administered twice a day, starting with an individual dose that they had reached at the completion of study N01395 (feeder study). The BRV dose could have been increased or decreased in increments of 50mg/day based on the individual subject’s seizure control and/or tolerability, but was to not exceed 200mg/day. | ||||||||||||||||||||||||||||||
Arm type |
Experimental | ||||||||||||||||||||||||||||||
Investigational medicinal product name |
Brivaracetam
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Investigational medicinal product code |
BRV
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Other name |
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Pharmaceutical forms |
Film-coated tablet
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Routes of administration |
Oral use
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Dosage and administration details |
10 mg, 25 mg and 50 mg BRV tablets were used in this study. Subjects started with an individual dose that they had reached at the completion of study N01395 (feeder study). During the study the BRV dose could have been increased or decreased in increments of 50mg/day based on the individual subject’s seizure control and/or tolerability, but was to not exceed 200mg/day. The BRV 10mg dose (20mg/day) was used only for down-titration.
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Baseline characteristics reporting groups
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Reporting group title |
Brivaracetam Focal Epilepsy
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Reporting group description |
This arm includes subjects with focal epilepsy, who received a flexible dose of Brivaracetam (BRV) tablets, administered twice a day, starting with an individual dose that they had reached at the completion of study N01395 (feeder study). The BRV dose could have been increased or decreased in increments of 50mg/day based on the individual subject’s seizure control and/or tolerability, but was to not exceed 200mg/day. | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Reporting group title |
Brivaracetam Generalized Epilepsy
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Reporting group description |
This arm includes subjects with generalized epilepsy, who received a flexible dose of Brivaracetam (BRV) tablets, administered twice a day, starting with an individual dose that they had reached at the completion of study N01395 (feeder study). The BRV dose could have been increased or decreased in increments of 50mg/day based on the individual subject’s seizure control and/or tolerability, but was to not exceed 200mg/day. | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||
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End points reporting groups
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Reporting group title |
Brivaracetam Focal Epilepsy
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Reporting group description |
This arm includes subjects with focal epilepsy, who received a flexible dose of Brivaracetam (BRV) tablets, administered twice a day, starting with an individual dose that they had reached at the completion of study N01395 (feeder study). The BRV dose could have been increased or decreased in increments of 50mg/day based on the individual subject’s seizure control and/or tolerability, but was to not exceed 200mg/day. | ||
Reporting group title |
Brivaracetam Generalized Epilepsy
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Reporting group description |
This arm includes subjects with generalized epilepsy, who received a flexible dose of Brivaracetam (BRV) tablets, administered twice a day, starting with an individual dose that they had reached at the completion of study N01395 (feeder study). The BRV dose could have been increased or decreased in increments of 50mg/day based on the individual subject’s seizure control and/or tolerability, but was to not exceed 200mg/day. | ||
Subject analysis set title |
Brivaracetam Focal Epilepsy (SS)
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Subject analysis set type |
Safety analysis | ||
Subject analysis set description |
This arm includes subjects with focal epilepsy, who received a flexible dose of Brivaracetam (BRV) tablets, administered twice a day, starting with an individual dose that they had reached at the completion of study N01395 (feeder study). The BRV dose could have been increased or decreased in increments of 50mg/day based on the individual subject’s seizure control and/or tolerability, but was to not exceed 200mg/day. This arm is part of the Safety Set (SS).
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Subject analysis set title |
Brivaracetam Generalized Epilepsy (SS)
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Subject analysis set type |
Safety analysis | ||
Subject analysis set description |
This arm includes subjects with generalized epilepsy, who received a flexible dose of Brivaracetam (BRV) tablets, administered twice a day, starting with an individual dose that they had reached at the completion of study N01395 (feeder study). The BRV dose could have been increased or decreased in increments of 50mg/day based on the individual subject’s seizure control and/or tolerability, but was to not exceed 200mg/day. This arm is part of the Safety Set (SS).
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Subject analysis set title |
Brivaracetam Focal Epilepsy (EAS)
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Subject analysis set type |
Full analysis | ||
Subject analysis set description |
This arm includes subjects with focal epilepsy, who received a flexible dose of Brivaracetam (BRV) tablets, administered twice a day, starting with an individual dose that they had reached at the completion of study N01395 (feeder study). The BRV dose could have been increased or decreased in increments of 50mg/day based on the individual subject’s seizure control and/or tolerability, but was to not exceed 200mg/day. This arm is part of the Efficacy Analysis Set (EAS).
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End point title |
Incidence of Treatment Emergent Adverse Events (TEAEs) during Evaluation Period [1] | |||||||||||||||
End point description |
TEAEs were defined as AEs that had onset on or after the day of first study medication dose. An 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. Results are presented as the percentage of subjects with at least one treatment-emergent adverse event during this study.
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End point type |
Primary
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End point timeframe |
From Entry Visit (Month 0) to the Last Evaluation Period Visit or Early Discontinuation Visit (up to 46 months)
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Notes [1] - No statistical analyses have been specified for this primary end point. It is expected there is at least one statistical analysis for each primary end point. Justification: No formal statistical hypothesis testing was planned for this study. Results were summarized as descriptive statistics only. |
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No statistical analyses for this end point |
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End point title |
Percentage of subjects withdrawn due to an Adverse Event (AE) during the Evaluation Period [2] | |||||||||||||||
End point description |
An AE was defined as any untoward medical occurrence in a patient or clinical investigation subject administered a pharmaceutical product that did not necessarily have a causal relationship with this treatment. Results are presented as the percentage of subjects withdrawn due to an AE.
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End point type |
Primary
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End point timeframe |
From Entry Visit (Month 0) to the Last Evaluation Period Visit or Early Discontinuation Visit (up to 46 months)
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Notes [2] - No statistical analyses have been specified for this primary end point. It is expected there is at least one statistical analysis for each primary end point. Justification: No formal statistical hypothesis testing was planned for this study. Results were summarized as descriptive statistics only. |
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No statistical analyses for this end point |
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End point title |
Occurrence of a Serious Adverse Event (SAE) during the Evaluation Period [3] | |||||||||||||||
End point description |
SAEs include medical occurrences that result in death, are life threatening, require hospitalization or prolongation of hospitalization or result in disability/incapacity or are a congenital anomaly/birth defects. Results are presented as the percentage of subjects with at least one SAE during this study.
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End point type |
Primary
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End point timeframe |
From Entry Visit (Month 0) to the Last Evaluation Period Visit or Early Discontinuation Visit (up to 46 months)
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Notes [3] - No statistical analyses have been specified for this primary end point. It is expected there is at least one statistical analysis for each primary end point. Justification: No formal statistical hypothesis testing was planned for this study. Results were summarized as descriptive statistics only. |
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No statistical analyses for this end point |
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End point title |
Frequency of Partial-Onset Seizure (POS) Type I per 28 days during the Evaluation Period for subjects with focal-onset Epilepsy | ||||||||||
End point description |
The POS frequency is standardized to a 28-day duration. Results are presented as the median number of seizures per 28 days.
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End point type |
Secondary
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End point timeframe |
From Entry Visit (Month 0) to the Last Evaluation Period Visit or Early Discontinuation Visit (up to 46 months)
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No statistical analyses for this end point |
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End point title |
Percentage of change in Partial-Onset-Seizure (POS) Type I frequency per 28 days from Baseline of the previous study to the Evaluation Period for subjects with focal-onset Epilepsy entering N01372 from a study where Baseline seizure data was collected | ||||||||||
End point description |
The POS frequency is standardized to a 28-day duration. Results are presented as the median percentage of reduction per 28 days. Negative values indicate improvement from Baseline.
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End point type |
Secondary
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End point timeframe |
From Baseline of the previous study to the Last Evaluation Period Visit or Early Discontinuation Visit (up to 49 months)
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No statistical analyses for this end point |
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End point title |
50 % responder rate in Partial-Onset-Seizure (POS) Type I frequency from Baseline of the previous study to the Evaluation Period for subjects with focal-onset Epilepsy entering N01372 from a study where Baseline seizure data was collected | ||||||||||
End point description |
The POS frequency is standardized to a 28-day duration. A responder is defined as a subject with a >=50% reduction in seizure frequency from the Baseline Period of the previous study. Results are presented as the percentage of subjects with 50 % responder rate in POS Type I frequency.
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End point type |
Secondary
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End point timeframe |
From Baseline of the previous study to the Last Evaluation Period Visit or Early Discontinuation Visit (up to 49 months)
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No statistical analyses for this end point |
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Adverse events information
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Timeframe for reporting adverse events |
Adverse events collection started at Day 0 and continued up to 30 days after last intake of study medication.
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Assessment type |
Non-systematic | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Dictionary used for adverse event reporting
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Dictionary name |
MedDRA | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Dictionary version |
15.0
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Reporting groups
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Reporting group title |
Brivaracetam Generalized Epilepsy (SS)
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Reporting group description |
This arm includes subjects with generalized epilepsy, who received a flexible dose of Brivaracetam (BRV) tablets, administered twice a day, starting with an individual dose that they had reached at the completion of study N01395 (feeder study). The BRV dose could have been increased or decreased in increments of 50mg/day based on the individual subject’s seizure control and/or tolerability, but was to not exceed 200mg/day. This arm is part of the Safety Set (SS). | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Reporting group title |
Brivaracetam Focal Epilepsy (SS)
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Reporting group description |
This arm includes subjects with focal epilepsy, who received a flexible dose of Brivaracetam (BRV) tablets, administered twice a day, starting with an individual dose that they had reached at the completion of study N01395 (feeder study). The BRV dose could have been increased or decreased in increments of 50mg/day based on the individual subject’s seizure control and/or tolerability, but was to not exceed 200mg/day. This arm is part of the Safety Set (SS). | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
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Frequency threshold for reporting non-serious adverse events: 5% | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
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Substantial protocol amendments (globally) |
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Were there any global substantial amendments to the protocol? Yes | |||
Date |
Amendment |
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14 Nov 2013 |
This Amendment was implemented after the date of first subject first visit (FSFV, 25 subjects had enrolled in the study as of the date of this amendment). The rationale for this amendment was to clarify that data for the following variables were to only be collected and analyzed for subjects with epilepsy that entered N01372 from a study in which a Baseline value for that variable was previously collected:
- Percent reduction in Type I partial-onset seizures (POS) frequency per 28 days from Baseline of the previous study into the Evaluation Period
- Responder rate in POS (Type I) frequency over the Evaluation Period
- Percent reduction in generalized (Type II) seizure days per 28 days from Baseline of the previous study to the Evaluation Period
- Responder rate for generalized (Type II) seizure days over the Evaluation Period
- Patient Weighted Quality of Life in Epilepsy Inventory-Form 31 (QOLIE-31-P) score
- Hospital stays and healthcare provider consultations.
Additionally, Inclusion Criterion 7 was added, which required subjects to be able to take the oral film-coated tablets of Brivaracetam (BRV). References to specific BRV studies were removed and a statement was added to clarify that the study was to enroll subjects who had completed the Treatment Period of an applicable BRV study. Administrative changes included an update to the Clinical Trial Biostatistician and Study Physician. |
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Interruptions (globally) |
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Were there any global interruptions to the trial? No | |||
Limitations and caveats |
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Limitations of the trial such as small numbers of subjects analysed or technical problems leading to unreliable data. | |||
None reported |