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    Clinical Trial Results:
    An open-label, multicenter, single-arm study to evaluate the reduction in nonpsychotic behavioral side effects in subjects with epilepsy switching from Levetiracetam to Brivaracetam due to nonpsychotic behavioral side effects phase 3b

    Summary
    EudraCT number
    2011-005177-23
    Trial protocol
    GB   DE   ES   IT  
    Global end of trial date
    15 Nov 2013

    Results information
    Results version number
    v1(current)
    This version publication date
    28 Jun 2016
    First version publication date
    30 Jul 2015
    Other versions

    Trial information

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    Trial identification
    Sponsor protocol code
    N01395
    Additional study identifiers
    ISRCTN number
    -
    US NCT number
    NCT01653262
    WHO universal trial number (UTN)
    -
    Sponsors
    Sponsor organisation name
    UCB Pharma SA
    Sponsor organisation address
    Allée de la Recherche 60, Brussels, Belgium, B-1070
    Public contact
    Clinical Trial Registries and Results Disclosure, UCB BIOSCIENCES GmbH, +49 2173 4815 15, clinicaltrials@ucb.com
    Scientific contact
    Clinical Trial Registries and Results Disclosure, UCB BIOSCIENCES GmbH, +49 2173 48 15 15, clinicaltrials@ucb.com
    Paediatric regulatory details
    Is trial part of an agreed paediatric investigation plan (PIP)
    No
    Does article 45 of REGULATION (EC) No 1901/2006 apply to this trial?
    No
    Does article 46 of REGULATION (EC) No 1901/2006 apply to this trial?
    No
    Results analysis stage
    Analysis stage
    Final
    Date of interim/final analysis
    26 Jan 2014
    Is this the analysis of the primary completion data?
    No
    Global end of trial reached?
    Yes
    Global end of trial date
    15 Nov 2013
    Was the trial ended prematurely?
    No
    General information about the trial
    Main objective of the trial
    The primary objective was to evaluate the reduction of nonpsychotic behavioral side effects in subjects with epilepsy who switched to Brivaracetam (BRV) 200 mg/day after discontinuing Levetiracetam (LEV) 1 g/day to 3 g/day due to these nonpsychotic behavioral side effects.
    Protection of trial subjects
    In Phase 2/3 studies, a favorable safety and tolerability profile has been demonstrated for Brivaracetam (BRV). Therefore dose adjustments within the range of BRV 50 mg/day to 200 mg/day were permitted based on clinical response and tolerability in order to minimize distress.
    Background therapy
    Patient receiving levetiracetam at the recommended therapeutic dose (dose ranging from 1 g/day to 3 g/day) for up to 16 weeks prior to study entry, and treated with not more than 2 other concomitant anti-epileptic drugs (AEDs).
    Evidence for comparator
    Not applicable
    Actual start date of recruitment
    24 Jul 2012
    Long term follow-up planned
    Yes
    Long term follow-up rationale
    Safety
    Long term follow-up duration
    3 Years
    Independent data monitoring committee (IDMC) involvement?
    No
    Population of trial subjects
    Number of subjects enrolled per country
    Country: Number of subjects enrolled
    France: 4
    Country: Number of subjects enrolled
    Germany: 3
    Country: Number of subjects enrolled
    Spain: 2
    Country: Number of subjects enrolled
    United States: 20
    Worldwide total number of subjects
    29
    EEA total number of subjects
    9
    Number of subjects enrolled per age group
    In utero
    0
    Preterm newborn - gestational age < 37 wk
    0
    Newborns (0-27 days)
    0
    Infants and toddlers (28 days-23 months)
    0
    Children (2-11 years)
    0
    Adolescents (12-17 years)
    0
    Adults (18-64 years)
    29
    From 65 to 84 years
    0
    85 years and over
    0

    Subject disposition

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    Recruitment
    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
    Screening 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.

    Period 1
    Period 1 title
    Overall Study (overall period)
    Is this the baseline period?
    Yes
    Allocation method
    Non-randomised - controlled
    Blinding used
    Not blinded

    Arms
    Arm title
    Brivaracetam
    Arm description
    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.
    Arm type
    Experimental

    Investigational medicinal product name
    Brivaracetam
    Investigational medicinal product code
    ucb 34714
    Other name
    BRV
    Pharmaceutical forms
    Film-coated tablet
    Routes of administration
    Oral use
    Dosage and administration details
    The study drug was oral film-coated tablets of BRV 10 mg and BRV 25 mg. The subjects were treated with Brivaracetam (BRV) tablets 200 mg/day during 12 weeks.

    Number of subjects in period 1
    Brivaracetam
    Started
    29
    Completed
    26
    Not completed
    3
         Lack of efficacy
    1
         SAE, non-fatal
    1
         AE, non-serious non-fatal
    1

    Baseline characteristics

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    Baseline characteristics reporting groups
    Reporting group title
    Brivaracetam
    Reporting group description
    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.

    Reporting group values
    Brivaracetam Total
    Number of subjects
    29 29
    Age Categorical
    Units: Subjects
        <=18 years
    0 0
        Between 18 and 65 years
    29 29
        >= 65 years
    0 0
    Age Continuous
    Units: years
        arithmetic mean (standard deviation)
    35.8 ± 11.8 -
    Gender Categorical
    Units: Subjects
        Female
    14 14
        Male
    15 15

    End points

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    End points reporting groups
    Reporting group title
    Brivaracetam
    Reporting group description
    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.

    Subject analysis set title
    Full Analysis Set ( Brivaracetam treated subjects)
    Subject analysis set type
    Full analysis
    Subject analysis set description
    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. 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.

    Subject analysis set title
    Safety Set (Brivaracetam treated subjects)
    Subject analysis set type
    Safety analysis
    Subject analysis set description
    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. The Safety Set (SS) consisted of all subjects who received at least 1 dose of Brivaracetam.

    Subject analysis set title
    Efficacy Analysis Set (Brivaracetam treated subjects)
    Subject analysis set type
    Sub-group analysis
    Subject analysis set description
    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. 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).

    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

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    End point title
    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 [1]
    End point description
    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
    End point type
    Primary
    End point timeframe
    From Study Entry (Visit1, Week -1) to the end of the Treatment Period (Visit 6, Week 12) or Early Discontinuation Visit
    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 in tables as descriptive statistics only.
    End point values
    Full Analysis Set ( Brivaracetam treated subjects)
    Number of subjects analysed
    29
    Units: percentage of subjects
    number (not applicable)
        percentage of subjects
    93.1
    No statistical analyses for this end point

    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

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    End point title
    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
    End point description
    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.
    End point type
    Secondary
    End point timeframe
    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
    End point values
    Full Analysis Set ( Brivaracetam treated subjects)
    Number of subjects analysed
    29
    Units: subjects
        Improvement
    8
        Unchanged
    2
        Worsening
    0
        Resolved
    19
    No statistical analyses for this end point

    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

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    End point title
    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
    End point description
    There are seven levels for the I-GEBSE: - Marked improvement - Moderate improvement - Slight improvement - No change - Slight worsening - Moderate worsening - Marked worsening
    End point type
    Secondary
    End point timeframe
    From Study Entry (Visit1, Week -1) to the end of the Treatment Period (Visit 6, Week 12) or Early Discontinuation Visit
    End point values
    Full Analysis Set ( Brivaracetam treated subjects)
    Number of subjects analysed
    29
    Units: subjects
        Marked improvement
    10
        Moderate improvement
    10
        Slight improvement
    4
        No change
    2
        Slight worsening
    1
        Moderate worsening
    0
        Marked worsening
    1
        Missing
    1
    No statistical analyses for this end point

    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

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    End point title
    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
    End point description
    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.
    End point type
    Secondary
    End point timeframe
    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
    End point values
    Full Analysis Set ( Brivaracetam treated subjects)
    Number of subjects analysed
    29
    Units: subjects
        Complete Abatement
    18
    No statistical analyses for this end point

    Secondary: Number of subjects who are free from nonpsychotic behavioral side effects over the entire Treatment Period

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    End point title
    Number of subjects who are free from nonpsychotic behavioral side effects over the entire Treatment Period
    End point description
    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.
    End point type
    Secondary
    End point timeframe
    From Visit 2 (Week 0) to Visit 6 (Week 12)
    End point values
    Full Analysis Set ( Brivaracetam treated subjects)
    Number of subjects analysed
    29
    Units: subjects
        Freedom from NBSE
    3
    No statistical analyses for this end point

    Secondary: Incidence of Treatment Emergent Adverse Events during the Study Period

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    End point title
    Incidence of Treatment Emergent Adverse Events during the Study Period
    End point description
    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.
    End point type
    Secondary
    End point timeframe
    From Study Entry (Visit1, Week -1) to the end of the Treatment Period (Visit 6, Week 12) or Early Discontinuation Visit
    End point values
    Safety Set (Brivaracetam treated subjects)
    Number of subjects analysed
    29
    Units: events
        Treatment-Emergent Adverse Events
    67
    No statistical analyses for this end point

    Secondary: Withdrawal due to an Adverse Event (AE) during the Study Period

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    End point title
    Withdrawal due to an Adverse Event (AE) during the Study Period
    End point description
    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.
    End point type
    Secondary
    End point timeframe
    From Study Entry (Visit1, Week -1) to the end of the Treatment Period (Visit 6, Week 12) or Early Discontinuation Visit
    End point values
    Safety Set (Brivaracetam treated subjects)
    Number of subjects analysed
    29
    Units: subjects
        Subjects who withdrew due to AE
    2
    No statistical analyses for this end point

    Secondary: Occurrence of Serious Adverse Events during the Study Period

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    End point title
    Occurrence of Serious Adverse Events during the Study Period
    End point description
    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.
    End point type
    Secondary
    End point timeframe
    From Study Entry (Visit1, Week -1) to the end of the Treatment Period (Visit 6, Week 12) or Early Discontinuation Visit
    End point values
    Safety Set (Brivaracetam treated subjects)
    Number of subjects analysed
    29
    Units: events
        Serious Adverse Events
    1
    No statistical analyses for this end point

    Secondary: Partial Onset Seizure (POS) frequency over the Treatment Period for subjects with focal Epilepsy

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    End point title
    Partial Onset Seizure (POS) frequency over the Treatment Period for subjects with focal Epilepsy
    End point description
    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)
    End point type
    Secondary
    End point timeframe
    From 4 weeks prior to Visit 2 (Week 0) to the end of the Treatment Period (Visit 6, Week 12) or Early Discontinuation Visit
    End point values
    Efficacy Analysis Set (Brivaracetam treated subjects)
    Number of subjects analysed
    15
    Units: POS frequency
    median (inter-quartile range (Q1-Q3))
        Median (Inter-Quartile Range)
    6 (2.2 to 17.7)
    No statistical analyses for this end point

    Secondary: Generalized seizure days over the Treatment Period for subjects with idiopathic generalized Epilepsy

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    End point title
    Generalized seizure days over the Treatment Period for subjects with idiopathic generalized Epilepsy
    End point description
    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.
    End point type
    Secondary
    End point timeframe
    From 4 weeks prior to Visit 2 (Week 0) to the end of the Treatment Period (Visit 6, Week 12) or Early Discontinuation Visit
    End point values
    Brivaracetam
    Number of subjects analysed
    0 [2]
    Units: days
    median (inter-quartile range (Q1-Q3))
        Median (Inter-Quartile Range)
    ( to )
    Notes
    [2] - Please refer to End point description
    No statistical analyses for this end point

    Adverse events

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    Adverse events information
    Timeframe for reporting adverse events
    Adverse Events were collected from Screening Period (Week -1) over the 12-weeks Treatment Period until the Safety Visit (Week 15-18 + max 7 days).
    Adverse event reporting additional description
    Adverse Events refer to the Safety Set (SS) consisting of all subjects who received at least 1 dose of Brivaracetam.
    Assessment type
    Non-systematic
    Dictionary used for adverse event reporting
    Dictionary name
    MedDRA
    Dictionary version
    15.0
    Reporting groups
    Reporting group title
    Brivaracetam
    Reporting group description
    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.

    Serious adverse events
    Brivaracetam
    Total subjects affected by serious adverse events
         subjects affected / exposed
    1 / 29 (3.45%)
         number of deaths (all causes)
    0
         number of deaths resulting from adverse events
    0
    Psychiatric disorders
    Suicide attempt
         subjects affected / exposed
    1 / 29 (3.45%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Suicidal ideation
         subjects affected / exposed
    1 / 29 (3.45%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Frequency threshold for reporting non-serious adverse events: 5%
    Non-serious adverse events
    Brivaracetam
    Total subjects affected by non serious adverse events
         subjects affected / exposed
    13 / 29 (44.83%)
    Nervous system disorders
    Headache
         subjects affected / exposed
    5 / 29 (17.24%)
         occurrences all number
    7
    Tremor
         subjects affected / exposed
    2 / 29 (6.90%)
         occurrences all number
    2
    Dizziness
         subjects affected / exposed
    2 / 29 (6.90%)
         occurrences all number
    2
    General disorders and administration site conditions
    Fatigue
         subjects affected / exposed
    3 / 29 (10.34%)
         occurrences all number
    3
    Psychiatric disorders
    Depression
         subjects affected / exposed
    2 / 29 (6.90%)
         occurrences all number
    2
    Insomnia
         subjects affected / exposed
    2 / 29 (6.90%)
         occurrences all number
    2
    Musculoskeletal and connective tissue disorders
    Back pain
         subjects affected / exposed
    3 / 29 (10.34%)
         occurrences all number
    4
    Infections and infestations
    Nasopharyngitis
         subjects affected / exposed
    2 / 29 (6.90%)
         occurrences all number
    2

    More information

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    Substantial protocol amendments (globally)

    Were there any global substantial amendments to the protocol? Yes
    Date
    Amendment
    28 Sep 2012
    The protocol was amended for the following reasons: - To introduce a visit window of up to an additional 7 days maximum to the end of the Study Drug-Free Period to facilitate planning in compliance with the protocol. - To introduce a visit window of ±3 days for V2 to V7 in order to bring N01395 in line with the visit windows applied to other studies using BRV and to take into account practical considerations of requiring subjects to return to the clinic (in order to allow greater flexibility). - To clarify the timing of V7 throughout the protocol. - To update details of some of the team members as the Study Sponsor Physician, Clinical Project Manager (CPM), Clinical Program Director, and Clinical Trial Biostatistician had changed since the protocol was written. - To make some minor revisions to the schematic diagram for the study to show the plan for the visits at the end of the study more clearly and to clarify wording on a footnote pertaining to the inclusion/exclusion criteria.
    28 Sep 2012
    The protocol was amended for the following reasons: - To change the wording in the inclusion and exclusion criteria to make clear that subjects may have only been receiving LEV for up to 16 weeks prior to V1 at a dose of 1 g/day to 3 g/day. Previously, subjects who took LEV for more than 12 weeks prior to V1 were to be excluded; however, 12 weeks was considered by the Investigators to exclude a number of subjects who developed nonpsychotic behavioral side effects due to LEV, which were recognized at a time that it was too late to schedule and perform a Screening Visit no later than 12 weeks after the start date of LEV. This was partially due to the broad spectrum of nonpsychotic behavioral side effects and the different manifestations of nonpsychotic behavioral side effects that could have been expressed by the patient and/or a relative or close friend. It was necessary to state in the inclusion criteria that the maximum period of 16 weeks should have applied only for the recommended therapeutic dose ranging from 1 g/day to 3 g/day as doses below this range were not considered to be therapeutic. Changes were also made throughout the protocol to reflect the change from a 12-week period to a 16-week period and to specify that the Baseline for nonpsychotic behavioral side effects started when the first LEV dose at the therapeutic approved dose (1 g/day to 3 g/day) was started. - To include a clear definition of abstinence as an acceptable method of contraception, where abstinence was defined as “true abstinence” according to Medicines and Healthcare products Regulatory Agency guidance. - To update wording pertaining to suicide attempts and suicidal ideation captured by the Columbia-Suicide Severity Rating Scale (C-SSRS), in order to ensure the protocol was consistent with this global change for all UCB protocols.
    28 Sep 2012
    The protocol was amended for the following reasons: - To include further details on the permitted dose adjustments during the Treatment Period in the Treatment(s) to be administered section (Section 7.2) to be consistent with the text in Study description (Section 5.1) of the protocol. - To change the restriction for concomitant non-AEDs as the endpoints for the N01395 study did not require that strong hepatic inducers (which could have caused fluctuations in BRV concentrations) were to be restricted. - To clarify the documentation of the Patient Global Evaluation Scale (P-GES), Investigator Global Evaluation Scale (I-GES), and Investigator Global Evaluation of nonpsychotic Behavioral Side Effects (I-GEBSE) questionnaires during the study and to include the 7 items on the I-GEBSE to be consistent with the level of detail of presentation of the P-GES and I-GES. The numbering of the list of items in the P-GES and I-GES was removed in order to make the presentation consistent with the eCRF, which did not contain numbering in the lists. - To update the name of the Global Clinical Safety and Pharmacovigilance department to Drug Safety (DS) due to a change in the organizational structure at UCB, and to update the contact details for serious adverse event (SAE) reporting due to the formation of a new data processing team at UCB. - To correct a typographical error in the schedule of study assessments and to make some minor style and formatting changes throughout the protocol in order to ensure the document styles were consistent with the current template requirements.
    29 Apr 2013
    The protocol was amended for the following reason: - Based on review of the study objectives, the exploratory nature of the study design, and unanticipated recruitment challenges, the sample size was reassessed. The sample size for N01395 was reduced from the previous total of 100 subjects entering the BRV Treatment Period to a minimum of 32 subjects with the expectation that at least 30 subjects would receive at least 1 dose of BRV. This amendment was not due to any changes in the adverse event (AE), safety, or tolerability profile for BRV.

    Interruptions (globally)

    Were there any global interruptions to the trial? No

    Limitations and caveats

    Limitations of the trial such as small numbers of subjects analysed or technical problems leading to unreliable data.
    None reported
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