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    Clinical Trial Results:
    A Multicentre, Randomized, Double-blind, Placebo Controlled, Parallel-group Study in Children With Inadequately Controlled Partial Onset Seizures to Investigate Efficacy, Safety and Tolerability of TRI476 (Oxcarbazepine) as Adjunctive Therapy

    Summary
    EudraCT number
    		 2015-004484-37
    Trial protocol
    		 Outside EU/EEA  
    Global end of trial date
    17 Oct 2012

    Results information
    Results version number
    		 v1(current)
    This version publication date
    27 Dec 2016
    First version publication date
    27 Dec 2016
    Other versions

    Trial information

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    Trial identification
    Sponsor protocol code
    CTRI476B1301
    Additional study identifiers
    ISRCTN number
    		 -
    US NCT number
    		 NCT00975715
    WHO universal trial number (UTN)
    		 -
    Sponsors
    Sponsor organisation name
    Novartis Pharmaceuticals AG
    Sponsor organisation address
    CH-4002, Basel, Switzerland,
    Public contact
    Clinical Disclosure Office, Novartis Pharmaceuticals AG, +41 613241111,
    Scientific contact
    Clinical Disclosure Office, Novartis Pharmaceuticals AG, +41 613241111,
    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
    17 Oct 2012
    Is this the analysis of the primary completion data?
    No
    Global end of trial reached?
    Yes
    Global end of trial date
    17 Oct 2012
    Was the trial ended prematurely?
    No
    General information about the trial
    Main objective of the trial
    The purpose of this study is is to demonstrate the superiority of TRI476 oral suspension over placebo based on the percent reduction in partial onset seizure frequency at Week 8 in pediatric epileptic patients with partial onset seizures refractory to other antiepileptics.
    Protection of trial subjects
    The study was in compliance with the ethical principles derived from the Declaration of Helsinki and the International Conference on Harmonization (ICH) Good Clinical Practice (GCP) Guidelines. All the local regulatory requirements pertinent to safety of trial subjects were also followed during the conduct of the trial.
    Background therapy
    		 -
    Evidence for comparator
    		 -
    Actual start date of recruitment
    12 Sep 2009
    Long term follow-up planned
    No
    Independent data monitoring committee (IDMC) involvement?
    No
    Population of trial subjects
    Number of subjects enrolled per country
    Country: Number of subjects enrolled
    Japan: 99
    Worldwide total number of subjects
    99
    EEA total number of subjects
    0
    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)
    69
    Adolescents (12-17 years)
    30
    Adults (18-64 years)
    0
    From 65 to 84 years
    0
    85 years and over
    0

    Subject disposition

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    Recruitment
    Recruitment details
    		 -

    Pre-assignment
    Screening details
    		 The study consisted of 3 phases: an 8-week screening phase, an 8-week double-blind phase (a 2-week titration phase, a 6-week maintenance phase), and a 3- to 5-week follow-up phase.

    Period 1
    Period 1 title
    Titration Period
    Is this the baseline period?
    		 Yes
    Allocation method
    Randomised - controlled
    Blinding used
    		 Double blind
    Roles blinded
    		 Subject, Investigator

    Arms
    Are arms mutually exclusive
    Yes

    Arm title
    		 TRI476
    Arm description
    		 Participants received TRI476 based on body weight with titration up to the maintenance dose, in addition to their traditional antiepileptics dosage.
    Arm type
    		 Experimental

    Investigational medicinal product name
    TRI476
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Oral suspension
    Routes of administration
    Oral use
    Dosage and administration details
    TRI476 oral suspension doses, based on body weight twice daily.

    Investigational medicinal product name
    Benzodiazepines
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Oral solution
    Routes of administration
    Oral use
    Dosage and administration details
    Benzodiazepines could be used as needed as rescue medication during the duration of the study.

    Arm title
    		 Placebo
    Arm description
    		 Participants received placebo to TRI476 without any adjustment to the dosing regimen, in addition to their traditional antiepileptics dosage.
    Arm type
    		 Placebo

    Investigational medicinal product name
    Placebo to TRI476
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Oral suspension
    Routes of administration
    Oral use
    Dosage and administration details
    Placebo oral suspension, taken twice daily.

    Investigational medicinal product name
    Benzodiazepines
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Oral solution
    Routes of administration
    Oral use
    Dosage and administration details
    Benzodiazepines could be used as needed as rescue medication during the duration of the study.

    Number of subjects in period 1
    		TRI476 Placebo
    Started
    48
    51
    Completed
    41
    51
    Not completed
    7
    0
         Protocol violation
    1
    -
         Adverse event, non-fatal
    6
    -
    Period 2
    Period 2 title
    Maintenance Period
    Is this the baseline period?
    		 No
    Allocation method
    Randomised - controlled
    Blinding used
    		 Double blind
    Roles blinded
    		 Subject, Investigator

    Arms
    Are arms mutually exclusive
    Yes

    Arm title
    		 TRI476
    Arm description
    		 Participants received TRI476 based on body weight with titration up to the maintenance dose, in addition to their traditional antiepileptics dosage.
    Arm type
    		 Experimental

    Investigational medicinal product name
    TRI476
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Oral suspension
    Routes of administration
    Oral use
    Dosage and administration details
    TRI476 oral suspension doses, based on body weight twice daily.

    Investigational medicinal product name
    Benzodiazepines
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Oral solution
    Routes of administration
    Oral use
    Dosage and administration details
    Benzodiazepines could be used as needed as rescue medication during the duration of the study.

    Arm title
    		 Placebo
    Arm description
    		 Participants received placebo to TRI476 without any adjustment to the dosing regimen, in addition to their traditional antiepileptics dosage.
    Arm type
    		 Placebo

    Investigational medicinal product name
    Placebo to TRI476
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Oral suspension
    Routes of administration
    Oral use
    Dosage and administration details
    Placebo oral suspension, taken twice daily.

    Investigational medicinal product name
    Benzodiazepines
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Oral solution
    Routes of administration
    Oral use
    Dosage and administration details
    Benzodiazepines could be used as needed as rescue medication during the duration of the study.

    Number of subjects in period 2
    		TRI476 Placebo
    Started
    41
    51
    Completed
    39
    50
    Not completed
    2
    1
         Adverse event, non-fatal
    2
    1

    Baseline characteristics

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    Baseline characteristics reporting groups
    Reporting group title
    TRI476
    Reporting group description
    		 Participants received TRI476 based on body weight with titration up to the maintenance dose, in addition to their traditional antiepileptics dosage.

    Reporting group title
    Placebo
    Reporting group description
    		 Participants received placebo to TRI476 without any adjustment to the dosing regimen, in addition to their traditional antiepileptics dosage.

    Reporting group values
    		 TRI476 Placebo Total
    Number of subjects
    		 48 51 99
    Age categorical
    Units: Subjects
        Children (2-11 years)
    		 31 38 69
        Adolescents (12-17 years)
    		 17 13 30
    Age continuous
    Units: years
        arithmetic mean (standard deviation)
    		 9.8 ( 2.91 ) 9.2 ( 2.83 ) -
    Gender categorical
    Units: Subjects
        Female
    		 22 24 46
        Male
    		 26 27 53

    End points

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    End points reporting groups
    Reporting group title
    TRI476
    Reporting group description
    		 Participants received TRI476 based on body weight with titration up to the maintenance dose, in addition to their traditional antiepileptics dosage.

    Reporting group title
    Placebo
    Reporting group description
    		 Participants received placebo to TRI476 without any adjustment to the dosing regimen, in addition to their traditional antiepileptics dosage.
    Reporting group title
    TRI476
    Reporting group description
    		 Participants received TRI476 based on body weight with titration up to the maintenance dose, in addition to their traditional antiepileptics dosage.

    Reporting group title
    Placebo
    Reporting group description
    		 Participants received placebo to TRI476 without any adjustment to the dosing regimen, in addition to their traditional antiepileptics dosage.

    Primary: Percent Change in Partial Onset Seizure Frequency Per 28 Days From Baseline to the Double-blind Phase, by Treatment Group

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    End point title
    		 Percent Change in Partial Onset Seizure Frequency Per 28 Days From Baseline to the Double-blind Phase, by Treatment Group [1]
    End point description
    Percent change in partial onset seizure frequency per 28 days during the double-blind phase from the screening phase, was calculated according to the following formula: “Percent change in partial onset seizure frequency per 28 days from the screening phase” = (partial onset seizure frequency per 28 days during the double-blind phase - partial onset seizure frequency per 28 days during the screening phase) / partial onset seizure frequency per 28 days during the double-blind phase x 100 “Partial onset seizure frequency per 28 days” = Number of partial onset seizures during each phase (screening phase or double-blind phase) / number of days during the screening or double-blind phase × 28.
    End point type
    Primary
    End point timeframe
    screening and 28 days
    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 statistical analysis provided for Percent Change in Partial Onset Seizure Frequency Per 28 Days From Baseline to the Double-blind Phase, by Treatment Group.
    End point values
    		 TRI476 Placebo
    Number of subjects analysed
    47 [2]
    51
    Units: percentage change per 28 days
        arithmetic mean (standard deviation)
    -2.85 ( 63.546 )
    14.82 ( 73.333 )
    Notes
    [2] - The Full Analysis set included all participants who received study drug.
    No statistical analyses for this end point

    Secondary: Partial Seizure Frequency Per 28 Days, by Study Period (Every 28 Days) and Treatment Group

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    End point title
    		 Partial Seizure Frequency Per 28 Days, by Study Period (Every 28 Days) and Treatment Group
    End point description
    Partial onset seizure frequency per 28 days during a period between baseline and Week 4 was measured. Partial onset seizure frequency per 28 days (count/28 days)” = Number of partial onset seizures during each phase (screening phase or double-blind phase) / Number of days during the phase x 28.
    End point type
    Secondary
    End point timeframe
    baseline, 28 days and 56 days
    End point values
    		 TRI476 Placebo
    Number of subjects analysed
    47 [3]
    51
    Units: seizures per 28 days
    arithmetic mean (standard deviation)
        Baseline to Week 4 (day 0 to day 28)
    65.58 ( 109.457 )
    90.61 ( 283.187 )
        Week 4 to Week 8 (day 28 to day 56)
    45.4 ( 70.209 )
    98.73 ( 291.781 )
    Notes
    [3] - The Full Analysis set included all participants who received study drug.
    No statistical analyses for this end point

    Secondary: Percent of Participants With Response During Double-blind Phase, by Treatment Group

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    End point title
    		 Percent of Participants With Response During Double-blind Phase, by Treatment Group
    End point description
    Responder rate was defined as the percent of participants with an at least 50% reduction in partial onset seizure frequency per 28 days from the screening phase.
    End point type
    Secondary
    End point timeframe
    screening to 28 days
    End point values
    		 TRI476 Placebo
    Number of subjects analysed
    47 [4]
    51
    Units: percentage of participants
        number (not applicable)
    23.4
    3.9
    Notes
    [4] - The Full Analysis set included all participants who received study drug.
    No statistical analyses for this end point

    Secondary: Percent Change in Partial Onset Seizure Frequency During the Double-blind Phase by Seizure Type

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    End point title
    		 Percent Change in Partial Onset Seizure Frequency During the Double-blind Phase by Seizure Type
    End point description
    Percent change in seizure frequency from baseline = 100 (T-B)/B, B=Seizure frequency per 28 days during baseline phase, T=Seizure frequency per 28 days during the double-blind phase. Seizure frequency per 28 days is calculated as: (seizure frequency during the double-blind phase / the number of days the seizure information were provided) x 28. Only patients with both baseline and corresponding post-baseline values are included.
    End point type
    Secondary
    End point timeframe
    28 days
    End point values
    		 TRI476 Placebo
    Number of subjects analysed
    47 [5]
    51
    Units: percentage change in seizure frequency
    arithmetic mean (standard deviation)
        Simple partial seizures
    -9.73 ( 51.329 )
    -16.89 ( 45.822 )
        Complex partial seizures
    -6.86 ( 78.583 )
    30.59 ( 91.551 )
        Secondarily generalized seizures
    -29.54 ( 64.66 )
    12.11 ( 82.879 )
    Notes
    [5] - Includes all participants who received study drug and had baseline and post baseline data available
    No statistical analyses for this end point

    Secondary: Number of Participants With Clinical Global Impression of Change (CGIC) at Final Assessment, by Treatment Group

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    End point title
    		 Number of Participants With Clinical Global Impression of Change (CGIC) at Final Assessment, by Treatment Group
    End point description
    Clinical Global Impression of Change (CGI) is rated on a 7-point scale, with the severity of illness scale using a range of responses from 1 (normal) through to 7 (amongst the most severely ill patients). CGI-C scores range from 1 (very much improved) through to 7 (very much worse).
    End point type
    Secondary
    End point timeframe
    56 days
    End point values
    		 TRI476 Placebo
    Number of subjects analysed
    47 [6]
    51
    Units: participants
    number (not applicable)
        Marked improvement
    9
    2
        Moderate improvement
    8
    2
        Slight improvement
    8
    6
        No change
    21
    38
        Slight aggravation
    1
    3
        Moderate aggravation
    0
    0
        Marked aggravation
    0
    0
    Notes
    [6] - Included all participants who received study drug and had data available for analysis.
    No statistical analyses for this end point

    Adverse events

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    Adverse events information
    Timeframe for reporting adverse events
    Timeframe for AE
    Adverse event reporting additional description
    AE additional description
    Assessment type
    		 Systematic
    Dictionary used for adverse event reporting
    Dictionary name
    		 MedDRA
    Dictionary version
    15.0
    Reporting groups
    Reporting group title
    TRI476
    Reporting group description
    		 TRI476

    Reporting group title
    Placebo
    Reporting group description
    		 Placebo

    Serious adverse events
    		 TRI476 Placebo
    Total subjects affected by serious adverse events
         subjects affected / exposed
    1 / 47 (2.13%)
    1 / 51 (1.96%)
         number of deaths (all causes)
    0
    0
         number of deaths resulting from adverse events
    0
    0
    Nervous system disorders
    Somnolence
         subjects affected / exposed
    1 / 47 (2.13%)
    0 / 51 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Infections and infestations
    Bronchopneumonia
         subjects affected / exposed
    0 / 47 (0.00%)
    1 / 51 (1.96%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Frequency threshold for reporting non-serious adverse events: 3%
    Non-serious adverse events
    		 TRI476 Placebo
    Total subjects affected by non serious adverse events
         subjects affected / exposed
    38 / 47 (80.85%)
    27 / 51 (52.94%)
    Injury, poisoning and procedural complications
    Contusion
         subjects affected / exposed
    2 / 47 (4.26%)
    0 / 51 (0.00%)
         occurrences all number
    2
    0
    Head injury
         subjects affected / exposed
    2 / 47 (4.26%)
    0 / 51 (0.00%)
         occurrences all number
    2
    0
    Nervous system disorders
    Ataxia
         subjects affected / exposed
    2 / 47 (4.26%)
    0 / 51 (0.00%)
         occurrences all number
    3
    0
    Somnolence
         subjects affected / exposed
    20 / 47 (42.55%)
    5 / 51 (9.80%)
         occurrences all number
    20
    5
    Blood and lymphatic system disorders
    Leukopenia
         subjects affected / exposed
    2 / 47 (4.26%)
    0 / 51 (0.00%)
         occurrences all number
    2
    0
    General disorders and administration site conditions
    Pyrexia
         subjects affected / exposed
    2 / 47 (4.26%)
    2 / 51 (3.92%)
         occurrences all number
    2
    2
    Ear and labyrinth disorders
    Vertigo
         subjects affected / exposed
    2 / 47 (4.26%)
    0 / 51 (0.00%)
         occurrences all number
    3
    0
    Eye disorders
    Conjunctivitis
         subjects affected / exposed
    2 / 47 (4.26%)
    2 / 51 (3.92%)
         occurrences all number
    2
    2
    Diplopia
         subjects affected / exposed
    2 / 47 (4.26%)
    0 / 51 (0.00%)
         occurrences all number
    2
    0
    Gastrointestinal disorders
    Constipation
         subjects affected / exposed
    3 / 47 (6.38%)
    0 / 51 (0.00%)
         occurrences all number
    3
    0
    Nausea
         subjects affected / exposed
    2 / 47 (4.26%)
    3 / 51 (5.88%)
         occurrences all number
    2
    3
    Vomiting
         subjects affected / exposed
    5 / 47 (10.64%)
    3 / 51 (5.88%)
         occurrences all number
    5
    3
    Respiratory, thoracic and mediastinal disorders
    Upper respiratory tract inflammation
         subjects affected / exposed
    2 / 47 (4.26%)
    2 / 51 (3.92%)
         occurrences all number
    4
    3
    Skin and subcutaneous tissue disorders
    Drug eruption
         subjects affected / exposed
    2 / 47 (4.26%)
    1 / 51 (1.96%)
         occurrences all number
    2
    1
    Eczema
         subjects affected / exposed
    2 / 47 (4.26%)
    2 / 51 (3.92%)
         occurrences all number
    2
    2
    Rash
         subjects affected / exposed
    4 / 47 (8.51%)
    2 / 51 (3.92%)
         occurrences all number
    4
    2
    Infections and infestations
    Gastroenteritis
         subjects affected / exposed
    1 / 47 (2.13%)
    2 / 51 (3.92%)
         occurrences all number
    1
    2
    Influenza
         subjects affected / exposed
    2 / 47 (4.26%)
    3 / 51 (5.88%)
         occurrences all number
    2
    3
    Nasopharyngitis
         subjects affected / exposed
    5 / 47 (10.64%)
    9 / 51 (17.65%)
         occurrences all number
    5
    10
    Otitis media
         subjects affected / exposed
    2 / 47 (4.26%)
    0 / 51 (0.00%)
         occurrences all number
    2
    0
    Upper respiratory tract infection
         subjects affected / exposed
    4 / 47 (8.51%)
    5 / 51 (9.80%)
         occurrences all number
    6
    6
    Metabolism and nutrition disorders
    Hyponatraemia
         subjects affected / exposed
    2 / 47 (4.26%)
    0 / 51 (0.00%)
         occurrences all number
    2
    0

    More information

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    Substantial protocol amendments (globally)
    Were there any global substantial amendments to the protocol? No

    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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    The status and protocol content of GB trials is no longer updated since 1 January 2021. For the UK, as of 31 January 2021, EU Law applies only to the territory of Northern Ireland (NI) to the extent foreseen in the Protocol on Ireland/NI. Legal notice
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