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    Clinical Trial Results:
    An Uncontrolled, Open-Label Extension Study to Evaluate the Long-Term Safety, Tolerability, and Maintenance of Effect of BIIB074 (Vixotrigine) in Subjects With Neuropathic Pain From Lumbosacral Radiculopathy

    Summary
    EudraCT number
    		 2015-004796-68
    Trial protocol
    		 LV   GB   SK   AT   ES   CZ   BG   BE   NL   IT  
    Global end of trial date
    07 Feb 2019

    Results information
    Results version number
    		 v1(current)
    This version publication date
    19 Feb 2020
    First version publication date
    19 Feb 2020
    Other versions

    Trial information

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    Trial identification
    Sponsor protocol code
    1014802-204
    Additional study identifiers
    ISRCTN number
    		 -
    US NCT number
    		 NCT02957617
    WHO universal trial number (UTN)
    		 -
    Sponsors
    Sponsor organisation name
    Biogen
    Sponsor organisation address
    225 Binney Street, Cambridge, United States, 02142
    Public contact
    Biogen Study Medical Director, Biogen, +1 866-633-4636, clinicaltrials@biogen.com
    Scientific contact
    Biogen Study Medical Director, Biogen, +1 866-633-4636, clinicaltrials@biogen.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
    07 Feb 2019
    Is this the analysis of the primary completion data?
    No
    Global end of trial reached?
    Yes
    Global end of trial date
    07 Feb 2019
    Was the trial ended prematurely?
    Yes
    General information about the trial
    Main objective of the trial
    The primary objective of the study is to evaluate the long-term safety and tolerability of BIIB074 in subjects with neuropathic Pain From Lumbosacral Radiculopathy (PLSR). A secondary objective is to investigate the maintenance of effect during long-term treatment with BIIB074 in subjects with neuropathic PLSR. For all efficacy assessments, baseline will be prior to randomisation into Study 1014802-203. Another secondary objective is to evaluate the impact of treatment with BIIB074 on quality of life (QoL).
    Protection of trial subjects
    Written informed consent was obtained from each subject or subject’s legally authorized representative (e.g., parent or legal guardian), as applicable, prior to evaluations performed for eligibility. Subjects or the subject’s legally authorized representative were given adequate time to review the information in the informed consent/assent and were allowed to ask, and have answered, questions concerning all portions of the conduct of the study.
    Background therapy
    		 -
    Evidence for comparator
    		 -
    Actual start date of recruitment
    10 Feb 2017
    Long term follow-up planned
    No
    Independent data monitoring committee (IDMC) involvement?
    Yes
    Population of trial subjects
    Number of subjects enrolled per country
    Country: Number of subjects enrolled
    Bulgaria: 82
    Country: Number of subjects enrolled
    Czech Republic: 63
    Country: Number of subjects enrolled
    Serbia: 45
    Country: Number of subjects enrolled
    Georgia: 29
    Country: Number of subjects enrolled
    Slovakia: 29
    Country: Number of subjects enrolled
    Spain: 15
    Country: Number of subjects enrolled
    United Kingdom: 13
    Country: Number of subjects enrolled
    Romania: 10
    Country: Number of subjects enrolled
    Latvia: 7
    Country: Number of subjects enrolled
    Belgium: 5
    Country: Number of subjects enrolled
    France: 2
    Country: Number of subjects enrolled
    Estonia: 1
    Country: Number of subjects enrolled
    Italy: 1
    Worldwide total number of subjects
    302
    EEA total number of subjects
    228
    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)
    256
    From 65 to 84 years
    46
    85 years and over
    0

    Subject disposition

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    Recruitment
    Recruitment details
    		 Subjects were enrolled at 50 investigative sites in 13 countries in Eastern and Western Europe from 10 February 2017 to 07 February 2019.

    Pre-assignment
    Screening details
    		 Qualified subjects who participated in study 1014802-203 (203) were enrolled in this open-label extension study 1014802-204 (204). One subject who did not receive Study 203 randomised treatment was dosed in Study 204.

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

    Arms
    Are arms mutually exclusive
    Yes

    Arm title
    		 BIIB074 (203:Not Dosed Cohort)
    Arm description
    		 BIIB074 (vixotrigine) 350 mg orally twice daily (BID), which could be reduced to 200 mg based on tolerability for up to 12 months in Study 204. (Cohort includes subjects who were not dosed in Study 203.)
    Arm type
    		 Experimental

    Investigational medicinal product name
    BIIB074
    Investigational medicinal product code
    Other name
    CNV1014802, GSK1014802, vixotrigine
    Pharmaceutical forms
    Film-coated tablet
    Routes of administration
    Oral use
    Dosage and administration details
    BIIB074 tablets, orally, twice daily (BID) for up to 12 months.

    Arm title
    		 BIIB074 (203:Placebo Cohort)
    Arm description
    		 BIIB074 (vixotrigine) 350 mg orally BID, which could be reduced to 200 mg based on tolerability for up to 12 months in Study 204. (Cohort includes subjects who received Placebo for up to 12 weeks in Study 203.)
    Arm type
    		 Experimental

    Investigational medicinal product name
    BIIB074
    Investigational medicinal product code
    Other name
    CNV1014802, GSK1014802, vixotrigine
    Pharmaceutical forms
    Film-coated tablet
    Routes of administration
    Oral use
    Dosage and administration details
    BIIB074 tablets, orally, BID for up to 12 months.

    Arm title
    		 BIIB074 (203:BIIB074 200 mg Cohort)
    Arm description
    		 BIIB074 (vixotrigine) 350 mg orally BID, which could be reduced to 200 mg based on tolerability for up to 12 months in Study 204. (Cohort includes subjects who received BIIB074 200 mg for up to 12 weeks in Study 203.)
    Arm type
    		 Experimental

    Investigational medicinal product name
    BIIB074
    Investigational medicinal product code
    Other name
    CNV1014802, GSK1014802, vixotrigine
    Pharmaceutical forms
    Film-coated tablet
    Routes of administration
    Oral use
    Dosage and administration details
    BIIB074 tablets, orally ,BID for up to 12 months.

    Arm title
    		 BIIB074 (203:BIIB074 350 mg Cohort)
    Arm description
    		 BIIB074 (vixotrigine) 350 mg orally BID, which could be reduced to 200 mg based on tolerability for up to 12 months in Study 204. (Cohort includes subjects who received BIIB074 350 mg for up to 12 weeks in Study 203.)
    Arm type
    		 Experimental

    Investigational medicinal product name
    BIIB074
    Investigational medicinal product code
    Other name
    CNV1014802, GSK1014802, vixotrigine
    Pharmaceutical forms
    Film-coated tablet
    Routes of administration
    Oral use
    Dosage and administration details
    BIIB074 tablets, orally, BID for up to 12 months.

    Number of subjects in period 1
    		BIIB074 (203:Not Dosed Cohort) BIIB074 (203:Placebo Cohort) BIIB074 (203:BIIB074 200 mg Cohort) BIIB074 (203:BIIB074 350 mg Cohort)
    Started
    1
    104
    98
    99
    Completed
    0
    46
    43
    44
    Not completed
    1
    58
    55
    55
         Consent withdrawn by subject
    1
    7
    7
    5
         Adverse event
    -
    5
    8
    2
         Investigator decision
    -
    -
    1
    -
         other
    -
    38
    34
    34
         Lost to follow-up
    -
    -
    1
    -
         Lack of efficacy
    -
    8
    4
    14

    Baseline characteristics

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    Baseline characteristics reporting groups
    Reporting group title
    BIIB074 (203:Not Dosed Cohort)
    Reporting group description
    		 BIIB074 (vixotrigine) 350 mg orally twice daily (BID), which could be reduced to 200 mg based on tolerability for up to 12 months in Study 204. (Cohort includes subjects who were not dosed in Study 203.)

    Reporting group title
    BIIB074 (203:Placebo Cohort)
    Reporting group description
    		 BIIB074 (vixotrigine) 350 mg orally BID, which could be reduced to 200 mg based on tolerability for up to 12 months in Study 204. (Cohort includes subjects who received Placebo for up to 12 weeks in Study 203.)

    Reporting group title
    BIIB074 (203:BIIB074 200 mg Cohort)
    Reporting group description
    		 BIIB074 (vixotrigine) 350 mg orally BID, which could be reduced to 200 mg based on tolerability for up to 12 months in Study 204. (Cohort includes subjects who received BIIB074 200 mg for up to 12 weeks in Study 203.)

    Reporting group title
    BIIB074 (203:BIIB074 350 mg Cohort)
    Reporting group description
    		 BIIB074 (vixotrigine) 350 mg orally BID, which could be reduced to 200 mg based on tolerability for up to 12 months in Study 204. (Cohort includes subjects who received BIIB074 350 mg for up to 12 weeks in Study 203.)

    Reporting group values
    		 BIIB074 (203:Not Dosed Cohort) BIIB074 (203:Placebo Cohort) BIIB074 (203:BIIB074 200 mg Cohort) BIIB074 (203:BIIB074 350 mg Cohort) Total
    Number of subjects
    		 1 104 98 99 302
    Age Categorical
    Units: Subjects
        18 to 35 years
    		 0 5 5 3 13
        36 to 50 years
    		 1 39 28 37 105
        51 to 70 years
    		 0 54 65 56 175
        >70 years
    		 0 6 0 3 9
    Age Continuous
    99999 indicates that standard deviation is not calculated for 1 subject.
    Units: years
        arithmetic mean (standard deviation)
    		 36 ( 99999 ) 53.1 ( 11.00 ) 53.3 ( 9.81 ) 53.3 ( 9.16 ) -
    Gender Categorical
    Units: Subjects
        Female
    		 0 66 70 62 198
        Male
    		 1 38 28 37 104

    End points

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    End points reporting groups
    Reporting group title
    BIIB074 (203:Not Dosed Cohort)
    Reporting group description
    		 BIIB074 (vixotrigine) 350 mg orally twice daily (BID), which could be reduced to 200 mg based on tolerability for up to 12 months in Study 204. (Cohort includes subjects who were not dosed in Study 203.)

    Reporting group title
    BIIB074 (203:Placebo Cohort)
    Reporting group description
    		 BIIB074 (vixotrigine) 350 mg orally BID, which could be reduced to 200 mg based on tolerability for up to 12 months in Study 204. (Cohort includes subjects who received Placebo for up to 12 weeks in Study 203.)

    Reporting group title
    BIIB074 (203:BIIB074 200 mg Cohort)
    Reporting group description
    		 BIIB074 (vixotrigine) 350 mg orally BID, which could be reduced to 200 mg based on tolerability for up to 12 months in Study 204. (Cohort includes subjects who received BIIB074 200 mg for up to 12 weeks in Study 203.)

    Reporting group title
    BIIB074 (203:BIIB074 350 mg Cohort)
    Reporting group description
    		 BIIB074 (vixotrigine) 350 mg orally BID, which could be reduced to 200 mg based on tolerability for up to 12 months in Study 204. (Cohort includes subjects who received BIIB074 350 mg for up to 12 weeks in Study 203.)

    Primary: Number of Subjects Experiencing Adverse Events (AEs) and Serious Adverse Events (SAEs)

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    End point title
    		 Number of Subjects Experiencing Adverse Events (AEs) and Serious Adverse Events (SAEs) [1]
    End point description
    An AE is defined as any untoward medical occurrence in a clinical investigation subject administered a pharmaceutical product; it does not necessarily have to have a causal relationship with this treatment. An AE could therefore, be any unfavourable and unintended sign (including an abnormal laboratory finding), symptom, or disease temporally associated with the use of a medicinal (investigational) product. A SAE is any untoward medical occurrence or effect that at any dose results in death, is life-threatening, requires inpatient hospitalization or prolongation of existing hospitalization, results in persistent or significant disability / incapacity, is a congenital anomaly / birth defect or is medically important due to other reasons than the above mentioned criteria. Safety Population included all subjects who received at least 1 dose of study treatment in this open-label extension study.
    End point type
    Primary
    End point timeframe
    Up to 398 Days in Study 204
    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: Not all arms in the Baseline Period are applicable for this endpoint.
    End point values
    		 BIIB074 (203:Not Dosed Cohort) BIIB074 (203:Placebo Cohort) BIIB074 (203:BIIB074 200 mg Cohort) BIIB074 (203:BIIB074 350 mg Cohort)
    Number of subjects analysed
    1
    104
    98
    99
    Units: subjects
    number (not applicable)
        AEs
    0
    48
    45
    41
        SAEs
    0
    4
    1
    4
    No statistical analyses for this end point

    Secondary: Change from Baseline to Week 52 in the Weekly Average of the Daily Neuropathic Pain Score on the Pain Intensity Numerical Rating Scale (PI-NRS)

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    End point title
    		 Change from Baseline to Week 52 in the Weekly Average of the Daily Neuropathic Pain Score on the Pain Intensity Numerical Rating Scale (PI-NRS) [2]
    End point description
    Subjects were asked every evening to rate their overall neuropathic pain in the worse affected leg (identified on Day 1 of Study 203) for the last 24-hour period. PI-NRS is an 11-point pain intensity numerical rating scale (PI-NRS), where 0=no pain and 10=pain as bad as you can imagine. A negative change from Baseline indicates improvement. The efficacy population included all subjects who received at least 1 dose of study treatment in this extension Study 204, and who were randomised and received at least 1 dose of study treatment in the double-blind period in Study 203. Number of subjects analysed is the number of subjects with evaluable data at the given timepoint.
    End point type
    Secondary
    End point timeframe
    Baseline (1-week prior to randomisation in Study 203) to Week 52 in Study 204
    Notes
    [2] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
    Justification: Not all arms in the Baseline Period are applicable for this endpoint.
    End point values
    		 BIIB074 (203:Placebo Cohort) BIIB074 (203:BIIB074 200 mg Cohort) BIIB074 (203:BIIB074 350 mg Cohort)
    Number of subjects analysed
    50
    48
    47
    Units: score on a scale
        arithmetic mean (standard deviation)
    -3.50 ( 2.644 )
    -3.31 ( 2.292 )
    -3.28 ( 2.404 )
    No statistical analyses for this end point

    Secondary: Number of Subjects with 50% Neuropathic Pain Reduction Response

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    End point title
    		 Number of Subjects with 50% Neuropathic Pain Reduction Response [3]
    End point description
    Response is defined as a ≥50% reduction in the weekly average of the daily neuropathic pain score from Baseline to Week 52. The efficacy population included all subjects who received at least 1 dose of study treatment in this extension Study 204, and who were randomised and received at least 1 dose of study treatment in the double-blind period in Study 203. Number of subjects analysed is the number of subjects with evaluable data at the given timepoint.
    End point type
    Secondary
    End point timeframe
    Baseline (1-week prior to randomisation in 203) to Week 52 in Study 204
    Notes
    [3] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
    Justification: Not all arms in the Baseline Period are applicable for this endpoint.
    End point values
    		 BIIB074 (203:Placebo Cohort) BIIB074 (203:BIIB074 200 mg Cohort) BIIB074 (203:BIIB074 350 mg Cohort)
    Number of subjects analysed
    69
    64
    65
    Units: subjects
        number (not applicable)
    34
    28
    25
    No statistical analyses for this end point

    Secondary: Number of Subjects with 30% Neuropathic Pain Reduction Response

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    End point title
    		 Number of Subjects with 30% Neuropathic Pain Reduction Response [4]
    End point description
    Response is defined as a ≥30% reduction in the weekly average of the daily neuropathic pain score from Baseline to Week 52. The efficacy population included all subjects who received at least 1 dose of study treatment in this extension Study 204, and who were randomised and received at least 1 dose of study treatment in the double-blind period in Study 203. Number of subjects analysed is the number of subjects with evaluable data at the given timepoint.
    End point type
    Secondary
    End point timeframe
    Baseline (1-week prior to randomisation in 203) to Week 52 in Study 204
    Notes
    [4] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
    Justification: Not all arms in the Baseline Period are applicable for this endpoint.
    End point values
    		 BIIB074 (203:Placebo Cohort) BIIB074 (203:BIIB074 200 mg Cohort) BIIB074 (203:BIIB074 350 mg Cohort)
    Number of subjects analysed
    69
    64
    65
    Units: subjects
        number (not applicable)
    36
    34
    32
    No statistical analyses for this end point

    Secondary: Change from Baseline at Each Visit in the Weekly Average of the Daily Neuropathic Pain Score

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    End point title
    		 Change from Baseline at Each Visit in the Weekly Average of the Daily Neuropathic Pain Score [5]
    End point description
    Subjects were asked every evening to rate their overall neuropathic pain for the last 24-hour period using the 11-point PI-NRS, where 0=no pain and 10=pain as bad as you can imagine A negative change from Baseline indicates improvement. The efficacy population included all subjects who received at least 1 dose of study treatment in this extension Study 204, and who were randomised and received at least 1 dose of study treatment in the double-blind period in Study 203. Number of subjects analysed is the number of subjects with evaluable data at the given timepoint.
    End point type
    Secondary
    End point timeframe
    Baseline (1-week period prior to randomisation in 203) through Weeks 2, 4, 13, 26, 39 of Study 204
    Notes
    [5] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
    Justification: Not all arms in the Baseline Period are applicable for this endpoint.
    End point values
    		 BIIB074 (203:Placebo Cohort) BIIB074 (203:BIIB074 200 mg Cohort) BIIB074 (203:BIIB074 350 mg Cohort)
    Number of subjects analysed
    104
    98
    99
    Units: score on a scale
    arithmetic mean (standard deviation)
        Week 2 (n=99,96,95)
    -2.03 ( 2.085 )
    -1.79 ( 1.841 )
    -2.07 ( 2.003 )
        Week 4 (n=98,94,94)
    -2.40 ( 2.077 )
    -2.06 ( 1.846 )
    -2.26 ( 1.978 )
        Week 13 (n=94,88,84)
    -2.80 ( 2.127 )
    -2.46 ( 1.973 )
    -2.69 ( 1.881 )
        Week 26 (n=89,87,80)
    -3.13 ( 2.139 )
    -2.82 ( 2.113 )
    -3.09 ( 2.115 )
        Week 39 (n=64,58,61)
    -3.05 ( 2.437 )
    -3.21 ( 1.967 )
    -3.19 ( 2.202 )
    No statistical analyses for this end point

    Secondary: Change from Baseline to Week 52 in the Weekly Average of the Daily Pain Score for Low Back Pain

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    End point title
    		 Change from Baseline to Week 52 in the Weekly Average of the Daily Pain Score for Low Back Pain [6]
    End point description
    Subjects were asked every evening to rate their overall low back pain for the last 24-hour period using the 11-point PI-NRS, where 0=no pain and 10= pain as bad as you can imagine. A negative change from Baseline indicates improvement. The efficacy population included all subjects who received at least 1 dose of study treatment in this extension Study 204, and who were randomised and received at least 1 dose of study treatment in the double-blind period in Study 203. Number of subjects analysed is the number of subjects with evaluable data at the given timepoint.
    End point type
    Secondary
    End point timeframe
    Baseline (1-week prior to randomisation in Study 203) to Week 52 of Study 204
    Notes
    [6] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
    Justification: Not all arms in the Baseline Period are applicable for this endpoint.
    End point values
    		 BIIB074 (203:Placebo Cohort) BIIB074 (203:BIIB074 200 mg Cohort) BIIB074 (203:BIIB074 350 mg Cohort)
    Number of subjects analysed
    50
    48
    47
    Units: score on a scale
        arithmetic mean (standard deviation)
    -1.93 ( 2.308 )
    -2.12 ( 2.027 )
    -1.88 ( 2.350 )
    No statistical analyses for this end point

    Secondary: Number of Patient Global Impression of Change (PGIC) Responders

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    End point title
    		 Number of Patient Global Impression of Change (PGIC) Responders [7]
    End point description
    PGIC is a 7-point self-report scale depicting a subject's rating of overall improvement. Subjects rated their change as "very much improved," "much improved," "minimally improved," "no change," "minimally worse," "much worse," or "very much worse." A responder is defined as a subject with a response of “very much improved” or “much improved”. The efficacy population included all subjects who received at least 1 dose of study treatment in this extension Study 204, and who were randomised and received at least 1 dose of study treatment in the double-blind period in Study 203. Number of subjects analysed is the number of subjects with evaluable data at the given timepoint.
    End point type
    Secondary
    End point timeframe
    Baseline (Day 1 of Study 203) to Week 52 of Study 204
    Notes
    [7] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
    Justification: Not all arms in the Baseline Period are applicable for this endpoint.
    End point values
    		 BIIB074 (203:Placebo Cohort) BIIB074 (203:BIIB074 200 mg Cohort) BIIB074 (203:BIIB074 350 mg Cohort)
    Number of subjects analysed
    69
    64
    65
    Units: subjects
        number (not applicable)
    34
    27
    31
    No statistical analyses for this end point

    Secondary: Change from Baseline to Week 52 on the Oswestry Disability Index (ODI)

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    End point title
    		 Change from Baseline to Week 52 on the Oswestry Disability Index (ODI) [8]
    End point description
    The ODI is a 10-item questionnaire that evaluates how back (or leg) pain affects the ability to manage in everyday life: Pain intensity, Personal care, Lifting, Walking, Sitting, Standing, Sleeping, Sex life, Social life and Traveling. Each question is rated on a 6-point scale: 0(best) to 5(worst); with higher scores indicating higher level of pain for a total possible score of 0 to 50.
    End point type
    Secondary
    End point timeframe
    Baseline to Week 52
    Notes
    [8] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
    Justification: Not all arms in the Baseline Period are applicable for this endpoint.
    End point values
    		 BIIB074 (203:Placebo Cohort) BIIB074 (203:BIIB074 200 mg Cohort) BIIB074 (203:BIIB074 350 mg Cohort)
    Number of subjects analysed
    0 [9]
    0 [10]
    0 [11]
    Units: units on a scale
        arithmetic mean (standard deviation)
    ( )
    ( )
    ( )
    Notes
    [9] - Study was terminated; only Key Secondary endpoints were analysed.
    [10] - Study was terminated; only Key Secondary endpoints were analysed.
    [11] - Study was terminated; only Key Secondary endpoints were analysed.
    No statistical analyses for this end point

    Secondary: Change from Baseline to Week 52 in the Weekly Average of the Daily Sleep Score as Assessed by the Sleep Numerical Rating Scale (S-NRS)

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    End point title
    		 Change from Baseline to Week 52 in the Weekly Average of the Daily Sleep Score as Assessed by the Sleep Numerical Rating Scale (S-NRS) [12]
    End point description
    Subjects were asked every morning to rate on the 11-point S-NRS how leg pain interfered with their sleep quality where 0=did not interfere with sleep and 10=pain completely interfered with sleep.
    End point type
    Secondary
    End point timeframe
    Baseline to Week 52
    Notes
    [12] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
    Justification: Not all arms in the Baseline Period are applicable for this endpoint.
    End point values
    		 BIIB074 (203:Placebo Cohort) BIIB074 (203:BIIB074 200 mg Cohort) BIIB074 (203:BIIB074 350 mg Cohort)
    Number of subjects analysed
    0 [13]
    0 [14]
    0 [15]
    Units: score on a scale
        arithmetic mean (standard deviation)
    ( )
    ( )
    ( )
    Notes
    [13] - Study was terminated; only Key Secondary endpoints were analysed.
    [14] - Study was terminated; only Key Secondary endpoints were analysed.
    [15] - Study was terminated; only Key Secondary endpoints were analysed.
    No statistical analyses for this end point

    Secondary: Change from Baseline to Week 52 in the Brief Pain Inventory (BPI)-Interference Index

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    End point title
    		 Change from Baseline to Week 52 in the Brief Pain Inventory (BPI)-Interference Index [16]
    End point description
    BPI Interference Index is an 11-point numeric rating scale (0 - no interference to 10 - interferes completely) to assess pain-related interference in 7 areas: general activity, mood, walking ability, normal work, including outside the home and housework, relations with other people, enjoyment of life and sleep.
    End point type
    Secondary
    End point timeframe
    Baseline to Week 52
    Notes
    [16] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
    Justification: Not all arms in the Baseline Period are applicable for this endpoint.
    End point values
    		 BIIB074 (203:Placebo Cohort) BIIB074 (203:BIIB074 200 mg Cohort) BIIB074 (203:BIIB074 350 mg Cohort)
    Number of subjects analysed
    0 [17]
    0 [18]
    0 [19]
    Units: score on a scale
        arithmetic mean (standard deviation)
    ( )
    ( )
    ( )
    Notes
    [17] - Study was terminated; only Key Secondary endpoints were analysed.
    [18] - Study was terminated; only Key Secondary endpoints were analysed.
    [19] - Study was terminated; only Key Secondary endpoints were analysed.
    No statistical analyses for this end point

    Secondary: Change from Baseline to Week 52 in the BPI - Pain Index

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    End point title
    		 Change from Baseline to Week 52 in the BPI - Pain Index [20]
    End point description
    BPI- Pain Index for pain intensity, is used to assess potential pain quality descriptors that may describe subjects' pain on a scale of 0 (no pain) to 10 (pain as bad as you can imagine).
    End point type
    Secondary
    End point timeframe
    Baseline to Week 52
    Notes
    [20] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
    Justification: Not all arms in the Baseline Period are applicable for this endpoint.
    End point values
    		 BIIB074 (203:Placebo Cohort) BIIB074 (203:BIIB074 200 mg Cohort) BIIB074 (203:BIIB074 350 mg Cohort)
    Number of subjects analysed
    0 [21]
    0 [22]
    0 [23]
    Units: score on a scale
        arithmetic mean (standard deviation)
    ( )
    ( )
    ( )
    Notes
    [21] - Study was terminated; only Key Secondary endpoints were analysed.
    [22] - Study was terminated; only Key Secondary endpoints were analysed.
    [23] - Study was terminated; only Key Secondary endpoints were analysed.
    No statistical analyses for this end point

    Secondary: Change from Baseline to Week 52 on the EuroQoL 5-Dimension 5-Level Questionnaire (EQ-5D-5L) Health Index

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    End point title
    		 Change from Baseline to Week 52 on the EuroQoL 5-Dimension 5-Level Questionnaire (EQ-5D-5L) Health Index [24]
    End point description
    The EQ-5D-5L is a standardized instrument for use as a measure of health outcome. It is a health questionnaire that consists of the EQ-5D descriptive system and the EQ visual analogue scale (EQ VAS). The EQ-5D-5L descriptive system comprises the following 5 dimensions: mobility, self-care, usual activities, pain/discomfort and anxiety/depression. Each dimension has 5 levels (possible responses): no problems, slight problems, moderate problems, severe problems and extreme problems.
    End point type
    Secondary
    End point timeframe
    Baseline to Week 52
    Notes
    [24] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
    Justification: Not all arms in the Baseline Period are applicable for this endpoint.
    End point values
    		 BIIB074 (203:Placebo Cohort) BIIB074 (203:BIIB074 200 mg Cohort) BIIB074 (203:BIIB074 350 mg Cohort)
    Number of subjects analysed
    0 [25]
    0 [26]
    0 [27]
    Units: score on a scale
        arithmetic mean (standard deviation)
    ( )
    ( )
    ( )
    Notes
    [25] - Study was terminated; only Key Secondary endpoints were analysed.
    [26] - Study was terminated; only Key Secondary endpoints were analysed.
    [27] - Study was terminated; only Key Secondary endpoints were analysed.
    No statistical analyses for this end point

    Secondary: Change from Baseline to Week 52 in Short Form 36 Questionnaire (SF-36)

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    End point title
    		 Change from Baseline to Week 52 in Short Form 36 Questionnaire (SF-36) [28]
    End point description
    SF-36 is a self-administered, generic health status questionnaire consisting of 36 questions that measure 8 health concepts: physical functioning, role limitations due to physical problems, bodily pain, general health perception, vitality, social functioning, role limitations due to emotional problems and mental health. Each of the 8 health concepts has a total possible score of 0-100.
    End point type
    Secondary
    End point timeframe
    Baseline to Week 52
    Notes
    [28] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
    Justification: Not all arms in the Baseline Period are applicable for this endpoint.
    End point values
    		 BIIB074 (203:Placebo Cohort) BIIB074 (203:BIIB074 200 mg Cohort) BIIB074 (203:BIIB074 350 mg Cohort)
    Number of subjects analysed
    0 [29]
    0 [30]
    0 [31]
    Units: units on a scale
        arithmetic mean (standard deviation)
    ( )
    ( )
    ( )
    Notes
    [29] - Study was terminated; only Key Secondary endpoints were analysed
    [30] - Study was terminated; only Key Secondary endpoints were analysed
    [31] - Study was terminated; only Key Secondary endpoints were analysed
    No statistical analyses for this end point

    Adverse events

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    Adverse events information
    Timeframe for reporting adverse events
    Up to 398 Days in Study 204
    Adverse event reporting additional description
    Safety Population included all subjects who received at least 1 dose of study treatment in this open-label extension study.
    Assessment type
    		 Systematic
    Dictionary used for adverse event reporting
    Dictionary name
    		 MedDRA
    Dictionary version
    21.1
    Reporting groups
    Reporting group title
    BIIB074 (203:Not Dosed Cohort)
    Reporting group description
    		 BIIB074 (vixotrigine) 350 mg orally twice daily (BID), which could be reduced to 200 mg based on tolerability for up to 12 months in Study 204. (Cohort includes subjects who were not dosed in Study 203.)

    Reporting group title
    BIIB074 (203:Placebo Cohort)
    Reporting group description
    		 BIIB074 (vixotrigine) 350 mg orally BID, which could be reduced to 200 mg based on tolerability for up to 12 months in Study 204. (Cohort includes subjects who received Placebo for up to 12 weeks in Study 203.)

    Reporting group title
    BIIB074 (203:BIIB074 200 mg Cohort)
    Reporting group description
    		 BIIB074 (vixotrigine) 350 mg orally BID, which could be reduced to 200 mg based on tolerability for up to 12 months in Study 204. (Cohort includes subjects who received BIIB074 200 mg for up to 12 weeks in Study 203.)

    Reporting group title
    BIIB074 (203:BIIB074 350 mg Cohort)
    Reporting group description
    		 BIIB074 (vixotrigine) 350 mg orally BID, which could be reduced to 200 mg based on tolerability for up to 12 months in Study 204. (Cohort incudes subjects who received BIIB074 350 mg for up to 12 weeks in Study 203.)

    Serious adverse events
    		 BIIB074 (203:Not Dosed Cohort) BIIB074 (203:Placebo Cohort) BIIB074 (203:BIIB074 200 mg Cohort) BIIB074 (203:BIIB074 350 mg Cohort)
    Total subjects affected by serious adverse events
         subjects affected / exposed
    0 / 1 (0.00%)
    4 / 104 (3.85%)
    1 / 98 (1.02%)
    4 / 99 (4.04%)
         number of deaths (all causes)
    0
    0
    0
    0
         number of deaths resulting from adverse events
    0
    0
    0
    0
    Neoplasms benign, malignant and unspecified (incl cysts and polyps)
    Myelodysplastic syndrome
         subjects affected / exposed
    0 / 1 (0.00%)
    1 / 104 (0.96%)
    0 / 98 (0.00%)
    0 / 99 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Prostate cancer recurrent
         subjects affected / exposed
    0 / 1 (0.00%)
    0 / 104 (0.00%)
    1 / 98 (1.02%)
    0 / 99 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Nervous system disorders
    Haemorrhagic stroke
         subjects affected / exposed
    0 / 1 (0.00%)
    0 / 104 (0.00%)
    0 / 98 (0.00%)
    1 / 99 (1.01%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Lumbosacral radiculopathy
         subjects affected / exposed
    0 / 1 (0.00%)
    0 / 104 (0.00%)
    0 / 98 (0.00%)
    1 / 99 (1.01%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Immune system disorders
    Drug hypersensitivity
         subjects affected / exposed
    0 / 1 (0.00%)
    1 / 104 (0.96%)
    0 / 98 (0.00%)
    0 / 99 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Gastrointestinal disorders
    Inguinal hernia
         subjects affected / exposed
    0 / 1 (0.00%)
    1 / 104 (0.96%)
    0 / 98 (0.00%)
    0 / 99 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 2
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Musculoskeletal and connective tissue disorders
    Intervertebral disc protrusion
         subjects affected / exposed
    0 / 1 (0.00%)
    1 / 104 (0.96%)
    0 / 98 (0.00%)
    0 / 99 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Spinal osteoarthritis
         subjects affected / exposed
    0 / 1 (0.00%)
    0 / 104 (0.00%)
    0 / 98 (0.00%)
    1 / 99 (1.01%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Infections and infestations
    Sepsis
         subjects affected / exposed
    0 / 1 (0.00%)
    0 / 104 (0.00%)
    0 / 98 (0.00%)
    1 / 99 (1.01%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Frequency threshold for reporting non-serious adverse events: 5%
    Non-serious adverse events
    		 BIIB074 (203:Not Dosed Cohort) BIIB074 (203:Placebo Cohort) BIIB074 (203:BIIB074 200 mg Cohort) BIIB074 (203:BIIB074 350 mg Cohort)
    Total subjects affected by non serious adverse events
         subjects affected / exposed
    0 / 1 (0.00%)
    17 / 104 (16.35%)
    18 / 98 (18.37%)
    14 / 99 (14.14%)
    Nervous system disorders
    Dizziness
         subjects affected / exposed
    0 / 1 (0.00%)
    7 / 104 (6.73%)
    5 / 98 (5.10%)
    4 / 99 (4.04%)
         occurrences all number
    0
    8
    5
    8
    Headache
         subjects affected / exposed
    0 / 1 (0.00%)
    8 / 104 (7.69%)
    5 / 98 (5.10%)
    4 / 99 (4.04%)
         occurrences all number
    0
    11
    6
    4
    Gastrointestinal disorders
    Diarrhoea
         subjects affected / exposed
    0 / 1 (0.00%)
    2 / 104 (1.92%)
    5 / 98 (5.10%)
    2 / 99 (2.02%)
         occurrences all number
    0
    2
    6
    2
    Nausea
         subjects affected / exposed
    0 / 1 (0.00%)
    6 / 104 (5.77%)
    4 / 98 (4.08%)
    7 / 99 (7.07%)
         occurrences all number
    0
    7
    4
    11
    Musculoskeletal and connective tissue disorders
    Arthralgia
         subjects affected / exposed
    0 / 1 (0.00%)
    3 / 104 (2.88%)
    1 / 98 (1.02%)
    5 / 99 (5.05%)
         occurrences all number
    0
    6
    1
    7

    More information

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    Substantial protocol amendments (globally)
    Were there any global substantial amendments to the protocol? Yes
    Date
    Amendment
    05 Apr 2016
    Amendment 1 Version 2: • Clarification was added to clinic procedures and laboratory tests for safety assessments, eligibility criteria, prohibited medications, adverse event reporting, and treatment compliance, and to the timing of interim sample size re-estimation. • Information on serotonin syndrome was added, as requested by the FDA.
    14 Jul 2016
    Amendment 2 Version 3: •The maximum dose of paracetamol/acetaminophen in prolonged therapy was reduced to 2.5 g/day, and a restriction to the duration of prolonged therapy was added along with a related discontinuation criterion. •The number of contraceptives to be used for highly effective contraception was reduced from 2 to 1 (thereafter stated as “effective contraception”). •Additional follow-up phone call was added to assess safety (SAEs) and C-SSRS. •Updates to liver chemistry stopping criteria were made. •Information on the symptoms of serotenergic syndrome was included. •Guidance text related to inclusion criteria associated with QTc and C-SSRS was added. •Ethinyl estradiol as a prohibited medication was added. •Clarification around eligibility of male subjects whose partners are pregnant and the need for males to withdraw if their partner becomes pregnant during the study was added. •Changes to the withdrawal criteria and inclusion and exclusion criteria were made to consolidate the protocol across different countries.
    05 May 2017
    Amendment 3 Version 4: This amendment superseded Version 3 and was implemented to update the nonclinical experience. Specifically, further detail around metabolites and the in vivo safety pharmacology study findings were added to reflect updated data from toxicology studies as well as updated exposure and exposure margin calculations, which are based on current industry-accepted practices. Other major changes involved: •Adding assessments for unscheduled visits. •Updated text related to the dose regimen rationale to describe the probability of human exposure exceeding the exposure at which seizure was observed in 1 dog following administration of a 35 mg/kg BID dose. •Clarified text related disallowed concomitant therapy.
    24 May 2017
    Amendment 4 Version 5: This amendment superseded Version 4 and was implemented primarily to clarify that pregnancy of a female partner should not impact the study status of a male subject during his participation in the study.
    17 Oct 2017
    Amendment 5 Version 6: This amendment was not implemented. The primary reason for the amendment was to extend the duration of the study to 24 months from 12 months in order to collect more longitudinal data.
    07 Jun 2018
    Amendment 6 Version 7: This amendment superseded Version 5 and was implemented primarily to permit the concomitant use of inhibitors or inducers of cytochrome 3A4 (CYP3A4). Other major changes involved: •Adjustments to the order of safety assessments. •Updates to the nonclinical information related to toxicology. •Updates to the clinical information related to exposure, PK and safety data, including new SAEs. •Addition of a benefit/risk statement. •Removal of vital signs, ECG parameters, laboratory safety tests, and C-SSRS from the primary endpoint. •Changes to procedure or follow-up when a subject discontinues study treatment due to a rash. •Addition of text to describe how abuse potential will be assessed during the study.

    Interruptions (globally)
    Were there any global interruptions to the trial? Yes
    Date
    Interruption
    Restart date
    09 Jan 2019
    The study was terminated. The parent study did not meet its primary or secondary efficacy endpoints; therefore, Sponsor decision to discontinue development in this indication. 09 January 2019 was selected as the last possible dosing date.
    -

    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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