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    Clinical Trial Results:
    A Randomized, Double-Blind, Placebo-Controlled, Parallel-Group Study to Evaluate the Efficacy and Safety of Intravenously Administered BIIB092 in Participants with Progressive Supranuclear Palsy

    Summary
    EudraCT number
    2016-002554-21
    Trial protocol
    GB   DE   AT   ES   GR   FR   IT  
    Global end of trial date
    07 Feb 2020

    Results information
    Results version number
    v2(current)
    This version publication date
    31 Mar 2021
    First version publication date
    24 Sep 2020
    Other versions
    v1
    Version creation reason

    Trial information

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    Trial identification
    Sponsor protocol code
    251PP301
    Additional study identifiers
    ISRCTN number
    -
    US NCT number
    NCT03068468
    WHO universal trial number (UTN)
    -
    Other trial identifiers
    Bristol-Myers Squibb: CN002-012
    Sponsors
    Sponsor organisation name
    Biogen
    Sponsor organisation address
    250 Binney Street, Cambridge, United States, 02142
    Public contact
    Biogen Study Medical Director, Biogen, clinicaltrials@biogen.com
    Scientific contact
    Biogen Study Medical Director, Biogen, 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 2020
    Is this the analysis of the primary completion data?
    No
    Global end of trial reached?
    Yes
    Global end of trial date
    07 Feb 2020
    Was the trial ended prematurely?
    Yes
    General information about the trial
    Main objective of the trial
    To evaluate the efficacy of BIIB092, compared to placebo, as measured by a change from baseline in the PSP Rating Scale (PSPRS) at Week 52 and to assess the safety and tolerability of BIIB092, relative to placebo, by measuring the frequency of deaths, SAEs, and AEs leading to discontinuation, and Grade 3 & 4 laboratory abnormalities.
    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
    01 Jun 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
    United States: 129
    Country: Number of subjects enrolled
    Germany: 81
    Country: Number of subjects enrolled
    Spain: 65
    Country: Number of subjects enrolled
    France: 64
    Country: Number of subjects enrolled
    Japan: 39
    Country: Number of subjects enrolled
    United Kingdom: 26
    Country: Number of subjects enrolled
    Italy: 25
    Country: Number of subjects enrolled
    Canada: 16
    Country: Number of subjects enrolled
    Russian Federation: 16
    Country: Number of subjects enrolled
    Austria: 13
    Country: Number of subjects enrolled
    Korea, Republic of: 8
    Country: Number of subjects enrolled
    Greece: 7
    Country: Number of subjects enrolled
    Australia: 1
    Worldwide total number of subjects
    490
    EEA total number of subjects
    255
    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)
    119
    From 65 to 84 years
    371
    85 years and over
    0

    Subject disposition

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    Recruitment
    Recruitment details
    Subjects were enrolled at 89 investigative sites in the United States, Australia, Austria, Canada, France, Germany, Greece, Italy, Japan, Republic of Korea, Russia Federation, Spain and United Kingdom from June 01, 2017 to February 07, 2020.

    Pre-assignment
    Screening details
    A total of 490 subjects with Progressive Supranuclear Palsy disease were enrolled and randomised in the study. Of these, 486 subjects received the study drug in PC period. After completing PC period, 416 subjects entered and dosed in OLE period and no subjects completed the study due to early termination of the study.

    Period 1
    Period 1 title
    Placebo-Controlled (PC) Period
    Is this the baseline period?
    Yes
    Allocation method
    Randomised - controlled
    Blinding used
    Double blind
    Roles blinded
    Subject, Investigator, Carer, Assessor

    Arms
    Are arms mutually exclusive
    Yes

    Arm title
    Placebo (PC Period)
    Arm description
    Subjects assigned to BIIB092 matching placebo intravenous (IV) infusion once every 4 weeks for 48 weeks in double blind PC period and receive only placebo.
    Arm type
    Experimental

    Investigational medicinal product name
    Placebo
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Solution for infusion
    Routes of administration
    Intravenous use
    Dosage and administration details
    Subjects assigned to BIIB092 matching placebo IV infusion once every 4 weeks for 48 weeks.

    Arm title
    BIIB092 2000 mg (PC Period)
    Arm description
    Subjects who received at least one dose of BIIB092 2000 mg and were either assigned to BIIB092 2000 milligrams (mg) IV infusion or BIIB092 matching placebo IV infusion once every 4 weeks for 48 weeks in double blind PC period.
    Arm type
    Experimental

    Investigational medicinal product name
    BIIB092
    Investigational medicinal product code
    BIIB092
    Other name
    Pharmaceutical forms
    Solution for infusion
    Routes of administration
    Intravenous use
    Dosage and administration details
    Subjects who received at least one dose of BIIB092 2000 mg, once every 4 weeks for 48 weeks in double blind PC period.

    Investigational medicinal product name
    Placebo
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Solution for infusion
    Routes of administration
    Intravenous use
    Dosage and administration details
    Subjects who received BIIB092 matching placebo IV infusion once every 4 weeks for 48 weeks in double blind PC period.

    Number of subjects in period 1 [1]
    Placebo (PC Period) BIIB092 2000 mg (PC Period)
    Started
    165
    321
    Completed
    144
    279
    Not completed
    21
    42
         Death
    -
    1
         Lack of efficacy
    -
    1
         Withdrawal by Parent/Guardian
    1
    2
         Consent withdrawn by subject
    3
    11
         Adverse Event
    16
    21
         Reason not specified
    1
    6
    Notes
    [1] - The number of subjects reported to be in the baseline period are not the same as the worldwide number enrolled in the trial. It is expected that these numbers will be the same.
    Justification: The number of subjects who started the baseline period are the subjects who were treated in the study.
    Period 2
    Period 2 title
    Open-Label Extension (OLE) Period
    Is this the baseline period?
    No
    Allocation method
    Not applicable
    Blinding used
    Not blinded

    Arms
    Are arms mutually exclusive
    Yes

    Arm title
    BIIB092 Late Start (OLE Period)
    Arm description
    Late start subjects received only placebo in the placebo-controlled period and assigned to BIIB092 2000 mg IV infusion once every 4 weeks starting at Week 52 in the OLE period.
    Arm type
    Experimental

    Investigational medicinal product name
    BIIB092
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Solution for infusion
    Routes of administration
    Intravenous use
    Dosage and administration details
    Late start subjects received only placebo in the placebo-controlled period and assigned to BIIB092 2000 mg IV infusion once every 4 weeks starting at Week 52.

    Arm title
    BIIB092 Early Start (OLE Period)
    Arm description
    Early start subjects are those who received BIIB092 2000 mg in the placebo-controlled period and assigned to BIIB092 2000 mg IV infusion once every 4 weeks starting at Week 52 in the OLE period.
    Arm type
    Experimental

    Investigational medicinal product name
    BIIB092
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Solution for infusion
    Routes of administration
    Intravenous use
    Dosage and administration details
    Early start subjects are those who received BIIB092 2000 mg in the placebo-controlled period and assigned to BIIB092 2000 mg IV infusion once every 4 weeks starting at Week 52.

    Number of subjects in period 2 [2]
    BIIB092 Late Start (OLE Period) BIIB092 Early Start (OLE Period)
    Started
    140
    276
    Completed
    0
    0
    Not completed
    140
    276
         Death
    -
    1
         Failure to meet randomization criteria
    2
    -
         Lack of efficacy
    1
    2
         Withdrawal by Parent/Guardian
    -
    4
         Withdrawal by sponsor
    115
    228
         Consent withdrawn by subject
    7
    20
         Adverse Event
    13
    17
         Reason not specified
    1
    4
         Lost to follow-up
    1
    -
    Notes
    [2] - The number of subjects starting the period is not consistent with the number completing the preceding period. It is expected the number of subjects starting the subsequent period will be the same as the number completing the preceding period.
    Justification: The number of subjects starting the open-label extension period is not the same as the number of subjects who completed the placebo-controlled period because few of the subjects did not enter the open-label extension period.

    Baseline characteristics

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    Baseline characteristics reporting groups
    Reporting group title
    Placebo (PC Period)
    Reporting group description
    Subjects assigned to BIIB092 matching placebo intravenous (IV) infusion once every 4 weeks for 48 weeks in double blind PC period and receive only placebo.

    Reporting group title
    BIIB092 2000 mg (PC Period)
    Reporting group description
    Subjects who received at least one dose of BIIB092 2000 mg and were either assigned to BIIB092 2000 milligrams (mg) IV infusion or BIIB092 matching placebo IV infusion once every 4 weeks for 48 weeks in double blind PC period.

    Reporting group values
    Placebo (PC Period) BIIB092 2000 mg (PC Period) Total
    Number of subjects
    165 321
    Age categorical
    Units: Subjects
    Age Continuous
    Units: years
        arithmetic mean (standard deviation)
    68.9 ± 6.57 68.7 ± 7.02 -
    Sex: Female, Male
    Units: subjects
        Female
    74 136 210
        Male
    91 185 276
    Race
    Units: Subjects
        White
    138 281 419
        Black or African American
    1 1 2
        Asian Indian
    3 3 6
        Chinese
    0 1 1
        Japanese
    16 23 39
        Asian Other
    4 10 14
        Unknown
    3 2 5
    Ethnicity
    Units: Subjects
        Hispanic or Latino
    5 7 12
        Not Hispanic or Latino
    117 242 359
        Unknown or Not Reported
    43 72 115

    End points

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    End points reporting groups
    Reporting group title
    Placebo (PC Period)
    Reporting group description
    Subjects assigned to BIIB092 matching placebo intravenous (IV) infusion once every 4 weeks for 48 weeks in double blind PC period and receive only placebo.

    Reporting group title
    BIIB092 2000 mg (PC Period)
    Reporting group description
    Subjects who received at least one dose of BIIB092 2000 mg and were either assigned to BIIB092 2000 milligrams (mg) IV infusion or BIIB092 matching placebo IV infusion once every 4 weeks for 48 weeks in double blind PC period.
    Reporting group title
    BIIB092 Late Start (OLE Period)
    Reporting group description
    Late start subjects received only placebo in the placebo-controlled period and assigned to BIIB092 2000 mg IV infusion once every 4 weeks starting at Week 52 in the OLE period.

    Reporting group title
    BIIB092 Early Start (OLE Period)
    Reporting group description
    Early start subjects are those who received BIIB092 2000 mg in the placebo-controlled period and assigned to BIIB092 2000 mg IV infusion once every 4 weeks starting at Week 52 in the OLE period.

    Subject analysis set title
    BIIB092 Late Start
    Subject analysis set type
    Safety analysis
    Subject analysis set description
    Late start subjects received only placebo in the placebo-controlled period and assigned to BIIB092 2000 mg IV infusion once every 4 weeks starting at Week 52 in the OLE period.

    Subject analysis set title
    BIIB092 Early Start
    Subject analysis set type
    Safety analysis
    Subject analysis set description
    Early start subjects are those who received BIIB092 2000 mg in the placebo-controlled period and assigned to BIIB092 2000 mg IV infusion once every 4 weeks starting at Week 52 in the OLE period.

    Primary: Change From Baseline in Progressive Supranuclear Palsy Rating Scale (PSPRS) at Week 52

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    End point title
    Change From Baseline in Progressive Supranuclear Palsy Rating Scale (PSPRS) at Week 52
    End point description
    The PSPRS is a quantitative measure of disability in participants with PSP. The PSPRS comprises 28 items in 6 areas. Six items are rated on a 3-point scale (0-2) and 22 are rated on a 5-point scale (0-4). The 6 areas are the History/Daily Activities, Mentation, Bulbar, Ocular Motor, Limb Motor, and Gait. The 28-item PSPRS total score ranges from 0 (normal) to 100. Fifteen items are selected to form a 15-item PSPRS and three domains are identified: Gait/Limb function, Ocular Motor, and Bulbar. The total 15-item PSPRS score ranges from 0 (normal) to 52. A positive change from baseline indicates worsening. Intent-to-Treat (ITT) population included randomised subjects who had received at least 1 dose of blinded study treatment (BII092 or Placebo).
    End point type
    Primary
    End point timeframe
    Baseline, Week 52
    End point values
    Placebo (PC Period) BIIB092 2000 mg (PC Period)
    Number of subjects analysed
    139 [1]
    278 [2]
    Units: Score on a scale
    arithmetic mean (standard error)
        PSPRS: 28 items
    10.6 ± 0.8
    10.4 ± 0.6
        PSPRS: 15 items
    7.57 ± 0.52
    7.29 ± 0.38
    Notes
    [1] - 'Number of Subjects Analysed' signifies number of subjects who had response on Week 52.
    [2] - 'Number of Subjects Analysed' signifies number of subjects who had response on Week 52.
    Statistical analysis title
    28-items
    Statistical analysis description
    Adjusted mean for each treatment group, difference with Placebo,95% confidence interval and p-value at each time point were based on a mixed model for repeated measures model (MMRM), with change from baseline in 28-item PSPRS total score as dependent variable and with fixed effects of treatment group, time(categorical), treatment group-by-time interaction, baseline 28-item PSPRS, baseline 28-item PSPRS by time interaction, baseline Color Trails 2 test (<=170 or >170 seconds) and region.
    Comparison groups
    Placebo (PC Period) v BIIB092 2000 mg (PC Period)
    Number of subjects included in analysis
    417
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    P-value
    = 0.8483
    Method
    Mixed model for repeated measures (MMRM)
    Parameter type
    Difference
    Point estimate
    -0.2
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    -2
         upper limit
    1.6
    Statistical analysis title
    15-items
    Statistical analysis description
    Adjusted mean for each treatment group, difference with Placebo, 95% confidence interval and p-value at each time point were based on an MMRM model, with change from baseline in 15-item PSPRS total score as dependent variable and with fixed effects of treatment group, time (categorical), treatment group by-time interaction, baseline 15-item PSPRS, baseline 15-item PSPRS by time interaction, baseline Color Trails 2 test (<=170 or >170 seconds) and region.
    Comparison groups
    Placebo (PC Period) v BIIB092 2000 mg (PC Period)
    Number of subjects included in analysis
    417
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    P-value
    = 0.6503
    Method
    MMRM
    Parameter type
    Difference
    Point estimate
    -0.28
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    -1.5
         upper limit
    0.94

    Primary: Percentage of Subjects with Death, Serious Adverse Events (SAEs), Adverse Events (AEs) and Adverse Events (AEs) Leading to Discontinuation of Drug

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    End point title
    Percentage of Subjects with Death, Serious Adverse Events (SAEs), Adverse Events (AEs) and Adverse Events (AEs) Leading to Discontinuation of Drug [3]
    End point description
    AEs: any sign, symptom, or diagnosis/disease that is unfavorable or unintended, that is new, or if pre-existing, worsens in subjects administered a pharmaceutical product and that does not necessarily have a causal relationship with this treatment. SAEs: an event that results in death; an event that, in the view of the investigator, places the subject at immediate risk of death (a life-threatening event); an outcome that results in a congenital anomaly/birth defect diagnosed in a child of a subject; an event that requires or prolongs inpatient hospitalization; an event that results in persistent or significant disability/incapacity. Safety population. Subjects randomised to Placebo that received at least one dose of BIIB092 2000 mg during the PC period was counted in the BIIB092 2000 mg group for the safety population. Three subjects who received BIIB092 in Placebo group were counted in BIIB092 200 mg group.
    End point type
    Primary
    End point timeframe
    up to 52 weeks
    Notes
    [3] - No statistical analyses have been specified for this primary end point. It is expected there is at least one statistical analysis for each primary end point.
    Justification: Only descriptive statistical analysis was planned to be reported for this endpoint.
    End point values
    BIIB092 Late Start BIIB092 Early Start
    Number of subjects analysed
    162
    324
    Units: Percentage of subjects
    number (not applicable)
        Death
    4.9
    4.9
        SAEs
    32.1
    27.2
        AEs
    93.2
    92.9
        AEs Leading to Discontinuation of Drug
    11.1
    7.4
    No statistical analyses for this end point

    Secondary: Change From Baseline in Movement Disorder Society (MDS)-Sponsored Revision of the Unified Parkinson's Disease Rating Scale (MDS-UPDRS) Part II at Week 52

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    End point title
    Change From Baseline in Movement Disorder Society (MDS)-Sponsored Revision of the Unified Parkinson's Disease Rating Scale (MDS-UPDRS) Part II at Week 52
    End point description
    The MDS-UPRDRS Part 2 includes 13 items assessing motor aspects of experiences of daily living (M-EDL) these include speech, saliva and drooling, chewing and swallowing, handwriting, doing hobbies and other activities, eating tasks, tremor, dressing, hygiene, turning in bed, getting out of bed, walking and balance, and freezing. All items have 5 responses with uniform anchors of 0= normal, 1= slight, 2= mild, 3= moderate, and 4= severe. Total score ranges from 0 to 52, higher score indicating severe conditions. A positive change from baseline indicates worsening. ITT population included randomised subjects who had received at least 1 dose of blinded study treatment (BII092 or Placebo).
    End point type
    Secondary
    End point timeframe
    Baseline, Week 52
    End point values
    Placebo (PC Period) BIIB092 2000 mg (PC Period)
    Number of subjects analysed
    143 [4]
    270 [5]
    Units: Score on a scale
        arithmetic mean (standard error)
    6.7 ± 0.6
    7.0 ± 0.4
    Notes
    [4] - 'Number of Subjects Analysed' signifies the total number of subjects analysed in this endpoint.
    [5] - 'Number of Subjects Analysed' signifies the total number of subjects analysed in this endpoint.
    Statistical analysis title
    BIIB092 Late Start vs BIIB092 Early Start
    Statistical analysis description
    Adjusted mean for each treatment group, difference with Placebo, 95% confidence interval and p-value at each time point were based on an MMRM model, with change from baseline in MDS-UPDRS as dependent variable and with fixed effects of treatment group, time (categorical), treatment group-by-time interaction, baseline MDS-UPDRS, baseline MDS-UPDRS by time interaction, baseline Color Trails 2 test (<=170 or >170 seconds) and region.
    Comparison groups
    Placebo (PC Period) v BIIB092 2000 mg (PC Period)
    Number of subjects included in analysis
    413
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    P-value
    = 0.6031
    Method
    MMRM
    Parameter type
    Difference
    Point estimate
    0.4
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    -1
         upper limit
    1.7

    Secondary: Clinical Global Impression of Change (CGI-C) Scale Score

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    End point title
    Clinical Global Impression of Change (CGI-C) Scale Score
    End point description
    The CGI-C scale measures the change in the patient's clinical status from a specific point in time. Using a 7-point scale, ranging from 1 (very much improved) to 7 (very much worse), with a score of 4 indicating no change. ITT population included randomised subjects who had received at least 1 dose of blinded study treatment (BII092 or Placebo).
    End point type
    Secondary
    End point timeframe
    Week 52
    End point values
    Placebo (PC Period) BIIB092 2000 mg (PC Period)
    Number of subjects analysed
    138 [6]
    271 [7]
    Units: Score on a scale
        arithmetic mean (standard error)
    5.3 ± 0.1
    5.2 ± 0.1
    Notes
    [6] - 'Number of Subjects Analysed' signifies the total number of subjects analysed in this endpoint.
    [7] - 'Number of Subjects Analysed' signifies the total number of subjects analysed in this endpoint.
    Statistical analysis title
    BIIB092 Late Start vs BIIB092 Early Start
    Statistical analysis description
    Adjusted mean for each treatment group, difference with Placebo, 95% confidence interval and p-value at each time point were based on an MMRM model, with CGI-C as dependent variable and with fixed effects of treatment group, time (categorical), treatment group-by-time interaction, baseline CGI-S, baseline CGI-S by time interaction, baseline Color Trails 2 test (<=170 or >170 seconds) and region.
    Comparison groups
    Placebo (PC Period) v BIIB092 2000 mg (PC Period)
    Number of subjects included in analysis
    409
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    P-value
    = 0.7743
    Method
    MMRM
    Parameter type
    Difference
    Point estimate
    0
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    -0.2
         upper limit
    0.1

    Secondary: Change From Baseline in Progressive Supranuclear Palsy (PSP)-Cognitive Composite Battery Z-Score at Week 52

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    End point title
    Change From Baseline in Progressive Supranuclear Palsy (PSP)-Cognitive Composite Battery Z-Score at Week 52
    End point description
    The PSP cognitive composite battery is used to identify and characterize abnormal cognitive decline in PSP subjects. The PSP cognitive composite battery includes 13 sub-tests in total: 11 tests from the RBANS (only the picture naming is excluded), letter number sequencing test, and phonemic fluency test. Three domains are identified: Memory and learning, Visual-Motor function, and Working memory and Executive. A z-score transformation is applied for each component test at each visit, and the final total composite z-score is the average of the three-domain z-scores. A z-score of 0 is equal to the estimated mean adjusted by age and is considered average for this study population. Lower values are indicative of cognitive decline. A negative change from baseline indicates worsening. ITT population included randomised subjects who had received at least 1 dose of blinded study treatment (BII092 or Placebo).
    End point type
    Secondary
    End point timeframe
    Baseline, Week 52
    End point values
    Placebo (PC Period) BIIB092 2000 mg (PC Period)
    Number of subjects analysed
    134 [8]
    249 [9]
    Units: z-score
        arithmetic mean (standard error)
    -0.283 ± 0.032
    -0.245 ± 0.024
    Notes
    [8] - 'Number of Subjects Analysed' signifies the total number of subjects analysed in this endpoint.
    [9] - 'Number of Subjects Analysed' signifies the total number of subjects analysed in this endpoint.
    Statistical analysis title
    BIIB092 Late Start vs BIIB092 Early Start
    Statistical analysis description
    Adjusted mean for each treatment group, difference with Placebo, 95% confidence interval and p-value at each time point were based on an MMRM model, with change from baseline in PSP-cognitive composite battery as dependent variable and with fixed effects of treatment group, time (categorical), treatment group-by-time interaction, baseline PSP-cognitive composite battery, baseline PSP-cognitive composite battery by time interaction, baseline Color Trails 2 test (<=170 or >170 seconds) and region.
    Comparison groups
    Placebo (PC Period) v BIIB092 2000 mg (PC Period)
    Number of subjects included in analysis
    383
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    P-value
    = 0.318
    Method
    MMRM
    Parameter type
    Difference
    Point estimate
    0.038
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    -0.036
         upper limit
    0.112

    Secondary: Change From Baseline in Repeatable Battery for the Assessment of Neuropsychological Disease Severity (RBANS) Scale at Week 52

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    End point title
    Change From Baseline in Repeatable Battery for the Assessment of Neuropsychological Disease Severity (RBANS) Scale at Week 52
    End point description
    The RBANS provides both a total scale score and scores for 5 different cognitive domains. Specifically, the test measures immediate memory, visuospatial/constructional ability, language, attention, and delayed memory. Scores from all subtests are aggregated into a total composite score. RBANS data were age-normed and analysed as index scores (also referred to as standard scores), which have a mean of 100 and a standard deviation of 15. Higher scores on each sub measure and index better performance. A negative change from baseline indicates worsening. ITT population included randomised subjects who had received at least 1 dose of blinded study treatment (BII092 or Placebo).
    End point type
    Secondary
    End point timeframe
    Baseline, Week 52
    End point values
    Placebo (PC Period) BIIB092 2000 mg (PC Period)
    Number of subjects analysed
    111 [10]
    222 [11]
    Units: Score on a scale
        arithmetic mean (standard error)
    -3.1 ± 0.7
    -3.2 ± 0.5
    Notes
    [10] - 'Number of Subjects Analysed' signifies the total number of subjects analysed in this endpoint.
    [11] - 'Number of Subjects Analysed' signifies the total number of subjects analysed in this endpoint.
    Statistical analysis title
    BIIB092 Late Start vs BIIB092 Early Start
    Statistical analysis description
    Adjusted mean for each treatment group, difference with Placebo, 95% confidence interval and p-value at each time point were based on an MMRM model, with change from baseline in RBANS as dependent variable and with fixed effects of treatment group, time (categorical), treatment group-by-time interaction, baseline RBANS , baseline RBANS by time interaction, baseline Color Trails 2 test (<=170 or >170 seconds and region.
    Comparison groups
    Placebo (PC Period) v BIIB092 2000 mg (PC Period)
    Number of subjects included in analysis
    333
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    P-value
    = 0.827
    Method
    MMRM
    Parameter type
    Difference
    Point estimate
    -0.2
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    -1.8
         upper limit
    1.4

    Secondary: Change From Baseline in Progressive Supranuclear Palsy Quality of Life Scale (PSP-QoL) Score

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    End point title
    Change From Baseline in Progressive Supranuclear Palsy Quality of Life Scale (PSP-QoL) Score
    End point description
    The PSP-QoL is a patient-reported outcome measure specifically for assessing the health-related quality of life in people living with PSP.It is validated 45-item questionnaire and visual analog scale(VAS)that is comprised of 2 subscales:physical health state (22 items), which covers mobility,dysarthria,dysphagia,visual disturbances,self-care and activities of daily living,and mental health state (23 items),which covers emotional,cognitive and social functioning.Items are given a 6-reponse option format (No Problem,Slight Problem,Moderate Problem,Marked Problem,Extreme Problem and Not Applicable).The subscale results are derived by summing the respective items for that subscale and transforming the scores into a range of 0 to 100, the higher the scores=greater impact of the disease. The PSP-QoL also comprises of a Life Satisfaction rating gauge, which is a VAS with a range of 0 (worst) to 100 (best). ITT population. Here, ‘n’=number of subjects analysed for each parameter.
    End point type
    Secondary
    End point timeframe
    Baseline, Week 52
    End point values
    Placebo (PC Period) BIIB092 2000 mg (PC Period)
    Number of subjects analysed
    142 [12]
    264 [13]
    Units: Score on a scale
    arithmetic mean (standard error)
        Physical Scale Score (n=142, 264)
    11.3 ± 1.5
    11.2 ± 1.1
        Mental Scale Score (n=140, 264)
    5.6 ± 1.4
    6.1 ± 1.0
        Satisfaction With Your Life Today(n=141,264)
    -3.7 ± 1.8
    -5.4 ± 1.3
    Notes
    [12] - 'Number of Subjects Analysed' signifies number of subjects who had response on Week 52.
    [13] - 'Number of Subjects Analysed' signifies number of subjects who had response on Week 52.
    Statistical analysis title
    BIIB092 Late Start vs BIIB092 Early Start
    Statistical analysis description
    Physical scale score: Adjusted mean for each treatment group, difference with Placebo, 95% confidence interval and p-value at each time point were based on an MMRM model, with change from baseline in PSP-QoL as dependent variable and with fixed effects of treatment group, time (categorical), treatment group-by-time interaction, baseline for PSP-QoL, baseline PSP-QoL by time interaction, baseline Color Trails 2 test (<=170 or >170 seconds) and region.
    Comparison groups
    Placebo (PC Period) v BIIB092 2000 mg (PC Period)
    Number of subjects included in analysis
    406
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    P-value
    = 0.9304
    Method
    MMRM
    Parameter type
    Difference
    Point estimate
    -0.2
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    -3.6
         upper limit
    3.3
    Statistical analysis title
    BIIB092 Late Start vs BIIB092 Early Start
    Statistical analysis description
    Mental scale score: Adjusted mean for each treatment group, difference with Placebo, 95% confidence interval and p-value at each time point were based on an MMRM model, with change from baseline in PSPQoL as dependent variable and with fixed effects of treatment group, time (categorical), treatment group-bytime interaction, baseline for PSP-QoL, baseline PSP-QoL by time interaction, baseline Color Trails 2 test (<=170 or >170 seconds) and region.
    Comparison groups
    Placebo (PC Period) v BIIB092 2000 mg (PC Period)
    Number of subjects included in analysis
    406
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    P-value
    = 0.7859
    Method
    MMRM
    Parameter type
    Difference
    Point estimate
    0.5
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    -2.8
         upper limit
    3.7
    Statistical analysis title
    BIIB092 Late Start vs BIIB092 Early Start
    Statistical analysis description
    Satisfaction With Your Life Today: Adjusted mean for each treatment group, difference with Placebo, 95% confidence interval and p-value at each time point were based on an MMRM model, with change from baseline in PSPQoL as dependent variable and with fixed effects of treatment group, time (categorical), treatment group-bytime interaction, baseline for PSP-QoL, baseline PSP-QoL by time interaction, baseline Color Trails 2 test (<=170 or >170 seconds) and region.
    Comparison groups
    Placebo (PC Period) v BIIB092 2000 mg (PC Period)
    Number of subjects included in analysis
    406
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    P-value
    = 0.4297
    Method
    MMRM
    Parameter type
    Difference
    Point estimate
    -1.7
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    -5.8
         upper limit
    2.5

    Secondary: Change From Baseline in Schwab and England Activities of Daily Living (SEADL) Scale Score at Week 48

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    End point title
    Change From Baseline in Schwab and England Activities of Daily Living (SEADL) Scale Score at Week 48
    End point description
    The SEADL scale is a means of assessing a person's ability to perform daily activities in terms of speed and independence, with 100% indicating total independence, falling to 0%, which indicates a state of complete dependence. The individual is asked to rate his or her function using an 11-point scale (10% increments), from 100% (completely independent; able to do all chores without slowness, difficulty, or impairment; essentially normal; unaware of any difficulty) to 0% (vegetative functions such as swallowing, bladder and bowels are not functioning; bedridden). A negative change from baseline indicates worsening. ITT population included randomised subjects who had received at least 1 dose of blinded study treatment (BII092 or Placebo).
    End point type
    Secondary
    End point timeframe
    Baseline, Week 48
    End point values
    Placebo (PC Period) BIIB092 2000 mg (PC Period)
    Number of subjects analysed
    140 [14]
    277 [15]
    Units: Score on a scale
        arithmetic mean (standard error)
    -13.7 ± 1.4
    -11.7 ± 1.0
    Notes
    [14] - 'Number of Subjects Analysed' signifies the total number of subjects analysed in this endpoint.
    [15] - 'Number of Subjects Analysed' signifies the total number of subjects analysed in this endpoint.
    Statistical analysis title
    BIIB092 Late Start vs BIIB092 Early Start
    Statistical analysis description
    Adjusted mean for each treatment group, difference with Placebo, 95% confidence interval and p-value at each time point were based on an MMRM model, with change from baseline in SEADL as dependent variable and with fixed effects of treatment group, time (categorical), treatment group-by-time interaction, baseline for SEADL , baseline SEADL by time interaction, baseline Color Trails 2 test (<=170 or >170 seconds) and region.
    Comparison groups
    Placebo (PC Period) v BIIB092 2000 mg (PC Period)
    Number of subjects included in analysis
    417
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    P-value
    = 0.2084
    Method
    MMRM
    Parameter type
    Difference
    Point estimate
    2
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    -1.1
         upper limit
    5.2

    Secondary: Change From Baseline in Clinical Global Impression of Severity (CGI-S) Score at Week 52

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    End point title
    Change From Baseline in Clinical Global Impression of Severity (CGI-S) Score at Week 52
    End point description
    The Clinical Global Impression of Severity (CGI-S) Rating evaluates the severity of individual symptoms and treatment response in subjects with mental disorders. The CGI-S is a 7-point scale that that requires the clinician to rate the severity of the patient's illness at the time of assessment. A rating of 1 is considered normal, or with the least severe symptoms, a rating of 7 is extremely ill, or the worst symptoms. ITT population included randomised subjects who had received at least 1 dose of blinded study treatment (BII092 or Placebo).
    End point type
    Secondary
    End point timeframe
    Baseline, Week 52
    End point values
    Placebo (PC Period) BIIB092 2000 mg (PC Period)
    Number of subjects analysed
    140 [16]
    269 [17]
    Units: Score on a scale
        arithmetic mean (standard error)
    0.6 ± 0.1
    0.6 ± 0.0
    Notes
    [16] - 'Number of Subjects Analysed' signifies the total number of subjects analysed in this endpoint.
    [17] - 'Number of Subjects Analysed' signifies the total number of subjects analysed in this endpoint.
    Statistical analysis title
    BIIB092 Late Start vs BIIB092 Early Start
    Statistical analysis description
    Adjusted mean for each treatment group, difference with Placebo, 95% confidence interval and p-value at each time point were based on an MMRM model, with change from baseline in CGI-S as dependent variable and with fixed effects of treatment group, time (categorical), treatment group-by-time interaction, baseline for CGI-S, baseline CGI-S by time interaction, baseline Color Trails 2 test (<=170 or >170 seconds) and region.
    Comparison groups
    Placebo (PC Period) v BIIB092 2000 mg (PC Period)
    Number of subjects included in analysis
    409
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    P-value
    = 0.5701
    Method
    MMRM
    Parameter type
    Difference
    Point estimate
    0
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    -0.2
         upper limit
    0.1

    Secondary: Change From Baseline in Phonemic Fluency Test Score at Week 48

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    End point title
    Change From Baseline in Phonemic Fluency Test Score at Week 48
    End point description
    Phonemic fluency is a sensitive test for assessing frontal lobe dysfunction. Subjects are given a letter of the alphabet and asked to name as many words as they can that start with that letter in 1 minute. The score for each trial is auto-calculated as follows: Trial 1: Total number of correct responses for the first letter (range 0 to 40); Trial 2: Total number of correct responses for the second letter (range 0 to 40). The total score from the two trials was used for analysis (range 0 to 80). More number of words correlates to better phonemic fluency. A negative change from baseline indicates worsening. ITT population included randomised subjects who had received at least 1 dose of blinded study treatment (BII092 or Placebo).
    End point type
    Secondary
    End point timeframe
    Baseline, Week 48
    End point values
    Placebo (PC Period) BIIB092 2000 mg (PC Period)
    Number of subjects analysed
    141 [18]
    273 [19]
    Units: Score on a scale
        arithmetic mean (standard deviation)
    -0.9 ± 0.4
    0.0 ± 0.3
    Notes
    [18] - 'Number of Subjects Analysed' signifies the total number of subjects analysed in this endpoint.
    [19] - 'Number of Subjects Analysed' signifies the total number of subjects analysed in this endpoint.
    Statistical analysis title
    BIIB092(Late Start Vs Early Start)
    Statistical analysis description
    Adjusted mean for each treatment group, difference with Placebo, 95% confidence interval and p-value at each time point were based on an MMRM model, with change from baseline in Phonemic Fluency Test as dependent variable and with fixed effects of treatment group, time (categorical), treatment group-by-time interaction, baseline Phonemic Fluency Test, baseline Phonemic Fluency Test by time interaction, baseline Color Trails 2 test (<=170 or >170 seconds) and region.
    Comparison groups
    Placebo (PC Period) v BIIB092 2000 mg (PC Period)
    Number of subjects included in analysis
    414
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    P-value
    = 0.0517
    Method
    MMRM
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    0
         upper limit
    1.8

    Secondary: Change From Baseline in Letter-Number Sequencing Test at Week 48

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    End point title
    Change From Baseline in Letter-Number Sequencing Test at Week 48
    End point description
    Letter number is a test of working memory which involves ordering a series of up to 8 letters and numbers in which the numbers are repeated back first in order starting with the lowest number, then followed by the letters in alphabetical order. LNS consists of 10 items and each item has 3 trials rated as Incorrect (0) or Correct (1). The LNS total raw score (range 0 to 30) is auto-calculated by summing the 10 individual item scores (range 0 to 3 for each item). Higher number of correct items correlated to better performance and a negative change from baseline indicates worsening. ITT population included randomised subjects who had received at least 1 dose of blinded study treatment (BII092 or Placebo).
    End point type
    Secondary
    End point timeframe
    Baseline, Week 48
    End point values
    Placebo (PC Period) BIIB092 2000 mg (PC Period)
    Number of subjects analysed
    139 [20]
    271 [21]
    Units: Score on a scale
        arithmetic mean (standard error)
    -1.9 ± 0.4
    -1.1 ± 0.3
    Notes
    [20] - 'Number of Subjects Analysed' signifies the total number of subjects analysed in this endpoint.
    [21] - 'Number of Subjects Analysed' signifies the total number of subjects analysed in this endpoint.
    Statistical analysis title
    BIIB092 Late Start vs BIIB092 Early Start
    Statistical analysis description
    Adjusted mean for each treatment group, difference with Placebo, 95% confidence interval and p-value at each time point were based on an MMRM model, with change from baseline in Letter Number Sequence as dependent variable and with fixed effects of treatment group, time (categorical), treatment group-by-time interaction, baseline Letter Number Sequence, baseline Letter Number Sequence by time interaction, baseline Color Trails 2 test (<=170 or >170 seconds) and region.
    Comparison groups
    Placebo (PC Period) v BIIB092 2000 mg (PC Period)
    Number of subjects included in analysis
    410
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    P-value
    = 0.0387
    Method
    MMRM
    Parameter type
    Difference
    Point estimate
    0.9
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    0
         upper limit
    1.7

    Secondary: Change From Baseline in Color Trails at Week 48

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    End point title
    Change From Baseline in Color Trails at Week 48
    End point description
    The Color Trails test is a language free version of the Trail Making Test and was developed to allow for broader cross-cultural assessment. For Part 1 (color trails test 1), the respondent uses a pencil to rapidly connect circles numbered 1-25 in sequence. For Part 2 (color trails test 2), the respondent rapidly connects number circles in sequence, but alternates between pink and yellow background. The length of time to complete each trial is recorded, along with qualitative features of performance indicative of brain dysfunction, such as near-misses, prompts, number sequence errors, and color sequence errors. Less time indicates better performance. A positive change from baseline indicates worsening. ITT population included randomised subjects who had received at least 1 dose of blinded study treatment (BII092 or Placebo).
    End point type
    Secondary
    End point timeframe
    Baseline, Week 48
    End point values
    Placebo (PC Period) BIIB092 2000 mg (PC Period)
    Number of subjects analysed
    143 [22]
    279 [23]
    Units: Seconds
    arithmetic mean (standard error)
        Color Trails Test 1
    16.8 ± 3.6
    16.9 ± 2.7
        Color Trails Test 2
    10.6 ± 2.4
    10.5 ± 1.8
    Notes
    [22] - 'Number of Subjects Analysed' signifies the total number of subjects analysed in this endpoint.
    [23] - 'Number of Subjects Analysed' signifies the total number of subjects analysed in this endpoint.
    Statistical analysis title
    BIIB092 Late Start vs BIIB092 Early Start
    Statistical analysis description
    Color Trails Test 1: Adjusted mean for each treatment group, difference with Placebo, 95% confidence interval and p-value at each time point were based on an MMRM model, with change from baseline in Color trails Test 1 as dependent variable and with fixed effects of treatment group, time (categorical), treatment group-by-time interaction, baseline for Color Trails Test 1, baseline Color Trails Test 1 by time interaction, baseline Color Trails 2 test (<=170 or >170 seconds) and region.
    Comparison groups
    Placebo (PC Period) v BIIB092 2000 mg (PC Period)
    Number of subjects included in analysis
    422
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    P-value
    = 0.9815
    Method
    MMRM
    Parameter type
    Difference
    Point estimate
    0.1
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    -8.1
         upper limit
    8.3
    Statistical analysis title
    BIIB092 Late Start vs BIIB092 Early Start
    Statistical analysis description
    Color Trails Test 2: Adjusted mean for each treatment group, difference with Placebo, 95% confidence interval and p-value at each time point were based on an MMRM model, with change from baseline in Color Trails Test 2 as dependent variable and with fixed effects of treatment group, time (categorical), treatment group-by-time interaction, baseline for Color Trails Test 2, baseline Color Trails Test 2 by time interaction, and region.
    Comparison groups
    Placebo (PC Period) v BIIB092 2000 mg (PC Period)
    Number of subjects included in analysis
    422
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    P-value
    = 0.9869
    Method
    MMRM
    Parameter type
    Difference
    Point estimate
    0
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    -5.7
         upper limit
    5.6

    Secondary: Change From Baseline in Montreal Cognitive Assessment (MoCA) Score at Week 48

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    End point title
    Change From Baseline in Montreal Cognitive Assessment (MoCA) Score at Week 48
    End point description
    The MOCA was designed as a rapid screening instrument for mild cognitive dysfunction. It assesses different cognitive domains: attention and concentration, executive function, memory, language, visuoconstructional skills, conceptual thinking, calculations, and orientation. Scores on the MOCA range from 0-30, with higher score being better performance. A negative change from baseline indicates worsening. ITT population included randomised subjects who had received at least 1 dose of blinded study treatment (BII092 or Placebo).
    End point type
    Secondary
    End point timeframe
    Baseline, Week 48
    End point values
    Placebo (PC Period) BIIB092 2000 mg (PC Period)
    Number of subjects analysed
    136 [24]
    264 [25]
    Units: Score on a scale
        arithmetic mean (standard error)
    -1.0 ± 0.3
    -0.5 ± 0.2
    Notes
    [24] - 'Number of Subjects Analysed' signifies the total number of subjects analysed in this endpoint.
    [25] - 'Number of Subjects Analysed' signifies the total number of subjects analysed in this endpoint.
    Statistical analysis title
    BIIB092 Late Start vs BIIB092 Early Start
    Statistical analysis description
    Adjusted mean for each treatment group, difference with Placebo, 95% confidence interval and p-value at each time point were based on an MMRM model, with change from baseline in MoCA as dependent variable and with fixed effects of treatment group, time (categorical), treatment group-by-time interaction, baseline for MoCA, baseline MoCA by time interaction,baseline Color Trails 2 test (<=170 or >170 seconds) and region.
    Comparison groups
    Placebo (PC Period) v BIIB092 2000 mg (PC Period)
    Number of subjects included in analysis
    400
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    P-value
    = 0.1763
    Method
    MMRM
    Parameter type
    Difference
    Point estimate
    0.5
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    -0.2
         upper limit
    1.2

    Secondary: Number of Participants with Treatment Emergent Antibodies (anti-BIIB092) Positive Results in Serum

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    End point title
    Number of Participants with Treatment Emergent Antibodies (anti-BIIB092) Positive Results in Serum
    End point description
    ADA population – subset of the safety population with at least one evaluable post-baseline evaluable ADA samples.
    End point type
    Secondary
    End point timeframe
    Up to Week 48
    End point values
    BIIB092 Late Start BIIB092 Early Start
    Number of subjects analysed
    162
    323
    Units: Subjects
    7
    0
    No statistical analyses for this end point

    Secondary: Change From Baseline of Brain Volumes as Determined by MRI at Week 52

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    End point title
    Change From Baseline of Brain Volumes as Determined by MRI at Week 52
    End point description
    A 3 dimension (3D) T1-weighted MRI was performed to estimate brain volumes (e.g., ventricles, whole brain, midbrain, pons, superior cerebellar peduncle, third ventricle, and frontal lobes). Efficacy MRI population is the subset of the ITT population who had a least one measurable brain volumetric measurement. Here, 'n' signifies the number of subjects analysed for each parameter.
    End point type
    Secondary
    End point timeframe
    Baseline, Week 52
    End point values
    Placebo (PC Period) BIIB092 2000 mg (PC Period)
    Number of subjects analysed
    114 [26]
    238 [27]
    Units: Cubic centimeter (cm^3)
    arithmetic mean (standard error)
        Ventricles Volume: Change at Week 52 (n =103,222)
    3.823 ± 0.302
    3.802 ± 0.216
        Whole Brain Volume: Change at Week 52(n =101,210)
    -18.612 ± 1.296
    -19.126 ± 0.950
        Midbrain Volume: Change at Week 52 (n =108, 224)
    -0.116 ± 0.008
    -0.120 ± 0.006
        Pons Volume: Change at Week 52 (n =100, 223)
    -0.198 ± 0.017
    -0.198 ± 0.012
        Cerebellar Peduncle Volume:ChangeWeek52(n=101,216)
    -0.005 ± 0.002
    -0.004 ± 0.002
        Third Ventricle Volume:Change at Week52(n=114,238)
    0.140 ± 0.014
    0.146 ± 0.010
        Frontal Lobe Volume: Change at Week 52 (n =89,178)
    1.184 ± 0.279
    1.143 ± 0.205
    Notes
    [26] - 'Number of Subjects Analysed' signifies number of subjects who had response on Week 52.
    [27] - 'Number of Subjects Analysed' signifies number of subjects who had response on Week 52.
    Statistical analysis title
    Ventricles Volume
    Statistical analysis description
    Adjusted mean for each treatment group, difference with Placebo, 95% confidence interval and p-value at each time point were based on an MMRM model, with change from baseline in MRI region as dependent variable and with fixed effects of treatment group, time (categorical), treatment group-by-time interaction, baseline for MRI region, baseline MRI region by time interaction, baseline Color Trails 2 test (<=170 or >170 seconds) and region.
    Comparison groups
    Placebo (PC Period) v BIIB092 2000 mg (PC Period)
    Number of subjects included in analysis
    352
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    P-value
    = 0.9527
    Method
    MMRM
    Parameter type
    Difference
    Point estimate
    -0.021
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    -0.726
         upper limit
    0.684
    Statistical analysis title
    Whole Brain Volume
    Statistical analysis description
    Adjusted mean for each treatment group, difference with Placebo, 95% confidence interval and p-value at each time point were based on an MMRM model, with change from baseline in MRI region as dependent variable and with fixed effects of treatment group, time (categorical), treatment group-by-time interaction, baseline for MRI region, baseline MRI region by time interaction, baseline Color Trails 2 test (<=170 or >170 seconds) and region.
    Comparison groups
    Placebo (PC Period) v BIIB092 2000 mg (PC Period)
    Number of subjects included in analysis
    352
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    P-value
    = 0.7357
    Method
    MMRM
    Parameter type
    Difference
    Point estimate
    -0.514
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    -3.506
         upper limit
    2.478
    Statistical analysis title
    Midbrain Volume
    Statistical analysis description
    Adjusted mean for each treatment group, difference with Placebo, 95% confidence interval and p-value at each time point were based on an MMRM model, with change from baseline in MRI region as dependent variable and with fixed effects of treatment group, time (categorical), treatment group-by-time interaction, baseline for MRI region, baseline MRI region by time interaction, baseline Color Trails 2 test (<=170 or >170 seconds) and region.
    Comparison groups
    Placebo (PC Period) v BIIB092 2000 mg (PC Period)
    Number of subjects included in analysis
    352
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    P-value
    = 0.6439
    Method
    MMRM
    Parameter type
    Difference
    Point estimate
    -0.004
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    -0.023
         upper limit
    0.014
    Statistical analysis title
    Pons Volume
    Statistical analysis description
    Adjusted mean for each treatment group, difference with Placebo, 95% confidence interval and p-value at each time point were based on an MMRM model, with change from baseline in MRI region as dependent variable and with fixed effects of treatment group, time (categorical), treatment group-by-time interaction, baseline for MRI region, baseline MRI region by time interaction, baseline Color Trails 2 test (<=170 or >170 seconds) and region.
    Comparison groups
    Placebo (PC Period) v BIIB092 2000 mg (PC Period)
    Number of subjects included in analysis
    352
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    P-value
    = 0.9864
    Method
    MMRM
    Parameter type
    Difference
    Point estimate
    0
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    -0.039
         upper limit
    0.04
    Statistical analysis title
    Cerebellar Peduncle Volume
    Statistical analysis description
    Adjusted mean for each treatment group, difference with Placebo, 95% confidence interval and p-value at each time point were based on an MMRM model, with change from baseline in MRI region as dependent variable and with fixed effects of treatment group, time (categorical), treatment group-by-time interaction, baseline for MRI region, baseline MRI region by time interaction, baseline Color Trails 2 test (<=170 or >170 seconds) and region.
    Comparison groups
    Placebo (PC Period) v BIIB092 2000 mg (PC Period)
    Number of subjects included in analysis
    352
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    P-value
    = 0.7529
    Method
    MMRM
    Parameter type
    Difference
    Point estimate
    0.001
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    -0.004
         upper limit
    0.006
    Statistical analysis title
    Third Ventricle Volume
    Statistical analysis description
    Adjusted mean for each treatment group, difference with Placebo, 95% confidence interval and p-value at each time point were based on an MMRM model, with change from baseline in MRI region as dependent variable and with fixed effects of treatment group, time (categorical), treatment group-by-time interaction, baseline for MRI region, baseline MRI region by time interaction, baseline Color Trails 2 test (<=170 or >170 seconds) and region.
    Comparison groups
    Placebo (PC Period) v BIIB092 2000 mg (PC Period)
    Number of subjects included in analysis
    352
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    P-value
    = 0.685
    Method
    MMRM
    Parameter type
    Difference
    Point estimate
    0.006
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    -0.025
         upper limit
    0.038
    Statistical analysis title
    Frontal Lobe Volume
    Statistical analysis description
    Adjusted mean for each treatment group, difference with Placebo, 95% confidence interval and p-value at each time point were based on an MMRM model, with change from baseline in MRI region as dependent variable and with fixed effects of treatment group, time (categorical), treatment group-by-time interaction, baseline for MRI region, baseline MRI region by time interaction, baseline Color Trails 2 test (<=170 or >170 seconds) and region.
    Comparison groups
    Placebo (PC Period) v BIIB092 2000 mg (PC Period)
    Number of subjects included in analysis
    352
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    P-value
    = 0.9
    Method
    MMRM
    Parameter type
    Difference
    Point estimate
    -0.041
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    -0.68
         upper limit
    0.598

    Adverse events

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    Adverse events information
    Timeframe for reporting adverse events
    up to 140 weeks
    Adverse event reporting additional description
    Subjects randomised to Placebo that received at least 1 dose of BIIB092 2000 mg during the PC period was counted in the BIIB092 2000 mg group for the safety population. Subjects exposed are subjects who received drug in respective study periods. Subjects affected were counted only once within each system organ class/preferred term/study period.
    Assessment type
    Systematic
    Dictionary used for adverse event reporting
    Dictionary name
    MedDRA
    Dictionary version
    22.1
    Reporting groups
    Reporting group title
    Placebo (PC Period)
    Reporting group description
    Subjects assigned to BIIB092 matching placebo IV infusion once every 4 weeks for 48 weeks in double-blind PC period and received only placebo.

    Reporting group title
    BIIB092 2000 mg (PC Period)
    Reporting group description
    Subjects who received at least one dose of BIIB092 2000 mg and were either assigned to BIIB092 2000 mg IV infusion or BIIB092 matching placebo IV infusion once every 4 weeks for 48 weeks in double blind PC period.

    Reporting group title
    BIIB092 late start (OLE Period)
    Reporting group description
    Late start subjects received only placebo in the PC period and assigned to BIIB092 2000 mg IV infusion once every 4 weeks starting at Week 52 in the OLE period.

    Reporting group title
    BIIB092 early start (OLE Period)
    Reporting group description
    Early start subjects are those who received BIIB092 2000 mg in the PC period and assigned to BIIB092 2000 mg IV infusion once every 4 weeks starting at Week 52 in the OLE period.

    Serious adverse events
    Placebo (PC Period) BIIB092 2000 mg (PC Period) BIIB092 late start (OLE Period) BIIB092 early start (OLE Period)
    Total subjects affected by serious adverse events
         subjects affected / exposed
    52 / 162 (32.10%)
    88 / 324 (27.16%)
    40 / 137 (29.20%)
    63 / 279 (22.58%)
         number of deaths (all causes)
    8
    16
    10
    16
         number of deaths resulting from adverse events
    Vascular disorders
    Aortic aneurysm
         subjects affected / exposed
    0 / 162 (0.00%)
    1 / 324 (0.31%)
    0 / 137 (0.00%)
    0 / 279 (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
    Deep vein thrombosis
         subjects affected / exposed
    0 / 162 (0.00%)
    2 / 324 (0.62%)
    0 / 137 (0.00%)
    1 / 279 (0.36%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 2
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Haematoma
         subjects affected / exposed
    1 / 162 (0.62%)
    0 / 324 (0.00%)
    0 / 137 (0.00%)
    1 / 279 (0.36%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Orthostatic hypotension
         subjects affected / exposed
    0 / 162 (0.00%)
    1 / 324 (0.31%)
    0 / 137 (0.00%)
    0 / 279 (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
    Neoplasms benign, malignant and unspecified (incl cysts and polyps)
    Breast cancer
         subjects affected / exposed
    1 / 162 (0.62%)
    0 / 324 (0.00%)
    0 / 137 (0.00%)
    0 / 279 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Breast neoplasm
         subjects affected / exposed
    1 / 162 (0.62%)
    0 / 324 (0.00%)
    0 / 137 (0.00%)
    0 / 279 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Colorectal cancer
         subjects affected / exposed
    0 / 162 (0.00%)
    0 / 324 (0.00%)
    0 / 137 (0.00%)
    1 / 279 (0.36%)
         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
    Lung adenocarcinoma
         subjects affected / exposed
    0 / 162 (0.00%)
    1 / 324 (0.31%)
    0 / 137 (0.00%)
    0 / 279 (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
    Malignant melanoma
         subjects affected / exposed
    0 / 162 (0.00%)
    1 / 324 (0.31%)
    0 / 137 (0.00%)
    0 / 279 (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
    Malignant melanoma in situ
         subjects affected / exposed
    1 / 162 (0.62%)
    0 / 324 (0.00%)
    0 / 137 (0.00%)
    0 / 279 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Metastatic gastric cancer
         subjects affected / exposed
    0 / 162 (0.00%)
    0 / 324 (0.00%)
    0 / 137 (0.00%)
    1 / 279 (0.36%)
         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
    Pancreatic carcinoma
         subjects affected / exposed
    0 / 162 (0.00%)
    0 / 324 (0.00%)
    1 / 137 (0.73%)
    1 / 279 (0.36%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 1
    Pituitary tumour benign
         subjects affected / exposed
    1 / 162 (0.62%)
    0 / 324 (0.00%)
    0 / 137 (0.00%)
    0 / 279 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Prostate cancer
         subjects affected / exposed
    0 / 162 (0.00%)
    1 / 324 (0.31%)
    1 / 137 (0.73%)
    0 / 279 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    General disorders and administration site conditions
    Cyst
         subjects affected / exposed
    0 / 162 (0.00%)
    1 / 324 (0.31%)
    0 / 137 (0.00%)
    0 / 279 (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
    Death
         subjects affected / exposed
    0 / 162 (0.00%)
    2 / 324 (0.62%)
    1 / 137 (0.73%)
    2 / 279 (0.72%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 2
    0 / 1
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 2
    0 / 1
    0 / 2
    Drowning
         subjects affected / exposed
    0 / 162 (0.00%)
    0 / 324 (0.00%)
    1 / 137 (0.73%)
    0 / 279 (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
    Euthanasia
         subjects affected / exposed
    0 / 162 (0.00%)
    0 / 324 (0.00%)
    0 / 137 (0.00%)
    1 / 279 (0.36%)
         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 / 1
    Gait disturbance
         subjects affected / exposed
    0 / 162 (0.00%)
    2 / 324 (0.62%)
    0 / 137 (0.00%)
    0 / 279 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 4
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Gait inability
         subjects affected / exposed
    0 / 162 (0.00%)
    0 / 324 (0.00%)
    0 / 137 (0.00%)
    1 / 279 (0.36%)
         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
    General physical health deterioration
         subjects affected / exposed
    1 / 162 (0.62%)
    1 / 324 (0.31%)
    0 / 137 (0.00%)
    0 / 279 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Multiple organ dysfunction syndrome
         subjects affected / exposed
    0 / 162 (0.00%)
    0 / 324 (0.00%)
    1 / 137 (0.73%)
    1 / 279 (0.36%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 1
    Systemic inflammatory response syndrome
         subjects affected / exposed
    0 / 162 (0.00%)
    1 / 324 (0.31%)
    0 / 137 (0.00%)
    0 / 279 (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
    Psychiatric disorders
    Agitation
         subjects affected / exposed
    1 / 162 (0.62%)
    0 / 324 (0.00%)
    0 / 137 (0.00%)
    1 / 279 (0.36%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Anxiety
         subjects affected / exposed
    0 / 162 (0.00%)
    0 / 324 (0.00%)
    0 / 137 (0.00%)
    1 / 279 (0.36%)
         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
    Assisted suicide
         subjects affected / exposed
    0 / 162 (0.00%)
    0 / 324 (0.00%)
    0 / 137 (0.00%)
    1 / 279 (0.36%)
         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 / 1
    Confusional state
         subjects affected / exposed
    0 / 162 (0.00%)
    0 / 324 (0.00%)
    0 / 137 (0.00%)
    1 / 279 (0.36%)
         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
    Hallucination
         subjects affected / exposed
    0 / 162 (0.00%)
    0 / 324 (0.00%)
    1 / 137 (0.73%)
    0 / 279 (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
    Insomnia
         subjects affected / exposed
    0 / 162 (0.00%)
    0 / 324 (0.00%)
    0 / 137 (0.00%)
    1 / 279 (0.36%)
         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
    Mental status changes
         subjects affected / exposed
    0 / 162 (0.00%)
    1 / 324 (0.31%)
    0 / 137 (0.00%)
    1 / 279 (0.36%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Suicidal ideation
         subjects affected / exposed
    0 / 162 (0.00%)
    2 / 324 (0.62%)
    2 / 137 (1.46%)
    1 / 279 (0.36%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 2
    0 / 2
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Suicide attempt
         subjects affected / exposed
    0 / 162 (0.00%)
    2 / 324 (0.62%)
    1 / 137 (0.73%)
    0 / 279 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 2
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Reproductive system and breast disorders
    Acquired phimosis
         subjects affected / exposed
    1 / 162 (0.62%)
    0 / 324 (0.00%)
    0 / 137 (0.00%)
    0 / 279 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Benign prostatic hyperplasia
         subjects affected / exposed
    0 / 162 (0.00%)
    1 / 324 (0.31%)
    0 / 137 (0.00%)
    0 / 279 (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
    Prostatitis
         subjects affected / exposed
    0 / 162 (0.00%)
    1 / 324 (0.31%)
    0 / 137 (0.00%)
    1 / 279 (0.36%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Injury, poisoning and procedural complications
    Ankle fracture
         subjects affected / exposed
    0 / 162 (0.00%)
    0 / 324 (0.00%)
    1 / 137 (0.73%)
    0 / 279 (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
    Cervical vertebral fracture
         subjects affected / exposed
    0 / 162 (0.00%)
    3 / 324 (0.93%)
    0 / 137 (0.00%)
    2 / 279 (0.72%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 3
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Clavicle fracture
         subjects affected / exposed
    0 / 162 (0.00%)
    1 / 324 (0.31%)
    0 / 137 (0.00%)
    0 / 279 (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
    Concussion
         subjects affected / exposed
    0 / 162 (0.00%)
    1 / 324 (0.31%)
    0 / 137 (0.00%)
    0 / 279 (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
    Contusion
         subjects affected / exposed
    1 / 162 (0.62%)
    1 / 324 (0.31%)
    0 / 137 (0.00%)
    0 / 279 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Craniocerebral injury
         subjects affected / exposed
    0 / 162 (0.00%)
    1 / 324 (0.31%)
    0 / 137 (0.00%)
    0 / 279 (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 / 1
    0 / 0
    0 / 0
    Facial bones fracture
         subjects affected / exposed
    1 / 162 (0.62%)
    0 / 324 (0.00%)
    0 / 137 (0.00%)
    0 / 279 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Fall
         subjects affected / exposed
    10 / 162 (6.17%)
    41 / 324 (12.65%)
    8 / 137 (5.84%)
    11 / 279 (3.94%)
         occurrences causally related to treatment / all
    0 / 11
    0 / 45
    0 / 8
    0 / 11
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Femoral neck fracture
         subjects affected / exposed
    1 / 162 (0.62%)
    3 / 324 (0.93%)
    0 / 137 (0.00%)
    0 / 279 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 3
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Femur fracture
         subjects affected / exposed
    0 / 162 (0.00%)
    1 / 324 (0.31%)
    0 / 137 (0.00%)
    2 / 279 (0.72%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    Fracture
         subjects affected / exposed
    1 / 162 (0.62%)
    0 / 324 (0.00%)
    0 / 137 (0.00%)
    0 / 279 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Hip fracture
         subjects affected / exposed
    0 / 162 (0.00%)
    2 / 324 (0.62%)
    1 / 137 (0.73%)
    0 / 279 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 2
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Human bite
         subjects affected / exposed
    0 / 162 (0.00%)
    0 / 324 (0.00%)
    1 / 137 (0.73%)
    0 / 279 (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 / 1
    0 / 0
    Humerus fracture
         subjects affected / exposed
    0 / 162 (0.00%)
    1 / 324 (0.31%)
    0 / 137 (0.00%)
    1 / 279 (0.36%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Joint dislocation
         subjects affected / exposed
    1 / 162 (0.62%)
    0 / 324 (0.00%)
    0 / 137 (0.00%)
    0 / 279 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Lumbar vertebral fracture
         subjects affected / exposed
    1 / 162 (0.62%)
    0 / 324 (0.00%)
    1 / 137 (0.73%)
    1 / 279 (0.36%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Musculoskeletal foreign body
         subjects affected / exposed
    0 / 162 (0.00%)
    1 / 324 (0.31%)
    0 / 137 (0.00%)
    0 / 279 (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
    Open globe injury
         subjects affected / exposed
    0 / 162 (0.00%)
    1 / 324 (0.31%)
    0 / 137 (0.00%)
    1 / 279 (0.36%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Periprosthetic fracture
         subjects affected / exposed
    1 / 162 (0.62%)
    0 / 324 (0.00%)
    0 / 137 (0.00%)
    0 / 279 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Post procedural haemorrhage
         subjects affected / exposed
    1 / 162 (0.62%)
    0 / 324 (0.00%)
    0 / 137 (0.00%)
    0 / 279 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Radius fracture
         subjects affected / exposed
    0 / 162 (0.00%)
    3 / 324 (0.93%)
    0 / 137 (0.00%)
    0 / 279 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 3
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Rib fracture
         subjects affected / exposed
    1 / 162 (0.62%)
    4 / 324 (1.23%)
    2 / 137 (1.46%)
    0 / 279 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 4
    0 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Road traffic accident
         subjects affected / exposed
    1 / 162 (0.62%)
    0 / 324 (0.00%)
    0 / 137 (0.00%)
    0 / 279 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Scapula fracture
         subjects affected / exposed
    0 / 162 (0.00%)
    0 / 324 (0.00%)
    0 / 137 (0.00%)
    1 / 279 (0.36%)
         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
    Skin laceration
         subjects affected / exposed
    1 / 162 (0.62%)
    4 / 324 (1.23%)
    0 / 137 (0.00%)
    1 / 279 (0.36%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 4
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Spinal compression fracture
         subjects affected / exposed
    0 / 162 (0.00%)
    1 / 324 (0.31%)
    1 / 137 (0.73%)
    2 / 279 (0.72%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 1
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Spinal fracture
         subjects affected / exposed
    0 / 162 (0.00%)
    1 / 324 (0.31%)
    1 / 137 (0.73%)
    0 / 279 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 2
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Subdural haematoma
         subjects affected / exposed
    1 / 162 (0.62%)
    2 / 324 (0.62%)
    1 / 137 (0.73%)
    0 / 279 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 2
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Tendon injury
         subjects affected / exposed
    0 / 162 (0.00%)
    1 / 324 (0.31%)
    0 / 137 (0.00%)
    0 / 279 (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
    Tendon rupture
         subjects affected / exposed
    0 / 162 (0.00%)
    1 / 324 (0.31%)
    0 / 137 (0.00%)
    0 / 279 (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
    Thermal burn
         subjects affected / exposed
    1 / 162 (0.62%)
    0 / 324 (0.00%)
    0 / 137 (0.00%)
    0 / 279 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Thoracic vertebral fracture
         subjects affected / exposed
    0 / 162 (0.00%)
    1 / 324 (0.31%)
    0 / 137 (0.00%)
    0 / 279 (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
    Tibia fracture
         subjects affected / exposed
    0 / 162 (0.00%)
    1 / 324 (0.31%)
    0 / 137 (0.00%)
    0 / 279 (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
    Traumatic haematoma
         subjects affected / exposed
    0 / 162 (0.00%)
    1 / 324 (0.31%)
    0 / 137 (0.00%)
    0 / 279 (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
    Traumatic intracranial haemorrhage
         subjects affected / exposed
    0 / 162 (0.00%)
    1 / 324 (0.31%)
    0 / 137 (0.00%)
    0 / 279 (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
    Wrist fracture
         subjects affected / exposed
    1 / 162 (0.62%)
    0 / 324 (0.00%)
    0 / 137 (0.00%)
    0 / 279 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Wrong dose
         subjects affected / exposed
    0 / 162 (0.00%)
    0 / 324 (0.00%)
    0 / 137 (0.00%)
    1 / 279 (0.36%)
         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
    Investigations
    Blood creatine phosphokinase increased
         subjects affected / exposed
    0 / 162 (0.00%)
    0 / 324 (0.00%)
    1 / 137 (0.73%)
    0 / 279 (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
    Haemoglobin decreased
         subjects affected / exposed
    1 / 162 (0.62%)
    0 / 324 (0.00%)
    0 / 137 (0.00%)
    0 / 279 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Liver function test increased
         subjects affected / exposed
    0 / 162 (0.00%)
    0 / 324 (0.00%)
    0 / 137 (0.00%)
    1 / 279 (0.36%)
         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
    Lumbar puncture
         subjects affected / exposed
    0 / 162 (0.00%)
    0 / 324 (0.00%)
    0 / 137 (0.00%)
    1 / 279 (0.36%)
         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
    Cardiac disorders
    Acute myocardial infarction
         subjects affected / exposed
    0 / 162 (0.00%)
    0 / 324 (0.00%)
    2 / 137 (1.46%)
    0 / 279 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Atrial fibrillation
         subjects affected / exposed
    0 / 162 (0.00%)
    0 / 324 (0.00%)
    1 / 137 (0.73%)
    0 / 279 (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
    Atrioventricular block complete
         subjects affected / exposed
    0 / 162 (0.00%)
    0 / 324 (0.00%)
    0 / 137 (0.00%)
    1 / 279 (0.36%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Atrioventricular block second degree
         subjects affected / exposed
    1 / 162 (0.62%)
    0 / 324 (0.00%)
    0 / 137 (0.00%)
    0 / 279 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Cardiac arrest
         subjects affected / exposed
    0 / 162 (0.00%)
    0 / 324 (0.00%)
    1 / 137 (0.73%)
    0 / 279 (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
    Cardiac failure
         subjects affected / exposed
    0 / 162 (0.00%)
    0 / 324 (0.00%)
    0 / 137 (0.00%)
    1 / 279 (0.36%)
         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
    Cardio-respiratory arrest
         subjects affected / exposed
    0 / 162 (0.00%)
    0 / 324 (0.00%)
    1 / 137 (0.73%)
    0 / 279 (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 / 1
    0 / 0
    Hypertensive heart disease
         subjects affected / exposed
    1 / 162 (0.62%)
    0 / 324 (0.00%)
    0 / 137 (0.00%)
    0 / 279 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    Myocardial ischaemia
         subjects affected / exposed
    0 / 162 (0.00%)
    0 / 324 (0.00%)
    1 / 137 (0.73%)
    0 / 279 (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 / 1
    0 / 0
    Respiratory, thoracic and mediastinal disorders
    Acute respiratory failure
         subjects affected / exposed
    0 / 162 (0.00%)
    2 / 324 (0.62%)
    1 / 137 (0.73%)
    4 / 279 (1.43%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 2
    0 / 1
    0 / 4
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    Aspiration
         subjects affected / exposed
    3 / 162 (1.85%)
    0 / 324 (0.00%)
    1 / 137 (0.73%)
    1 / 279 (0.36%)
         occurrences causally related to treatment / all
    0 / 4
    0 / 0
    0 / 2
    0 / 1
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 1
    Choking
         subjects affected / exposed
    1 / 162 (0.62%)
    0 / 324 (0.00%)
    1 / 137 (0.73%)
    0 / 279 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Chronic obstructive pulmonary disease
         subjects affected / exposed
    2 / 162 (1.23%)
    1 / 324 (0.31%)
    0 / 137 (0.00%)
    0 / 279 (0.00%)
         occurrences causally related to treatment / all
    0 / 3
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    Dyspnoea
         subjects affected / exposed
    0 / 162 (0.00%)
    2 / 324 (0.62%)
    0 / 137 (0.00%)
    0 / 279 (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
    Pleural effusion
         subjects affected / exposed
    0 / 162 (0.00%)
    0 / 324 (0.00%)
    1 / 137 (0.73%)
    0 / 279 (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
    Pneumonia aspiration
         subjects affected / exposed
    8 / 162 (4.94%)
    6 / 324 (1.85%)
    5 / 137 (3.65%)
    12 / 279 (4.30%)
         occurrences causally related to treatment / all
    0 / 9
    0 / 6
    0 / 6
    0 / 13
         deaths causally related to treatment / all
    0 / 4
    0 / 2
    0 / 1
    0 / 0
    Pneumothorax
         subjects affected / exposed
    1 / 162 (0.62%)
    0 / 324 (0.00%)
    0 / 137 (0.00%)
    0 / 279 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Pulmonary embolism
         subjects affected / exposed
    0 / 162 (0.00%)
    2 / 324 (0.62%)
    0 / 137 (0.00%)
    1 / 279 (0.36%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 2
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 1
    Pulmonary oedema
         subjects affected / exposed
    1 / 162 (0.62%)
    0 / 324 (0.00%)
    0 / 137 (0.00%)
    0 / 279 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Respiratory arrest
         subjects affected / exposed
    0 / 162 (0.00%)
    1 / 324 (0.31%)
    0 / 137 (0.00%)
    0 / 279 (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
    Respiratory depression
         subjects affected / exposed
    0 / 162 (0.00%)
    0 / 324 (0.00%)
    0 / 137 (0.00%)
    1 / 279 (0.36%)
         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 / 1
    Respiratory distress
         subjects affected / exposed
    1 / 162 (0.62%)
    0 / 324 (0.00%)
    0 / 137 (0.00%)
    0 / 279 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Respiratory failure
         subjects affected / exposed
    3 / 162 (1.85%)
    1 / 324 (0.31%)
    0 / 137 (0.00%)
    0 / 279 (0.00%)
         occurrences causally related to treatment / all
    0 / 3
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 2
    0 / 0
    0 / 0
    0 / 0
    Blood and lymphatic system disorders
    Anaemia
         subjects affected / exposed
    0 / 162 (0.00%)
    0 / 324 (0.00%)
    0 / 137 (0.00%)
    1 / 279 (0.36%)
         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
    Iron deficiency anaemia
         subjects affected / exposed
    1 / 162 (0.62%)
    1 / 324 (0.31%)
    1 / 137 (0.73%)
    0 / 279 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Nervous system disorders
    Akathisia
         subjects affected / exposed
    0 / 162 (0.00%)
    0 / 324 (0.00%)
    0 / 137 (0.00%)
    1 / 279 (0.36%)
         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
    Cerebral disorder
         subjects affected / exposed
    1 / 162 (0.62%)
    0 / 324 (0.00%)
    0 / 137 (0.00%)
    0 / 279 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Cerebrovascular accident
         subjects affected / exposed
    0 / 162 (0.00%)
    1 / 324 (0.31%)
    0 / 137 (0.00%)
    2 / 279 (0.72%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Dyskinesia
         subjects affected / exposed
    0 / 162 (0.00%)
    1 / 324 (0.31%)
    0 / 137 (0.00%)
    0 / 279 (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
    Encephalopathy
         subjects affected / exposed
    0 / 162 (0.00%)
    0 / 324 (0.00%)
    0 / 137 (0.00%)
    1 / 279 (0.36%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Epilepsy
         subjects affected / exposed
    0 / 162 (0.00%)
    2 / 324 (0.62%)
    0 / 137 (0.00%)
    0 / 279 (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
    Lumbosacral radiculopathy
         subjects affected / exposed
    1 / 162 (0.62%)
    0 / 324 (0.00%)
    0 / 137 (0.00%)
    0 / 279 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Metabolic encephalopathy
         subjects affected / exposed
    0 / 162 (0.00%)
    0 / 324 (0.00%)
    0 / 137 (0.00%)
    1 / 279 (0.36%)
         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
    Monoparesis
         subjects affected / exposed
    0 / 162 (0.00%)
    0 / 324 (0.00%)
    0 / 137 (0.00%)
    1 / 279 (0.36%)
         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
    Movement disorder
         subjects affected / exposed
    1 / 162 (0.62%)
    0 / 324 (0.00%)
    0 / 137 (0.00%)
    0 / 279 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Neurological decompensation
         subjects affected / exposed
    0 / 162 (0.00%)
    0 / 324 (0.00%)
    1 / 137 (0.73%)
    0 / 279 (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 / 1
    0 / 0
    Noninfective encephalitis
         subjects affected / exposed
    1 / 162 (0.62%)
    0 / 324 (0.00%)
    0 / 137 (0.00%)
    0 / 279 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    1 / 1
    0 / 0
    0 / 0
    0 / 0
    Peroneal nerve palsy
         subjects affected / exposed
    0 / 162 (0.00%)
    0 / 324 (0.00%)
    1 / 137 (0.73%)
    0 / 279 (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
    Progressive supranuclear palsy
         subjects affected / exposed
    3 / 162 (1.85%)
    6 / 324 (1.85%)
    5 / 137 (3.65%)
    4 / 279 (1.43%)
         occurrences causally related to treatment / all
    0 / 4
    0 / 6
    0 / 5
    0 / 4
         deaths causally related to treatment / all
    0 / 0
    0 / 4
    0 / 3
    0 / 3
    Seizure
         subjects affected / exposed
    0 / 162 (0.00%)
    0 / 324 (0.00%)
    0 / 137 (0.00%)
    2 / 279 (0.72%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Somnolence
         subjects affected / exposed
    0 / 162 (0.00%)
    0 / 324 (0.00%)
    1 / 137 (0.73%)
    0 / 279 (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
    Status epilepticus
         subjects affected / exposed
    0 / 162 (0.00%)
    0 / 324 (0.00%)
    1 / 137 (0.73%)
    0 / 279 (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
    Subarachnoid haemorrhage
         subjects affected / exposed
    0 / 162 (0.00%)
    1 / 324 (0.31%)
    0 / 137 (0.00%)
    0 / 279 (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
    Syncope
         subjects affected / exposed
    1 / 162 (0.62%)
    2 / 324 (0.62%)
    1 / 137 (0.73%)
    2 / 279 (0.72%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 2
    0 / 1
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Transient ischaemic attack
         subjects affected / exposed
    1 / 162 (0.62%)
    0 / 324 (0.00%)
    1 / 137 (0.73%)
    0 / 279 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Gastrointestinal disorders
    Colitis microscopic
         subjects affected / exposed
    0 / 162 (0.00%)
    0 / 324 (0.00%)
    1 / 137 (0.73%)
    0 / 279 (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
    Constipation
         subjects affected / exposed
    1 / 162 (0.62%)
    1 / 324 (0.31%)
    0 / 137 (0.00%)
    0 / 279 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Diarrhoea
         subjects affected / exposed
    0 / 162 (0.00%)
    0 / 324 (0.00%)
    0 / 137 (0.00%)
    1 / 279 (0.36%)
         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
    Dysphagia
         subjects affected / exposed
    5 / 162 (3.09%)
    3 / 324 (0.93%)
    1 / 137 (0.73%)
    4 / 279 (1.43%)
         occurrences causally related to treatment / all
    1 / 5
    0 / 3
    0 / 1
    0 / 4
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    Faecaloma
         subjects affected / exposed
    1 / 162 (0.62%)
    0 / 324 (0.00%)
    0 / 137 (0.00%)
    0 / 279 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Femoral hernia
         subjects affected / exposed
    0 / 162 (0.00%)
    1 / 324 (0.31%)
    0 / 137 (0.00%)
    0 / 279 (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
    Gastritis
         subjects affected / exposed
    0 / 162 (0.00%)
    1 / 324 (0.31%)
    0 / 137 (0.00%)
    0 / 279 (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
    Hernial eventration
         subjects affected / exposed
    0 / 162 (0.00%)
    0 / 324 (0.00%)
    0 / 137 (0.00%)
    1 / 279 (0.36%)
         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
    Hiatus hernia
         subjects affected / exposed
    1 / 162 (0.62%)
    0 / 324 (0.00%)
    0 / 137 (0.00%)
    0 / 279 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Large intestine polyp
         subjects affected / exposed
    0 / 162 (0.00%)
    0 / 324 (0.00%)
    0 / 137 (0.00%)
    1 / 279 (0.36%)
         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
    Melaena
         subjects affected / exposed
    1 / 162 (0.62%)
    0 / 324 (0.00%)
    0 / 137 (0.00%)
    0 / 279 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Umbilical hernia
         subjects affected / exposed
    0 / 162 (0.00%)
    0 / 324 (0.00%)
    0 / 137 (0.00%)
    1 / 279 (0.36%)
         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
    Upper gastrointestinal haemorrhage
         subjects affected / exposed
    1 / 162 (0.62%)
    0 / 324 (0.00%)
    0 / 137 (0.00%)
    0 / 279 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Volvulus
         subjects affected / exposed
    1 / 162 (0.62%)
    0 / 324 (0.00%)
    0 / 137 (0.00%)
    0 / 279 (0.00%)
         occurrences causally related to treatment / all
    0 / 3
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Vomiting
         subjects affected / exposed
    1 / 162 (0.62%)
    0 / 324 (0.00%)
    0 / 137 (0.00%)
    0 / 279 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Renal and urinary disorders
    Acute kidney injury
         subjects affected / exposed
    0 / 162 (0.00%)
    2 / 324 (0.62%)
    0 / 137 (0.00%)
    1 / 279 (0.36%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 2
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Calculus urinary
         subjects affected / exposed
    1 / 162 (0.62%)
    0 / 324 (0.00%)
    0 / 137 (0.00%)
    0 / 279 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Hydronephrosis
         subjects affected / exposed
    0 / 162 (0.00%)
    0 / 324 (0.00%)
    0 / 137 (0.00%)
    1 / 279 (0.36%)
         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
    Nephrolithiasis
         subjects affected / exposed
    0 / 162 (0.00%)
    1 / 324 (0.31%)
    0 / 137 (0.00%)
    0 / 279 (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
    Renal impairment
         subjects affected / exposed
    0 / 162 (0.00%)
    0 / 324 (0.00%)
    0 / 137 (0.00%)
    1 / 279 (0.36%)
         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
    Ureterolithiasis
         subjects affected / exposed
    0 / 162 (0.00%)
    0 / 324 (0.00%)
    0 / 137 (0.00%)
    1 / 279 (0.36%)
         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
    Urge incontinence
         subjects affected / exposed
    1 / 162 (0.62%)
    0 / 324 (0.00%)
    0 / 137 (0.00%)
    0 / 279 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Urinary retention
         subjects affected / exposed
    1 / 162 (0.62%)
    1 / 324 (0.31%)
    0 / 137 (0.00%)
    1 / 279 (0.36%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Hepatobiliary disorders
    Cholelithiasis
         subjects affected / exposed
    0 / 162 (0.00%)
    1 / 324 (0.31%)
    0 / 137 (0.00%)
    0 / 279 (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
    Skin and subcutaneous tissue disorders
    Dermal cyst
         subjects affected / exposed
    1 / 162 (0.62%)
    0 / 324 (0.00%)
    0 / 137 (0.00%)
    0 / 279 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Musculoskeletal and connective tissue disorders
    Arthralgia
         subjects affected / exposed
    0 / 162 (0.00%)
    2 / 324 (0.62%)
    0 / 137 (0.00%)
    0 / 279 (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
    Chondrocalcinosis
         subjects affected / exposed
    0 / 162 (0.00%)
    1 / 324 (0.31%)
    0 / 137 (0.00%)
    0 / 279 (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
    Haematoma muscle
         subjects affected / exposed
    0 / 162 (0.00%)
    1 / 324 (0.31%)
    0 / 137 (0.00%)
    0 / 279 (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
    Muscle rigidity
         subjects affected / exposed
    0 / 162 (0.00%)
    0 / 324 (0.00%)
    0 / 137 (0.00%)
    1 / 279 (0.36%)
         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
    Osteitis
         subjects affected / exposed
    0 / 162 (0.00%)
    0 / 324 (0.00%)
    0 / 137 (0.00%)
    1 / 279 (0.36%)
         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
    Osteoarthritis
         subjects affected / exposed
    0 / 162 (0.00%)
    0 / 324 (0.00%)
    0 / 137 (0.00%)
    1 / 279 (0.36%)
         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
    Pain in extremity
         subjects affected / exposed
    0 / 162 (0.00%)
    0 / 324 (0.00%)
    1 / 137 (0.73%)
    0 / 279 (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
    Metabolism and nutrition disorders
    Dehydration
         subjects affected / exposed
    0 / 162 (0.00%)
    1 / 324 (0.31%)
    1 / 137 (0.73%)
    1 / 279 (0.36%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Diabetes mellitus inadequate control
         subjects affected / exposed
    1 / 162 (0.62%)
    0 / 324 (0.00%)
    0 / 137 (0.00%)
    0 / 279 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Failure to thrive
         subjects affected / exposed
    0 / 162 (0.00%)
    2 / 324 (0.62%)
    0 / 137 (0.00%)
    0 / 279 (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 / 2
    0 / 0
    0 / 0
    Infections and infestations
    Abscess neck
         subjects affected / exposed
    1 / 162 (0.62%)
    1 / 324 (0.31%)
    0 / 137 (0.00%)
    0 / 279 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Bacteraemia
         subjects affected / exposed
    0 / 162 (0.00%)
    0 / 324 (0.00%)
    0 / 137 (0.00%)
    2 / 279 (0.72%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    Bacterial infection
         subjects affected / exposed
    1 / 162 (0.62%)
    0 / 324 (0.00%)
    0 / 137 (0.00%)
    0 / 279 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Bronchitis
         subjects affected / exposed
    0 / 162 (0.00%)
    1 / 324 (0.31%)
    0 / 137 (0.00%)
    2 / 279 (0.72%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Clostridium difficile colitis
         subjects affected / exposed
    0 / 162 (0.00%)
    0 / 324 (0.00%)
    0 / 137 (0.00%)
    1 / 279 (0.36%)
         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
    Cystitis
         subjects affected / exposed
    0 / 162 (0.00%)
    1 / 324 (0.31%)
    0 / 137 (0.00%)
    0 / 279 (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
    Diverticulitis
         subjects affected / exposed
    0 / 162 (0.00%)
    1 / 324 (0.31%)
    0 / 137 (0.00%)
    0 / 279 (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
    Escherichia urinary tract infection
         subjects affected / exposed
    0 / 162 (0.00%)
    0 / 324 (0.00%)
    0 / 137 (0.00%)
    1 / 279 (0.36%)
         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
    Gastroenteritis
         subjects affected / exposed
    1 / 162 (0.62%)
    0 / 324 (0.00%)
    0 / 137 (0.00%)
    0 / 279 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Infection
         subjects affected / exposed
    1 / 162 (0.62%)
    0 / 324 (0.00%)
    0 / 137 (0.00%)
    0 / 279 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Influenza
         subjects affected / exposed
    1 / 162 (0.62%)
    1 / 324 (0.31%)
    0 / 137 (0.00%)
    1 / 279 (0.36%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Parainfluenzae virus infection
         subjects affected / exposed
    0 / 162 (0.00%)
    0 / 324 (0.00%)
    0 / 137 (0.00%)
    1 / 279 (0.36%)
         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
    Pneumonia
         subjects affected / exposed
    0 / 162 (0.00%)
    10 / 324 (3.09%)
    5 / 137 (3.65%)
    6 / 279 (2.15%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 11
    0 / 5
    0 / 7
         deaths causally related to treatment / all
    0 / 0
    0 / 2
    0 / 0
    0 / 2
    Pneumonia influenzal
         subjects affected / exposed
    0 / 162 (0.00%)
    1 / 324 (0.31%)
    0 / 137 (0.00%)
    0 / 279 (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
    Pulmonary sepsis
         subjects affected / exposed
    0 / 162 (0.00%)
    1 / 324 (0.31%)
    0 / 137 (0.00%)
    0 / 279 (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 / 1
    0 / 0
    0 / 0
    Pulmonary tuberculosis
         subjects affected / exposed
    0 / 162 (0.00%)
    1 / 324 (0.31%)
    0 / 137 (0.00%)
    0 / 279 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    1 / 1
    0 / 0
    0 / 0
    Respiratory syncytial virus bronchitis
         subjects affected / exposed
    0 / 162 (0.00%)
    1 / 324 (0.31%)
    0 / 137 (0.00%)
    0 / 279 (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
    Respiratory tract infection
         subjects affected / exposed
    0 / 162 (0.00%)
    2 / 324 (0.62%)
    0 / 137 (0.00%)
    0 / 279 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 3
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Sepsis
         subjects affected / exposed
    0 / 162 (0.00%)
    2 / 324 (0.62%)
    1 / 137 (0.73%)
    2 / 279 (0.72%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 2
    0 / 1
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    Septic shock
         subjects affected / exposed
    0 / 162 (0.00%)
    0 / 324 (0.00%)
    1 / 137 (0.73%)
    0 / 279 (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
    Subcutaneous abscess
         subjects affected / exposed
    1 / 162 (0.62%)
    0 / 324 (0.00%)
    0 / 137 (0.00%)
    0 / 279 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Urinary tract infection
         subjects affected / exposed
    3 / 162 (1.85%)
    1 / 324 (0.31%)
    2 / 137 (1.46%)
    4 / 279 (1.43%)
         occurrences causally related to treatment / all
    0 / 3
    0 / 1
    0 / 2
    0 / 4
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Urosepsis
         subjects affected / exposed
    0 / 162 (0.00%)
    0 / 324 (0.00%)
    0 / 137 (0.00%)
    1 / 279 (0.36%)
         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 / 1
    Viral infection
         subjects affected / exposed
    0 / 162 (0.00%)
    1 / 324 (0.31%)
    0 / 137 (0.00%)
    0 / 279 (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
    Wound infection staphylococcal
         subjects affected / exposed
    0 / 162 (0.00%)
    1 / 324 (0.31%)
    0 / 137 (0.00%)
    0 / 279 (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
    Frequency threshold for reporting non-serious adverse events: 5%
    Non-serious adverse events
    Placebo (PC Period) BIIB092 2000 mg (PC Period) BIIB092 late start (OLE Period) BIIB092 early start (OLE Period)
    Total subjects affected by non serious adverse events
         subjects affected / exposed
    127 / 162 (78.40%)
    235 / 324 (72.53%)
    69 / 137 (50.36%)
    130 / 279 (46.59%)
    Vascular disorders
    Haematoma
         subjects affected / exposed
    11 / 162 (6.79%)
    24 / 324 (7.41%)
    7 / 137 (5.11%)
    11 / 279 (3.94%)
         occurrences all number
    17
    35
    9
    14
    Injury, poisoning and procedural complications
    Contusion
         subjects affected / exposed
    24 / 162 (14.81%)
    41 / 324 (12.65%)
    15 / 137 (10.95%)
    24 / 279 (8.60%)
         occurrences all number
    42
    63
    19
    33
    Fall
         subjects affected / exposed
    83 / 162 (51.23%)
    174 / 324 (53.70%)
    45 / 137 (32.85%)
    79 / 279 (28.32%)
         occurrences all number
    204
    359
    91
    138
    Head injury
         subjects affected / exposed
    8 / 162 (4.94%)
    21 / 324 (6.48%)
    4 / 137 (2.92%)
    8 / 279 (2.87%)
         occurrences all number
    10
    24
    5
    8
    Skin abrasion
         subjects affected / exposed
    10 / 162 (6.17%)
    28 / 324 (8.64%)
    7 / 137 (5.11%)
    12 / 279 (4.30%)
         occurrences all number
    26
    46
    10
    18
    Skin laceration
         subjects affected / exposed
    18 / 162 (11.11%)
    40 / 324 (12.35%)
    8 / 137 (5.84%)
    14 / 279 (5.02%)
         occurrences all number
    26
    52
    15
    16
    Nervous system disorders
    Dizziness
         subjects affected / exposed
    13 / 162 (8.02%)
    18 / 324 (5.56%)
    0 / 137 (0.00%)
    3 / 279 (1.08%)
         occurrences all number
    17
    20
    0
    4
    Headache
         subjects affected / exposed
    22 / 162 (13.58%)
    31 / 324 (9.57%)
    3 / 137 (2.19%)
    13 / 279 (4.66%)
         occurrences all number
    31
    46
    3
    22
    Psychiatric disorders
    Insomnia
         subjects affected / exposed
    14 / 162 (8.64%)
    16 / 324 (4.94%)
    4 / 137 (2.92%)
    10 / 279 (3.58%)
         occurrences all number
    14
    18
    4
    11
    Gastrointestinal disorders
    Constipation
         subjects affected / exposed
    15 / 162 (9.26%)
    36 / 324 (11.11%)
    4 / 137 (2.92%)
    16 / 279 (5.73%)
         occurrences all number
    15
    38
    4
    19
    Diarrhoea
         subjects affected / exposed
    9 / 162 (5.56%)
    23 / 324 (7.10%)
    4 / 137 (2.92%)
    9 / 279 (3.23%)
         occurrences all number
    11
    26
    6
    9
    Musculoskeletal and connective tissue disorders
    Arthralgia
         subjects affected / exposed
    7 / 162 (4.32%)
    18 / 324 (5.56%)
    0 / 137 (0.00%)
    3 / 279 (1.08%)
         occurrences all number
    9
    19
    0
    3
    Musculoskeletal pain
         subjects affected / exposed
    6 / 162 (3.70%)
    19 / 324 (5.86%)
    2 / 137 (1.46%)
    3 / 279 (1.08%)
         occurrences all number
    7
    19
    2
    3
    Back pain
         subjects affected / exposed
    9 / 162 (5.56%)
    15 / 324 (4.63%)
    3 / 137 (2.19%)
    11 / 279 (3.94%)
         occurrences all number
    11
    16
    8
    11
    Pain in extremity
         subjects affected / exposed
    7 / 162 (4.32%)
    17 / 324 (5.25%)
    0 / 137 (0.00%)
    5 / 279 (1.79%)
         occurrences all number
    7
    17
    0
    5
    Infections and infestations
    Nasopharyngitis
         subjects affected / exposed
    14 / 162 (8.64%)
    28 / 324 (8.64%)
    6 / 137 (4.38%)
    16 / 279 (5.73%)
         occurrences all number
    15
    32
    6
    19
    Urinary tract infection
         subjects affected / exposed
    31 / 162 (19.14%)
    56 / 324 (17.28%)
    15 / 137 (10.95%)
    36 / 279 (12.90%)
         occurrences all number
    44
    85
    18
    40

    More information

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    Substantial protocol amendments (globally)

    Were there any global substantial amendments to the protocol? Yes
    Date
    Amendment
    25 Aug 2017
    Sponsor name from BMS to Biogen. This includes replacing the BMS title page with the Biogen title page, inserting the Biogen Sponsor Signature Page and Biogen Sponsor Information section, changing the compound name from BMS-986168 to BIIB092 throughout the document, and changing the study name from CN002012 to 251PP301.
    13 Sep 2017
    Sponsor name changed from BMS to Biogen. This includes replacing the BMS title page with the Biogen title page, inserting the Biogen Sponsor Signature Page and Biogen Sponsor Information section, changing the compound name from BMS-986168 to BIIB092 throughout the document, and changing the study name from CN002012 to 251PP301.
    14 Nov 2017
    Missing safety assessment, 12-lead electrocardiogram (ECG), and instruction to the assess infusion site to the double-blind schedule of events was added.
    16 May 2018
    Increase in the study sample size.
    24 May 2018
    An error was corrected in the decision criteria that would allow a subject who no longer has an active hepatitis C infection to enroll in the study.
    01 Feb 2019
    The study treatment product provided for use in the open-label extension period, to include the 2000 milligram per vial (mg/vial).

    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.
    Study got terminated as the primary endpoint was not met. PC period was completed at the time of termination. The study was not terminated due to a safety concern.
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