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    Clinical Trial Results:
    An Extension Study to Assess the Long-Term Safety, Tolerability, Pharmacokinetics, and Effect on Disease Progression of BIIB067 Administered to Previously Treated Adults With Amyotrophic Lateral Sclerosis Caused by Superoxide Dismutase 1 Mutation

    Summary
    EudraCT number
    		 2016-003225-41
    Trial protocol
    		 BE   GB   DE   DK   PL   ES   IT  
    Global end of trial date
    12 Aug 2024

    Results information
    Results version number
    		 v1(current)
    This version publication date
    28 Aug 2025
    First version publication date
    28 Aug 2025
    Other versions

    Trial information

    		 Close Top of page
    Trial identification
    Sponsor protocol code
    233AS102
    Additional study identifiers
    ISRCTN number
    		 -
    US NCT number
    		 NCT03070119
    WHO universal trial number (UTN)
    		 -
    Sponsors
    Sponsor organisation name
    Biogen
    Sponsor organisation address
    225 Binney Street, Cambridge, United States, 02142
    Public contact
    Study Medical Director, Biogen, clinicaltrials@biogen.com
    Scientific contact
    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
    12 Aug 2024
    Is this the analysis of the primary completion data?
    No
    Global end of trial reached?
    Yes
    Global end of trial date
    12 Aug 2024
    Was the trial ended prematurely?
    No
    General information about the trial
    Main objective of the trial
    The primary objective of the study was to evaluate the long-term safety and tolerability of BIIB067 (tofersen) in participants with amyotrophic lateral sclerosis (ALS) and confirmed superoxide dismutase 1 (SOD1) mutation. The secondary objectives were to evaluate the pharmacokinetic (PK), pharmacodynamic (PD), biomarker effects, and efficacy of BIIB067 administered to participants with ALS and a confirmed SOD1 mutation.
    Protection of trial subjects
    Written informed consent was obtained from each subject’s parent or legal guardian prior to evaluations being performed for eligibility. Adequate time to review the information in the informed consent and ask questions concerning all portions of the conduct of the study was provided. Through the informed consent process, awareness of the purpose of the study, the procedures, the benefits and risks of the study, the discomforts and the precautions taken was made. Any side effects or other health issues occurring during the study were followed up by the study doctor. Subjects were able to stop taking part in the study at any time without giving any reason.
    Background therapy
    		 -
    Evidence for comparator
    		 -
    Actual start date of recruitment
    08 Mar 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
    Belgium: 11
    Country: Number of subjects enrolled
    Canada: 21
    Country: Number of subjects enrolled
    Denmark: 1
    Country: Number of subjects enrolled
    France: 5
    Country: Number of subjects enrolled
    Germany: 10
    Country: Number of subjects enrolled
    Italy: 5
    Country: Number of subjects enrolled
    Japan: 7
    Country: Number of subjects enrolled
    United Kingdom: 12
    Country: Number of subjects enrolled
    United States: 67
    Worldwide total number of subjects
    139
    EEA total number of subjects
    32
    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)
    122
    From 65 to 84 years
    17
    85 years and over
    0

    Subject disposition

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    Recruitment
    Recruitment details
    		 Participants were enrolled and took part at the investigative sites in Belgium, Canada, France, Germany, Italy, Japan, Denmark, the United Kingdom, and the United States from 08 Mar 2017 to 12 Aug 2024.

    Pre-assignment
    Screening details
    		 A total of 139 participants were randomized in the study, of which 95 participants rolled over from Part C and 44 participants rolled over from Parts A and B of the parent study 233AS101 (NCT02623699).

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

    Arms
    Are arms mutually exclusive
    Yes

    Arm title
    		 233AS101: Part C (Prior Placebo)
    Arm description
    		 Participants who were randomized to placebo in Part C of the parent study 233AS101 received 3 loading doses of BIIB067, 100mg, Q2W, on Days 1, 15, and 29 by IT bolus injection in this study followed by up to 90 maintenance doses of BIIB067, Q4W, until the last enrolled participant had their Week 152 maintenance dose visit.
    Arm type
    		 Experimental

    Investigational medicinal product name
    BIIB067
    Investigational medicinal product code
    ISIS666853
    Other name
    Tofersen, QALSODY
    Pharmaceutical forms
    Solution for injection
    Routes of administration
    Intrathecal use
    Dosage and administration details
    Subjects were administered BIIB067, 100 mg, as specified in treatment arm.

    Arm title
    		 233AS101: Part C (Prior BIIB067 100 mg)
    Arm description
    		 Participants who were randomized to BIIB067 100 mg in Part C of the parent study 233AS101 received 2 loading doses of BIIB067, 100 mg, on Days 1 and 29, and one dose of BIIB067-matched placebo on Day 15 by IT bolus injection in this study followed by up to 90 maintenance doses of BIIB067,Q4W, until the last enrolled participant had their Week 152 maintenance dose visit.
    Arm type
    		 Experimental

    Investigational medicinal product name
    BIIB067-matching Placebo
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Solution for injection
    Routes of administration
    Intrathecal use
    Dosage and administration details
    Subjects were administered BIIB067-matching placebo as specified in treatment arm.

    Investigational medicinal product name
    BIIB067
    Investigational medicinal product code
    ISIS666853
    Other name
    Tofersen, QALSODY
    Pharmaceutical forms
    Solution for injection
    Routes of administration
    Intrathecal use
    Dosage and administration details
    Subjects were administered BIIB067, 100 mg, as specified in treatment arm.

    Arm title
    		 233AS101: Part A and B (All doses)
    Arm description
    		 Participants who were randomized to BIIB067 or placebo in Part A (at doses 10 mg, 20 mg, 40 mg and 60 mg) or Part B (at doses 20 mg, 40 mg, 60 mg and 100 mg) of the parent study 233AS101 received 3 loading doses of BIIB067, 20 mg, 40 mg, 60 mg, or 100 mg, eventually escalated to 100 mg, 2 weeks apart, and up to 90 maintenance doses, Q4W, by IT bolus injection until the last enrolled participant had their Week 152 maintenance dose visit in this study.
    Arm type
    		 Experimental

    Investigational medicinal product name
    BIIB067
    Investigational medicinal product code
    ISIS666853
    Other name
    Tofersen, QALSODY
    Pharmaceutical forms
    Solution for injection
    Routes of administration
    Intrathecal use
    Dosage and administration details
    Subjects were administered BIIB067, 100 mg, as specified in treatment arm.

    Number of subjects in period 1
    		233AS101: Part C (Prior Placebo) 233AS101: Part C (Prior BIIB067 100 mg) 233AS101: Part A and B (All doses)
    Started
    32
    63
    44
    Completed
    12
    34
    26
    Not completed
    20
    29
    18
         Adverse event, serious fatal
    7
    14
    5
         Adverse event, non-fatal
    -
    -
    1
         Investigator Decision
    -
    -
    1
         Lost to follow-up
    -
    1
    -
         Disease Progression
    5
    7
    7
         Reason not Specified
    2
    2
    1
         Consent Withdrawn
    6
    5
    3

    Baseline characteristics

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    Baseline characteristics reporting groups
    Reporting group title
    233AS101: Part C (Prior Placebo)
    Reporting group description
    		 Participants who were randomized to placebo in Part C of the parent study 233AS101 received 3 loading doses of BIIB067, 100mg, Q2W, on Days 1, 15, and 29 by IT bolus injection in this study followed by up to 90 maintenance doses of BIIB067, Q4W, until the last enrolled participant had their Week 152 maintenance dose visit.

    Reporting group title
    233AS101: Part C (Prior BIIB067 100 mg)
    Reporting group description
    		 Participants who were randomized to BIIB067 100 mg in Part C of the parent study 233AS101 received 2 loading doses of BIIB067, 100 mg, on Days 1 and 29, and one dose of BIIB067-matched placebo on Day 15 by IT bolus injection in this study followed by up to 90 maintenance doses of BIIB067,Q4W, until the last enrolled participant had their Week 152 maintenance dose visit.

    Reporting group title
    233AS101: Part A and B (All doses)
    Reporting group description
    		 Participants who were randomized to BIIB067 or placebo in Part A (at doses 10 mg, 20 mg, 40 mg and 60 mg) or Part B (at doses 20 mg, 40 mg, 60 mg and 100 mg) of the parent study 233AS101 received 3 loading doses of BIIB067, 20 mg, 40 mg, 60 mg, or 100 mg, eventually escalated to 100 mg, 2 weeks apart, and up to 90 maintenance doses, Q4W, by IT bolus injection until the last enrolled participant had their Week 152 maintenance dose visit in this study.

    Reporting group values
    		 233AS101: Part C (Prior Placebo) 233AS101: Part C (Prior BIIB067 100 mg) 233AS101: Part A and B (All doses) Total
    Number of subjects
    		 32 63 44
    Age Categorical
    Units: Subjects
    Age continuous
    Units: years
        arithmetic mean (standard deviation)
    		 52.8 ( 11.00 ) 48.1 ( 11.80 ) 49.8 ( 11.04 ) -
    Gender categorical
    Units: Subjects
        Male
    		 17 39 25 81
        Female
    		 15 24 19 58
    Ethnicity
    Units: Subjects
        Hispanic or Latino
    		 1 3 0 4
        Not Hispanic or Latino
    		 25 40 26 91
        Unknown or Not Reported
    		 6 20 18 44
    Race
    Units: Subjects
        Asian
    		 4 4 1 9
        Black or African American
    		 0 1 0 1
        Native Hawaiian or Other Pacific Islander
    		 0 0 1 1
        White
    		 22 37 23 82
        Not Reported
    		 6 20 18 44
        Other
    		 0 1 1 2

    End points

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    End points reporting groups
    Reporting group title
    233AS101: Part C (Prior Placebo)
    Reporting group description
    		 Participants who were randomized to placebo in Part C of the parent study 233AS101 received 3 loading doses of BIIB067, 100mg, Q2W, on Days 1, 15, and 29 by IT bolus injection in this study followed by up to 90 maintenance doses of BIIB067, Q4W, until the last enrolled participant had their Week 152 maintenance dose visit.

    Reporting group title
    233AS101: Part C (Prior BIIB067 100 mg)
    Reporting group description
    		 Participants who were randomized to BIIB067 100 mg in Part C of the parent study 233AS101 received 2 loading doses of BIIB067, 100 mg, on Days 1 and 29, and one dose of BIIB067-matched placebo on Day 15 by IT bolus injection in this study followed by up to 90 maintenance doses of BIIB067,Q4W, until the last enrolled participant had their Week 152 maintenance dose visit.

    Reporting group title
    233AS101: Part A and B (All doses)
    Reporting group description
    		 Participants who were randomized to BIIB067 or placebo in Part A (at doses 10 mg, 20 mg, 40 mg and 60 mg) or Part B (at doses 20 mg, 40 mg, 60 mg and 100 mg) of the parent study 233AS101 received 3 loading doses of BIIB067, 20 mg, 40 mg, 60 mg, or 100 mg, eventually escalated to 100 mg, 2 weeks apart, and up to 90 maintenance doses, Q4W, by IT bolus injection until the last enrolled participant had their Week 152 maintenance dose visit in this study.

    Subject analysis set title
    233AS101&233AS102(Part C):Placebo+Delayed-start BIIB067 100mg
    Subject analysis set type
    		 Intention-to-treat
    Subject analysis set description
    Participants who were randomized to placebo in Part C of the parent study 233AS101 received 3 loading doses of BIIB067, 100 mg, Q2W, on Days 1, 15, and 29 by IT bolus injection in this study followed by up to 90 maintenance doses of BIIB067, Q4W, until the last enrolled participant had their Week 152 maintenance dose visit.

    Subject analysis set title
    233AS101 & 233AS102 (Part C): Early-start BIIB067 100 mg
    Subject analysis set type
    		 Intention-to-treat
    Subject analysis set description
    Participants who were randomized to BIIB067 100 mg in Part C of the parent study 233AS101 received 2 loading doses of BIIB067, 100 mg, on Days 1 and 29, and one dose of BIIB067-matched placebo on Day 15 by IT bolus injection in this study followed by up to 90 maintenance doses of BIIB067,Q4W, until the last enrolled participant had their Week 152 maintenance dose visit.

    Primary: Number of Participants With Treatment Emergent Adverse Events (TEAEs) and Treatment Emergent Serious AEs (TESAEs) 

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    End point title
    		 Number of Participants With Treatment Emergent Adverse Events (TEAEs) and Treatment Emergent Serious AEs (TESAEs)  [1]
    End point description
    AE: any untoward medical occurrence in a participant or clinical investigation participant administered a pharmaceutical product & that does not necessarily have a causal relationship with this treatment. An AE can therefore be any unfavorable & unintended sign (including an abnormal laboratory finding), symptom, or disease temporally associated with the use of a medicinal (investigational) product, whether or not related to the medicinal (investigational) product. An SAE is any untoward medical occurrence that at any dose results in death, life-threatening event, requires inpatient hospitalization, significant disability/incapacity or congenital anomaly. TEAEs were defined as any AE or SAE with an onset date & time that was on or after the first dose of study drug, or any pre-existing condition that worsened in severity after the first dose of study drug. Safety population included all participants who were enrolled and received at least one dose of study treatment in 233AS102.
    End point type
    Primary
    End point timeframe
    From first dose of the study drug in the current study up to end of follow-up period (up to Week 364)
    Notes
    [1] - No statistical analyses have been specified for this primary end point. It is expected there is at least one statistical analysis for each primary end point.
    Justification: Only descriptive statistics were planned for this endpoint.
    End point values
    		 233AS101: Part C (Prior Placebo) 233AS101: Part C (Prior BIIB067 100 mg) 233AS101: Part A and B (All doses)
    Number of subjects analysed
    32
    63
    44
    Units: participants
        TEAEs
    31
    63
    43
        TESAEs
    16
    33
    22
    No statistical analyses for this end point

    Secondary: Plasma Concentration of BIIB067

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    End point title
    		 Plasma Concentration of BIIB067 [2]
    End point description
    As planned, the plasma concentration of BIIB067 was summarised for 233AS101 Part C participants only. The pharmacokinetic (PK) population included all participants who received at least 1 dose of study treatment and had at least 1 post-dosing PK concentration measurement. ‘Subjects analysed’ signifies the number of participants evaluable for this outcome measure at the specified time point.
    End point type
    Secondary
    End point timeframe
    Week 4
    Notes
    [2] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
    Justification: Part C arms were planned to be analysed for this end point.
    End point values
    		 233AS101: Part C (Prior Placebo) 233AS101: Part C (Prior BIIB067 100 mg)
    Number of subjects analysed
    28
    60
    Units: nanograms per milliliter (ng/mL)
    arithmetic mean (standard error)
        Week 4
    1.22 ( 0.118 )
    2.05 ( 0.516 )
    No statistical analyses for this end point

    Secondary: Concentration of BIIB067 in Cerebrospinal Fluid (CSF)

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    End point title
    		 Concentration of BIIB067 in Cerebrospinal Fluid (CSF) [3]
    End point description
    As planned, the CSF concentration of BIIB067 was summarised for 233AS101 Part C participants only. The PK population included all participants who received at least 1 dose of study treatment and had at least 1 post-dosing PK concentration measurement. ‘Subjects analysed’ signifies number of participants evaluable for this outcome measure at the specified timepoint.
    End point type
    Secondary
    End point timeframe
    Week 4
    Notes
    [3] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
    Justification: Part C arms were planned to be analysed for this end point.
    End point values
    		 233AS101: Part C (Prior Placebo) 233AS101: Part C (Prior BIIB067 100 mg)
    Number of subjects analysed
    25
    47
    Units: ng/mL
    arithmetic mean (standard error)
        Week 4
    19.35 ( 2.829 )
    9.18 ( 0.711 )
    No statistical analyses for this end point

    Secondary: 233AS101 and 233AS102 Integrated Summary of Efficacy (ISE): Total CSF Superoxide Dismutase 1 (SOD1) Protein Ratio to Baseline

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    End point title
    		 233AS101 and 233AS102 Integrated Summary of Efficacy (ISE): Total CSF Superoxide Dismutase 1 (SOD1) Protein Ratio to Baseline
    End point description
    This endpoint as not a standalone analysis for 233AS102. Analysis was performed on the data collected from both 233AS101 and 233AS102 studies. This is reported as a part of the final integrated analyses. Baseline is defined as the Day 1 of 233AS101 Part C. Data has been reported for Weeks 52, 104 and 148 from the 233AS101 Part C baseline. Integrated analysis was performed on overall ITT population which included all Part C subjects of 233AS101 and subjects who rolled over from 233AS101 Part C into 233AS102. 'Subjects analysed' exceeds total number of subjects who started 233AS102 as it indicates subjects randomised in Part C of 233AS101 study. Number analyzed 'n' indicates the number of subjects evaluable for this endpoint at specified time point.
    End point type
    Secondary
    End point timeframe
    Baseline, Weeks 52, 104 and 148
    End point values
    		 233AS101&233AS102(Part C):Placebo+Delayed-start BIIB067 100mg 233AS101 & 233AS102 (Part C): Early-start BIIB067 100 mg
    Number of subjects analysed
    36
    72
    Units: ratio
    geometric mean (confidence interval 95%)
        Week 52 (n = 25, 52)
    0.78 (0.64 to 0.96)
    0.67 (0.57 to 0.79)
        Week 104 (n = 17, 44)
    0.81 (0.67 to 0.97)
    0.74 (0.65 to 0.84)
        Week 148 (n = 11, 41)
    0.75 (0.61 to 0.92)
    0.79 (0.69 to 0.91)
    Statistical analysis title
    		 Week 52
    Statistical analysis description
    The analysis was based on an analysis of covariance (ANCOVA) model with natural log transformed data. The model included covariates for the corresponding baseline value i.e. log value, and use of riluzole or edaravone. Multiple imputation (MI) including treatment group, use of riluzole or edaravone, and the relevant baseline and postbaseline values for the endpoint was used for missing data.
    Comparison groups
    233AS101&233AS102(Part C):Placebo+Delayed-start BIIB067 100mg v 233AS101 & 233AS102 (Part C): Early-start BIIB067 100 mg
    Number of subjects included in analysis
    108
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    Method
    Parameter type
    		 Least square (LS) geometric mean ratio
    Point estimate
    0.86
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.69
         upper limit
    		 1.08
    Statistical analysis title
    		 Week 148
    Statistical analysis description
    The analysis was based on an ANCOVA model with natural log transformed data. The model included covariates for the corresponding baseline value i.e. log value, and use of riluzole or edaravone. Multiple imputation including treatment group, use of riluzole or edaravone, and the relevant baseline and postbaseline values for the endpoint was used for missing data.
    Comparison groups
    233AS101&233AS102(Part C):Placebo+Delayed-start BIIB067 100mg v 233AS101 & 233AS102 (Part C): Early-start BIIB067 100 mg
    Number of subjects included in analysis
    108
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.6344 [4]
    Method
    		 ANCOVA
    Parameter type
    		 LS geometric mean ratio
    Point estimate
    1.06
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.84
         upper limit
    		 1.34
    Notes
    [4] - ANCOVA model using MI.
    Statistical analysis title
    		 Week 104
    Statistical analysis description
    The analysis was based on an ANCOVA model with natural log transformed data. The model included covariates for the corresponding baseline value i.e. log value, and use of riluzole or edaravone. Multiple imputation including treatment group, use of riluzole or edaravone, and the relevant baseline and postbaseline values for the endpoint was used for missing data.
    Comparison groups
    233AS101&233AS102(Part C):Placebo+Delayed-start BIIB067 100mg v 233AS101 & 233AS102 (Part C): Early-start BIIB067 100 mg
    Number of subjects included in analysis
    108
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.3711 [5]
    Method
    		 ANCOVA
    Parameter type
    		 LS geometric mean ratio
    Point estimate
    0.91
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.75
         upper limit
    		 1.11
    Notes
    [5] - ANCOVA model using MI.

    Secondary: 233AS101 and 233AS102 ISE: Neurofilament Light Chain (NfL) Plasma Concentration Ratio to Baseline

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    End point title
    		 233AS101 and 233AS102 ISE: Neurofilament Light Chain (NfL) Plasma Concentration Ratio to Baseline
    End point description
    This endpoint was not a standalone analysis for 233AS102. Analysis was performed on the data collected from both 233AS101 and 233AS102 studies. This is reported as a part of the final integrated analyses. Baseline is defined as the Day 1 of 233AS101 Part C. Data has been reported for Weeks 52, 104 and 148 from the 233AS101 Part C baseline. Integrated analysis was performed on overall ITT population which included all Part C subjects of 233AS101 and subjects who rolled over from 233AS101 Part C into 233AS102. 'Subjects analysed' exceeds total number of subjects who started 233AS102 as it indicates subjects randomised in Part C of 233AS101 study. Number analyzed 'n' indicates the number of subjects evaluable for this endpoint at specified time point.
    End point type
    Secondary
    End point timeframe
    Baseline, Weeks 52, 104 and 148
    End point values
    		 233AS101&233AS102(Part C):Placebo+Delayed-start BIIB067 100mg 233AS101 & 233AS102 (Part C): Early-start BIIB067 100 mg
    Number of subjects analysed
    36
    72
    Units: ratio
    geometric mean (confidence interval 95%)
        Week 52 (n = 23, 50)
    0.62 (0.49 to 0.78)
    0.50 (0.42 to 0.60)
        Week 104 (n = 18, 42)
    0.41 (0.30 to 0.55)
    0.33 (0.27 to 0.42)
        Week 148 (n = 11, 41)
    0.36 (0.25 to 0.53)
    0.33 (0.26 to 0.43)
    Statistical analysis title
    		 Week 52
    Statistical analysis description
    The analysis was based on an ANCOVA model with natural log transformed data. The model included covariates for the corresponding baseline value i.e. log value, and use of riluzole or edaravone. Multiple imputation including treatment group, use of riluzole or edaravone, and the relevant baseline and postbaseline values for the endpoint was used for missing data.
    Comparison groups
    233AS101&233AS102(Part C):Placebo+Delayed-start BIIB067 100mg v 233AS101 & 233AS102 (Part C): Early-start BIIB067 100 mg
    Number of subjects included in analysis
    108
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    Method
    Parameter type
    		 LS geometric mean ratio
    Point estimate
    0.8
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.63
         upper limit
    		 1.03
    Statistical analysis title
    		 Week 104
    Statistical analysis description
    The analysis was based on an ANCOVA model with natural log transformed data. The model included covariates for the corresponding baseline value i.e. log value, and use of riluzole or edaravone. Multiple imputation including treatment group, use of riluzole or edaravone, and the relevant baseline and postbaseline values for the endpoint was used for missing data.
    Comparison groups
    233AS101&233AS102(Part C):Placebo+Delayed-start BIIB067 100mg v 233AS101 & 233AS102 (Part C): Early-start BIIB067 100 mg
    Number of subjects included in analysis
    108
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.2306 [6]
    Method
    		 ANCOVA
    Parameter type
    		 LS geometric mean ratio
    Point estimate
    0.83
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.6
         upper limit
    		 1.13
    Notes
    [6] - ANCOVA model using MI.
    Statistical analysis title
    		 Week 148
    Statistical analysis description
    The analysis was based on an ANCOVA model with natural log transformed data. The model included covariates for the corresponding baseline value i.e. log value, and use of riluzole or edaravone. Multiple imputation including treatment group, use of riluzole or edaravone, and the relevant baseline and postbaseline values for the endpoint was used for missing data.
    Comparison groups
    233AS101&233AS102(Part C):Placebo+Delayed-start BIIB067 100mg v 233AS101 & 233AS102 (Part C): Early-start BIIB067 100 mg
    Number of subjects included in analysis
    108
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.673 [7]
    Method
    		 ANCOVA
    Parameter type
    		 LS geometric mean ratio
    Point estimate
    0.92
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.61
         upper limit
    		 1.38
    Notes
    [7] - ANCOVA model using MI.

    Secondary: 233AS101 and 233AS102 ISE: Change From Baseline in Total Amyotropic Lateral Sclerosis Functional Rating Scale - Revised (ALSFRS-R) Score

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    End point title
    		 233AS101 and 233AS102 ISE: Change From Baseline in Total Amyotropic Lateral Sclerosis Functional Rating Scale - Revised (ALSFRS-R) Score
    End point description
    ALSFRS-R measures 4 functional domains-respiratory, bulbar function, gross motor skills,& fine motor skills. There are 12 questions, each scored from 0 (no function) to 4 (full function).ALSFRS-R total score= sum of 4 functional domain scores, ranging from 0 to 48, where higher scores=better function. Negative change from baseline=disease progression. This endpoint was not a standalone analysis for 233AS102. Analysis was performed on data collected from 233AS101 & 233AS102 studies. This is reported as a part of final integrated analyses. Baseline=Day 1 of 233AS101 Part C. Data reported for Weeks 52, 104& 148 from 233AS101 Part C baseline. Integrated analysis was performed on overall ITT population. 'Subjects analysed' exceeds total number of subjects who started 233AS102 as it indicates subjects randomised in Part C of 233AS101 study. Number analyzed 'n' indicates the number of subjects evaluable for this endpoint at specified time point.
    End point type
    Secondary
    End point timeframe
    Baseline, Weeks 52, 104 and 148
    End point values
    		 233AS101&233AS102(Part C):Placebo+Delayed-start BIIB067 100mg 233AS101 & 233AS102 (Part C): Early-start BIIB067 100 mg
    Number of subjects analysed
    36
    72
    Units: score on a scale
    least squares mean (standard error)
        Week 52 (n=28, 57)
    -9.5 ( 1.46 )
    -5.9 ( 1.16 )
        Week 104 (n=20, 49)
    -13.1 ( 2.12 )
    -9.4 ( 1.69 )
        Week 148 (n=13, 46)
    -13.5 ( 2.28 )
    -9.9 ( 1.77 )
    Statistical analysis title
    		 Week 52
    Statistical analysis description
    The analysis was based on an ANCOVA model that included treatment as a fixed effect and adjusted for the following covariates: baseline plasma NfL, baseline ALSFRS-R total score, and use of riluzole or edaravone. Multiple imputation including treatment group, use of riluzole or edaravone, baseline NfL, and the relevant baseline and postbaseline values for the endpoint was used for missing data.
    Comparison groups
    233AS101&233AS102(Part C):Placebo+Delayed-start BIIB067 100mg v 233AS101 & 233AS102 (Part C): Early-start BIIB067 100 mg
    Number of subjects included in analysis
    108
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    Method
    Parameter type
    		 LS mean difference
    Point estimate
    3.6
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.5
         upper limit
    		 6.7
    Variability estimate
    Standard error of the mean
    Dispersion value
    1.58
    Statistical analysis title
    		 Week 148
    Statistical analysis description
    The analysis was based on an ANCOVA model that included treatment as a fixed effect and adjusted for the following covariates: baseline plasma NfL, baseline ALSFRS-R total score, and use of riluzole or edaravone. Multiple imputation including treatment group, use of riluzole or edaravone, baseline NfL, and the relevant baseline and postbaseline values for the endpoint was used for missing data.
    Comparison groups
    233AS101&233AS102(Part C):Placebo+Delayed-start BIIB067 100mg v 233AS101 & 233AS102 (Part C): Early-start BIIB067 100 mg
    Number of subjects included in analysis
    108
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.1432 [8]
    Method
    		 ANCOVA
    Parameter type
    		 LS mean difference
    Point estimate
    3.6
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -1.2
         upper limit
    		 8.4
    Variability estimate
    Standard error of the mean
    Dispersion value
    2.46
    Notes
    [8] - ANCOVA model using MI.
    Statistical analysis title
    		 Week 104
    Statistical analysis description
    The analysis was based on an ANCOVA model that included treatment as a fixed effect and adjusted for the following covariates: baseline plasma NfL, baseline ALSFRS-R total score, and use of riluzole or edaravone. Multiple imputation including treatment group, use of riluzole or edaravone, baseline NfL, and the relevant baseline and postbaseline values for the endpoint was used for missing data.
    Comparison groups
    233AS101&233AS102(Part C):Placebo+Delayed-start BIIB067 100mg v 233AS101 & 233AS102 (Part C): Early-start BIIB067 100 mg
    Number of subjects included in analysis
    108
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.1054 [9]
    Method
    		 ANCOVA
    Parameter type
    		 LS mean difference
    Point estimate
    3.7
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -0.8
         upper limit
    		 8.2
    Variability estimate
    Standard error of the mean
    Dispersion value
    2.28
    Notes
    [9] - ANCOVA model using MI.

    Secondary: 233AS101 and 233AS102 ISE: Change From Baseline in Percent Predicted Slow Vital Capacity (SVC)

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    End point title
    		 233AS101 and 233AS102 ISE: Change From Baseline in Percent Predicted Slow Vital Capacity (SVC)
    End point description
    Vital capacity was measured by means of SVC test, administered in upright position. Upright SVC was determined by performing 3 to 5 measures, per criteria established by American Thoracic Society &European Respiratory Society. Percent predicted SVC=[observed SVC/predicted SVC]*100%. Predicted SVC was adjusted by sex, age, height, programmed into & performed by equipment used. Negative change from baseline=worsening of respiratory capacity. This endpoint was not standalone analysis for 233AS102. Analysis was performed on data collected from 233AS101& 233AS102 studies. This is reported as part of final integrated analyses. Baseline=Day 1 of 233AS101 Part C. Data has been reported for Weeks 52,104 & 148 from 233AS101 Part C baseline.Integrated analysis performed on overall ITT population. 'Subjects analysed' exceeds number of subjects started 233AS102 as it indicates subjects randomised in Part C of 233AS101. Number analyzed 'n'=number of subjects evaluable at specified time point.
    End point type
    Secondary
    End point timeframe
    Baseline, Weeks 52, 104 and 148
    End point values
    		 233AS101&233AS102(Part C):Placebo+Delayed-start BIIB067 100mg 233AS101 & 233AS102 (Part C): Early-start BIIB067 100 mg
    Number of subjects analysed
    36
    72
    Units: percentage of predicted volume
    least squares mean (standard error)
        Week 52 (n = 20, 38)
    -18.7 ( 3.70 )
    -10.6 ( 2.99 )
        Week 104 (n = 10, 31)
    -23.7 ( 5.90 )
    -14.4 ( 4.46 )
        Week 148 (n = 10, 32)
    -18.1 ( 5.74 )
    -13.8 ( 4.07 )
    Statistical analysis title
    		 Week 52
    Statistical analysis description
    The analysis was based on an ANCOVA model that included treatment as a fixed effect and adjusted for the following covariates: baseline plasma NfL, baseline percent predicted SVC and use of riluzole or edaravone. Multiple imputation including treatment group, use of riluzole or edaravone, baseline NfL, and the relevant baseline and postbaseline values for the endpoint was used for missing data.
    Comparison groups
    233AS101&233AS102(Part C):Placebo+Delayed-start BIIB067 100mg v 233AS101 & 233AS102 (Part C): Early-start BIIB067 100 mg
    Number of subjects included in analysis
    108
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    Method
    Parameter type
    		 LS mean difference
    Point estimate
    8.1
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.3
         upper limit
    		 15.9
    Variability estimate
    Standard error of the mean
    Dispersion value
    3.99
    Statistical analysis title
    		 Week 104
    Statistical analysis description
    The analysis was based on an ANCOVA model that included treatment as a fixed effect and adjusted for the following covariates: baseline plasma NfL, baseline percent predicted SVC and use of riluzole or edaravone. Multiple imputation including treatment group, use of riluzole or edaravone, baseline NfL, and the relevant baseline and postbaseline values for the endpoint was used for missing data.
    Comparison groups
    233AS101&233AS102(Part C):Placebo+Delayed-start BIIB067 100mg v 233AS101 & 233AS102 (Part C): Early-start BIIB067 100 mg
    Number of subjects included in analysis
    108
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.0963 [10]
    Method
    		 ANCOVA
    Parameter type
    		 LS mean difference
    Point estimate
    9.3
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -1.7
         upper limit
    		 20.4
    Variability estimate
    Standard error of the mean
    Dispersion value
    5.6
    Notes
    [10] - ANCOVA model using MI.
    Statistical analysis title
    		 Week 148
    Statistical analysis description
    The analysis was based on an ANCOVA model that included treatment as a fixed effect and adjusted for the following covariates: baseline plasma NfL, baseline percent predicted SVC and use of riluzole or edaravone. Multiple imputation including treatment group, use of riluzole or edaravone, baseline NfL, and the relevant baseline and postbaseline values for the endpoint was used for missing data.
    Comparison groups
    233AS101&233AS102(Part C):Placebo+Delayed-start BIIB067 100mg v 233AS101 & 233AS102 (Part C): Early-start BIIB067 100 mg
    Number of subjects included in analysis
    108
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.4388 [11]
    Method
    		 ANCOVA
    Parameter type
    		 LS mean difference
    Point estimate
    4.3
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -6.6
         upper limit
    		 15.2
    Variability estimate
    Standard error of the mean
    Dispersion value
    5.56
    Notes
    [11] - ANCOVA model using MI.

    Secondary: 233AS101 and 233AS102 ISE: Change From Baseline in Handheld Dynamometry (HHD) Overall Megascore

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    End point title
    		 233AS101 and 233AS102 ISE: Change From Baseline in Handheld Dynamometry (HHD) Overall Megascore
    End point description
    Quantitative muscle strength was evaluated using HHD Megascore, which tests isometric strength of multiple muscles using standard participant positioning. Approximately 8 muscle groups were examined (per each side) in both upper & lower extremities. Muscle strength values were normalized to Z scores as (post-baseline measurements-mean)/SD & averaged to provide HHD overall megascore. Overall megascore was created by averaging all eight bilateral measurement Z scores, if no more than 10 (≤ 10) measures are missing. Negative change from baseline= decreased muscle strength. This endpoint was not a standalone analysis for 233AS102. Analysis was performed on data collected from 233AS101 & 233AS102 studies. This is reported as part of final integrated analyses. Baseline=Day 1 of 233AS101 Part C. Data has been reported for Weeks 52, 104 & 148 from 233AS101 Part C baseline. Integrated analysis was performed on overall ITT population (all Part C 233AS101 subjects & rolled over Part C subjects)
    End point type
    Secondary
    End point timeframe
    Baseline, Weeks 52, 104 and 148
    End point values
    		 233AS101&233AS102(Part C):Placebo+Delayed-start BIIB067 100mg 233AS101 & 233AS102 (Part C): Early-start BIIB067 100 mg
    Number of subjects analysed
    36
    72
    Units: score on a scale
    least squares mean (standard error)
        Week 52 (n = 25, 42)
    -0.41 ( 0.101 )
    -0.15 ( 0.079 )
        Week 104 (n = 10, 32)
    -0.56 ( 0.154 )
    -0.42 ( 0.112 )
        Week 148 (n = 10, 36)
    -0.43 ( 0.089 )
    -0.38 ( 0.062 )
    Statistical analysis title
    		 Week 52
    Statistical analysis description
    The analysis was based on an ANCOVA model that included treatment as a fixed effect and adjusted for the following covariates: baseline plasma NfL, baseline HHD overall megascore and use of riluzole or edaravone. Multiple imputation including treatment group, use of riluzole or edaravone, baseline NfL, and the relevant baseline and postbaseline values for the endpoint was used for missing data.
    Comparison groups
    233AS101&233AS102(Part C):Placebo+Delayed-start BIIB067 100mg v 233AS101 & 233AS102 (Part C): Early-start BIIB067 100 mg
    Number of subjects included in analysis
    108
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    Method
    Parameter type
    		 LS mean difference
    Point estimate
    0.26
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.051
         upper limit
    		 0.477
    Variability estimate
    Standard error of the mean
    Dispersion value
    0.109
    Statistical analysis title
    		 Week 104
    Statistical analysis description
    The analysis was based on an ANCOVA model that included treatment as a fixed effect and adjusted for the following covariates: baseline plasma NfL, baseline HHD overall megascore and use of riluzole or edaravone. Multiple imputation including treatment group, use of riluzole or edaravone, baseline NfL, and the relevant baseline and postbaseline values for the endpoint was used for missing data.
    Comparison groups
    233AS101&233AS102(Part C):Placebo+Delayed-start BIIB067 100mg v 233AS101 & 233AS102 (Part C): Early-start BIIB067 100 mg
    Number of subjects included in analysis
    108
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.3207 [12]
    Method
    		 ANCOVA
    Parameter type
    		 LS mean difference
    Point estimate
    0.14
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -0.141
         upper limit
    		 0.43
    Variability estimate
    Standard error of the mean
    Dispersion value
    0.145
    Notes
    [12] - ANCOVA model using MI.
    Statistical analysis title
    		 Week 148
    Statistical analysis description
    The analysis was based on an ANCOVA model that included treatment as a fixed effect and adjusted for the following covariates: baseline plasma NfL, baseline HHD overall megascore and use of riluzole or edaravone. Multiple imputation including treatment group, use of riluzole or edaravone, baseline NfL, and the relevant baseline and postbaseline values for the endpoint was used for missing data.
    Comparison groups
    233AS101&233AS102(Part C):Placebo+Delayed-start BIIB067 100mg v 233AS101 & 233AS102 (Part C): Early-start BIIB067 100 mg
    Number of subjects included in analysis
    108
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.5452 [13]
    Method
    		 ANCOVA
    Parameter type
    		 LS mean difference
    Point estimate
    0.06
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -0.124
         upper limit
    		 0.234
    Variability estimate
    Standard error of the mean
    Dispersion value
    0.091
    Notes
    [13] - ANCOVA model using MI.

    Secondary: 233AS101 and 233AS102 ISE: Change From Baseline in Individual Muscle Strength Assessed by HHD

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    End point title
    		 233AS101 and 233AS102 ISE: Change From Baseline in Individual Muscle Strength Assessed by HHD
    End point description
    Individual muscle strength was evaluated using handheld dynamometer, which tests the isometric strength of multiple muscles using standard participant positioning. Eight muscle groups were examined (per each side) in both upper and lower extremities. Negative change from baseline indicated decreased muscle strength. This outcome measure was not a standalone analysis for 233AS102. Analysis was performed on data collected from both 233AS101 & 233AS102 studies. This is reported as a part of final integrated analyses. Baseline=Day 1 of 233AS101 Part C. Data is reported for Weeks 52, 104&148 from 233AS101 Part C baseline. The analyses was based on observed data. Integrated analysis was performed on overall ITT population. 'Subjects analysed' exceeds number of subjects who started 233AS102 as it indicates subjects randomised in Part C of 233AS101 study. 'n'=the number of subjects evaluable at specified time point.
    End point type
    Secondary
    End point timeframe
    Baseline, Weeks 52, 104 and 148
    End point values
    		 233AS101&233AS102(Part C):Placebo+Delayed-start BIIB067 100mg 233AS101 & 233AS102 (Part C): Early-start BIIB067 100 mg
    Number of subjects analysed
    36
    72
    Units: kilogram (kg)
    arithmetic mean (standard deviation)
        Left Shoulder Flexion: Week 52 (n = 25, 41)
    -3.42 ( 6.671 )
    -0.51 ( 8.484 )
        Left Shoulder Flexion: Week 104 (n = 10, 32)
    0.17 ( 5.714 )
    -4.16 ( 14.329 )
        Left Shoulder Flexion: Week 148 (n = 10, 36)
    -2.48 ( 5.075 )
    -4.12 ( 8.543 )
        Left Elbow Flexion: Week 52 (n = 25, 42)
    -3.89 ( 6.747 )
    -0.24 ( 8.031 )
        Left Elbow Flexion: Week 104 (n = 10, 32)
    -1.26 ( 7.361 )
    -3.12 ( 13.334 )
        Left Elbow Flexion: Week 148 (n = 10, 36)
    0.65 ( 4.560 )
    -3.33 ( 8.753 )
        Left Wrist Extension: Week 52 (n = 25, 41)
    -3.66 ( 4.775 )
    -0.41 ( 7.170 )
        Left Wrist Extension: Week 104 (n = 10, 32)
    -0.86 ( 5.279 )
    -1.74 ( 8.517 )
        Left Wrist Extension: Week 148 (n = 10, 36)
    0.95 ( 5.242 )
    -2.49 ( 6.086 )
        Lt.AbductionIndex1stDorsalInterosseousWk52n=25,42
    -0.96 ( 1.450 )
    -0.93 ( 4.448 )
        Lt.AbductionIndex1stDorsalInterosseosWk104n=10,32
    -0.63 ( 1.266 )
    -0.62 ( 2.279 )
        Lt.AbductionIndex1stDorsalInterosseosWk148n=10,36
    -0.41 ( 1.604 )
    -1.28 ( 4.913 )
        Lt.AbductionThumbAbductorPollicusBrvisWk52n=25,41
    -1.15 ( 1.486 )
    -0.70 ( 2.497 )
        LtAbductionThumbAbductorPollicusBrvisWk104n=10,32
    -0.69 ( 1.089 )
    -0.19 ( 2.382 )
        LtAbductionThumbAbductorPollicusBrvisWk148n=10,36
    -1.10 ( 2.324 )
    -0.78 ( 3.049 )
        LtAbduction5thDigitAbductorDigitiMiniWk52n=25,41
    -0.66 ( 1.208 )
    -0.49 ( 2.296 )
        LtAbduction5thDigitAbductorDigitiMiniWk104n=10,31
    -0.47 ( 1.226 )
    -0.50 ( 1.999 )
        LtAbduction5thDigitAbductorDigitiMiniWk148n=10,36
    -0.43 ( 1.496 )
    -0.66 ( 2.394 )
        Left Knee Extension: Week 52 (n = 25, 42)
    -4.94 ( 8.015 )
    1.80 ( 10.744 )
        Left Knee Extension: Week 104 (n = 10, 32)
    -2.41 ( 6.545 )
    -1.54 ( 13.222 )
        Left Knee Extension: Week 148 (n = 10, 35)
    -2.48 ( 7.339 )
    -2.01 ( 9.711 )
        Left Ankle Dorsiflexion: Week 52 (n = 25, 42)
    -2.82 ( 7.560 )
    0.72 ( 7.701 )
        Left Ankle Dorsiflexion: Week 104 (n = 10, 31)
    -5.47 ( 3.590 )
    -4.20 ( 11.516 )
        Left Ankle Dorsiflexion: Week 148 (n = 10, 35)
    -5.43 ( 5.303 )
    -2.33 ( 9.533 )
        Right Shoulder Flexion: Week 52 (n = 25, 41)
    -4.74 ( 5.494 )
    -0.96 ( 5.728 )
        Right Shoulder Flexion: Week 104 (n = 10, 32)
    -2.72 ( 4.638 )
    -2.81 ( 9.304 )
        Right Shoulder Flexion: Week 148 (n = 10, 36)
    -3.02 ( 5.066 )
    -3.18 ( 8.139 )
        Right Elbow Flexion: Week 52 (n = 25, 41)
    -4.03 ( 5.663 )
    -1.20 ( 7.015 )
        Right Elbow Flexion: Week 104 (n = 10, 31)
    -1.32 ( 6.289 )
    -3.04 ( 9.717 )
        Right Elbow Flexion: Week 148 (n = 10, 35)
    0.49 ( 3.407 )
    -3.28 ( 8.704 )
        Right Wrist Extension: Week 52 (n = 25, 42)
    -3.82 ( 5.892 )
    -0.63 ( 4.870 )
        Right Wrist Extension: Week 104 (n = 10, 32)
    -0.76 ( 4.086 )
    -1.65 ( 6.267 )
        Right Wrist Extension: Week 148 (n = 10, 36)
    0.09 ( 5.096 )
    -1.89 ( 5.033 )
        Rt.AbductionIndex1stDorsalInterosseosWk52n=25,42
    -0.86 ( 1.381 )
    -0.36 ( 1.405 )
        Rt.AbductionIndex1stDorsalInterosseosWk104n=10,31
    -0.38 ( 1.057 )
    -0.45 ( 1.569 )
        Rt.AbductionIndex1stDorsalInterosseosWk148n=10,36
    -0.23 ( 1.545 )
    -0.46 ( 1.193 )
        Rt.AbductionThumbAbductorPollicusBrvisWk52n=25,41
    -0.98 ( 1.425 )
    -1.24 ( 4.595 )
        RtAbductionThumbAbductorPollicusBrvisWk104n=10,32
    -0.31 ( 0.947 )
    -0.24 ( 2.016 )
        RtAbductionThumbAbductorPollicusBrvisWk148n=10,36
    -0.86 ( 1.861 )
    -1.10 ( 5.247 )
        RtAbduction5thDigitAbductorDigitiMiniWk52n=25,41
    -0.78 ( 1.210 )
    -1.12 ( 5.112 )
        RtAbduction5thDigitAbductorDigitiMiniWk104n=10,31
    -0.54 ( 1.059 )
    -0.21 ( 1.639 )
        RtAbduction5thDigitAbductorDigitiMiniWk148n=10,36
    -0.69 ( 1.009 )
    -1.36 ( 5.634 )
        Right Knee Extension: Week 52 (n = 25, 42)
    -4.90 ( 5.964 )
    1.05 ( 8.973 )
        Right Knee Extension: Week 104 (n = 10, 32)
    -2.16 ( 9.453 )
    -3.09 ( 13.046 )
        Right Knee Extension: Week 148 (n = 10, 35)
    -0.19 ( 7.407 )
    -1.60 ( 7.685 )
        Right Ankle Dorsiflexion: Week 52 (n = 25, 42)
    -5.68 ( 8.907 )
    -1.05 ( 5.923 )
        Right Ankle Dorsiflexion: Week 104 (n = 10, 32)
    -5.86 ( 3.501 )
    -3.78 ( 13.008 )
        Right Ankle Dorsiflexion: Week 148 (n = 10, 36)
    -6.74 ( 7.308 )
    -3.40 ( 8.172 )
    No statistical analyses for this end point

    Secondary: 233AS101 and 233AS102 ISE: Time to Death or Permanent Ventilation

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    End point title
    		 233AS101 and 233AS102 ISE: Time to Death or Permanent Ventilation
    End point description
    Permanent ventilation: ≥ 22 hours of mechanical ventilation [invasive /noninvasive] per day for ≥ 21 consecutive days. Event of permanent ventilation based on an adjudicated event (i.e., adjudicated by Endpoint Adjudication Committee (EAC) as having met permanent ventilation criteria defined in protocol). Time to death or permanent ventilation=time to earliest occurrence of death/permanent ventilation. Start date for calculating time to death or permanent ventilation in days=date of first dose. Subjects without event were censored at last known alive dates. This endpoint not standalone analysis for 233AS102.Analysis performed on data collected from 233AS101 &233AS102 studies. This is reported as part of final integrated analyses. Overall ITT population. Subjects analysed exceeds total number of subjects who started 233AS102 as it indicates subjects who were randomised in Part C of 233AS101 study. '9999' means due to low number of events, median & upper range of 95% CI not estimable.
    End point type
    Secondary
    End point timeframe
    From the baseline of the study 233AS101 up to the end of the follow-up period of the current study (up to Week 364)
    End point values
    		 233AS101&233AS102(Part C):Placebo+Delayed-start BIIB067 100mg 233AS101 & 233AS102 (Part C): Early-start BIIB067 100 mg
    Number of subjects analysed
    36
    72
    Units: weeks
        median (confidence interval 95%)
    9999 (135.6 to 9999)
    9999 (253.6 to 9999)
    Statistical analysis title
    		 Time to Death or Permanent Ventilation
    Statistical analysis description
    Time to Death or Permanent Ventilation was summarized using the Kaplan-Meier product limit method.
    Comparison groups
    233AS101&233AS102(Part C):Placebo+Delayed-start BIIB067 100mg v 233AS101 & 233AS102 (Part C): Early-start BIIB067 100 mg
    Number of subjects included in analysis
    108
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.4202 [14]
    Method
    		 Logrank
    Parameter type
    		 Hazard ratio (HR)
    Point estimate
    0.64
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.282
         upper limit
    		 1.461
    Notes
    [14] - The analysis was based on a log rank test stratified by median baseline plasma NfL.

    Secondary: 233AS101 and 233AS102 ISE: Time to Death

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    End point title
    		 233AS101 and 233AS102 ISE: Time to Death
    End point description
    Time to death was defined as time from first dose received in 233AS101 to death. Subjects who do not meet the endpoint definition were censored at the subject’s last known alive date. Only events that were adjudicated by the EAC are included. This endpoint was not a standalone analysis for 233AS102. Analysis was performed on the data collected from 233AS101 and 233AS102 studies. This is reported as a part of the final integrated analyses. Time to death was summarized using the Kaplan-Meier product limit method. Integrated analysis was performed on overall ITT population which included all Part C participants of 233AS101 and participants who rolled over from 233AS101 Part C into 233AS102. 'Subjects analysed' exceeds the total number of participants who started 233AS102 as it indicates participants who were randomised in the Part C of 233AS101 study. '9999' signifies that due to the low number of events, the median and 95% CI were not estimable.
    End point type
    Secondary
    End point timeframe
    From the baseline of the study 233AS101 up to the end of the follow-up period of the current study (up to Week 364)
    End point values
    		 233AS101&233AS102(Part C):Placebo+Delayed-start BIIB067 100mg 233AS101 & 233AS102 (Part C): Early-start BIIB067 100 mg
    Number of subjects analysed
    36
    72
    Units: weeks
        median (confidence interval 95%)
    9999 (9999 to 9999)
    9999 (260.7 to 9999)
    Statistical analysis title
    		 Time to Death
    Statistical analysis description
    Time to death was summarized using the Kaplan-Meier product limit method.
    Comparison groups
    233AS101&233AS102(Part C):Placebo+Delayed-start BIIB067 100mg v 233AS101 & 233AS102 (Part C): Early-start BIIB067 100 mg
    Number of subjects included in analysis
    108
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.3108 [15]
    Method
    		 Logrank
    Parameter type
    		 Hazard ratio (HR)
    Point estimate
    0.52
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.199
         upper limit
    		 1.357
    Notes
    [15] - The analysis was based on a log rank test stratified by median baseline plasma NfL.

    Adverse events

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    Adverse events information
    Timeframe for reporting adverse events
    From first dose of the study drug in the current study up to end of follow-up period (up to Week 364)
    Adverse event reporting additional description
    The safety population included all participants who were enrolled and received at least one dose of study treatment in 233AS102.
    Assessment type
    		 Systematic
    Dictionary used for adverse event reporting
    Dictionary name
    		 MedDRA
    Dictionary version
    27.0
    Reporting groups
    Reporting group title
    233AS101: Part C (Prior Placebo)
    Reporting group description
    		 Participants who were randomised to placebo in Part C of the parent study 233AS101 received 3 loading doses of BIIB067, 100 mg, Q2W, on Days 1, 15, and 29 by IT bolus injection in this study followed by up to 90 maintenance doses of BIIB067, Q4W, until the last participant enrolled had their Week 152 maintenance dose visit.

    Reporting group title
    233AS101: Parts A and B (All Doses)
    Reporting group description
    		 Participants who were randomized to BIIB067 or placebo in Part A (at doses 10 mg, 20 mg, 40 mg and 60 mg) or Part B (at doses 20 mg, 40 mg, 60 mg and 100 mg) of the parent study 233AS101 received 3 loading doses of BIIB067, 20 mg, 40 mg, 60 mg, or 100 mg, eventually escalated to 100 mg, 2 weeks apart, and up to 90 maintenance doses, Q4W, by IT bolus injection until the last enrolled participant had their Week 152 maintenance dose visit in this study.

    Reporting group title
    233AS101: Part C (Prior BIIB067 100 mg)
    Reporting group description
    		 Participants who were randomised to BIIB067, 100 mg in Part C of the parent study 233AS101 received 2 loading doses of BIIB067, 100 mg on Days 1 and 29, and one dose of BIIB067-matched placebo on Day 15 by IT bolus injection in this study followed by up to 90 maintenance doses of BIIB067, Q4W, until the last participant enrolled had their Week 152 maintenance dose visit.

    Serious adverse events
    		 233AS101: Part C (Prior Placebo) 233AS101: Parts A and B (All Doses) 233AS101: Part C (Prior BIIB067 100 mg)
    Total subjects affected by serious adverse events
         subjects affected / exposed
    16 / 32 (50.00%)
    22 / 44 (50.00%)
    33 / 63 (52.38%)
         number of deaths (all causes)
    7
    5
    14
         number of deaths resulting from adverse events
    0
    0
    0
    Neoplasms benign, malignant and unspecified (incl cysts and polyps)
    Breast cancer recurrent
         subjects affected / exposed
    0 / 32 (0.00%)
    0 / 44 (0.00%)
    1 / 63 (1.59%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Uterine cancer
         subjects affected / exposed
    0 / 32 (0.00%)
    1 / 44 (2.27%)
    0 / 63 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Uterine leiomyoma
         subjects affected / exposed
    0 / 32 (0.00%)
    0 / 44 (0.00%)
    1 / 63 (1.59%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Surgical and medical procedures
    Euthanasia
         subjects affected / exposed
    0 / 32 (0.00%)
    1 / 44 (2.27%)
    0 / 63 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    General disorders and administration site conditions
    Sudden death
         subjects affected / exposed
    0 / 32 (0.00%)
    0 / 44 (0.00%)
    1 / 63 (1.59%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    Death
         subjects affected / exposed
    0 / 32 (0.00%)
    0 / 44 (0.00%)
    1 / 63 (1.59%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    Respiratory, thoracic and mediastinal disorders
    Acute respiratory distress syndrome
         subjects affected / exposed
    0 / 32 (0.00%)
    0 / 44 (0.00%)
    1 / 63 (1.59%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Acute respiratory failure
         subjects affected / exposed
    1 / 32 (3.13%)
    0 / 44 (0.00%)
    6 / 63 (9.52%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 6
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    Aspiration
         subjects affected / exposed
    0 / 32 (0.00%)
    0 / 44 (0.00%)
    1 / 63 (1.59%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Chronic respiratory failure
         subjects affected / exposed
    1 / 32 (3.13%)
    0 / 44 (0.00%)
    1 / 63 (1.59%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Dyspnoea
         subjects affected / exposed
    0 / 32 (0.00%)
    1 / 44 (2.27%)
    1 / 63 (1.59%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Hypoxia
         subjects affected / exposed
    0 / 32 (0.00%)
    0 / 44 (0.00%)
    1 / 63 (1.59%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Oesophagobronchial fistula
         subjects affected / exposed
    0 / 32 (0.00%)
    1 / 44 (2.27%)
    0 / 63 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Pneumonitis aspiration
         subjects affected / exposed
    0 / 32 (0.00%)
    1 / 44 (2.27%)
    1 / 63 (1.59%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Pneumothorax
         subjects affected / exposed
    0 / 32 (0.00%)
    0 / 44 (0.00%)
    1 / 63 (1.59%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Respiratory distress
         subjects affected / exposed
    0 / 32 (0.00%)
    2 / 44 (4.55%)
    0 / 63 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Respiratory arrest
         subjects affected / exposed
    0 / 32 (0.00%)
    0 / 44 (0.00%)
    2 / 63 (3.17%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 2
    Pulmonary embolism
         subjects affected / exposed
    2 / 32 (6.25%)
    2 / 44 (4.55%)
    1 / 63 (1.59%)
         occurrences causally related to treatment / all
    0 / 3
    0 / 2
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Respiratory failure
         subjects affected / exposed
    6 / 32 (18.75%)
    5 / 44 (11.36%)
    6 / 63 (9.52%)
         occurrences causally related to treatment / all
    0 / 6
    0 / 6
    0 / 6
         deaths causally related to treatment / all
    0 / 6
    0 / 2
    0 / 4
    Psychiatric disorders
    Mental status changes
         subjects affected / exposed
    1 / 32 (3.13%)
    0 / 44 (0.00%)
    0 / 63 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Anxiety
         subjects affected / exposed
    0 / 32 (0.00%)
    0 / 44 (0.00%)
    1 / 63 (1.59%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Abnormal behaviour
         subjects affected / exposed
    0 / 32 (0.00%)
    0 / 44 (0.00%)
    1 / 63 (1.59%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Investigations
    Staphylococcus test positive
         subjects affected / exposed
    0 / 32 (0.00%)
    1 / 44 (2.27%)
    0 / 63 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Injury, poisoning and procedural complications
    Ankle fracture
         subjects affected / exposed
    0 / 32 (0.00%)
    1 / 44 (2.27%)
    0 / 63 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Fall
         subjects affected / exposed
    0 / 32 (0.00%)
    4 / 44 (9.09%)
    1 / 63 (1.59%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 5
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Head injury
         subjects affected / exposed
    0 / 32 (0.00%)
    1 / 44 (2.27%)
    0 / 63 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Hip fracture
         subjects affected / exposed
    0 / 32 (0.00%)
    1 / 44 (2.27%)
    0 / 63 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Tibia fracture
         subjects affected / exposed
    0 / 32 (0.00%)
    0 / 44 (0.00%)
    1 / 63 (1.59%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Stoma site pain
         subjects affected / exposed
    0 / 32 (0.00%)
    0 / 44 (0.00%)
    1 / 63 (1.59%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Skull fracture
         subjects affected / exposed
    0 / 32 (0.00%)
    1 / 44 (2.27%)
    0 / 63 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Lumbar vertebral fracture
         subjects affected / exposed
    0 / 32 (0.00%)
    0 / 44 (0.00%)
    1 / 63 (1.59%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Cardiac disorders
    Arrhythmia
         subjects affected / exposed
    0 / 32 (0.00%)
    1 / 44 (2.27%)
    0 / 63 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Cardiac failure acute
         subjects affected / exposed
    0 / 32 (0.00%)
    1 / 44 (2.27%)
    0 / 63 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Cardiac arrest
         subjects affected / exposed
    1 / 32 (3.13%)
    0 / 44 (0.00%)
    2 / 63 (3.17%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    0 / 2
    Atrial fibrillation
         subjects affected / exposed
    0 / 32 (0.00%)
    0 / 44 (0.00%)
    1 / 63 (1.59%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Cardio-respiratory arrest
         subjects affected / exposed
    0 / 32 (0.00%)
    0 / 44 (0.00%)
    2 / 63 (3.17%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    Myopericarditis
         subjects affected / exposed
    0 / 32 (0.00%)
    1 / 44 (2.27%)
    0 / 63 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Nervous system disorders
    Amyotrophic lateral sclerosis
         subjects affected / exposed
    1 / 32 (3.13%)
    1 / 44 (2.27%)
    0 / 63 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 1
    0 / 1
    0 / 0
    Brain hypoxia
         subjects affected / exposed
    0 / 32 (0.00%)
    0 / 44 (0.00%)
    1 / 63 (1.59%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    Encephalopathy
         subjects affected / exposed
    0 / 32 (0.00%)
    0 / 44 (0.00%)
    1 / 63 (1.59%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Headache
         subjects affected / exposed
    1 / 32 (3.13%)
    1 / 44 (2.27%)
    0 / 63 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Intracranial pressure increased
         subjects affected / exposed
    1 / 32 (3.13%)
    1 / 44 (2.27%)
    1 / 63 (1.59%)
         occurrences causally related to treatment / all
    2 / 2
    1 / 1
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Migraine
         subjects affected / exposed
    0 / 32 (0.00%)
    1 / 44 (2.27%)
    0 / 63 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Neuromyelitis optica spectrum disorder
         subjects affected / exposed
    1 / 32 (3.13%)
    0 / 44 (0.00%)
    0 / 63 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Neurosarcoidosis
         subjects affected / exposed
    0 / 32 (0.00%)
    1 / 44 (2.27%)
    0 / 63 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Radiculopathy
         subjects affected / exposed
    0 / 32 (0.00%)
    1 / 44 (2.27%)
    0 / 63 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Vocal cord paralysis
         subjects affected / exposed
    0 / 32 (0.00%)
    1 / 44 (2.27%)
    0 / 63 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Eye disorders
    Papilloedema
         subjects affected / exposed
    1 / 32 (3.13%)
    0 / 44 (0.00%)
    0 / 63 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Gastrointestinal disorders
    Abdominal pain
         subjects affected / exposed
    1 / 32 (3.13%)
    0 / 44 (0.00%)
    0 / 63 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Faecaloma
         subjects affected / exposed
    1 / 32 (3.13%)
    1 / 44 (2.27%)
    0 / 63 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Dysphagia
         subjects affected / exposed
    1 / 32 (3.13%)
    3 / 44 (6.82%)
    7 / 63 (11.11%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 3
    0 / 7
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Constipation
         subjects affected / exposed
    2 / 32 (6.25%)
    0 / 44 (0.00%)
    0 / 63 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Gastritis
         subjects affected / exposed
    0 / 32 (0.00%)
    1 / 44 (2.27%)
    0 / 63 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Gastric ulcer perforation
         subjects affected / exposed
    0 / 32 (0.00%)
    0 / 44 (0.00%)
    1 / 63 (1.59%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Gastric perforation
         subjects affected / exposed
    0 / 32 (0.00%)
    1 / 44 (2.27%)
    0 / 63 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Gastrooesophageal reflux disease
         subjects affected / exposed
    0 / 32 (0.00%)
    1 / 44 (2.27%)
    0 / 63 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Pancreatitis
         subjects affected / exposed
    0 / 32 (0.00%)
    1 / 44 (2.27%)
    0 / 63 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Large intestine perforation
         subjects affected / exposed
    1 / 32 (3.13%)
    0 / 44 (0.00%)
    0 / 63 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Hepatobiliary disorders
    Bile duct stone
         subjects affected / exposed
    0 / 32 (0.00%)
    1 / 44 (2.27%)
    0 / 63 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Cholecystitis
         subjects affected / exposed
    0 / 32 (0.00%)
    0 / 44 (0.00%)
    1 / 63 (1.59%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Renal and urinary disorders
    Calculus urinary
         subjects affected / exposed
    0 / 32 (0.00%)
    0 / 44 (0.00%)
    1 / 63 (1.59%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Nephrolithiasis
         subjects affected / exposed
    1 / 32 (3.13%)
    1 / 44 (2.27%)
    0 / 63 (0.00%)
         occurrences causally related to treatment / all
    0 / 3
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Ureterolithiasis
         subjects affected / exposed
    1 / 32 (3.13%)
    0 / 44 (0.00%)
    0 / 63 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Musculoskeletal and connective tissue disorders
    Muscular weakness
         subjects affected / exposed
    0 / 32 (0.00%)
    1 / 44 (2.27%)
    0 / 63 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 3
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Intervertebral disc protrusion
         subjects affected / exposed
    0 / 32 (0.00%)
    0 / 44 (0.00%)
    1 / 63 (1.59%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Back pain
         subjects affected / exposed
    1 / 32 (3.13%)
    1 / 44 (2.27%)
    0 / 63 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Infections and infestations
    H1n1 influenza
         subjects affected / exposed
    0 / 32 (0.00%)
    0 / 44 (0.00%)
    1 / 63 (1.59%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Covid-19 pneumonia
         subjects affected / exposed
    0 / 32 (0.00%)
    1 / 44 (2.27%)
    0 / 63 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Covid-19
         subjects affected / exposed
    1 / 32 (3.13%)
    0 / 44 (0.00%)
    2 / 63 (3.17%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Meningitis aseptic
         subjects affected / exposed
    1 / 32 (3.13%)
    0 / 44 (0.00%)
    0 / 63 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Pneumonia
         subjects affected / exposed
    2 / 32 (6.25%)
    1 / 44 (2.27%)
    2 / 63 (3.17%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 1
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    Pharyngeal abscess
         subjects affected / exposed
    0 / 32 (0.00%)
    0 / 44 (0.00%)
    1 / 63 (1.59%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Peritonitis
         subjects affected / exposed
    1 / 32 (3.13%)
    0 / 44 (0.00%)
    0 / 63 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Myelitis
         subjects affected / exposed
    1 / 32 (3.13%)
    1 / 44 (2.27%)
    1 / 63 (1.59%)
         occurrences causally related to treatment / all
    1 / 1
    1 / 1
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Pneumonia aspiration
         subjects affected / exposed
    3 / 32 (9.38%)
    2 / 44 (4.55%)
    8 / 63 (12.70%)
         occurrences causally related to treatment / all
    0 / 3
    0 / 2
    0 / 12
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    0 / 2
    Pneumonia bacterial
         subjects affected / exposed
    1 / 32 (3.13%)
    0 / 44 (0.00%)
    0 / 63 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Pneumonia pseudomonal
         subjects affected / exposed
    0 / 32 (0.00%)
    0 / 44 (0.00%)
    1 / 63 (1.59%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Pulmonary sepsis
         subjects affected / exposed
    0 / 32 (0.00%)
    0 / 44 (0.00%)
    1 / 63 (1.59%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    Pyelonephritis
         subjects affected / exposed
    0 / 32 (0.00%)
    0 / 44 (0.00%)
    1 / 63 (1.59%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Respiratory tract infection
         subjects affected / exposed
    0 / 32 (0.00%)
    0 / 44 (0.00%)
    1 / 63 (1.59%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Sepsis
         subjects affected / exposed
    0 / 32 (0.00%)
    0 / 44 (0.00%)
    1 / 63 (1.59%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Septic shock
         subjects affected / exposed
    1 / 32 (3.13%)
    0 / 44 (0.00%)
    2 / 63 (3.17%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    Staphylococcal infection
         subjects affected / exposed
    0 / 32 (0.00%)
    0 / 44 (0.00%)
    1 / 63 (1.59%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Staphylococcal sepsis
         subjects affected / exposed
    0 / 32 (0.00%)
    0 / 44 (0.00%)
    1 / 63 (1.59%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Streptococcal bacteraemia
         subjects affected / exposed
    0 / 32 (0.00%)
    0 / 44 (0.00%)
    1 / 63 (1.59%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Urinary tract infection
         subjects affected / exposed
    1 / 32 (3.13%)
    1 / 44 (2.27%)
    1 / 63 (1.59%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Frequency threshold for reporting non-serious adverse events: 5%
    Non-serious adverse events
    		 233AS101: Part C (Prior Placebo) 233AS101: Parts A and B (All Doses) 233AS101: Part C (Prior BIIB067 100 mg)
    Total subjects affected by non serious adverse events
         subjects affected / exposed
    31 / 32 (96.88%)
    43 / 44 (97.73%)
    63 / 63 (100.00%)
    Vascular disorders
    Hypertension
         subjects affected / exposed
    1 / 32 (3.13%)
    7 / 44 (15.91%)
    3 / 63 (4.76%)
         occurrences all number
    1
    8
    4
    Hypotension
         subjects affected / exposed
    1 / 32 (3.13%)
    0 / 44 (0.00%)
    4 / 63 (6.35%)
         occurrences all number
    1
    0
    5
    General disorders and administration site conditions
    Influenza like illness
         subjects affected / exposed
    2 / 32 (6.25%)
    5 / 44 (11.36%)
    2 / 63 (3.17%)
         occurrences all number
    2
    7
    2
    Fatigue
         subjects affected / exposed
    10 / 32 (31.25%)
    13 / 44 (29.55%)
    16 / 63 (25.40%)
         occurrences all number
    10
    26
    31
    Chills
         subjects affected / exposed
    1 / 32 (3.13%)
    5 / 44 (11.36%)
    5 / 63 (7.94%)
         occurrences all number
    1
    11
    5
    Malaise
         subjects affected / exposed
    2 / 32 (6.25%)
    2 / 44 (4.55%)
    0 / 63 (0.00%)
         occurrences all number
    15
    2
    0
    Vaccination site pain
         subjects affected / exposed
    0 / 32 (0.00%)
    1 / 44 (2.27%)
    4 / 63 (6.35%)
         occurrences all number
    0
    1
    5
    Pyrexia
         subjects affected / exposed
    8 / 32 (25.00%)
    11 / 44 (25.00%)
    11 / 63 (17.46%)
         occurrences all number
    84
    26
    13
    Peripheral swelling
         subjects affected / exposed
    2 / 32 (6.25%)
    5 / 44 (11.36%)
    3 / 63 (4.76%)
         occurrences all number
    4
    5
    3
    Pain
         subjects affected / exposed
    3 / 32 (9.38%)
    2 / 44 (4.55%)
    5 / 63 (7.94%)
         occurrences all number
    4
    2
    8
    Oedema peripheral
         subjects affected / exposed
    2 / 32 (6.25%)
    6 / 44 (13.64%)
    3 / 63 (4.76%)
         occurrences all number
    2
    8
    9
    Immune system disorders
    Seasonal allergy
         subjects affected / exposed
    1 / 32 (3.13%)
    2 / 44 (4.55%)
    5 / 63 (7.94%)
         occurrences all number
    1
    3
    7
    Respiratory, thoracic and mediastinal disorders
    Cough
         subjects affected / exposed
    3 / 32 (9.38%)
    6 / 44 (13.64%)
    5 / 63 (7.94%)
         occurrences all number
    3
    13
    6
    Dyspnoea
         subjects affected / exposed
    3 / 32 (9.38%)
    5 / 44 (11.36%)
    11 / 63 (17.46%)
         occurrences all number
    3
    5
    17
    Laryngospasm
         subjects affected / exposed
    0 / 32 (0.00%)
    2 / 44 (4.55%)
    4 / 63 (6.35%)
         occurrences all number
    0
    4
    6
    Nasal congestion
         subjects affected / exposed
    1 / 32 (3.13%)
    5 / 44 (11.36%)
    4 / 63 (6.35%)
         occurrences all number
    1
    6
    4
    Oropharyngeal pain
         subjects affected / exposed
    2 / 32 (6.25%)
    6 / 44 (13.64%)
    5 / 63 (7.94%)
         occurrences all number
    2
    9
    6
    Rhinorrhoea
         subjects affected / exposed
    0 / 32 (0.00%)
    1 / 44 (2.27%)
    4 / 63 (6.35%)
         occurrences all number
    0
    1
    5
    Sinus congestion
         subjects affected / exposed
    0 / 32 (0.00%)
    1 / 44 (2.27%)
    4 / 63 (6.35%)
         occurrences all number
    0
    1
    4
    Psychiatric disorders
    Anxiety
         subjects affected / exposed
    1 / 32 (3.13%)
    3 / 44 (6.82%)
    6 / 63 (9.52%)
         occurrences all number
    1
    4
    7
    Depression
         subjects affected / exposed
    0 / 32 (0.00%)
    5 / 44 (11.36%)
    5 / 63 (7.94%)
         occurrences all number
    0
    5
    5
    Insomnia
         subjects affected / exposed
    3 / 32 (9.38%)
    5 / 44 (11.36%)
    6 / 63 (9.52%)
         occurrences all number
    4
    5
    8
    Panic attack
         subjects affected / exposed
    0 / 32 (0.00%)
    3 / 44 (6.82%)
    1 / 63 (1.59%)
         occurrences all number
    0
    5
    1
    Investigations
    Csf protein increased
         subjects affected / exposed
    7 / 32 (21.88%)
    15 / 44 (34.09%)
    15 / 63 (23.81%)
         occurrences all number
    7
    19
    16
    Csf glucose increased
         subjects affected / exposed
    0 / 32 (0.00%)
    2 / 44 (4.55%)
    4 / 63 (6.35%)
         occurrences all number
    0
    3
    4
    Blood urine present
         subjects affected / exposed
    0 / 32 (0.00%)
    4 / 44 (9.09%)
    2 / 63 (3.17%)
         occurrences all number
    0
    4
    2
    Alanine aminotransferase increased
         subjects affected / exposed
    2 / 32 (6.25%)
    2 / 44 (4.55%)
    4 / 63 (6.35%)
         occurrences all number
    2
    2
    5
    Aspartate aminotransferase increased
         subjects affected / exposed
    0 / 32 (0.00%)
    2 / 44 (4.55%)
    4 / 63 (6.35%)
         occurrences all number
    0
    2
    5
    Blood glucose increased
         subjects affected / exposed
    1 / 32 (3.13%)
    4 / 44 (9.09%)
    2 / 63 (3.17%)
         occurrences all number
    1
    4
    4
    Csf white blood cell count increased
         subjects affected / exposed
    2 / 32 (6.25%)
    11 / 44 (25.00%)
    15 / 63 (23.81%)
         occurrences all number
    2
    15
    16
    White blood cell count increased
         subjects affected / exposed
    0 / 32 (0.00%)
    1 / 44 (2.27%)
    4 / 63 (6.35%)
         occurrences all number
    0
    1
    4
    Oxygen saturation decreased
         subjects affected / exposed
    2 / 32 (6.25%)
    0 / 44 (0.00%)
    1 / 63 (1.59%)
         occurrences all number
    2
    0
    1
    Hepatic enzyme increased
         subjects affected / exposed
    0 / 32 (0.00%)
    3 / 44 (6.82%)
    3 / 63 (4.76%)
         occurrences all number
    0
    3
    3
    Injury, poisoning and procedural complications
    Foot fracture
         subjects affected / exposed
    1 / 32 (3.13%)
    4 / 44 (9.09%)
    1 / 63 (1.59%)
         occurrences all number
    2
    5
    1
    Fall
         subjects affected / exposed
    18 / 32 (56.25%)
    28 / 44 (63.64%)
    25 / 63 (39.68%)
         occurrences all number
    35
    120
    94
    Contusion
         subjects affected / exposed
    7 / 32 (21.88%)
    13 / 44 (29.55%)
    8 / 63 (12.70%)
         occurrences all number
    9
    18
    13
    Post procedural complication
         subjects affected / exposed
    0 / 32 (0.00%)
    3 / 44 (6.82%)
    0 / 63 (0.00%)
         occurrences all number
    0
    7
    0
    Post lumbar puncture syndrome
         subjects affected / exposed
    6 / 32 (18.75%)
    13 / 44 (29.55%)
    15 / 63 (23.81%)
         occurrences all number
    21
    123
    90
    Neurological procedural complication
         subjects affected / exposed
    2 / 32 (6.25%)
    0 / 44 (0.00%)
    4 / 63 (6.35%)
         occurrences all number
    2
    0
    4
    Muscle strain
         subjects affected / exposed
    1 / 32 (3.13%)
    5 / 44 (11.36%)
    3 / 63 (4.76%)
         occurrences all number
    3
    5
    3
    Ligament sprain
         subjects affected / exposed
    1 / 32 (3.13%)
    4 / 44 (9.09%)
    3 / 63 (4.76%)
         occurrences all number
    1
    7
    3
    Immunisation reaction
         subjects affected / exposed
    1 / 32 (3.13%)
    5 / 44 (11.36%)
    2 / 63 (3.17%)
         occurrences all number
    3
    7
    4
    Head injury
         subjects affected / exposed
    2 / 32 (6.25%)
    2 / 44 (4.55%)
    1 / 63 (1.59%)
         occurrences all number
    2
    2
    1
    Post procedural contusion
         subjects affected / exposed
    3 / 32 (9.38%)
    2 / 44 (4.55%)
    2 / 63 (3.17%)
         occurrences all number
    4
    2
    2
    Post procedural pruritus
         subjects affected / exposed
    2 / 32 (6.25%)
    0 / 44 (0.00%)
    0 / 63 (0.00%)
         occurrences all number
    2
    0
    0
    Post procedural swelling
         subjects affected / exposed
    0 / 32 (0.00%)
    4 / 44 (9.09%)
    1 / 63 (1.59%)
         occurrences all number
    0
    5
    1
    Procedural nausea
         subjects affected / exposed
    0 / 32 (0.00%)
    2 / 44 (4.55%)
    4 / 63 (6.35%)
         occurrences all number
    0
    8
    5
    Procedural pain
         subjects affected / exposed
    14 / 32 (43.75%)
    28 / 44 (63.64%)
    33 / 63 (52.38%)
         occurrences all number
    48
    216
    264
    Skin abrasion
         subjects affected / exposed
    1 / 32 (3.13%)
    6 / 44 (13.64%)
    4 / 63 (6.35%)
         occurrences all number
    1
    7
    14
    Skin laceration
         subjects affected / exposed
    1 / 32 (3.13%)
    3 / 44 (6.82%)
    3 / 63 (4.76%)
         occurrences all number
    1
    6
    3
    Traumatic lumbar puncture
         subjects affected / exposed
    0 / 32 (0.00%)
    3 / 44 (6.82%)
    0 / 63 (0.00%)
         occurrences all number
    0
    3
    0
    Nervous system disorders
    Balance disorder
         subjects affected / exposed
    2 / 32 (6.25%)
    4 / 44 (9.09%)
    2 / 63 (3.17%)
         occurrences all number
    2
    4
    2
    Burning sensation
         subjects affected / exposed
    1 / 32 (3.13%)
    3 / 44 (6.82%)
    1 / 63 (1.59%)
         occurrences all number
    1
    4
    1
    Dizziness
         subjects affected / exposed
    5 / 32 (15.63%)
    13 / 44 (29.55%)
    13 / 63 (20.63%)
         occurrences all number
    10
    29
    18
    Dysarthria
         subjects affected / exposed
    2 / 32 (6.25%)
    0 / 44 (0.00%)
    4 / 63 (6.35%)
         occurrences all number
    2
    0
    5
    Intracranial pressure increased
         subjects affected / exposed
    2 / 32 (6.25%)
    0 / 44 (0.00%)
    4 / 63 (6.35%)
         occurrences all number
    2
    0
    4
    Hypoaesthesia
         subjects affected / exposed
    4 / 32 (12.50%)
    5 / 44 (11.36%)
    2 / 63 (3.17%)
         occurrences all number
    6
    9
    2
    Headache
         subjects affected / exposed
    17 / 32 (53.13%)
    31 / 44 (70.45%)
    35 / 63 (55.56%)
         occurrences all number
    72
    157
    195
    Migraine
         subjects affected / exposed
    1 / 32 (3.13%)
    4 / 44 (9.09%)
    2 / 63 (3.17%)
         occurrences all number
    1
    9
    2
    Paraesthesia
         subjects affected / exposed
    3 / 32 (9.38%)
    5 / 44 (11.36%)
    7 / 63 (11.11%)
         occurrences all number
    4
    10
    22
    Muscle spasticity
         subjects affected / exposed
    2 / 32 (6.25%)
    2 / 44 (4.55%)
    3 / 63 (4.76%)
         occurrences all number
    3
    17
    33
    Muscle contractions involuntary
         subjects affected / exposed
    2 / 32 (6.25%)
    4 / 44 (9.09%)
    6 / 63 (9.52%)
         occurrences all number
    2
    4
    9
    Tremor
         subjects affected / exposed
    2 / 32 (6.25%)
    4 / 44 (9.09%)
    1 / 63 (1.59%)
         occurrences all number
    2
    4
    3
    Sensory disturbance
         subjects affected / exposed
    2 / 32 (6.25%)
    1 / 44 (2.27%)
    1 / 63 (1.59%)
         occurrences all number
    16
    4
    1
    Sciatica
         subjects affected / exposed
    0 / 32 (0.00%)
    3 / 44 (6.82%)
    2 / 63 (3.17%)
         occurrences all number
    0
    4
    2
    Radicular pain
         subjects affected / exposed
    1 / 32 (3.13%)
    3 / 44 (6.82%)
    0 / 63 (0.00%)
         occurrences all number
    1
    4
    0
    Pleocytosis
         subjects affected / exposed
    3 / 32 (9.38%)
    7 / 44 (15.91%)
    5 / 63 (7.94%)
         occurrences all number
    3
    11
    5
    Ear and labyrinth disorders
    Vertigo
         subjects affected / exposed
    0 / 32 (0.00%)
    5 / 44 (11.36%)
    3 / 63 (4.76%)
         occurrences all number
    0
    6
    4
    Eye disorders
    Conjunctivitis allergic
         subjects affected / exposed
    2 / 32 (6.25%)
    0 / 44 (0.00%)
    0 / 63 (0.00%)
         occurrences all number
    2
    0
    0
    Papilloedema
         subjects affected / exposed
    2 / 32 (6.25%)
    1 / 44 (2.27%)
    3 / 63 (4.76%)
         occurrences all number
    2
    1
    5
    Dry eye
         subjects affected / exposed
    1 / 32 (3.13%)
    3 / 44 (6.82%)
    0 / 63 (0.00%)
         occurrences all number
    1
    4
    0
    Vision blurred
         subjects affected / exposed
    2 / 32 (6.25%)
    1 / 44 (2.27%)
    3 / 63 (4.76%)
         occurrences all number
    3
    2
    4
    Diplopia
         subjects affected / exposed
    2 / 32 (6.25%)
    0 / 44 (0.00%)
    1 / 63 (1.59%)
         occurrences all number
    2
    0
    1
    Gastrointestinal disorders
    Abdominal pain upper
         subjects affected / exposed
    3 / 32 (9.38%)
    4 / 44 (9.09%)
    3 / 63 (4.76%)
         occurrences all number
    4
    8
    4
    Abdominal distension
         subjects affected / exposed
    2 / 32 (6.25%)
    1 / 44 (2.27%)
    2 / 63 (3.17%)
         occurrences all number
    2
    1
    2
    Abdominal pain
         subjects affected / exposed
    1 / 32 (3.13%)
    4 / 44 (9.09%)
    5 / 63 (7.94%)
         occurrences all number
    1
    5
    6
    Abdominal discomfort
         subjects affected / exposed
    0 / 32 (0.00%)
    4 / 44 (9.09%)
    1 / 63 (1.59%)
         occurrences all number
    0
    4
    1
    Constipation
         subjects affected / exposed
    10 / 32 (31.25%)
    11 / 44 (25.00%)
    12 / 63 (19.05%)
         occurrences all number
    11
    16
    13
    Diarrhoea
         subjects affected / exposed
    12 / 32 (37.50%)
    7 / 44 (15.91%)
    7 / 63 (11.11%)
         occurrences all number
    18
    7
    10
    Nausea
         subjects affected / exposed
    7 / 32 (21.88%)
    17 / 44 (38.64%)
    13 / 63 (20.63%)
         occurrences all number
    20
    41
    36
    Gastrooesophageal reflux disease
         subjects affected / exposed
    0 / 32 (0.00%)
    4 / 44 (9.09%)
    8 / 63 (12.70%)
         occurrences all number
    0
    4
    9
    Dysphagia
         subjects affected / exposed
    1 / 32 (3.13%)
    3 / 44 (6.82%)
    7 / 63 (11.11%)
         occurrences all number
    1
    8
    9
    Dyspepsia
         subjects affected / exposed
    2 / 32 (6.25%)
    3 / 44 (6.82%)
    2 / 63 (3.17%)
         occurrences all number
    3
    4
    3
    Salivary hypersecretion
         subjects affected / exposed
    1 / 32 (3.13%)
    2 / 44 (4.55%)
    13 / 63 (20.63%)
         occurrences all number
    1
    3
    14
    Toothache
         subjects affected / exposed
    0 / 32 (0.00%)
    4 / 44 (9.09%)
    3 / 63 (4.76%)
         occurrences all number
    0
    4
    3
    Vomiting
         subjects affected / exposed
    2 / 32 (6.25%)
    7 / 44 (15.91%)
    3 / 63 (4.76%)
         occurrences all number
    2
    9
    3
    Hepatobiliary disorders
    Hepatic steatosis
         subjects affected / exposed
    3 / 32 (9.38%)
    0 / 44 (0.00%)
    2 / 63 (3.17%)
         occurrences all number
    3
    0
    2
    Skin and subcutaneous tissue disorders
    Blister
         subjects affected / exposed
    1 / 32 (3.13%)
    3 / 44 (6.82%)
    0 / 63 (0.00%)
         occurrences all number
    1
    3
    0
    Decubitus ulcer
         subjects affected / exposed
    2 / 32 (6.25%)
    1 / 44 (2.27%)
    1 / 63 (1.59%)
         occurrences all number
    2
    1
    4
    Erythema
         subjects affected / exposed
    2 / 32 (6.25%)
    2 / 44 (4.55%)
    0 / 63 (0.00%)
         occurrences all number
    2
    2
    0
    Pruritus
         subjects affected / exposed
    2 / 32 (6.25%)
    1 / 44 (2.27%)
    3 / 63 (4.76%)
         occurrences all number
    10
    2
    4
    Urticaria
         subjects affected / exposed
    2 / 32 (6.25%)
    0 / 44 (0.00%)
    0 / 63 (0.00%)
         occurrences all number
    2
    0
    0
    Rash
         subjects affected / exposed
    2 / 32 (6.25%)
    6 / 44 (13.64%)
    6 / 63 (9.52%)
         occurrences all number
    3
    7
    9
    Renal and urinary disorders
    Pollakiuria
         subjects affected / exposed
    1 / 32 (3.13%)
    5 / 44 (11.36%)
    2 / 63 (3.17%)
         occurrences all number
    1
    5
    2
    Nephrolithiasis
         subjects affected / exposed
    3 / 32 (9.38%)
    3 / 44 (6.82%)
    3 / 63 (4.76%)
         occurrences all number
    3
    9
    3
    Micturition urgency
         subjects affected / exposed
    0 / 32 (0.00%)
    3 / 44 (6.82%)
    0 / 63 (0.00%)
         occurrences all number
    0
    3
    0
    Haematuria
         subjects affected / exposed
    0 / 32 (0.00%)
    3 / 44 (6.82%)
    1 / 63 (1.59%)
         occurrences all number
    0
    3
    1
    Dysuria
         subjects affected / exposed
    2 / 32 (6.25%)
    1 / 44 (2.27%)
    1 / 63 (1.59%)
         occurrences all number
    2
    1
    1
    Musculoskeletal and connective tissue disorders
    Arthralgia
         subjects affected / exposed
    12 / 32 (37.50%)
    17 / 44 (38.64%)
    19 / 63 (30.16%)
         occurrences all number
    26
    41
    43
    Back pain
         subjects affected / exposed
    14 / 32 (43.75%)
    26 / 44 (59.09%)
    27 / 63 (42.86%)
         occurrences all number
    35
    83
    59
    Joint swelling
         subjects affected / exposed
    3 / 32 (9.38%)
    3 / 44 (6.82%)
    5 / 63 (7.94%)
         occurrences all number
    3
    3
    5
    Muscle spasms
         subjects affected / exposed
    8 / 32 (25.00%)
    11 / 44 (25.00%)
    11 / 63 (17.46%)
         occurrences all number
    12
    21
    19
    Muscle twitching
         subjects affected / exposed
    1 / 32 (3.13%)
    1 / 44 (2.27%)
    4 / 63 (6.35%)
         occurrences all number
    1
    1
    5
    Muscular weakness
         subjects affected / exposed
    5 / 32 (15.63%)
    4 / 44 (9.09%)
    10 / 63 (15.87%)
         occurrences all number
    5
    10
    34
    Musculoskeletal chest pain
         subjects affected / exposed
    2 / 32 (6.25%)
    5 / 44 (11.36%)
    3 / 63 (4.76%)
         occurrences all number
    2
    5
    4
    Musculoskeletal pain
         subjects affected / exposed
    1 / 32 (3.13%)
    7 / 44 (15.91%)
    3 / 63 (4.76%)
         occurrences all number
    17
    10
    12
    Musculoskeletal stiffness
         subjects affected / exposed
    1 / 32 (3.13%)
    6 / 44 (13.64%)
    4 / 63 (6.35%)
         occurrences all number
    1
    101
    4
    Myalgia
         subjects affected / exposed
    4 / 32 (12.50%)
    12 / 44 (27.27%)
    14 / 63 (22.22%)
         occurrences all number
    4
    45
    40
    Neck pain
         subjects affected / exposed
    3 / 32 (9.38%)
    6 / 44 (13.64%)
    5 / 63 (7.94%)
         occurrences all number
    4
    6
    7
    Pain in extremity
         subjects affected / exposed
    12 / 32 (37.50%)
    19 / 44 (43.18%)
    17 / 63 (26.98%)
         occurrences all number
    43
    78
    44
    Infections and infestations
    Bronchitis
         subjects affected / exposed
    1 / 32 (3.13%)
    6 / 44 (13.64%)
    3 / 63 (4.76%)
         occurrences all number
    1
    8
    5
    Cellulitis
         subjects affected / exposed
    0 / 32 (0.00%)
    4 / 44 (9.09%)
    1 / 63 (1.59%)
         occurrences all number
    0
    4
    1
    Covid-19
         subjects affected / exposed
    7 / 32 (21.88%)
    13 / 44 (29.55%)
    26 / 63 (41.27%)
         occurrences all number
    11
    17
    34
    Cystitis
         subjects affected / exposed
    3 / 32 (9.38%)
    0 / 44 (0.00%)
    1 / 63 (1.59%)
         occurrences all number
    3
    0
    4
    Gastroenteritis viral
         subjects affected / exposed
    0 / 32 (0.00%)
    4 / 44 (9.09%)
    3 / 63 (4.76%)
         occurrences all number
    0
    4
    3
    Influenza
         subjects affected / exposed
    1 / 32 (3.13%)
    4 / 44 (9.09%)
    3 / 63 (4.76%)
         occurrences all number
    1
    4
    4
    Lower respiratory tract infection
         subjects affected / exposed
    1 / 32 (3.13%)
    4 / 44 (9.09%)
    2 / 63 (3.17%)
         occurrences all number
    1
    11
    3
    Nasopharyngitis
         subjects affected / exposed
    6 / 32 (18.75%)
    20 / 44 (45.45%)
    11 / 63 (17.46%)
         occurrences all number
    13
    41
    17
    Oral candidiasis
         subjects affected / exposed
    2 / 32 (6.25%)
    0 / 44 (0.00%)
    2 / 63 (3.17%)
         occurrences all number
    2
    0
    2
    Oral herpes
         subjects affected / exposed
    0 / 32 (0.00%)
    4 / 44 (9.09%)
    0 / 63 (0.00%)
         occurrences all number
    0
    5
    0
    Pneumonia
         subjects affected / exposed
    3 / 32 (9.38%)
    5 / 44 (11.36%)
    4 / 63 (6.35%)
         occurrences all number
    3
    5
    5
    Pneumonia aspiration
         subjects affected / exposed
    2 / 32 (6.25%)
    0 / 44 (0.00%)
    3 / 63 (4.76%)
         occurrences all number
    3
    0
    4
    Rhinitis
         subjects affected / exposed
    3 / 32 (9.38%)
    1 / 44 (2.27%)
    2 / 63 (3.17%)
         occurrences all number
    5
    1
    2
    Sinusitis
         subjects affected / exposed
    4 / 32 (12.50%)
    3 / 44 (6.82%)
    4 / 63 (6.35%)
         occurrences all number
    6
    8
    5
    Suspected covid-19
         subjects affected / exposed
    2 / 32 (6.25%)
    1 / 44 (2.27%)
    1 / 63 (1.59%)
         occurrences all number
    2
    1
    1
    Tooth infection
         subjects affected / exposed
    0 / 32 (0.00%)
    3 / 44 (6.82%)
    1 / 63 (1.59%)
         occurrences all number
    0
    4
    2
    Viral upper respiratory tract infection
         subjects affected / exposed
    0 / 32 (0.00%)
    4 / 44 (9.09%)
    0 / 63 (0.00%)
         occurrences all number
    0
    4
    0
    Viral infection
         subjects affected / exposed
    1 / 32 (3.13%)
    4 / 44 (9.09%)
    1 / 63 (1.59%)
         occurrences all number
    1
    7
    1
    Urinary tract infection
         subjects affected / exposed
    5 / 32 (15.63%)
    12 / 44 (27.27%)
    8 / 63 (12.70%)
         occurrences all number
    12
    22
    14
    Upper respiratory tract infection
         subjects affected / exposed
    0 / 32 (0.00%)
    9 / 44 (20.45%)
    7 / 63 (11.11%)
         occurrences all number
    0
    11
    13
    Metabolism and nutrition disorders
    Hypokalaemia
         subjects affected / exposed
    2 / 32 (6.25%)
    2 / 44 (4.55%)
    2 / 63 (3.17%)
         occurrences all number
    2
    3
    2
    Decreased appetite
         subjects affected / exposed
    3 / 32 (9.38%)
    0 / 44 (0.00%)
    1 / 63 (1.59%)
         occurrences all number
    3
    0
    1

    More information

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    Substantial protocol amendments (globally)
    Were there any global substantial amendments to the protocol? Yes
    Date
    Amendment
    21 Apr 2017
    Eliminated the requirement to review data from Day 106 through Day 169 of Study 233AS101 before dosing the first and second subject enrolling in each cohort of Study 233AS102. Clarified criteria for enrolling subjects who complete only Part A of Study 233AS101. A condition under which subjects may be rescreened was added.
    12 Mar 2018
    Extend the treatment period by 12 months for all participants in the study. Added a fourth treatment group of BIIB067 100 mg. Removed anti-BIIB067 antibody sampling from the Screening Visit. Included information on edaravone as a current therapy for ALS. Added description of a 9-month nonclinical toxicology study in cynomolgus monkeys (NHPs). Deleted laboratory assessments, vital signs, and physical examinations from the primary endpoint. The number of sites participating in this study was decreased to 16. Changes were made describing the process for participants switching to a higher-dose cohort. An eligibility criterion was added specifying the 16-week washout prior to the participant’s first dose in this study. In addition, an eligibility criterion was updated to permit the use of edaravone provided it is not administered on dosing days. Updates were made to the exclusion criteria for hepatitis C- and B. In addition, presence of implanted venous devices was added as an exclusion criterion. The types of neurological examinations to be conducted at study sites were added. Coagulation assessments were separated from other hematology assessments. Text was added stating that participants will be informed about the collection of race and ethnicity data.
    11 Jan 2019
    Extend the study duration that allowed any and all participants to receive treatment until either the participant’s Final Visit at Week 248 or until the last subject randomised has had his or her Week 92 Visit, whichever occurs first. The phase of development was updated to accurately reflect the need of the long-term extension study. Study rationale text was updated with the evaluation of PD, PK, and effect of disease progression of BIIB067. Updated the dose for all participants in Study 233AS102 to 100 mg BIIB067. Clarified that study objectives were being assessed in subjects with ALS and confirmed SOD1 mutation. The secondary objective was updated to include disease progression. As a result, the ALSFRS-R scores, SVC, and HHD scores exploratory endpoints were changed to secondary endpoints, and the VAFS and overall survival were added as secondary endpoints. Deleted uncontrolled from the study design, and allowed participation of participants who have completed Part C of Study 233AS101; added text for all participants who have completed Parts A, B, or C of Study 233AS101 to receive 100 mg BIIB067, regardless of their treatment dose in Study 233AS101 or prior dosing in Study 233AS102; and specified that participants who have completed Part C of Study 233AS101 do not need to undergo a washout period but are required to undergo a loading dose period. Inclusion and exclusion criteria were updated to align with Part C of Study 233AS101 and as per study requirements. Clarified that the loading dose will occur during the first 4 weeks of treatment and that the Maintenance Dose Period will be extended to approximately 58 doses. Details of the prior dosing regimen were removed. The sample size was increased from 84 to 144 participants. Added an independent data monitoring committee (IDMC) and removed the reference to the Safety Surveillance Team (SST).
    08 Nov 2019
    Updated the secondary endpoints to include; revised the definition of HHD and ventilation assistance-free survival (VAFS) secondary endpoints. Statistical methodology was updated to allow the analysis of efficacy using the change from baseline. Sample size was increased from 144 to 183 participants. Exclusion criterion 1, excluding participants with current or prior hepatitis B infection, and exclusion criterion 8, excluding the presence of an implanted intravenous port/catheter were removed. Section 13.4, Genomic and Pharmacogenomic Assessments, was added. Change describing the “effects on disease progression of BIIB067” was updated throughout to “efficacy of BIIB067. Study Overview, was updated with the total number of countries and number of planned sites globally and to clarify that the last Maintenance Dose Visit for participants will occur at Week 236 OR when the last participant enrolled has had his or her Week 92 Maintenance Dose Visit, whichever occurs first. Dosing section, was updated to clarify that Day 1 of this study should occur no earlier than 28 days after the participant’s last dose (i.e., Day 169 [Week 24 Visit]) in Study 233AS101 to prevent participants from being dosed too soon. Analysis Population section, was updated to remove the requirement that participants must have at least 1 available postdosing evaluation of the respective clinical function endpoint to be included in the analysis population.
    04 Aug 2021
    Extended the maintenance dosing portion of the treatment period of the study by up to 124 weeks while minimizing the burden on participants. Information on the duration of BIIB067 administration was added. Consistent with Study 233AS101, the protocol was revised to reflect that plasma NfL will be evaluated as a secondary biomarker endpoint. The time-to-event endpoints were renamed so that VAFS was relabeled as time to death or permanent ventilation, and overall survival was renamed as time to death. The efficacy endpoint was updated to change over time in total ALSFRS-R scores. The PD endpoint was updated to change from baseline in SOD1 protein in CSF. References to the last study visit from Part C of Study 233AS101 were updated since either Week 28 or Week 32 Visit could be considered the End of Study Visit. A clarification was added to describe procedures for adverse events (AEs) that are ongoing when the participant completes or discontinues the study. A clarification was added to state that serious AEs (SAEs) are to be recorded on an SAE form (instead of the case report form [CRF]) and must be reported to the Sponsor according to national law (in addition to the prespecified timeframe). Details on the analysis population were expanded to include relevant information on the integrated analyses of the 233AS101 and 233AS102 studies, as well as clarification on the subgroup analysis for 233AS102 alone. Details on the analysis of covariance and Kaplan-Meier curves were clarified. References to “dose level” in the descriptions of analyses were removed and replaced with more general identifiers such as “treatment group” or removed entirely. The summary of the analyses was also revised to reflect the key statistical estimates.

    Interruptions (globally)
    Were there any global interruptions to the trial? No

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