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    Clinical Trial Results:
    A Phase 2, Randomized, Double-Blind, Multiple-Dose, Placebo-Controlled Study to Evaluate the Safety and Efficacy of BIIB104 in Subjects With Cognitive Impairment Associated With Schizophrenia (CIAS)

    Summary
    EudraCT number
    		 2018-003825-27
    Trial protocol
    		 DE   GB  
    Global end of trial date
    07 Apr 2022

    Results information
    Results version number
    		 v1(current)
    This version publication date
    14 Apr 2023
    First version publication date
    14 Apr 2023
    Other versions

    Trial information

    		 Close Top of page
    Trial identification
    Sponsor protocol code
    263CS201
    Additional study identifiers
    ISRCTN number
    		 -
    US NCT number
    		 NCT03745820
    WHO universal trial number (UTN)
    		 -
    Sponsors
    Sponsor organisation name
    Biogen
    Sponsor organisation address
    250 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
    07 Apr 2022
    Is this the analysis of the primary completion data?
    No
    Global end of trial reached?
    Yes
    Global end of trial date
    07 Apr 2022
    Was the trial ended prematurely?
    No
    General information about the trial
    Main objective of the trial
    The primary objective of the study is to evaluate the efficacy of BIIB104 in subjects with CIAS, using the Working Memory Domain of the MATRICS Consensus Cognitive Battery (MCCB).
    Protection of trial subjects
    Written informed consent was obtained from each subject or subject’s legally authorized representative (e.g., legal guardian), as applicable, prior to evaluations performed for eligibility. Subjects or the subject’s legally authorized representative were given adequate time to review the information in the informed consent/assent and were allowed to ask, and have answered, questions concerning all portions of the conduct of the study.
    Background therapy
    		 -
    Evidence for comparator
    		 -
    Actual start date of recruitment
    15 Nov 2018
    Long term follow-up planned
    No
    Independent data monitoring committee (IDMC) involvement?
    Yes
    Population of trial subjects
    Number of subjects enrolled per country
    Country: Number of subjects enrolled
    United States: 143
    Country: Number of subjects enrolled
    Japan: 23
    Country: Number of subjects enrolled
    Spain: 18
    Country: Number of subjects enrolled
    Germany: 9
    Country: Number of subjects enrolled
    United Kingdom: 2
    Worldwide total number of subjects
    195
    EEA total number of subjects
    27
    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)
    195
    From 65 to 84 years
    0
    85 years and over
    0

    Subject disposition

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    Recruitment
    Recruitment details
    		 Participants took part in the study at 53 investigative sites in the United States, Japan, Spain, Germany, and the United Kingdom from 15 Nov 2018 to 07 April 2022.

    Pre-assignment
    Screening details
    		 A total of 554 participants were screened out of which, 195 participants were randomised and dosed to receive BIIB104 or placebo.

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

    Arms
    Are arms mutually exclusive
    Yes

    Arm title
    		 Placebo
    Arm description
    		 Participants received BIIB104 matching placebo capsules, twice a day (BID), orally for 12 weeks.
    Arm type
    		 Placebo

    Investigational medicinal product name
    Placebo
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Capsule
    Routes of administration
    Oral use
    Dosage and administration details
    Administered as specified in the treatment arm.

    Arm title
    		 BIIB104 0.15 mg
    Arm description
    		 Participants received 0.15 milligrams (mg) capsules of BIIB104, BID, orally for 12 weeks.
    Arm type
    		 Experimental

    Investigational medicinal product name
    BIIB104 0.15 mg
    Investigational medicinal product code
    Other name
    PF-04958242
    Pharmaceutical forms
    Capsule
    Routes of administration
    Oral use
    Dosage and administration details
    Administered as specified in the treatment arm.

    Arm title
    		 BIIB104 0.5 mg
    Arm description
    		 Participants received 0.5 mg capsules of BIIB104, BID, orally for 12 weeks.
    Arm type
    		 Experimental

    Investigational medicinal product name
    BIIB104 0.5 mg
    Investigational medicinal product code
    Other name
    PF-04958242
    Pharmaceutical forms
    Capsule
    Routes of administration
    Oral use
    Dosage and administration details
    Administered as specified in the treatment arm.

    Number of subjects in period 1
    		Placebo BIIB104 0.15 mg BIIB104 0.5 mg
    Started
    64
    66
    65
    Completed
    52
    52
    51
    Not completed
    12
    14
    14
         Consent withdrawn by subject
    4
    4
    4
         Non-Compliance with Study Drug
    4
    3
    -
         Adverse events
    -
    -
    2
         Adverse event
    -
    3
    -
         Lost to follow-up
    2
    -
    3
         Physician decision unrelated to safety/efficacy
    -
    -
    4
         Reason not Specified
    2
    4
    1

    Baseline characteristics

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    Baseline characteristics reporting groups
    Reporting group title
    Placebo
    Reporting group description
    		 Participants received BIIB104 matching placebo capsules, twice a day (BID), orally for 12 weeks.

    Reporting group title
    BIIB104 0.15 mg
    Reporting group description
    		 Participants received 0.15 milligrams (mg) capsules of BIIB104, BID, orally for 12 weeks.

    Reporting group title
    BIIB104 0.5 mg
    Reporting group description
    		 Participants received 0.5 mg capsules of BIIB104, BID, orally for 12 weeks.

    Reporting group values
    		 Placebo BIIB104 0.15 mg BIIB104 0.5 mg Total
    Number of subjects
    		 64 66 65
    Age Categorical
    Units: Subjects
    Age continuous
    Units: years
        arithmetic mean (standard deviation)
    		 40.6 ( 9.47 ) 37.7 ( 9.41 ) 41.3 ( 9.63 ) -
    Gender categorical
    Units: Subjects
        Female
    		 20 21 18 59
        Male
    		 44 45 47 136
    Ethnicity (NIH/OMB)
    Units: Subjects
        Hispanic or Latino
    		 10 9 6 25
        Not Hispanic or Latino
    		 45 47 49 141
        Unknown or Not Reported
    		 9 10 10 29
    Race/Ethnicity, Customized
    Units: Subjects
        Asian
    		 10 8 13 31
        Black or African American
    		 29 27 26 82
        Native Hawaiian or Other Pacific Islander
    		 1 0 1 2
        White
    		 15 19 15 49
        Other
    		 0 2 0 2
        Unknown
    		 9 10 10 29
    MATRICS Consensus Cognitive Battery (MCCB) Working Memory Domain Score
    The MCCB is a cognitive battery that assesses 7 domains recommended by the Measurement and Treatment Research to Improve Cognition in Schizophrenia (MATRICS) initiative (i.e., Working Memory, Verbal Learning, Speed of Processing, Attention/Vigilance, Visual Learning, Social Cognition, and Reasoning and Problem Solving). MCCB was administered via laptop computer and paper-and-pencil assessments. MCCB composite T scores are between 40 and 60 (normal range). Higher scores indicate better cognitive functioning. The working memory domain score of the MCCB is reported.
    Units: score on a scale
        arithmetic mean (full range (min-max))
    		 39.6 (17 to 70) 38.5 (12 to 60) 39.8 (17 to 58) -
    Subject analysis sets

    Subject analysis set title
    Placebo
    Subject analysis set type
    		 Safety analysis
    Subject analysis set description
    Participants received BIIB104 matching placebo capsules, BID, orally for 12 weeks.

    Subject analysis set title
    BIIB104 0.15 mg
    Subject analysis set type
    		 Safety analysis
    Subject analysis set description
    Participants received 0.15 mg capsules of BIIB104, BID, orally for 12 weeks.

    Subject analysis set title
    BIIB104 0.5 mg
    Subject analysis set type
    		 Safety analysis
    Subject analysis set description
    Participants received 0.5 mg capsules of BIIB104, BID, orally for 12 weeks.

    Subject analysis sets values
    		 Placebo BIIB104 0.15 mg BIIB104 0.5 mg
    Number of subjects
    63
    66
    66
    Age Categorical
    Units: Subjects
    Age continuous
    Units: years
        arithmetic mean (standard deviation)
    0 ( )
    0 ( )
    0 ( )
    Gender categorical
    Units: Subjects
        Female
    0
    0
    0
        Male
    0
    0
    0
    Ethnicity (NIH/OMB)
    Units: Subjects
        Hispanic or Latino
    0
    0
    0
        Not Hispanic or Latino
    0
    0
    0
        Unknown or Not Reported
    0
    0
    0
    Race/Ethnicity, Customized
    Units: Subjects
        Asian
    0
    0
    0
        Black or African American
    0
    0
    0
        Native Hawaiian or Other Pacific Islander
    0
    0
    0
        White
    0
    0
    0
        Other
    0
    0
    0
        Unknown
    0
    0
    0
    MATRICS Consensus Cognitive Battery (MCCB) Working Memory Domain Score
    The MCCB is a cognitive battery that assesses 7 domains recommended by the Measurement and Treatment Research to Improve Cognition in Schizophrenia (MATRICS) initiative (i.e., Working Memory, Verbal Learning, Speed of Processing, Attention/Vigilance, Visual Learning, Social Cognition, and Reasoning and Problem Solving). MCCB was administered via laptop computer and paper-and-pencil assessments. MCCB composite T scores are between 40 and 60 (normal range). Higher scores indicate better cognitive functioning. The working memory domain score of the MCCB is reported.
    Units: score on a scale
        arithmetic mean (full range (min-max))
    0 ( to )
    0 ( to )
    0 ( to )

    End points

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    End points reporting groups
    Reporting group title
    Placebo
    Reporting group description
    		 Participants received BIIB104 matching placebo capsules, twice a day (BID), orally for 12 weeks.

    Reporting group title
    BIIB104 0.15 mg
    Reporting group description
    		 Participants received 0.15 milligrams (mg) capsules of BIIB104, BID, orally for 12 weeks.

    Reporting group title
    BIIB104 0.5 mg
    Reporting group description
    		 Participants received 0.5 mg capsules of BIIB104, BID, orally for 12 weeks.

    Subject analysis set title
    Placebo
    Subject analysis set type
    		 Safety analysis
    Subject analysis set description
    Participants received BIIB104 matching placebo capsules, BID, orally for 12 weeks.

    Subject analysis set title
    BIIB104 0.15 mg
    Subject analysis set type
    		 Safety analysis
    Subject analysis set description
    Participants received 0.15 mg capsules of BIIB104, BID, orally for 12 weeks.

    Subject analysis set title
    BIIB104 0.5 mg
    Subject analysis set type
    		 Safety analysis
    Subject analysis set description
    Participants received 0.5 mg capsules of BIIB104, BID, orally for 12 weeks.

    Primary: Change From Baseline in Change From Baseline in Measurement and Treatment Research to Improve Cognition in Schizophrenia (MATRICS) Consensus Cognitive Battery (MCCB) Working Memory Domain Score at Week 12

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    End point title
    		 Change From Baseline in Change From Baseline in Measurement and Treatment Research to Improve Cognition in Schizophrenia (MATRICS) Consensus Cognitive Battery (MCCB) Working Memory Domain Score at Week 12
    End point description
    The MCCB is a cognitive battery that assesses 7 domains recommended by the MATRICS initiative (i.e., Working Memory, Verbal Learning, Speed of Processing, Attention/Vigilance, Visual Learning, Social Cognition, and Reasoning and Problem Solving). MCCB was administered via laptop computer and paper-and-pencil assessments. T-scores for the individual tests were calculated according to the developer's recommended scoring algorithms. MCCB composite T scores are between 40 and 60 (normal range). Higher scores indicate better cognitive functioning. The working memory domain score of the MCCB is reported in this outcome measure. ITT population included all randomised participants who received at least one dose of study treatment (BIIB104 or placebo). Here, “Overall Number of Participants Analysed” signifies the number of participants analysed in this outcome measure.
    End point type
    Primary
    End point timeframe
    Baseline and Week 12
    End point values
    		 Placebo BIIB104 0.15 mg BIIB104 0.5 mg
    Number of subjects analysed
    50
    50
    49
    Units: score on a scale
        least squares mean (standard error)
    1.17 ( 0.939 )
    0.91 ( 0.936 )
    0.84 ( 0.934 )
    Statistical analysis title
    		 Placebo vs BIIB104 0.5 mg
    Statistical analysis description
    Mixed Model Repeated Measures(MMRM)model was used to analyse change from baseline of outcome measure(OM)using fixed effects of treatment group,region,study visit,study visit-by-treatment interaction,baseline value of OM,baseline-by-visit interaction.
    Comparison groups
    Placebo v BIIB104 0.5 mg
    Number of subjects included in analysis
    99
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.8053
    Method
    		 MMRM
    Parameter type
    		 LS Mean Difference
    Point estimate
    -0.33
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -2.94
         upper limit
    		 2.29
    Variability estimate
    Standard error of the mean
    Dispersion value
    1.323
    Statistical analysis title
    		 Placebo vs BIIB104 0.15 mg
    Statistical analysis description
    A MMRM model was used to analyse the change from baseline of the OM of interest, using fixed effects of treatment group, region, study visit, study visit-by-treatment interaction, baseline value of OM, baseline-by-visit interaction.
    Comparison groups
    Placebo v BIIB104 0.15 mg
    Number of subjects included in analysis
    100
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.8472
    Method
    		 MMRM
    Parameter type
    		 Least Squares (LS) Mean Difference
    Point estimate
    -0.26
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -2.88
         upper limit
    		 2.37
    Variability estimate
    Standard error of the mean
    Dispersion value
    1.328

    Secondary: Number of Participants With Adverse Events (AEs) and Serious Adverse Events (SAEs)

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    End point title
    		 Number of Participants With Adverse Events (AEs) and Serious Adverse Events (SAEs)
    End point description
    An AE is any untoward medical occurrence in a participant or clinical investigation participant administered a pharmaceutical product and that does not necessarily have a causal relationship with this treatment. An SAE is any untoward medical occurrence that at any dose results in death, places the participant at immediate risk of death, requires inpatient hospitalization or prolongation of existing hospitalization, results in persistent or significant disability/incapacity, results in a congenital anomaly/birth defect, or is a medically important event. The safety population included all randomised participants who received at least 1 dose of study treatment (BIIB104 or placebo).
    End point type
    Secondary
    End point timeframe
    From first dose of study drug through end of the study (up to Week 14)
    End point values
    		 Placebo BIIB104 0.15 mg BIIB104 0.5 mg
    Number of subjects analysed
    63
    66
    66
    Units: participants
        AEs
    28
    32
    28
        SAEs
    1
    1
    2
    No statistical analyses for this end point

    Secondary: Mean Total Score Assessed by Scale for the Assessment and Rating of Ataxia (SARA)

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    End point title
    		 Mean Total Score Assessed by Scale for the Assessment and Rating of Ataxia (SARA)
    End point description
    The SARA is a clinical scale that is based on a semiquantitative assessment of cerebellar ataxia on an impairment level and complements the brief neurological examination. The SARA scale is an eight-item clinical rating scale (gait, stance, sitting, speech, finger-chase test, nose-finger test, fast alternating movements, and heel-shin test) with a total score range of 0-40, where 0 is the best neurological status and 40 is the worst neurological status. The safety population included all randomised participants who received at least 1 dose of study treatment (BIIB104 or placebo). Here, “Overall number of participants analysed” signifies the number of participants analysed in this outcome measure and “number analysed” signifies the number of participants analysed at specified time-point.
    End point type
    Secondary
    End point timeframe
    Baseline, Weeks 2, 6, 12 and safety follow-up (Week 14)
    End point values
    		 Placebo BIIB104 0.15 mg BIIB104 0.5 mg
    Number of subjects analysed
    62
    64
    65
    Units: score on a scale
    arithmetic mean (standard deviation)
        Baseline
    0.5 ( 1.03 )
    0.4 ( 1.15 )
    0.3 ( 0.92 )
        Week 2 (n=57,59,62)
    0.4 ( 0.85 )
    0.5 ( 1.10 )
    0.3 ( 0.68 )
        Week 6 (n=52,56,60)
    0.4 ( 0.71 )
    0.3 ( 0.90 )
    0.2 ( 0.58 )
        Week 12 (n=52,51,54)
    0.4 ( 0.80 )
    0.3 ( 0.82 )
    0.2 ( 0.72 )
        Week 14 (n=55,58,57)
    0.4 ( 0.85 )
    0.3 ( 0.91 )
    0.2 ( 0.69 )
    No statistical analyses for this end point

    Secondary: Change From Baseline in University of California, San Diego Performance Based Skills Assessment-Brief International Version (UPSA-Bi) Assessment at Week 12

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    End point title
    		 Change From Baseline in University of California, San Diego Performance Based Skills Assessment-Brief International Version (UPSA-Bi) Assessment at Week 12
    End point description
    The UPSA-Bi, international version, an abbreviated version of the UPSA-Validation of Intermediate Measures, is a measure of functional capacity and assesses skills used in community tasks. This assessment measures 2 general skills that were previously identified as essential to functioning in the community: financial skills and communication skills. The UPSA-Bi assessment is scored from 0-100, higher scores indicating higher functional status. ITT population included all randomised participants who received at least one dose of study treatment (BIIB104 or placebo). Here, “Overall Number of Participants Analysed” signifies the number of participants analysed in this outcome measure.
    End point type
    Secondary
    End point timeframe
    Baseline and Week 12
    End point values
    		 Placebo BIIB104 0.15 mg BIIB104 0.5 mg
    Number of subjects analysed
    49
    50
    49
    Units: score on a scale
        least squares mean (standard error)
    2.07 ( 1.303 )
    5.50 ( 1.292 )
    5.49 ( 1.305 )
    Statistical analysis title
    		 Placebo vs BIIB104 0.5 mg
    Statistical analysis description
    An analysis of covariance (ANCOVA) model was applied adjusting for treatment group and baseline value of the OM.
    Comparison groups
    Placebo v BIIB104 0.5 mg
    Number of subjects included in analysis
    98
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.0659
    Method
    		 ANCOVA
    Parameter type
    		 LS Mean Difference
    Point estimate
    3.42
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -0.23
         upper limit
    		 7.06
    Variability estimate
    Standard error of the mean
    Dispersion value
    1.844
    Statistical analysis title
    		 Placebo vs BIIB104 0.15 mg
    Statistical analysis description
    An ANCOVA model was applied adjusting for treatment group and baseline value of the OM.
    Comparison groups
    Placebo v BIIB104 0.15 mg
    Number of subjects included in analysis
    99
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.0637
    Method
    		 ANCOVA
    Parameter type
    		 LS Mean Difference
    Point estimate
    3.43
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -0.2
         upper limit
    		 7.06
    Variability estimate
    Standard error of the mean
    Dispersion value
    1.835

    Secondary: Number of Participants With at Least one Event of Suicidal Ideation and/or Suicidal Behavior as Assessed by Columbia-Suicide Severity Rating Scale (C-SSRS) Score

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    End point title
    		 Number of Participants With at Least one Event of Suicidal Ideation and/or Suicidal Behavior as Assessed by Columbia-Suicide Severity Rating Scale (C-SSRS) Score
    End point description
    The C-SSRS is an interview-based rating scale to systematically assess suicidal ideation and suicidal behavior. Suicidal ideation is classified on a 5-item scale: 1 (wish to be dead), 2 (nonspecific active suicidal thoughts), 3 (active suicidal ideation with any methods [not plan] without intent to act), 4 (active suicidal ideation with some intent to act, without specific plan), and 5 (active suicidal ideation with specific plan and intent). Suicidal behavior is classified on a 6-item scale: 1 (actual attempt), 2 (interrupted attempt), 3 (aborted attempt), 4 (preparatory acts or behavior), 5 (suicidal behavior), and 6 (suicide). The data analysed signifies the participants with at least one event of suicidal ideation and/or suicidal behavior.The safety population included all randomised participants who received at least 1 dose of study treatment (BIIB104 or placebo).Here, “Overall Number of Participants Analysed” signifies the number of participants analysed in this outcome measure.
    End point type
    Secondary
    End point timeframe
    Up to Week 14
    End point values
    		 Placebo BIIB104 0.15 mg BIIB104 0.5 mg
    Number of subjects analysed
    63
    65
    65
    Units: participants
    3
    4
    0
    No statistical analyses for this end point

    Secondary: Change From Baseline in Schizophrenia Cognition Rating Scale (SCoRS) Assessment Score at Week 12

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    End point title
    		 Change From Baseline in Schizophrenia Cognition Rating Scale (SCoRS) Assessment Score at Week 12
    End point description
    The SCoRS is an interview-based assessment of cognition that involves interviews with participants and informants. The SCoRS includes 20 items designed to specifically assess aspects of cognitive functioning found in each of the seven MCCB cognitive domains including the following: Memory: 4 items; Learning: 2 items; Attention: 3 items; Working memory: 2 items; Problem solving: 3 items; Processing/motor speed: 2 items; Social cognition: 3 items; Language: 1 item. Total score range is 20-80, lower scores indicating higher functional status. The data reported in this outcome measure are for global rating score. ITT population included all randomised participants who received at least one dose of study treatment (BIIB104 or placebo). Here, “Overall Number of Participants Analysed” signifies the number of participants analysed in this outcome measure.
    End point type
    Secondary
    End point timeframe
    Baseline and Week 12
    End point values
    		 Placebo BIIB104 0.15 mg BIIB104 0.5 mg
    Number of subjects analysed
    49
    48
    50
    Units: score on a scale
        least squares mean (standard error)
    -0.51 ( 0.146 )
    -0.42 ( 0.148 )
    -0.41 ( 0.145 )
    Statistical analysis title
    		 Placebo vs BIIB104 0.5 mg
    Statistical analysis description
    An ANCOVA model was applied adjusting for treatment group and baseline value of the OM.
    Comparison groups
    Placebo v BIIB104 0.5 mg
    Number of subjects included in analysis
    99
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.614
    Method
    		 ANCOVA
    Parameter type
    		 LS Mean Difference
    Point estimate
    0.206
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -0.3
         upper limit
    		 0.51
    Variability estimate
    Standard error of the mean
    Dispersion value
    0.1
    Statistical analysis title
    		 Placebo vs BIIB104 0.15 mg
    Statistical analysis description
    An ANCOVA model was applied adjusting for treatment group and baseline value of the OM.
    Comparison groups
    Placebo v BIIB104 0.15 mg
    Number of subjects included in analysis
    97
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.6653
    Method
    		 ANCOVA
    Parameter type
    		 LS Mean Difference
    Point estimate
    0.208
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -0.32
         upper limit
    		 0.5
    Variability estimate
    Standard error of the mean
    Dispersion value
    0.09

    Secondary: Change From Baseline in MCCB Neurocognitive Composite Scores at Week 12

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    End point title
    		 Change From Baseline in MCCB Neurocognitive Composite Scores at Week 12
    End point description
    The MCCB is a cognitive battery that assesses 7 domains recommended by the MATRICS initiative (i.e., Working Memory, Verbal Learning, Speed of Processing, Attention/Vigilance, Visual Learning, Social Cognition, and Reasoning and Problem Solving). MCCB was administered via laptop computer and paper-and-pencil assessments. T-scores for the individual tests were calculated according to the developer's recommended scoring algorithms. MCCB composite T scores are between 40 and 60 (normal range). Higher scores indicate better cognitive functioning. The MCCB composite score contains all of the tests and domains of the MCCB. ITT population included all randomised participants who received at least one dose of study treatment (BIIB104 or placebo). Here, “Overall Number of Participants Analysed” signifies the number of participants analysed in this outcome measure.
    End point type
    Secondary
    End point timeframe
    Baseline and Week 12
    End point values
    		 Placebo BIIB104 0.15 mg BIIB104 0.5 mg
    Number of subjects analysed
    50
    50
    49
    Units: score on a scale
        least squares mean (standard error)
    2.90 ( 0.733 )
    1.80 ( 0.728 )
    3.39 ( 0.727 )
    Statistical analysis title
    		 Placebo vs BIIB104 0.5 mg
    Statistical analysis description
    A MMRM model was used to analyse the change from baseline of the OM of interest, using fixed effects of treatment group, region, study visit, study visit-by-treatment interaction, baseline value of OM, baseline-by-visit interaction.
    Comparison groups
    Placebo v BIIB104 0.5 mg
    Number of subjects included in analysis
    99
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.6349
    Method
    		 MMRM
    Parameter type
    		 LS Mean Difference
    Point estimate
    0.49
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -1.55
         upper limit
    		 2.53
    Variability estimate
    Standard error of the mean
    Dispersion value
    1.032
    Statistical analysis title
    		 Placebo vs BIIB104 0.15 mg
    Statistical analysis description
    A MMRM model was used to analyse the change from baseline of the OM of interest, using fixed effects of treatment group, region, study visit, study visit-by-treatment interaction, baseline value of OM, baseline-by-visit interaction.
    Comparison groups
    Placebo v BIIB104 0.15 mg
    Number of subjects included in analysis
    100
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.2886
    Method
    		 MMRM
    Parameter type
    		 LS Mean Difference
    Point estimate
    -1.1
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -3.14
         upper limit
    		 0.94
    Variability estimate
    Standard error of the mean
    Dispersion value
    1.033

    Secondary: Change From Baseline in MCCB Individual Domain Scores (Excluding Working Memory Domain) at Week 12

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    End point title
    		 Change From Baseline in MCCB Individual Domain Scores (Excluding Working Memory Domain) at Week 12
    End point description
    The MCCB is a cognitive battery that assesses 7 domains recommended by the MATRICS initiative (i.e., working memory, verbal learning, speed of processing, attention/vigilance, visual learning, social cognition, and reasoning and problem solving). MCCB was administered via laptop computer and paper-and-pencil assessments. T-scores for the individual tests were calculated according to the developer's recommended scoring algorithms. MCCB composite T scores are between 40 and 60 (normal range). Higher scores indicate better cognitive functioning. All the domain scores of the MCCB are reported in this outcome measure with the exception of working memory domain. ITT population included all randomised participants who received at least one dose of study treatment (BIIB104 or placebo). Here, “Overall Number of Participants Analysed” signifies the number of participants analysed in this outcome measure.
    End point type
    Secondary
    End point timeframe
    Baseline and Week 12
    End point values
    		 Placebo BIIB104 0.15 mg BIIB104 0.5 mg
    Number of subjects analysed
    50
    50
    49
    Units: score on a scale
    least squares mean (standard error)
        Verbal Learning: Change at Week 12
    0.95 ( 0.951 )
    1.41 ( 0.946 )
    0.41 ( 0.950 )
        Speed of Processing: Change at Week 12
    4.42 ( 0.824 )
    2.28 ( 0.819 )
    3.99 ( 0.817 )
        Attention/Vigilance: Change at Week 12
    0.62 ( 0.852 )
    0.53 ( 0.848 )
    1.55 ( 0.848 )
        Visual Learning: Change at Week 12
    1.70 ( 1.131 )
    0.19 ( 1.125 )
    1.77 ( 1.125 )
        Social Cognition: Change at Week 12
    -0.13 ( 0.959 )
    1.06 ( 0.953 )
    0.95 ( 0.955 )
        Reasoning and Problem Solving: Change at Week 12
    2.81 ( 1.019 )
    2.10 ( 1.1014 )
    4.40 ( 1.011 )
    Statistical analysis title
    		 Placebo vs BIIB104 0.15 mg
    Statistical analysis description
    Verbal Learning: A MMRM model was used to analyse the change from baseline of the OM of interest, using fixed effects of treatment group, region, study visit, study visit-by-treatment interaction, baseline value of OM, baseline-by-visit interaction.
    Comparison groups
    Placebo v BIIB104 0.15 mg
    Number of subjects included in analysis
    100
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.7372
    Method
    		 MMRM
    Parameter type
    		 LS Mean Difference
    Point estimate
    0.45
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -2.21
         upper limit
    		 3.11
    Variability estimate
    Standard error of the mean
    Dispersion value
    1.345
    Statistical analysis title
    		 Placebo vs BIIB104 0.5 mg
    Statistical analysis description
    Verbal Learning: A MMRM model was used to analyse the change from baseline of the OM of interest, using fixed effects of treatment group, region, study visit, study visit-by-treatment interaction, baseline value of OM, baseline-by-visit interaction.
    Comparison groups
    Placebo v BIIB104 0.5 mg
    Number of subjects included in analysis
    99
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.6894
    Method
    		 MMRM
    Parameter type
    		 LS Mean Difference
    Point estimate
    -0.54
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -3.2
         upper limit
    		 2.12
    Variability estimate
    Standard error of the mean
    Dispersion value
    1.346
    Statistical analysis title
    		 Placebo vs BIIB104 0.15 mg
    Statistical analysis description
    Speed of Processing: A MMRM model was used to analyse the change from baseline of the OM of interest, using fixed effects of treatment group, region, study visit, study visit-by-treatment interaction, baseline value of OM, baseline-by-visit interaction.
    Comparison groups
    Placebo v BIIB104 0.15 mg
    Number of subjects included in analysis
    100
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.0674
    Method
    		 MMRM
    Parameter type
    		 LS Mean Difference
    Point estimate
    -2.14
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -4.44
         upper limit
    		 0.16
    Variability estimate
    Standard error of the mean
    Dispersion value
    1.162
    Statistical analysis title
    		 Placebo vs BIIB104 0.5 mg
    Statistical analysis description
    Speed of Processing: A MMRM model was used to analyse the change from baseline of the OM of interest, using fixed effects of treatment group, region, study visit, study visit-by-treatment interaction, baseline value of OM, baseline-by-visit interaction.
    Comparison groups
    Placebo v BIIB104 0.5 mg
    Number of subjects included in analysis
    99
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.7132
    Method
    		 MMRM
    Parameter type
    		 LS Mean Difference
    Point estimate
    -0.43
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -2.72
         upper limit
    		 1.87
    Variability estimate
    Standard error of the mean
    Dispersion value
    1.161
    Statistical analysis title
    		 Placebo vs BIIB104 0.15 mg
    Statistical analysis description
    Attention/Vigilance: A MMRM model was used to analyse the change from baseline of the OM of interest, using fixed effects of treatment group, region, study visit, study visit-by-treatment interaction, baseline value of OM, baseline-by-visit interaction.
    Comparison groups
    Placebo v BIIB104 0.15 mg
    Number of subjects included in analysis
    100
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.9428
    Method
    		 MMRM
    Parameter type
    		 LS Mean Difference
    Point estimate
    -0.09
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -2.46
         upper limit
    		 2.29
    Variability estimate
    Standard error of the mean
    Dispersion value
    1.203
    Statistical analysis title
    		 Placebo vs BIIB104 0.5 mg
    Statistical analysis description
    Attention/Vigilance: A MMRM model was used to analyse the change from baseline of the OM of interest, using fixed effects of treatment group, region, study visit, study visit-by-treatment interaction, baseline value of OM, baseline-by-visit interaction.
    Comparison groups
    Placebo v BIIB104 0.5 mg
    Number of subjects included in analysis
    99
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.4425
    Method
    		 MMRM
    Parameter type
    		 LS Mean Difference
    Point estimate
    0.93
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -1.45
         upper limit
    		 3.3
    Variability estimate
    Standard error of the mean
    Dispersion value
    1.202
    Statistical analysis title
    		 Placebo vs BIIB104 0.15 mg
    Statistical analysis description
    Visual Learning: A MMRM model was used to analyse the change from baseline of the OM of interest, using fixed effects of treatment group, region, study visit, study visit-by-treatment interaction, baseline value of OM, baseline-by-visit interaction.
    Comparison groups
    Placebo v BIIB104 0.15 mg
    Number of subjects included in analysis
    100
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.3455
    Method
    		 MMRM
    Parameter type
    		 LS Mean Difference
    Point estimate
    -1.51
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -4.66
         upper limit
    		 1.64
    Variability estimate
    Standard error of the mean
    Dispersion value
    1.597
    Statistical analysis title
    		 Placebo vs BIIB104 0.5 mg
    Statistical analysis description
    Visual Learning: A MMRM model was used to analyse the change from baseline of the OM of interest, using fixed effects of treatment group, region, study visit, study visit-by-treatment interaction, baseline value of OM, baseline-by-visit interaction.
    Comparison groups
    Placebo v BIIB104 0.5 mg
    Number of subjects included in analysis
    99
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.9686
    Method
    		 MMRM
    Parameter type
    		 LS Mean Difference
    Point estimate
    0.06
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -3.09
         upper limit
    		 3.21
    Variability estimate
    Standard error of the mean
    Dispersion value
    1.595
    Statistical analysis title
    		 Placebo vs BIIB104 0.15 mg
    Statistical analysis description
    Social Cognition: A MMRM model was used to analyse the change from baseline of the OM of interest, using fixed effects of treatment group, region, study visit, study visit-by-treatment interaction, baseline value of OM, baseline-by-visit interaction.
    Comparison groups
    Placebo v BIIB104 0.15 mg
    Number of subjects included in analysis
    100
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.3832
    Method
    		 MMRM
    Parameter type
    		 LS Mean Difference
    Point estimate
    1.18
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -1.49
         upper limit
    		 3.85
    Variability estimate
    Standard error of the mean
    Dispersion value
    1.351
    Statistical analysis title
    		 Placebo vs BIIB104 0.5 mg
    Statistical analysis description
    Social Cognition: A MMRM model was used to analyse the change from baseline of the OM of interest, using fixed effects of treatment group, region, study visit, study visit-by-treatment interaction, baseline value of OM, baseline-by-visit interaction.
    Comparison groups
    Placebo v BIIB104 0.5 mg
    Number of subjects included in analysis
    99
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.4297
    Method
    		 MMRM
    Parameter type
    		 LS Mean DIfference
    Point estimate
    1.07
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -1.61
         upper limit
    		 3.75
    Variability estimate
    Standard error of the mean
    Dispersion value
    1.357
    Statistical analysis title
    		 Placebo vs BIIB104 0.15 mg
    Statistical analysis description
    Reasoning and Problem Solving: A MMRM model was used to analyse the change from baseline of the OM of interest, using fixed effects of treatment group, region, study visit, study visit-by-treatment interaction, baseline value of OM, baseline-by-visit interaction.
    Comparison groups
    Placebo v BIIB104 0.15 mg
    Number of subjects included in analysis
    100
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.6245
    Method
    		 MMRM
    Parameter type
    		 LS Mean Difference
    Point estimate
    -0.71
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -3.55
         upper limit
    		 2.14
    Variability estimate
    Standard error of the mean
    Dispersion value
    1.438
    Statistical analysis title
    		 Placebo vs BIIB104 0.5 mg
    Statistical analysis description
    Reasoning and Problem Solving: A MMRM model was used to analyse the change from baseline of the OM of interest, using fixed effects of treatment group, region, study visit, study visit-by-treatment interaction, baseline value of OM, baseline-by-visit interaction.
    Comparison groups
    Placebo v BIIB104 0.5 mg
    Number of subjects included in analysis
    99
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.2698
    Method
    		 MMRM
    Parameter type
    		 LS Mean Difference
    Point estimate
    1.59
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -1.25
         upper limit
    		 4.43
    Variability estimate
    Standard error of the mean
    Dispersion value
    1.436

    Secondary: Change From Baseline in Positive and Negative Syndrome Scale (PANSS) Total Score, Positive Subscale, and Negative Subscale Scores at Week 12

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    End point title
    		 Change From Baseline in Positive and Negative Syndrome Scale (PANSS) Total Score, Positive Subscale, and Negative Subscale Scores at Week 12
    End point description
    PANSS includes 3 subscales,30 items:7 items=Positive subscale (e.g., delusions, conceptual disorganization, hallucinatory behaviour);7 items=Negative subscales (e.g., blunted affect, emotional withdrawal, poor rapport, passive/apathetic social withdrawal);16 items=General Psychopathology subscale (e.g., somatic concern, anxiety, guilt feelings, mannerisms and posturing, motor retardation, uncooperativeness, disorientation, poor impulse control, preoccupation). Each item on these subscales is rated: 1 (absent) and -7(extreme). The score range is 7-49 for positive and negative subscales, score range is 16-112 for general psychopathology subscale. Total PANSS score (positive + negative + general psychopathology subscale scores) range from 30-210. Higher scores represent more severity in symptoms. ITT population. “Overall Number of Participants Analysed” = the number of participants analysed in this outcome measure.
    End point type
    Secondary
    End point timeframe
    Baseline and Week 12
    End point values
    		 Placebo BIIB104 0.15 mg BIIB104 0.5 mg
    Number of subjects analysed
    51
    51
    50
    Units: score on a scale
    least squares mean (standard error)
        Positive Symptoms Scale: Change at Week 12
    -0.65 ( 0.431 )
    -1.09 ( 0.430 )
    -0.98 ( 0.429 )
        Negative Symptoms Scale: Change at Week 12
    -0.90 ( 0.461 )
    -0.98 ( 0.461 )
    -1.40 ( 0.460 )
        Total Score: Change at Week 12
    -3.06 ( 1.429 )
    -4.26 ( 1.421 )
    -5.03 ( 1.427 )
    Statistical analysis title
    		 Placebo vs BIIB104 0.15 mg
    Statistical analysis description
    Positive Symptoms Subscale: A MMRM model was used to analyse the change from baseline of the OM of interest, using fixed effects of treatment group, region, study visit, study visit-by-treatment interaction, baseline value of OM, baseline-by-visit interaction.
    Comparison groups
    Placebo v BIIB104 0.15 mg
    Number of subjects included in analysis
    102
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.4654
    Method
    		 MMRM
    Parameter type
    		 LS Mean Difference
    Point estimate
    -0.45
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -1.65
         upper limit
    		 0.76
    Variability estimate
    Standard error of the mean
    Dispersion value
    0.61
    Statistical analysis title
    		 Placebo vs BIIB104 0.5 mg
    Statistical analysis description
    Positive Symptoms Subscale: A MMRM model was used to analyse the change from baseline of the OM of interest, using fixed effects of treatment group, region, study visit, study visit-by-treatment interaction, baseline value of OM, baseline-by-visit interaction.
    Comparison groups
    Placebo v BIIB104 0.5 mg
    Number of subjects included in analysis
    101
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.5886
    Method
    		 MMRM
    Parameter type
    		 LS Mean Difference
    Point estimate
    -0.33
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -1.53
         upper limit
    		 0.87
    Variability estimate
    Standard error of the mean
    Dispersion value
    0.608
    Statistical analysis title
    		 Placebo vs BIIB104 0.15 mg
    Statistical analysis description
    Negative Symptoms Subscale: A MMRM model was used to analyse the change from baseline of the OM of interest, using fixed effects of treatment group, region, study visit, study visit-by-treatment interaction, baseline value of OM, baseline-by-visit interaction.
    Comparison groups
    Placebo v BIIB104 0.15 mg
    Number of subjects included in analysis
    102
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.9079
    Method
    		 MMRM
    Parameter type
    		 LS Mean Difference
    Point estimate
    -0.08
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -1.37
         upper limit
    		 1.22
    Variability estimate
    Standard error of the mean
    Dispersion value
    0.655
    Statistical analysis title
    		 Placebo vs BIIB104 0.5 mg
    Statistical analysis description
    Negative Symptoms Subscale: A MMRM model was used to analyse the change from baseline of the OM of interest, using fixed effects of treatment group, region, study visit, study visit-by-treatment interaction, baseline value of OM, baseline-by-visit interaction.
    Comparison groups
    Placebo v BIIB104 0.5 mg
    Number of subjects included in analysis
    101
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.4441
    Method
    		 MMRM
    Parameter type
    		 LS Mean Difference
    Point estimate
    -0.5
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -1.78
         upper limit
    		 0.79
    Variability estimate
    Standard error of the mean
    Dispersion value
    0.65
    Statistical analysis title
    		 Placebo vs BIIB104 0.15 mg
    Statistical analysis description
    Total Score: A MMRM model was used to analyse the change from baseline of the OM of interest, using fixed effects of treatment group, region, study visit, study visit-by-treatment interaction, baseline value of OM, baseline-by-visit interaction.
    Comparison groups
    Placebo v BIIB104 0.15 mg
    Number of subjects included in analysis
    102
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.5537
    Method
    		 MMRM
    Parameter type
    		 LS Mean Difference
    Point estimate
    -1.2
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -5.18
         upper limit
    		 2.79
    Variability estimate
    Standard error of the mean
    Dispersion value
    2.017
    Statistical analysis title
    		 Placebo vs BIIB104 0.5 mg
    Statistical analysis description
    Total Score: A MMRM model was used to analyse the change from baseline of the OM of interest, using fixed effects of treatment group, region, study visit, study visit-by-treatment interaction, baseline value of OM, baseline-by-visit interaction.
    Comparison groups
    Placebo v BIIB104 0.5 mg
    Number of subjects included in analysis
    101
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.332
    Method
    		 MMRM
    Parameter type
    		 LS Mean Difference
    Point estimate
    -1.96
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -5.95
         upper limit
    		 2.02
    Variability estimate
    Standard error of the mean
    Dispersion value
    2.018

    Secondary: Change From Baseline in Clinical Global Impression-Severity (CGI-S) Scores at Week 12

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    End point title
    		 Change From Baseline in Clinical Global Impression-Severity (CGI-S) Scores at Week 12
    End point description
    The CGI-S consists of a single 7-point rating score of illness severity. The following question: "Considering your total clinical experience with this particular population, how mentally ill is your participant at this time?" is rated with a score from 1 to 7- 1: Normal, not ill at all; 2: Borderline mentally ill; 3: Mildly ill; 4: Moderately ill; 5: Markedly ill; 6: Severely ill; or 7: Among the most severely ill participants. Lower scores indicate less severity of illness. ITT population included all randomised participants who received at least one dose of study treatment (BIIB104 or placebo). Here, “Overall Number of Participants Analysed” signifies the number of participants analysed in this outcome measure.
    End point type
    Secondary
    End point timeframe
    Baseline and Week 12
    End point values
    		 Placebo BIIB104 0.15 mg BIIB104 0.5 mg
    Number of subjects analysed
    51
    50
    50
    Units: score on a scale
        least squares mean (standard error)
    -0.19 ( 0.091 )
    -0.16 ( 0.091 )
    -0.19 ( 0.091 )
    Statistical analysis title
    		 Placebo vs BIIB104 0.5 mg
    Statistical analysis description
    A MMRM model was used to analyse the change from baseline of the OM of interest, using fixed effects of treatment group, region, study visit, study visit-by-treatment interaction, baseline value of OM, baseline-by-visit interaction.
    Comparison groups
    Placebo v BIIB104 0.5 mg
    Number of subjects included in analysis
    101
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.9952
    Method
    		 MMRM
    Parameter type
    		 LS Mean Difference
    Point estimate
    0
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -0.25
         upper limit
    		 0.25
    Variability estimate
    Standard error of the mean
    Dispersion value
    0.128
    Statistical analysis title
    		 Placebo vs BIIB104 0.15 mg
    Statistical analysis description
    A MMRM model was used to analyse the change from baseline of the OM of interest, using fixed effects of treatment group, region, study visit, study visit-by-treatment interaction, baseline value of OM, baseline-by-visit interaction.
    Comparison groups
    Placebo v BIIB104 0.15 mg
    Number of subjects included in analysis
    101
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.8517
    Method
    		 MMRM
    Parameter type
    		 LS Mean Difference
    Point estimate
    0.02
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -0.23
         upper limit
    		 0.28
    Variability estimate
    Standard error of the mean
    Dispersion value
    0.128

    Secondary: Number of Participants With Response on Clinical Global Impression-Improvement (CGI-I) Scale at Week 12

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    End point title
    		 Number of Participants With Response on Clinical Global Impression-Improvement (CGI-I) Scale at Week 12
    End point description
    The CGI-I consists of a single 7-point rating score total improvement, regardless of whether or not the change is due entirely to drug treatment. The following question: "Compared to your participant's condition at the beginning of treatment, how much has your participant changed?" is rated with a score from 1 to 7- 1: Very much improved; 2: Much improved; 3: Minimally improved; 4: No change; 5: Minimally worse; 6: Much worse; or 7: Very much worse. Lower scores indicate greater improvement. ITT population included all randomised participants who received at least one dose of study treatment (BIIB104 or placebo). Here, “Overall Number of Participants Analysed” signifies the number of participants analysed in this outcome measure.
    End point type
    Secondary
    End point timeframe
    Week 12
    End point values
    		 Placebo BIIB104 0.15 mg BIIB104 0.5 mg
    Number of subjects analysed
    51
    50
    50
    Units: participants
        Very Much Improved
    1
    1
    0
        Much Improved
    11
    4
    4
        Minimally Improved
    13
    18
    18
        No Change
    22
    26
    26
        Minimally worse
    2
    1
    2
        Much Worse
    2
    0
    0
        Very Much Worse
    0
    0
    0
    No statistical analyses for this end point

    Adverse events

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    Adverse events information
    Timeframe for reporting adverse events
    From first dose of study drug through end of the study (up to Week 14)
    Adverse event reporting additional description
    Safety population. One participant randomised to placebo, inadvertently received one or more doses of active treatment. For participants affected, a participant was counted only once within each system organ class/preferred term/study period.
    Assessment type
    		 Systematic
    Dictionary used for adverse event reporting
    Dictionary name
    		 MedDRA
    Dictionary version
    25.0
    Reporting groups
    Reporting group title
    Placebo
    Reporting group description
    		 Participants received BIIB104 matching placebo capsules, BID, orally for 12 weeks.

    Reporting group title
    BIIB104 0.5 mg
    Reporting group description
    		 Participants received 0.5 mg capsules of BIIB104, BID, orally for 12 weeks.

    Reporting group title
    BIIB104 0.15 mg
    Reporting group description
    		 Participants received 0.15 mg capsules of BIIB104, BID, orally for 12 weeks.

    Serious adverse events
    		 Placebo BIIB104 0.5 mg BIIB104 0.15 mg
    Total subjects affected by serious adverse events
         subjects affected / exposed
    1 / 63 (1.59%)
    2 / 66 (3.03%)
    1 / 66 (1.52%)
         number of deaths (all causes)
    0
    0
    0
         number of deaths resulting from adverse events
    0
    0
    0
    Psychiatric disorders
    Schizophrenia
         subjects affected / exposed
    0 / 63 (0.00%)
    1 / 66 (1.52%)
    1 / 66 (1.52%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 2
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Psychiatric decompensation
         subjects affected / exposed
    0 / 63 (0.00%)
    1 / 66 (1.52%)
    0 / 66 (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
    Infections and infestations
    Appendicitis
    alternative dictionary used: MedDRA 25.0
         subjects affected / exposed
    1 / 63 (1.59%)
    0 / 66 (0.00%)
    0 / 66 (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
    Frequency threshold for reporting non-serious adverse events: 5%
    Non-serious adverse events
    		 Placebo BIIB104 0.5 mg BIIB104 0.15 mg
    Total subjects affected by non serious adverse events
         subjects affected / exposed
    2 / 63 (3.17%)
    8 / 66 (12.12%)
    2 / 66 (3.03%)
    Nervous system disorders
    Headache
         subjects affected / exposed
    1 / 63 (1.59%)
    4 / 66 (6.06%)
    1 / 66 (1.52%)
         occurrences all number
    1
    4
    1
    Psychiatric disorders
    Schizophrenia
         subjects affected / exposed
    1 / 63 (1.59%)
    4 / 66 (6.06%)
    1 / 66 (1.52%)
         occurrences all number
    1
    4
    1

    More information

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    Substantial protocol amendments (globally)
    Were there any global substantial amendments to the protocol? Yes
    Date
    Amendment
    10 Aug 2018
    The duration of the study treatment period was decreased from 24 weeks to 12 weeks and the duration of the safety follow-up period from 4 weeks to 2 weeks.
    12 Jun 2019
    The number of study sites were expanded from approximately 40 to approximately 80 and the inclusion of participants in Japan and possibly other countries.
    29 Oct 2019
    The study eligibility criteria was updated: 1) increased the maximum age for participants from 50 to 55 years, 2) the requirements for the identified informants were revised to reduce the burden on participants and informants, and 3) the requirements for oral fluency and reading assessment were revised to standardize test scoring across geographic regions. In addition, the changes for the Japan-specific protocol amendment (Version 3.1) were incorporated into this global version of the protocol.

    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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