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    Clinical Trial Results:
    A Randomized, Double-Blind, Placebo-Controlled Multiple Dose Study to Assess Efficacy, Safety, Tolerability, and Pharmacokinetics of ABBV-8E12 in Progressive Supranuclear Palsy

    Summary
    EudraCT number
    2016-001635-12
    Trial protocol
    DE   FR   IT   ES  
    Global end of trial date
    20 Nov 2019

    Results information
    Results version number
    v2(current)
    This version publication date
    03 Mar 2021
    First version publication date
    03 Dec 2020
    Other versions
    v1
    Version creation reason
    • New data added to full data set
    Additional data added for one ednpoint.

    Trial information

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    Trial identification
    Sponsor protocol code
    M15-562
    Additional study identifiers
    ISRCTN number
    -
    US NCT number
    NCT02985879
    WHO universal trial number (UTN)
    -
    Sponsors
    Sponsor organisation name
    AbbVie
    Sponsor organisation address
    AbbVie House, Vanwall Business Park, Vanwall Road, Maidenhead, Berkshire, United Kingdom, SL6-4UB
    Public contact
    Global Medical Services, AbbVie, 001 8006339110, abbvieclinicaltrials@abbvie.com
    Scientific contact
    Global Medical Services, AbbVie, 001 8006339110, abbvieclinicaltrials@abbvie.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
    20 Nov 2019
    Is this the analysis of the primary completion data?
    No
    Global end of trial reached?
    Yes
    Global end of trial date
    20 Nov 2019
    Was the trial ended prematurely?
    Yes
    General information about the trial
    Main objective of the trial
    This was a Phase 2, randomized, double-blind, placebo-controlled, multiple dose, multicenter study with a screening period of ≤ 8 wks, a 52-wk treatment (Tx) period, and 20-week follow-up after the last study drug dose (for those who prematurely discontinued from Tx, declined to participate in or did not qualify for a long term extension [LTE] study). Extended Tx was available for those who completed the 52-wk Tx and entered the long-term extension Study M15-563. There were 3 cohorts: Cohort 1, Cohort J1, and Cohort 2. Cohort 1 had augmented safety and pharmacokinetic (PK) assessments in the first 30 subjects enrolled into the study from countries other than Japan. Cohort J1 had augmented safety and PK assessments in the first 9 subjects enrolled into the study from Japan. Cohort 2 was all others enrolled in the study.This study was prematurely discontinued because the program for progressive supranuclear palsy was discontinued due to lack of efficacy of study drug.
    Protection of trial subjects
    Subject must have been able to understand the nature of the study and given the opportunity to have any questions answered. The subject voluntarily signed the Independent Ethics Committee (IEC)/Independent Review Board (IRB) approved Informed Consent, prior to the conduct of any study procedures (including any changes occurring in the subject's current therapeutic regimen). In the absence of subject's ability to provide the informed consent, the informed consent was signed by a person who had the legal right to act on behalf of the subject following national laws. In Germany, where the subject's legally authorized representative (LAR) is not permitted to sign the IEC/IRB approved Informed Consent form on behalf of the subject, evaluation by an independent psychiatrist was to be sought if the investigator who was evaluating the subject for inclusion in the study doubted the subject's cognitive ability to independently provide informed consent.
    Background therapy
    -
    Evidence for comparator
    -
    Actual start date of recruitment
    12 Dec 2016
    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
    Australia: 17
    Country: Number of subjects enrolled
    Canada: 32
    Country: Number of subjects enrolled
    France: 12
    Country: Number of subjects enrolled
    Germany: 18
    Country: Number of subjects enrolled
    Italy: 57
    Country: Number of subjects enrolled
    Japan: 33
    Country: Number of subjects enrolled
    Spain: 6
    Country: Number of subjects enrolled
    United States: 202
    Worldwide total number of subjects
    377
    EEA total number of subjects
    93
    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)
    99
    From 65 to 84 years
    276
    85 years and over
    2

    Subject disposition

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    Recruitment
    Recruitment details
    -

    Pre-assignment
    Screening details
    Safety dataset: all randomized participants who received at least one dose of study drug

    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, Monitor, Data analyst, Carer, Assessor

    Arms
    Are arms mutually exclusive
    Yes

    Arm title
    Placebo
    Arm description
    0.9% Sodium Chloride Injection/Solution for Infusion; intravenous infusions at Day 1, Day 15, and Day 29, then every 28 days for 52 weeks
    Arm type
    Placebo

    Investigational medicinal product name
    0.9% Sodium Chloride Injection/Solution for Infusion
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Solution for infusion
    Routes of administration
    Intravenous use
    Dosage and administration details
    Participants with 44-49 kg body weight (BW) had an intravenous infusion rate of 3.5 mL/min or 210 mL/hr; those with 50-58 kg BW, 4.0 mL/min or 240 mL/hr; and those with a BW >59 kg, 4.7 mL/min or 282 mL/hr.

    Arm title
    ABBV-8E12 2000 mg
    Arm description
    Intravenous infusions at Day 1, Day 15, and Day 29, then every 28 days for 52 weeks; 300 mg/15 mL (participants in countries other than Japan or Spain); 1000 mg/10 mL (for participants in Japan or Spain)
    Arm type
    Experimental

    Investigational medicinal product name
    ABBV-8E12
    Investigational medicinal product code
    Other name
    Tilavonemab
    Pharmaceutical forms
    Solution for infusion
    Routes of administration
    Intravenous use
    Dosage and administration details
    Participants with 44-49 kg body weight (BW) had an intravenous infusion rate of 3.5 mL/min or 210 mL/hr; those with 50-58 kg BW, 4.0 mL/min or 240 mL/hr; and those with a BW >59 kg, 4.7 mL/min or 282 mL/hr. For participants in Cohort 2, ABBV-8E12 doses may have been decreased after the evaluation by the Data Monitoring Committee of available safety, tolerability and pharmacokinetic data.

    Arm title
    ABBV-8E12 4000 mg
    Arm description
    Intravenous infusions at Day 1, Day 15, and Day 29, then every 28 days for 52 weeks; 300 mg/15 mL (participants in countries other than Japan or Spain); 1000 mg/10 mL (for participants in Japan or Spain)
    Arm type
    Experimental

    Investigational medicinal product name
    ABBV-8E12
    Investigational medicinal product code
    Other name
    Tilavonemab
    Pharmaceutical forms
    Solution for infusion
    Routes of administration
    Intravenous use
    Dosage and administration details
    Participants with 44-49 kg body weight (BW) had an intravenous infusion rate of 3.5 mL/min or 210 mL/hr; those with 50-58 kg BW, 4.0 mL/min or 240 mL/hr; and those with a BW >59 kg, 4.7 mL/min or 282 mL/hr. For participants in Cohort 2, ABBV-8E12 doses may have been decreased after the evaluation by the Data Monitoring Committee of available safety, tolerability and pharmacokinetic data.

    Number of subjects in period 1
    Placebo ABBV-8E12 2000 mg ABBV-8E12 4000 mg
    Started
    126
    126
    125
    Completed
    50
    52
    48
    Not completed
    76
    74
    77
         Adverse event, non-fatal
    7
    8
    7
         Other, not specified
    62
    58
    58
         Withdrew consent
    6
    8
    10
         Lost to follow-up
    1
    -
    2

    Baseline characteristics

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    Baseline characteristics reporting groups
    Reporting group title
    Placebo
    Reporting group description
    0.9% Sodium Chloride Injection/Solution for Infusion; intravenous infusions at Day 1, Day 15, and Day 29, then every 28 days for 52 weeks

    Reporting group title
    ABBV-8E12 2000 mg
    Reporting group description
    Intravenous infusions at Day 1, Day 15, and Day 29, then every 28 days for 52 weeks; 300 mg/15 mL (participants in countries other than Japan or Spain); 1000 mg/10 mL (for participants in Japan or Spain)

    Reporting group title
    ABBV-8E12 4000 mg
    Reporting group description
    Intravenous infusions at Day 1, Day 15, and Day 29, then every 28 days for 52 weeks; 300 mg/15 mL (participants in countries other than Japan or Spain); 1000 mg/10 mL (for participants in Japan or Spain)

    Reporting group values
    Placebo ABBV-8E12 2000 mg ABBV-8E12 4000 mg Total
    Number of subjects
    126 126 125 377
    Age categorical
    Units: Subjects
    Age continuous
    Units: years
        arithmetic mean (standard deviation)
    68.1 ± 6.22 68.3 ± 7.25 70.0 ± 6.85 -
    Gender categorical
    Units: Subjects
        Female
    53 49 56 158
        Male
    73 77 69 219

    End points

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    End points reporting groups
    Reporting group title
    Placebo
    Reporting group description
    0.9% Sodium Chloride Injection/Solution for Infusion; intravenous infusions at Day 1, Day 15, and Day 29, then every 28 days for 52 weeks

    Reporting group title
    ABBV-8E12 2000 mg
    Reporting group description
    Intravenous infusions at Day 1, Day 15, and Day 29, then every 28 days for 52 weeks; 300 mg/15 mL (participants in countries other than Japan or Spain); 1000 mg/10 mL (for participants in Japan or Spain)

    Reporting group title
    ABBV-8E12 4000 mg
    Reporting group description
    Intravenous infusions at Day 1, Day 15, and Day 29, then every 28 days for 52 weeks; 300 mg/15 mL (participants in countries other than Japan or Spain); 1000 mg/10 mL (for participants in Japan or Spain)

    Subject analysis set title
    Cohort 1, ABBV-8E12 2000 mg
    Subject analysis set type
    Per protocol
    Subject analysis set description
    First 30 participants enrolled into the global study from countries other than Japan who received augmented safety and PK assessments and ABBV-8E12 at a dose of 2000 mg

    Subject analysis set title
    Cohort 1, ABBV-8E12 4000 mg
    Subject analysis set type
    Per protocol
    Subject analysis set description
    First 30 participants enrolled into the global study from countries other than Japan who received augmented safety and PK assessments and ABBV-8E12 at a dose of 4000 mg

    Subject analysis set title
    Cohort J1, ABBV-8E12 2000 mg
    Subject analysis set type
    Per protocol
    Subject analysis set description
    First 9 participants enrolled into the study from Japan who received augmented safety and PK assessments and ABBV-8E12 at a dose of 2000 mg

    Subject analysis set title
    Cohort J1, ABBV-8E12 4000 mg
    Subject analysis set type
    Per protocol
    Subject analysis set description
    First 9 participants enrolled into the study from Japan who received augmented safety and PK assessments and ABBV-8E12 at a dose of 4000 mg

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

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    End point title
    Change From Baseline to Week 52 in Progressive Supranuclear Palsy Rating Scale (PSPRS) Total Score
    End point description
    The PSPRS consists of 28 items grouped in six domains: daily activities (by history); behavior; bulbar; ocular motor; limb motor; and gait/midline. Items are scored on a 0 to 4 scale, except for six items that are scored on a 0 to 2 scale, with the total score ranging from 0 to 100. Higher scores indicate more severe disability or movement abnormality. Positive changes in score indicate worsening from baseline.
    End point type
    Primary
    End point timeframe
    Baseline, Week 52
    End point values
    Placebo ABBV-8E12 2000 mg ABBV-8E12 4000 mg
    Number of subjects analysed
    59 [1]
    56 [2]
    59 [3]
    Units: units on a scale
        least squares mean (standard error)
    10.5 ± 0.94
    10.5 ± 0.96
    11.4 ± 0.94
    Notes
    [1] - ITT set:randomized subjects who rcvd ≥1 dose of study drug with available data at baseline and Wk 52
    [2] - ITT set:randomized subjects who rcvd ≥1 dose of study drug with available data at baseline and Wk 52
    [3] - ITT set:randomized subjects who rcvd ≥1 dose of study drug with available data at baseline and Wk 52
    Statistical analysis title
    ABBV-8E12 2000 mg vs Placebo
    Statistical analysis description
    The primary efficacy analysis utilized a likelihood-based, mixed-effects model, repeated measures (MMRM) analysis of the change from baseline for each postbaseline value and compared each ABBV-8E12 dose group with the placebo group. The model, which used all observed data, included fixed, categorical effects for treatment, site, visit, baseline score-by-visit interaction and treatment-by-visit interaction, with continuous fixed covariates for the corresponding baseline score.
    Comparison groups
    Placebo v ABBV-8E12 2000 mg
    Number of subjects included in analysis
    115
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    P-value
    = 0.998
    Method
    Mixed-effects model, repeated measures
    Parameter type
    LS Mean Difference
    Point estimate
    0
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    -2.63
         upper limit
    2.63
    Variability estimate
    Standard error of the mean
    Dispersion value
    1.34
    Statistical analysis title
    ABBV-8E12 4000 mg vs Placebo
    Statistical analysis description
    The primary efficacy analysis utilized a likelihood-based, mixed-effects model, repeated measures (MMRM) analysis of the change from baseline for each postbaseline value and compared each ABBV-8E12 dose group with the placebo group. The model, which used all observed data, included fixed, categorical effects for treatment, site, visit, baseline score-by-visit interaction and treatment-by-visit interaction, with continuous fixed covariates for the corresponding baseline score.
    Comparison groups
    Placebo v ABBV-8E12 4000 mg
    Number of subjects included in analysis
    118
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    P-value
    = 0.464
    Method
    Mixed-effects model repeated measures
    Parameter type
    LS Mean Difference
    Point estimate
    1
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    -1.63
         upper limit
    3.58
    Variability estimate
    Standard error of the mean
    Dispersion value
    1.32

    Primary: Number of Participants With Adverse Events

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    End point title
    Number of Participants With Adverse Events [4]
    End point description
    An adverse event (AE) is defined as any untoward medical occurrence in a patient or clinical investigation subject administered a pharmaceutical product and which does not necessarily have a causal relationship with this treatment. The investigator assessed the relationship of each event to the use of study drug as either reasonable possibility or no reasonable possibility. A serious adverse event (SAE) is an event that results in death, is life-threatening, requires or prolongs hospitalization, results in a congenital anomaly, persistent or significant disability/incapacity or is an important medical event that, based on medical judgment, may jeopardize the subject and may require medical or surgical intervention to prevent any of the outcomes listed above. Treatment-emergent events (TEAEs) are defined as any event that began or worsened in severity from first dose of study drug until 20 weeks after the last dose. For more details on AEs please see the Adverse Event section.
    End point type
    Primary
    End point timeframe
    From the first dose of study drug until 20 weeks following discontinuation of study drug administration have elapsed (approximately 5 half-lives), up to 80 weeks
    Notes
    [4] - 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: Statistical analysis not applicable for this endpoint.
    End point values
    Placebo ABBV-8E12 2000 mg ABBV-8E12 4000 mg
    Number of subjects analysed
    126 [5]
    126 [6]
    125 [7]
    Units: participants
    108
    111
    111
    Notes
    [5] - Safety Dataset: all randomized subjects who received at least one dose of study drug
    [6] - Safety Dataset: all randomized subjects who received at least one dose of study drug
    [7] - Safety Dataset: all randomized subjects who received at least one dose of study drug
    No statistical analyses for this end point

    Secondary: Mean Change From Baseline to Week 52 in Midbrain Atrophy As Measured by Volumetric Magnetic Resonance Imaging (MRI)

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    End point title
    Mean Change From Baseline to Week 52 in Midbrain Atrophy As Measured by Volumetric Magnetic Resonance Imaging (MRI)
    End point description
    Magnetic resonance imaging (MRI) of several different brain regions was performed and volumetric analysis was conducted to quantify midbrain atrophy. Negative changes in values indicate a reduction in volume.
    End point type
    Secondary
    End point timeframe
    Baseline, Week 52
    End point values
    Placebo ABBV-8E12 2000 mg ABBV-8E12 4000 mg
    Number of subjects analysed
    53 [8]
    55 [9]
    54 [10]
    Units: mm^3
        least squares mean (standard error)
    -122.0 ± 9.64
    -129.1 ± 9.69
    -128.3 ± 9.69
    Notes
    [8] - ITT set:randomized subjects who rcvd ≥1 dose of study drug with available data at baseline and Wk 52
    [9] - ITT set:randomized subjects who rcvd ≥1 dose of study drug with available data at baseline and Wk 52
    [10] - ITT set:randomized subjects who rcvd ≥1 dose of study drug with available data at baseline and Wk 52
    Statistical analysis title
    ABBV-8E12 2000 mg vs Placebo
    Statistical analysis description
    The analysis utilized a likelihood-based, mixed-effects model, repeated measures (MMRM) analysis of the change from baseline for each postbaseline value and compared each ABBV-8E12 dose group with the placebo group. The model, which used all observed data, included fixed, categorical effects for treatment, site, visit, baseline score-by-visit interaction and treatment-by-visit interaction, with continuous fixed covariates for the corresponding baseline score.
    Comparison groups
    Placebo v ABBV-8E12 2000 mg
    Number of subjects included in analysis
    108
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    P-value
    = 0.597
    Method
    Mixed-effects model repeated measures
    Parameter type
    LS Mean Difference
    Point estimate
    -7.2
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    -33.86
         upper limit
    19.53
    Variability estimate
    Standard error of the mean
    Dispersion value
    13.54
    Statistical analysis title
    ABBV-8E12 4000 mg vs Placebo
    Statistical analysis description
    The analysis utilized a likelihood-based, mixed-effects model, repeated measures (MMRM) analysis of the change from baseline for each postbaseline value and compared each ABBV-8E12 dose group with the placebo group. The model, which used all observed data, included fixed, categorical effects for treatment, site, visit, baseline score-by-visit interaction and treatment-by-visit interaction, with continuous fixed covariates for the corresponding baseline score.
    Comparison groups
    ABBV-8E12 4000 mg v Placebo
    Number of subjects included in analysis
    107
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    P-value
    = 0.642
    Method
    Mixed-effects model repeated measures
    Parameter type
    LS Mean Difference
    Point estimate
    -6.3
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    -33.04
         upper limit
    20.42
    Variability estimate
    Standard error of the mean
    Dispersion value
    13.56

    Secondary: Clinical Global Impression of Change (CGI-C) Score at Week 52

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    End point title
    Clinical Global Impression of Change (CGI-C) Score at Week 52
    End point description
    The Clinical Global Impression of Change (CGI-C) score is a clinician's rating scale for assessing Global Improvement of Change. The CGI-C rates improvement by 7 categories: very much improved (1), much improved (2), minimally improved (3), no change (4), minimally worse (5), much worse (6), very much worse (7). The CGI-C score ranges from 1 to 7, with lower scores indicating improvement.
    End point type
    Secondary
    End point timeframe
    Week 52
    End point values
    Placebo ABBV-8E12 2000 mg ABBV-8E12 4000 mg
    Number of subjects analysed
    50 [11]
    48 [12]
    51 [13]
    Units: units on a scale
        least squares mean (standard error)
    5.1 ± 0.11
    5.1 ± 0.11
    5.0 ± 0.11
    Notes
    [11] - ITT set:randomized subjects who rcvd ≥1 dose of study drug with available data at Wk 52
    [12] - ITT set:randomized subjects who rcvd ≥1 dose of study drug with available data at Wk 52
    [13] - ITT set:randomized subjects who rcvd ≥1 dose of study drug with available data at Wk 52
    Statistical analysis title
    ABBV-8E12 2000 mg vs Placebo
    Statistical analysis description
    The analysis utilized a likelihood-based, mixed-effects model, repeated measures (MMRM) analysis of the change from baseline for each postbaseline value and compared each ABBV-8E12 dose group with the placebo group. The model, which used all observed data, included fixed, categorical effects for treatment, site, visit, baseline score-by-visit interaction and treatment-by-visit interaction, with continuous fixed covariates for the corresponding baseline score.
    Comparison groups
    Placebo v ABBV-8E12 2000 mg
    Number of subjects included in analysis
    98
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    P-value
    = 0.756
    Method
    Mixed-effects model repeated measures
    Parameter type
    LS Mean Difference
    Point estimate
    0
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    -0.36
         upper limit
    0.26
    Variability estimate
    Standard error of the mean
    Dispersion value
    0.16
    Statistical analysis title
    ABBV-8E12 4000 mg vs Placebo
    Statistical analysis description
    The analysis utilized a likelihood-based, mixed-effects model, repeated measures (MMRM) analysis of the change from baseline for each postbaseline value and compared each ABBV-8E12 dose group with the placebo group. The model, which used all observed data, included fixed, categorical effects for treatment, site, visit, baseline score-by-visit interaction and treatment-by-visit interaction, with continuous fixed covariates for the corresponding baseline score.
    Comparison groups
    Placebo v ABBV-8E12 4000 mg
    Number of subjects included in analysis
    101
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    P-value
    = 0.409
    Method
    Mixed-effects model repeated measures
    Parameter type
    LS Mean Difference
    Point estimate
    -0.1
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    -0.44
         upper limit
    0.18
    Variability estimate
    Standard error of the mean
    Dispersion value
    0.16

    Secondary: Time to Maximum Observed Serum Concentration (Tmax) for ABBV-8E12

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    End point title
    Time to Maximum Observed Serum Concentration (Tmax) for ABBV-8E12
    End point description
    The time to maximum plasma concentration (Tmax; measured in hours) is the time it takes for a drug to achieve Cmax, the maximum plasma concentration. Tmax was measured after the first and the fifth doses in Cohort 1 and Cohort J1.
    End point type
    Secondary
    End point timeframe
    First Dosing Interval, 2 weeks, Day 1-14; Fifth Dosing Interval, 4 weeks, Day 85-113
    End point values
    Cohort 1, ABBV-8E12 2000 mg Cohort 1, ABBV-8E12 4000 mg Cohort J1, ABBV-8E12 2000 mg Cohort J1, ABBV-8E12 4000 mg
    Number of subjects analysed
    11 [14]
    9 [15]
    3 [16]
    3 [17]
    Units: hours
    median (full range (min-max))
        1st Dosing Interval, 2 wks, d 1-14; n=11,9,3,3
    4.0 (3.2 to 6.1)
    4.1 (3.2 to 5.6)
    5.0 (4.0 to 5.2)
    4.8 (4.3 to 4.9)
        5th Dosing Interval, 4 wks, d 85-113; n= 9,7,2,2
    3.6 (2.9 to 5.5)
    4.0 (3.3 to 46.2)
    5.0 (4.4 to 5.7)
    3.4 (3.2 to 3.5)
    Notes
    [14] - Participants in Cohort 1 with available data
    [15] - Participants in Cohort 1 with available data
    [16] - Participants in Cohort J1 with available data
    [17] - Participants in Cohort J1 with available data
    No statistical analyses for this end point

    Secondary: Area Under the Concentration Time Curve (AUC) for ABBV-8E12

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    End point title
    Area Under the Concentration Time Curve (AUC) for ABBV-8E12
    End point description
    The area under the plasma concentration-time curve (AUC; measured in µg•day/mL) is a method of measurement to determine the total exposure of a drug in blood plasma. The AUC24 of ABBV-8E12 was estimated using noncompartmental methods after the first and the fifth doses in Cohort 1 and Cohort J1.
    End point type
    Secondary
    End point timeframe
    First Dosing Interval, 2 weeks, Day 1-14; Fifth Dosing Interval, 4 weeks, Day 85-113
    End point values
    Cohort 1, ABBV-8E12 2000 mg Cohort 1, ABBV-8E12 4000 mg Cohort J1, ABBV-8E12 2000 mg Cohort J1, ABBV-8E12 4000 mg
    Number of subjects analysed
    11 [18]
    9 [19]
    3 [20]
    3 [21]
    Units: µg•day/mL
    geometric mean (geometric coefficient of variation)
        1st Dosing Interval, 2 wks, d 1-14; n=11,9,3,3
    5070 ± 25
    10400 ± 21
    5950 ± 12
    10400 ± 11
        5th Dosing Interval, 4 wks, d 85-113; n= 10,8,3,3
    13900 ± 28
    31600 ± 36
    15200 ± 21
    23900 ± 15
    Notes
    [18] - Participants in Cohort 1 with available data
    [19] - Participants in Cohort 1 with available data
    [20] - Participants in Cohort J1 with available data
    [21] - Participants in Cohort J1 with available data
    No statistical analyses for this end point

    Secondary: Serum Concentration of ABBV-8E12 Prior to Infusion of a Day of Dosing (Ctrough)

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    End point title
    Serum Concentration of ABBV-8E12 Prior to Infusion of a Day of Dosing (Ctrough)
    End point description
    The concentration of ABBV-8E12 immediately prior to infusion of the fifth dose (Ctrough; measured in µg/mL) was estimated using non-compartmental methods in Cohort 1 and Cohort J1.
    End point type
    Secondary
    End point timeframe
    First day of the Fifth Dosing Interval, Day 85
    End point values
    Cohort 1, ABBV-8E12 2000 mg Cohort 1, ABBV-8E12 4000 mg Cohort J1, ABBV-8E12 2000 mg Cohort J1, ABBV-8E12 4000 mg
    Number of subjects analysed
    10 [22]
    8 [23]
    3 [24]
    3 [25]
    Units: µg/mL
        geometric mean (geometric coefficient of variation)
    353 ± 27
    657 ± 45
    345 ± 32
    595 ± 16
    Notes
    [22] - Participants in Cohort 1 with available data
    [23] - Participants in Cohort 1 with available data
    [24] - Participants in Cohort J1 with available data
    [25] - Participants in Cohort J1 with available data
    No statistical analyses for this end point

    Secondary: Maximum Observed Serum Concentration (Cmax) for ABBV-8E12

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    End point title
    Maximum Observed Serum Concentration (Cmax) for ABBV-8E12
    End point description
    The maximum observed serum concentration after the first and the fifth doses in Cohort 1 and Cohort J1 was determined.
    End point type
    Secondary
    End point timeframe
    First Dosing Interval, 2 weeks, Day 1-14; Fifth Dosing Interval, 4 weeks, Day 85-113
    End point values
    Cohort 1, ABBV-8E12 2000 mg Cohort 1, ABBV-8E12 4000 mg Cohort J1, ABBV-8E12 2000 mg Cohort J1, ABBV-8E12 4000 mg
    Number of subjects analysed
    11 [26]
    9 [27]
    3 [28]
    3 [29]
    Units: µg/mL
    geometric mean (geometric coefficient of variation)
        1st Dosing Interval, 2 wks, d 1-14; n=11,9,3,3
    714 ± 32
    1450 ± 20
    853 ± 6
    1580 ± 13
        5th Dosing Interval, 4 wks, d 85-113; n= 9,7,2,2
    1070 ± 56
    2350 ± 23
    1010 ± 21
    1960 ± 15
    Notes
    [26] - Participants in Cohort 1 with available data
    [27] - Participants in Cohort 1 with available data
    [28] - Participants in Cohort J1 with available data
    [29] - Participants in Cohort J1 with available data
    No statistical analyses for this end point

    Secondary: Mean Change From Baseline to Week 52 in Unified Parkinson's Disease Rating Scale (UPDRS) Part II (Activities of Daily Living)

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    End point title
    Mean Change From Baseline to Week 52 in Unified Parkinson's Disease Rating Scale (UPDRS) Part II (Activities of Daily Living)
    End point description
    The Unified Parkinson's Disease Rating Scale (UPDRS) is an Investigator-used rating tool to follow the longitudinal course of Parkinson's disease. The Part II score is the sum of the answers to the 13 questions related to Activities of Daily Living, and ranges from 0-52. Higher scores are associated with more disability. Positive changes in score indicate worsening from baseline
    End point type
    Secondary
    End point timeframe
    Baseline, Week 52
    End point values
    Placebo ABBV-8E12 2000 mg ABBV-8E12 4000 mg
    Number of subjects analysed
    63 [30]
    60 [31]
    60 [32]
    Units: units on a scale
        least squares mean (standard error)
    5.6 ± 0.62
    5.8 ± 0.63
    7.0 ± 0.63
    Notes
    [30] - ITT set:randomized subjects who rcvd ≥1 dose of study drug with available data at baseline and Wk 52
    [31] - ITT set:randomized subjects who rcvd ≥1 dose of study drug with available data at baseline and Wk 52
    [32] - ITT set:randomized subjects who rcvd ≥1 dose of study drug with available data at baseline and Wk 52
    Statistical analysis title
    ABBV-8E12 2000 mg vs Placebo
    Statistical analysis description
    The analysis utilized a likelihood-based, mixed-effects model, repeated measures (MMRM) analysis of the change from baseline for each postbaseline value and compared each ABBV-8E12 dose group with the placebo group. The model, which used all observed data, included fixed, categorical effects for treatment, site, visit, baseline score-by-visit interaction and treatment-by-visit interaction, with continuous fixed covariates for the corresponding baseline score.
    Comparison groups
    Placebo v ABBV-8E12 2000 mg
    Number of subjects included in analysis
    123
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    P-value
    = 0.812
    Method
    Mixed-effects model repeated measures
    Parameter type
    LS Mean Difference
    Point estimate
    0.2
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    -1.52
         upper limit
    1.93
    Variability estimate
    Standard error of the mean
    Dispersion value
    0.88
    Statistical analysis title
    ABBV-8E12 4000 mg vs Placebo
    Statistical analysis description
    The analysis utilized a likelihood-based, mixed-effects model, repeated measures (MMRM) analysis of the change from baseline for each postbaseline value and compared each ABBV-8E12 dose group with the placebo group. The model, which used all observed data, included fixed, categorical effects for treatment, site, visit, baseline score-by-visit interaction and treatment-by-visit interaction, with continuous fixed covariates for the corresponding baseline score.
    Comparison groups
    Placebo v ABBV-8E12 4000 mg
    Number of subjects included in analysis
    123
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    P-value
    = 0.104
    Method
    Mixed-effects model repeated measures
    Parameter type
    LS Mean Difference
    Point estimate
    1.4
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    -0.3
         upper limit
    3.16
    Variability estimate
    Standard error of the mean
    Dispersion value
    0.88

    Secondary: Mean Change From Baseline to Week 52 in Schwab and England Activities of Daily Living Scale (SEADL)

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    End point title
    Mean Change From Baseline to Week 52 in Schwab and England Activities of Daily Living Scale (SEADL)
    End point description
    The Schwab and England Activities of Daily Living (SEADL) consists of ten items intended to evaluate the daily life activities of a participant. The SEADL is composed of two sections: the first is a self-reported questionnaire in which participants grade their own daily life activities, such as dressing, using the toilet, resting, eating, and social activities (subjective assessment), and the second is an assessment of motor functions, such as postural balance, speaking, rigidity, and tremors, conducted by a clinician (objective assessment). It is a percentage scale divided into deciles, and the results are reported between 0% (bedridden) and 100% (healthy). Negative changes in values indicate a decline in health.
    End point type
    Secondary
    End point timeframe
    Baseline, Week 52
    End point values
    Placebo ABBV-8E12 2000 mg ABBV-8E12 4000 mg
    Number of subjects analysed
    58 [33]
    56 [34]
    60 [35]
    Units: percentage of independence
        least squares mean (standard error)
    -20.6 ± 1.79
    -18.0 ± 1.82
    -20.5 ± 1.77
    Notes
    [33] - ITT set:randomized subjects who rcvd ≥1 dose of study drug with available data at baseline and Wk 52
    [34] - ITT set:randomized subjects who rcvd ≥1 dose of study drug with available data at baseline and Wk 52
    [35] - ITT set:randomized subjects who rcvd ≥1 dose of study drug with available data at baseline and Wk 52
    Statistical analysis title
    ABBV-8E12 2000 mg vs Placebo
    Statistical analysis description
    The analysis utilized a likelihood-based, mixed-effects model, repeated measures (MMRM) analysis of the change from baseline for each postbaseline value and compared each ABBV-8E12 dose group with the placebo group. The model, which used all observed data, included fixed, categorical effects for treatment, site, visit, baseline score-by-visit interaction and treatment-by-visit interaction, with continuous fixed covariates for the corresponding baseline score.
    Comparison groups
    Placebo v ABBV-8E12 2000 mg
    Number of subjects included in analysis
    114
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    P-value
    = 0.323
    Method
    Mixed-effects model repeated measures
    Parameter type
    LS Mean Difference
    Point estimate
    2.5
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    -2.48
         upper limit
    7.51
    Variability estimate
    Standard error of the mean
    Dispersion value
    2.53
    Statistical analysis title
    ABBV-8E12 4000 mg vs Placebo
    Statistical analysis description
    The analysis utilized a likelihood-based, mixed-effects model, repeated measures (MMRM) analysis of the change from baseline for each postbaseline value and compared each ABBV-8E12 dose group with the placebo group. The model, which used all observed data, included fixed, categorical effects for treatment, site, visit, baseline score-by-visit interaction and treatment-by-visit interaction, with continuous fixed covariates for the corresponding baseline score.
    Comparison groups
    Placebo v ABBV-8E12 4000 mg
    Number of subjects included in analysis
    118
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    P-value
    = 0.974
    Method
    Mixed-effects model repeated measures
    Parameter type
    LS Mean Difference
    Point estimate
    0.1
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    -4.86
         upper limit
    5.02
    Variability estimate
    Standard error of the mean
    Dispersion value
    2.51

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

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    End point title
    Mean Change From Baseline to Week 52 in Clinical Global Impression of Severity (CGI-S) Score
    End point description
    The CGI-S is a clinician's rating of disease severity. The CGI-S rates severity of illness on a 7-point scale, using a range of responses from 1 (normal) through 7 (the most severely ill). This rating is based upon observed and reported symptoms, behavior, and function in the past 7 days. Positive changes in score indicate worsening from baseline.
    End point type
    Secondary
    End point timeframe
    Baseline, Week 52
    End point values
    Placebo ABBV-8E12 2000 mg ABBV-8E12 4000 mg
    Number of subjects analysed
    50 [36]
    48 [37]
    51 [38]
    Units: units on a scale
        least squares mean (standard error)
    0.6 ± 0.10
    0.6 ± 0.10
    0.6 ± 0.10
    Notes
    [36] - ITT set:randomized subjects who rcvd ≥1 dose of study drug with available data at baseline and Wk 52
    [37] - ITT set:randomized subjects who rcvd ≥1 dose of study drug with available data at baseline and Wk 52
    [38] - ITT set:randomized subjects who rcvd ≥1 dose of study drug with available data at baseline and Wk 52
    Statistical analysis title
    ABBV-8E12 2000 mg vs Placebo
    Statistical analysis description
    The analysis utilized a likelihood-based, mixed-effects model, repeated measures (MMRM) analysis of the change from baseline for each postbaseline value and compared each ABBV-8E12 dose group with the placebo group. The model, which used all observed data, included fixed, categorical effects for treatment, site, visit, baseline score-by-visit interaction and treatment-by-visit interaction, with continuous fixed covariates for the corresponding baseline score.
    Comparison groups
    Placebo v ABBV-8E12 2000 mg
    Number of subjects included in analysis
    98
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    P-value
    = 0.761
    Method
    Mixed-effects model repeated measures
    Parameter type
    LS Mean Difference
    Point estimate
    0
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    -0.31
         upper limit
    0.23
    Variability estimate
    Standard error of the mean
    Dispersion value
    0.14
    Statistical analysis title
    ABBV-8E12 4000 mg vs Placebo
    Statistical analysis description
    The analysis utilized a likelihood-based, mixed-effects model, repeated measures (MMRM) analysis of the change from baseline for each postbaseline value and compared each ABBV-8E12 dose group with the placebo group. The model, which used all observed data, included fixed, categorical effects for treatment, site, visit, baseline score-by-visit interaction and treatment-by-visit interaction, with continuous fixed covariates for the corresponding baseline score.
    Comparison groups
    ABBV-8E12 4000 mg v Placebo
    Number of subjects included in analysis
    101
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    P-value
    = 0.678
    Method
    Mixed-effects model repeated measures
    Parameter type
    LS Mean Difference
    Point estimate
    -0.1
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    -0.32
         upper limit
    0.21
    Variability estimate
    Standard error of the mean
    Dispersion value
    0.13

    Secondary: Mean Change From Baseline to Week 52 in Progressive Supranuclear Palsy Health Related Quality of Life Scale (PSPQoL) Total Score

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    End point title
    Mean Change From Baseline to Week 52 in Progressive Supranuclear Palsy Health Related Quality of Life Scale (PSPQoL) Total Score
    End point description
    The PSP-QoL is a validated patient-reported outcome measure, specifically designed to assess the quality of life of participants with PSP. There are 45 items and two subscales: physical and mental impact. Items are scored from 0 (no problem) to 4 (extreme problems). The total subscale sum scores are linearly converted into a 0 to 100 scale, and higher scores indicate a lower quality of life. Positive changes in score indicate a decline in quality of life.
    End point type
    Secondary
    End point timeframe
    Baseline, Week 52
    End point values
    Placebo ABBV-8E12 2000 mg ABBV-8E12 4000 mg
    Number of subjects analysed
    62 [39]
    59 [40]
    60 [41]
    Units: units on a scale
        least squares mean (standard error)
    9.2 ± 1.63
    10.3 ± 1.65
    10.0 ± 1.64
    Notes
    [39] - ITT set:randomized subjects who rcvd ≥1 dose of study drug with available data at baseline and Wk 52
    [40] - ITT set:randomized subjects who rcvd ≥1 dose of study drug with available data at baseline and Wk 52
    [41] - ITT set:randomized subjects who rcvd ≥1 dose of study drug with available data at baseline and Wk 52
    Statistical analysis title
    ABBV-8E12 2000 mg vs Placebo
    Statistical analysis description
    The analysis utilized a likelihood-based, mixed-effects model, repeated measures (MMRM) analysis of the change from baseline for each postbaseline value and compared each ABBV-8E12 dose group with the placebo group. The model, which used all observed data, included fixed, categorical effects for treatment, site, visit, baseline score-by-visit interaction and treatment-by-visit interaction, with continuous fixed covariates for the corresponding baseline score.
    Comparison groups
    Placebo v ABBV-8E12 2000 mg
    Number of subjects included in analysis
    121
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    P-value
    = 0.653
    Method
    Mixed-effects model repeated measures
    Parameter type
    LS Mean Difference
    Point estimate
    1
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    -3.5
         upper limit
    5.57
    Variability estimate
    Standard error of the mean
    Dispersion value
    2.3
    Statistical analysis title
    ABBV-8E12 4000 mg vs Placebo
    Statistical analysis description
    The primary efficacy analysis utilized a likelihood-based, mixed-effects model, repeated measures (MMRM) analysis of the change from baseline for each postbaseline value and compared each ABBV-8E12 dose group with the placebo group. The model, which used all observed data, included fixed, categorical effects for treatment, site, visit, baseline score-by-visit interaction and treatment-by-visit interaction, with continuous fixed covariates for the corresponding baseline score.
    Comparison groups
    Placebo v ABBV-8E12 4000 mg
    Number of subjects included in analysis
    122
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    P-value
    = 0.748
    Method
    Mixed-effects model repeated measures
    Parameter type
    LS Mean Difference
    Point estimate
    1
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    -3.5
         upper limit
    5.57
    Variability estimate
    Standard error of the mean
    Dispersion value
    2.3

    Secondary: Mean Change From Baseline to Week 52 in Progressive Supranuclear Palsy Staging System Score (PSP-SS) Score

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    End point title
    Mean Change From Baseline to Week 52 in Progressive Supranuclear Palsy Staging System Score (PSP-SS) Score
    End point description
    The Progressive Supranuclear Palsy Rating Scale (PSPRS) consists of 28 items grouped in six domains: daily activities (by history); behavior; bulbar; ocular motor; limb motor; and gait/midline. Items are scored on a 0 to 4 scale, except for four items that are scored on a 0 to 2 scale, with the total score ranging from 0 to 100. Higher scores indicate more severe disability or movement abnormality. The PSP-SS score is a composite of the dysphagia and gait items from the PSPRS. Positive changes in score indicate worsening from baseline.
    End point type
    Secondary
    End point timeframe
    Baseline, Week 52
    End point values
    Placebo ABBV-8E12 2000 mg ABBV-8E12 4000 mg
    Number of subjects analysed
    59 [42]
    57 [43]
    59 [44]
    Units: units on a scale
        least squares mean (standard error)
    0.8 ± 0.24
    0.9 ± 0.24
    1.0 ± 0.24
    Notes
    [42] - ITT set:randomized subjects who rcvd ≥1 dose of study drug with available data at baseline and Wk 52
    [43] - ITT set:randomized subjects who rcvd ≥1 dose of study drug with available data at baseline and Wk 52
    [44] - ITT set:randomized subjects who rcvd ≥1 dose of study drug with available data at baseline and Wk 52
    Statistical analysis title
    ABBV-8E12 2000 mg vs Placebo
    Statistical analysis description
    The analysis utilized a likelihood-based, mixed-effects model, repeated measures (MMRM) analysis of the change from baseline for each postbaseline value and compared each ABBV-8E12 dose group with the placebo group. The model, which used all observed data, included fixed, categorical effects for treatment, site, visit, baseline score-by-visit interaction and treatment-by-visit interaction, with continuous fixed covariates for the corresponding baseline score.
    Comparison groups
    Placebo v ABBV-8E12 2000 mg
    Number of subjects included in analysis
    116
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    P-value
    = 0.828
    Method
    Mixed-effects model repeated measures
    Parameter type
    LS Mean Difference
    Point estimate
    0.1
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    -0.6
         upper limit
    0.74
    Variability estimate
    Standard error of the mean
    Dispersion value
    0.34
    Statistical analysis title
    ABBV-8E12 4000 mg vs Placebo
    Statistical analysis description
    The primary efficacy analysis utilized a likelihood-based, mixed-effects model, repeated measures (MMRM) analysis of the change from baseline for each postbaseline value and compared each ABBV-8E12 dose group with the placebo group. The model, which used all observed data, included fixed, categorical effects for treatment, site, visit, baseline score-by- visit interaction and treatment-by-visit interaction, with continuous fixed covariates for the corresponding baseline score.
    Comparison groups
    Placebo v ABBV-8E12 4000 mg
    Number of subjects included in analysis
    118
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    P-value
    = 0.543
    Method
    Mixed-effects model repeated measures
    Parameter type
    LS Mean Difference
    Point estimate
    0.2
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    -0.46
         upper limit
    0.87
    Variability estimate
    Standard error of the mean
    Dispersion value
    0.34

    Secondary: Mean Change From Baseline to Week 52 in Third Ventricle Atrophy As Measured by Volumetric Magnetic Resonance Imaging (MRI)

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    End point title
    Mean Change From Baseline to Week 52 in Third Ventricle Atrophy As Measured by Volumetric Magnetic Resonance Imaging (MRI)
    End point description
    Magnetic resonance imaging (MRI) of several different brain regions was performed and volumetric analysis was conducted to quantify third ventricle atrophy. Positive changes in values indicate an increase in volume.
    End point type
    Secondary
    End point timeframe
    Baseline, Week 52
    End point values
    Placebo ABBV-8E12 2000 mg ABBV-8E12 4000 mg
    Number of subjects analysed
    54 [45]
    58 [46]
    53 [47]
    Units: mm^3
        least squares mean (standard error)
    157.9 ± 18.27
    152.4 ± 18.04
    125.0 ± 18.57
    Notes
    [45] - ITT set:randomized subjects who rcvd ≥1 dose of study drug with available data at baseline and Wk 52
    [46] - ITT set:randomized subjects who rcvd ≥1 dose of study drug with available data at baseline and Wk 52
    [47] - ITT set:randomized subjects who rcvd ≥1 dose of study drug with available data at baseline and Wk 52
    Statistical analysis title
    ABBV-8E12 2000 mg vs Placebo
    Statistical analysis description
    The analysis utilized a likelihood-based, mixed-effects model, repeated measures (MMRM) analysis of the change from baseline for each postbaseline value and compared each ABBV-8E12 dose group with the placebo group. The model, which used all observed data, included fixed, categorical effects for treatment, site, visit, baseline score-by-visit interaction and treatment-by-visit interaction, with continuous fixed covariates for the corresponding baseline score.
    Comparison groups
    ABBV-8E12 2000 mg v Placebo
    Number of subjects included in analysis
    112
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    P-value
    = 0.829
    Method
    Mixed-effects model repeated measures
    Parameter type
    LS Mean Difference
    Point estimate
    -5.5
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    -55.66
         upper limit
    44.63
    Variability estimate
    Standard error of the mean
    Dispersion value
    25.44
    Statistical analysis title
    ABBV-8E12 4000 mg vs Placebo
    Statistical analysis description
    The analysis utilized a likelihood-based, mixed-effects model, repeated measures (MMRM) analysis of the change from baseline for each postbaseline value and compared each ABBV-8E12 dose group with the placebo group. The model, which used all observed data, included fixed, categorical effects for treatment, site, visit, baseline score-by-visit interaction and treatment-by-visit interaction, with continuous fixed covariates for the corresponding baseline score.
    Comparison groups
    Placebo v ABBV-8E12 4000 mg
    Number of subjects included in analysis
    107
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    P-value
    = 0.206
    Method
    Mixed-effects model repeated measures
    Parameter type
    LS Mean Difference
    Point estimate
    -32.9
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    -83.94
         upper limit
    18.23
    Variability estimate
    Standard error of the mean
    Dispersion value
    25.92

    Secondary: Mean Change From Baseline to Week 52 in Superior Cerebellar Peduncle Atrophy As Measured by Volumetric Magnetic Resonance Imaging (MRI)

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    End point title
    Mean Change From Baseline to Week 52 in Superior Cerebellar Peduncle Atrophy As Measured by Volumetric Magnetic Resonance Imaging (MRI)
    End point description
    Magnetic resonance imaging (MRI) of several different brain regions was performed and volumetric analysis was conducted to quantify Superior cerebellar peduncle atrophy. Negative changes in values indicate a reduction in volume.
    End point type
    Secondary
    End point timeframe
    Baseline, Week 52
    End point values
    Placebo ABBV-8E12 2000 mg ABBV-8E12 4000 mg
    Number of subjects analysed
    51 [48]
    55 [49]
    54 [50]
    Units: mm^3
        least squares mean (standard error)
    -8.3 ± 2.78
    -4.3 ± 2.74
    -3.7 ± 2.74
    Notes
    [48] - ITT set:randomized subjects who rcvd ≥1 dose of study drug with available data at baseline and Wk 52
    [49] - ITT set:randomized subjects who rcvd ≥1 dose of study drug with available data at baseline and Wk 52
    [50] - ITT set:randomized subjects who rcvd ≥1 dose of study drug with available data at baseline and Wk 52
    Statistical analysis title
    ABBV-8E12 2000 mg vs Placebo
    Statistical analysis description
    The analysis utilized a likelihood-based, mixed-effects model, repeated measures (MMRM) analysis of the change from baseline for each postbaseline value and compared each ABBV-8E12 dose group with the placebo group. The model, which used all observed data, included fixed, categorical effects for treatment, site, visit, baseline score-by-visit interaction and treatment-by-visit interaction, with continuous fixed covariates for the corresponding baseline score.
    Comparison groups
    Placebo v ABBV-8E12 2000 mg
    Number of subjects included in analysis
    106
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    P-value
    = 0.304
    Method
    Mixed-effects model repeated measures
    Parameter type
    LS Mean Difference
    Point estimate
    4
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    -3.65
         upper limit
    11.65
    Variability estimate
    Standard error of the mean
    Dispersion value
    3.88
    Statistical analysis title
    ABBV-8E12 4000 mg vs Placebo
    Statistical analysis description
    The analysis utilized a likelihood-based, mixed-effects model, repeated measures (MMRM) analysis of the change from baseline for each postbaseline value and compared each ABBV-8E12 dose group with the placebo group. The model, which used all observed data, included fixed, categorical effects for treatment, site, visit, baseline score-by-visit interaction and treatment-by-visit interaction, with continuous fixed covariates for the corresponding baseline score.
    Comparison groups
    Placebo v ABBV-8E12 4000 mg
    Number of subjects included in analysis
    105
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    P-value
    = 0.243
    Method
    Mixed-effects model repeated measures
    Parameter type
    LS Mean Difference
    Point estimate
    4.5
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    -3.11
         upper limit
    12.19
    Variability estimate
    Standard error of the mean
    Dispersion value
    3.88

    Secondary: Mean Change From Baseline to Week 52 in Brainstem Atrophy As Measured by Volumetric Magnetic Resonance Imaging (MRI)

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    End point title
    Mean Change From Baseline to Week 52 in Brainstem Atrophy As Measured by Volumetric Magnetic Resonance Imaging (MRI)
    End point description
    Magnetic resonance imaging (MRI) of several different brain regions was performed and volumetric analysis was conducted to quantify brainstem atrophy. Negative changes in values indicate a reduction in volume.
    End point type
    Secondary
    End point timeframe
    Baseline, Week 52
    End point values
    Placebo ABBV-8E12 2000 mg ABBV-8E12 4000 mg
    Number of subjects analysed
    48 [51]
    49 [52]
    43 [53]
    Units: mm^3
        least squares mean (standard error)
    -374.5 ± 38.42
    -400.9 ± 38.60
    -341.3 ± 40.61
    Notes
    [51] - ITT set:randomized subjects who rcvd ≥1 dose of study drug with available data at baseline and Wk 52
    [52] - ITT set:randomized subjects who rcvd ≥1 dose of study drug with available data at baseline and Wk 52
    [53] - ITT set:randomized subjects who rcvd ≥1 dose of study drug with available data at baseline and Wk 52
    Statistical analysis title
    ABBV-8E12 2000 mg vs Placebo
    Statistical analysis description
    The analysis utilized a likelihood-based, mixed-effects model, repeated measures (MMRM) analysis of the change from baseline for each postbaseline value and compared each ABBV-8E12 dose group with the placebo group. The model, which used all observed data, included fixed, categorical effects for treatment, site, visit, baseline score-by-visit interaction and treatment-by-visit interaction, with continuous fixed covariates for the corresponding baseline score.
    Comparison groups
    Placebo v ABBV-8E12 2000 mg
    Number of subjects included in analysis
    97
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    P-value
    = 0.625
    Method
    Mixed-effects model repeated measures
    Parameter type
    LS Mean Difference
    Point estimate
    -26.4
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    -132.76
         upper limit
    79.94
    Variability estimate
    Standard error of the mean
    Dispersion value
    53.86
    Statistical analysis title
    ABBV-8E12 4000 mg vs Placebo
    Statistical analysis description
    The analysis utilized a likelihood-based, mixed-effects model, repeated measures (MMRM) analysis of the change from baseline for each postbaseline value and compared each ABBV-8E12 dose group with the placebo group. The model, which used all observed data, included fixed, categorical effects for treatment, site, visit, baseline score-by-visit interaction and treatment-by-visit interaction, with continuous fixed covariates for the corresponding baseline score.
    Comparison groups
    ABBV-8E12 4000 mg v Placebo
    Number of subjects included in analysis
    91
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    P-value
    = 0.55
    Method
    Mixed-effects model repeated measures
    Parameter type
    LS Mean Difference
    Point estimate
    33.2
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    -76.34
         upper limit
    142.71
    Variability estimate
    Standard error of the mean
    Dispersion value
    55.47

    Secondary: Mean Change From Baseline to Week 52 in Whole Brain Atrophy As Measured by Volumetric Magnetic Resonance Imaging (MRI)

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    End point title
    Mean Change From Baseline to Week 52 in Whole Brain Atrophy As Measured by Volumetric Magnetic Resonance Imaging (MRI)
    End point description
    Magnetic resonance imaging (MRI) of several different brain regions was performed and volumetric analysis was conducted to quantify whole brain atrophy. Negative changes in values indicate a reduction in volume.
    End point type
    Secondary
    End point timeframe
    Baseline, Week 52
    End point values
    Placebo ABBV-8E12 2000 mg ABBV-8E12 4000 mg
    Number of subjects analysed
    45 [54]
    46 [55]
    49 [56]
    Units: mm^3
        least squares mean (standard error)
    -22496.2 ± 1793.36
    -20757.1 ± 1783.00
    -18811.3 ± 1740.72
    Notes
    [54] - ITT set:randomized subjects who rcvd ≥1 dose of study drug with available data at baseline and Wk 52
    [55] - ITT set:randomized subjects who rcvd ≥1 dose of study drug with available data at baseline and Wk 52
    [56] - ITT set:randomized subjects who rcvd ≥1 dose of study drug with available data at baseline and Wk 52
    Statistical analysis title
    ABBV-8E12 2000 mg vs Placebo
    Statistical analysis description
    The analysis utilized a likelihood-based, mixed-effects model, repeated measures (MMRM) analysis of the change from baseline for each postbaseline value and compared each ABBV-8E12 dose group with the placebo group. The model, which used all observed data, included fixed, categorical effects for treatment, site, visit, baseline score-by-visit interaction and treatment-by-visit interaction, with continuous fixed covariates for the corresponding baseline score.
    Comparison groups
    Placebo v ABBV-8E12 2000 mg
    Number of subjects included in analysis
    91
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    P-value
    = 0.488
    Method
    Mixed-effects model repeated measures
    Parameter type
    LS Mean Difference
    Point estimate
    1739.1
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    -3201.75
         upper limit
    6680.02
    Variability estimate
    Standard error of the mean
    Dispersion value
    2502.95
    Statistical analysis title
    ABBV-8E12 4000 mg vs Placebo
    Statistical analysis description
    The analysis utilized a likelihood-based, mixed-effects model, repeated measures (MMRM) analysis of the change from baseline for each postbaseline value and compared each ABBV-8E12 dose group with the placebo group. The model, which used all observed data, included fixed, categorical effects for treatment, site, visit, baseline score-by-visit interaction and treatment-by-visit interaction, with continuous fixed covariates for the corresponding baseline score.
    Comparison groups
    Placebo v ABBV-8E12 4000 mg
    Number of subjects included in analysis
    94
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    P-value
    = 0.14
    Method
    Mixed-effects model repeated measures
    Parameter type
    LS Mean Difference
    Point estimate
    3684.9
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    -1225.46
         upper limit
    8595.29
    Variability estimate
    Standard error of the mean
    Dispersion value
    2487.32

    Secondary: Mean Change From Baseline to Week 52 in Frontal Lobe Atrophy As Measured by Volumetric Magnetic Resonance Imaging (MRI)

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    End point title
    Mean Change From Baseline to Week 52 in Frontal Lobe Atrophy As Measured by Volumetric Magnetic Resonance Imaging (MRI)
    End point description
    Magnetic resonance imaging (MRI) of several different brain regions was performed and volumetric analysis was conducted to quantify frontal lobe atrophy. Positive changes in values indicate an increase in volume.
    End point type
    Secondary
    End point timeframe
    Baseline, Week 52
    End point values
    Placebo ABBV-8E12 2000 mg ABBV-8E12 4000 mg
    Number of subjects analysed
    48 [57]
    49 [58]
    43 [59]
    Units: mm^3
        least squares mean (standard error)
    1052.6 ± 425.55
    1260.5 ± 423.96
    1186.1 ± 445.18
    Notes
    [57] - ITT set:randomized subjects who rcvd ≥1 dose of study drug with available data at baseline and Wk 52
    [58] - ITT set:randomized subjects who rcvd ≥1 dose of study drug with available data at baseline and Wk 52
    [59] - ITT set:randomized subjects who rcvd ≥1 dose of study drug with available data at baseline and Wk 52
    Statistical analysis title
    ABBV-8E12 2000 mg vs Placebo
    Statistical analysis description
    The analysis utilized a likelihood-based, mixed-effects model, repeated measures (MMRM) analysis of the change from baseline for each postbaseline value and compared each ABBV-8E12 dose group with the placebo group. The model, which used all observed data, included fixed, categorical effects for treatment, site, visit, baseline score-by-visit interaction and treatment-by-visit interaction, with continuous fixed covariates for the corresponding baseline score.
    Comparison groups
    Placebo v ABBV-8E12 2000 mg
    Number of subjects included in analysis
    97
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    P-value
    = 0.726
    Method
    Mixed-effects model repeated measures
    Parameter type
    LS Mean Difference
    Point estimate
    207.9
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    -962.98
         upper limit
    1378.88
    Variability estimate
    Standard error of the mean
    Dispersion value
    592.68
    Statistical analysis title
    ABBV-8E12 4000 mg vs Placebo
    Statistical analysis description
    The analysis utilized a likelihood-based, mixed-effects model, repeated measures (MMRM) analysis of the change from baseline for each postbaseline value and compared each ABBV-8E12 dose group with the placebo group. The model, which used all observed data, included fixed, categorical effects for treatment, site, visit, baseline score-by-visit interaction and treatment-by-visit interaction, with continuous fixed covariates for the corresponding baseline score.
    Comparison groups
    Placebo v ABBV-8E12 4000 mg
    Number of subjects included in analysis
    91
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    P-value
    = 0.828
    Method
    Mixed-effects model repeated measures
    Parameter type
    LS Mean Difference
    Point estimate
    133.6
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    -1075.26
         upper limit
    1342.4
    Variability estimate
    Standard error of the mean
    Dispersion value
    611.91

    Secondary: Mean Time to Loss of Ability to Walk Independently as Measured by Progressive Supranuclear Palsy Rating Scale (PSPRS) Item 26

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    End point title
    Mean Time to Loss of Ability to Walk Independently as Measured by Progressive Supranuclear Palsy Rating Scale (PSPRS) Item 26
    End point description
    The PSPRS consists of 28 items grouped in six domains: daily activities (by history); behavior; bulbar; ocular motor; limb motor; and gait/midline. Items are scored on a 0 to 4 scale, except for six items that are scored on a 0 to 2 scale, with the total score ranging from 0 to 100. Higher scores indicate more severe disability or movement abnormality. Item 26 pertains to gait, scored as either 0 (normal); 1 (slightly wide-based or irregular or slight pulsion on turns); 2 (must walk slowly or occasionally use walls or helper to avoid falling, especially on turns); 3 (must use assistance all or almost all the time); or 4 (unable to walk, even with walker; may be able to transfer).
    End point type
    Secondary
    End point timeframe
    From Baseline to Week 52
    End point values
    Placebo ABBV-8E12 2000 mg ABBV-8E12 4000 mg
    Number of subjects analysed
    126 [60]
    126 [61]
    125 [62]
    Units: days
        median (confidence interval 95%)
    169.0 (89.0 to 255.0)
    170.0 (87.0 to 253.0)
    203.0 (169.0 to 255.0)
    Notes
    [60] - ITT dataset: all randomized subjects who received at least 1 dose of study drug with available data
    [61] - ITT dataset: all randomized subjects who received at least 1 dose of study drug with available data
    [62] - ITT dataset: all randomized subjects who received at least 1 dose of study drug with available data
    No statistical analyses for this end point

    Adverse events

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    Adverse events information
    Timeframe for reporting adverse events
    Treatment-emergent adverse events and serious adverse events collected from 1st dose of study drug until 20 wks after discontinuation, up to 80 wks. Serious adverse events and protocol-related nonserious adverse events collected from informed consent.
    Adverse event reporting additional description
    TEAEs and TESAEs are defined as any AE or TESAE with onset or worsening reported by a participant from the time that the first dose of study is administered until 20 weeks (approximately 5 half-lives) have elapsed following discontinuation of study drug. TEAEs were collected whether elicited or spontaneously reported by the participant.
    Assessment type
    Systematic
    Dictionary used for adverse event reporting
    Dictionary name
    MedDRA
    Dictionary version
    22.0
    Reporting groups
    Reporting group title
    Placebo
    Reporting group description
    0.9% Sodium Chloride Injection/Solution for Infusion; intravenous infusions at Day 1, Day 15, and Day 29, then every 28 days for 52 weeks

    Reporting group title
    ABBV-8E12 2000mg
    Reporting group description
    Intravenous infusions at Day 1, Day 15, and Day 29, then every 28 days for 52 weeks; 300 mg/15 mL (participants in countries other than Japan or Spain); 1000 mg/10 mL (for participants in Japan or Spain)

    Reporting group title
    ABBV-8E12 4000mg
    Reporting group description
    Intravenous infusions at Day 1, Day 15, and Day 29, then every 28 days for 52 weeks; 300 mg/15 mL (participants in countries other than Japan or Spain); 1000 mg/10 mL (for participants in Japan or Spain)

    Serious adverse events
    Placebo ABBV-8E12 2000mg ABBV-8E12 4000mg
    Total subjects affected by serious adverse events
         subjects affected / exposed
    33 / 126 (26.19%)
    29 / 126 (23.02%)
    34 / 125 (27.20%)
         number of deaths (all causes)
    8
    9
    9
         number of deaths resulting from adverse events
    8
    9
    9
    Neoplasms benign, malignant and unspecified (incl cysts and polyps)
    BREAST CANCER
         subjects affected / exposed
    0 / 126 (0.00%)
    0 / 126 (0.00%)
    1 / 125 (0.80%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    PROSTATE CANCER
         subjects affected / exposed
    0 / 126 (0.00%)
    1 / 126 (0.79%)
    0 / 125 (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
    PROSTATE CANCER METASTATIC
         subjects affected / exposed
    1 / 126 (0.79%)
    0 / 126 (0.00%)
    0 / 125 (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
    Vascular disorders
    DEEP VEIN THROMBOSIS
         subjects affected / exposed
    1 / 126 (0.79%)
    0 / 126 (0.00%)
    0 / 125 (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
    HAEMORRHAGE
         subjects affected / exposed
    0 / 126 (0.00%)
    1 / 126 (0.79%)
    0 / 125 (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
    HYPERTENSION
         subjects affected / exposed
    0 / 126 (0.00%)
    0 / 126 (0.00%)
    1 / 125 (0.80%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    General disorders and administration site conditions
    DEATH
         subjects affected / exposed
    1 / 126 (0.79%)
    2 / 126 (1.59%)
    1 / 125 (0.80%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 2
    0 / 1
         deaths causally related to treatment / all
    0 / 1
    0 / 2
    0 / 1
    DISEASE PROGRESSION
         subjects affected / exposed
    0 / 126 (0.00%)
    0 / 126 (0.00%)
    1 / 125 (0.80%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    GAIT DISTURBANCE
         subjects affected / exposed
    0 / 126 (0.00%)
    0 / 126 (0.00%)
    1 / 125 (0.80%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    GENERAL PHYSICAL HEALTH DETERIORATION
         subjects affected / exposed
    0 / 126 (0.00%)
    0 / 126 (0.00%)
    1 / 125 (0.80%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    PYREXIA
         subjects affected / exposed
    0 / 126 (0.00%)
    0 / 126 (0.00%)
    2 / 125 (1.60%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Immune system disorders
    DRUG HYPERSENSITIVITY
         subjects affected / exposed
    0 / 126 (0.00%)
    0 / 126 (0.00%)
    1 / 125 (0.80%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Respiratory, thoracic and mediastinal disorders
    ACUTE RESPIRATORY DISTRESS SYNDROME
         subjects affected / exposed
    0 / 126 (0.00%)
    1 / 126 (0.79%)
    0 / 125 (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
    ASPIRATION
         subjects affected / exposed
    0 / 126 (0.00%)
    1 / 126 (0.79%)
    0 / 125 (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
    CHOKING
         subjects affected / exposed
    0 / 126 (0.00%)
    0 / 126 (0.00%)
    1 / 125 (0.80%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    COUGH
         subjects affected / exposed
    0 / 126 (0.00%)
    1 / 126 (0.79%)
    0 / 125 (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
    DYSPNOEA
         subjects affected / exposed
    0 / 126 (0.00%)
    0 / 126 (0.00%)
    1 / 125 (0.80%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    HYPOXIA
         subjects affected / exposed
    0 / 126 (0.00%)
    0 / 126 (0.00%)
    1 / 125 (0.80%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    INTERSTITIAL LUNG DISEASE
         subjects affected / exposed
    1 / 126 (0.79%)
    0 / 126 (0.00%)
    0 / 125 (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 ASPIRATION
         subjects affected / exposed
    2 / 126 (1.59%)
    3 / 126 (2.38%)
    1 / 125 (0.80%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 4
    0 / 1
         deaths causally related to treatment / all
    0 / 1
    0 / 1
    0 / 0
    PNEUMOTHORAX
         subjects affected / exposed
    0 / 126 (0.00%)
    0 / 126 (0.00%)
    1 / 125 (0.80%)
         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 EMBOLISM
         subjects affected / exposed
    1 / 126 (0.79%)
    1 / 126 (0.79%)
    0 / 125 (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
    RESPIRATORY ARREST
         subjects affected / exposed
    1 / 126 (0.79%)
    0 / 126 (0.00%)
    0 / 125 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    RESPIRATORY DISTRESS
         subjects affected / exposed
    0 / 126 (0.00%)
    0 / 126 (0.00%)
    1 / 125 (0.80%)
         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 FAILURE
         subjects affected / exposed
    0 / 126 (0.00%)
    1 / 126 (0.79%)
    1 / 125 (0.80%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    0 / 1
    Psychiatric disorders
    COMPLETED SUICIDE
         subjects affected / exposed
    0 / 126 (0.00%)
    1 / 126 (0.79%)
    0 / 125 (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
    DELIRIUM
         subjects affected / exposed
    1 / 126 (0.79%)
    0 / 126 (0.00%)
    0 / 125 (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
    MENTAL STATUS CHANGES
         subjects affected / exposed
    1 / 126 (0.79%)
    0 / 126 (0.00%)
    0 / 125 (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
    PSYCHOTIC DISORDER
         subjects affected / exposed
    1 / 126 (0.79%)
    0 / 126 (0.00%)
    0 / 125 (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
    SUICIDAL IDEATION
         subjects affected / exposed
    1 / 126 (0.79%)
    0 / 126 (0.00%)
    0 / 125 (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
    SUICIDE ATTEMPT
         subjects affected / exposed
    0 / 126 (0.00%)
    1 / 126 (0.79%)
    0 / 125 (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
    Investigations
    RESIDUAL URINE VOLUME
         subjects affected / exposed
    0 / 126 (0.00%)
    1 / 126 (0.79%)
    0 / 125 (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
    BRAIN CONTUSION
         subjects affected / exposed
    0 / 126 (0.00%)
    1 / 126 (0.79%)
    0 / 125 (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
    CERVICAL VERTEBRAL FRACTURE
         subjects affected / exposed
    0 / 126 (0.00%)
    2 / 126 (1.59%)
    1 / 125 (0.80%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 2
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    CLAVICLE FRACTURE
         subjects affected / exposed
    0 / 126 (0.00%)
    0 / 126 (0.00%)
    1 / 125 (0.80%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    CONCUSSION
         subjects affected / exposed
    1 / 126 (0.79%)
    1 / 126 (0.79%)
    0 / 125 (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
    CONTUSION
         subjects affected / exposed
    0 / 126 (0.00%)
    0 / 126 (0.00%)
    1 / 125 (0.80%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    FACIAL BONES FRACTURE
         subjects affected / exposed
    0 / 126 (0.00%)
    1 / 126 (0.79%)
    0 / 125 (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
    6 / 126 (4.76%)
    5 / 126 (3.97%)
    6 / 125 (4.80%)
         occurrences causally related to treatment / all
    0 / 7
    0 / 7
    0 / 7
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    FEMORAL NECK FRACTURE
         subjects affected / exposed
    0 / 126 (0.00%)
    1 / 126 (0.79%)
    0 / 125 (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
    FEMUR FRACTURE
         subjects affected / exposed
    2 / 126 (1.59%)
    1 / 126 (0.79%)
    2 / 125 (1.60%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 1
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    FIBULA FRACTURE
         subjects affected / exposed
    0 / 126 (0.00%)
    0 / 126 (0.00%)
    1 / 125 (0.80%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    FOREIGN BODY ASPIRATION
         subjects affected / exposed
    0 / 126 (0.00%)
    0 / 126 (0.00%)
    1 / 125 (0.80%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    GUN SHOT WOUND
         subjects affected / exposed
    0 / 126 (0.00%)
    1 / 126 (0.79%)
    0 / 125 (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
    HEAD INJURY
         subjects affected / exposed
    2 / 126 (1.59%)
    0 / 126 (0.00%)
    0 / 125 (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
    HIP FRACTURE
         subjects affected / exposed
    3 / 126 (2.38%)
    1 / 126 (0.79%)
    0 / 125 (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
    HUMERUS FRACTURE
         subjects affected / exposed
    0 / 126 (0.00%)
    1 / 126 (0.79%)
    1 / 125 (0.80%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    JOINT DISLOCATION
         subjects affected / exposed
    0 / 126 (0.00%)
    1 / 126 (0.79%)
    0 / 125 (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
    PERIPROSTHETIC FRACTURE
         subjects affected / exposed
    0 / 126 (0.00%)
    1 / 126 (0.79%)
    0 / 125 (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
    RADIUS FRACTURE
         subjects affected / exposed
    1 / 126 (0.79%)
    0 / 126 (0.00%)
    0 / 125 (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
    RIB FRACTURE
         subjects affected / exposed
    0 / 126 (0.00%)
    2 / 126 (1.59%)
    3 / 125 (2.40%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 2
    0 / 3
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    SKIN LACERATION
         subjects affected / exposed
    0 / 126 (0.00%)
    2 / 126 (1.59%)
    0 / 125 (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
    SKULL FRACTURE
         subjects affected / exposed
    0 / 126 (0.00%)
    0 / 126 (0.00%)
    1 / 125 (0.80%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    SPINAL FRACTURE
         subjects affected / exposed
    0 / 126 (0.00%)
    0 / 126 (0.00%)
    1 / 125 (0.80%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    SUBDURAL HAEMATOMA
         subjects affected / exposed
    3 / 126 (2.38%)
    0 / 126 (0.00%)
    2 / 125 (1.60%)
         occurrences causally related to treatment / all
    0 / 3
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    ULNA FRACTURE
         subjects affected / exposed
    1 / 126 (0.79%)
    0 / 126 (0.00%)
    0 / 125 (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
    UPPER LIMB FRACTURE
         subjects affected / exposed
    0 / 126 (0.00%)
    1 / 126 (0.79%)
    0 / 125 (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
    WRIST FRACTURE
         subjects affected / exposed
    0 / 126 (0.00%)
    1 / 126 (0.79%)
    1 / 125 (0.80%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Cardiac disorders
    ACUTE MYOCARDIAL INFARCTION
         subjects affected / exposed
    0 / 126 (0.00%)
    1 / 126 (0.79%)
    0 / 125 (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
    ATRIAL FIBRILLATION
         subjects affected / exposed
    1 / 126 (0.79%)
    1 / 126 (0.79%)
    0 / 125 (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
    CARDIAC FAILURE
         subjects affected / exposed
    0 / 126 (0.00%)
    1 / 126 (0.79%)
    0 / 125 (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 CONGESTIVE
         subjects affected / exposed
    0 / 126 (0.00%)
    1 / 126 (0.79%)
    0 / 125 (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
    CARDIO-RESPIRATORY ARREST
         subjects affected / exposed
    0 / 126 (0.00%)
    0 / 126 (0.00%)
    1 / 125 (0.80%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    CARDIOPULMONARY FAILURE
         subjects affected / exposed
    1 / 126 (0.79%)
    0 / 126 (0.00%)
    0 / 125 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    Nervous system disorders
    APHASIA
         subjects affected / exposed
    0 / 126 (0.00%)
    0 / 126 (0.00%)
    1 / 125 (0.80%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    BRAIN MIDLINE SHIFT
         subjects affected / exposed
    0 / 126 (0.00%)
    0 / 126 (0.00%)
    1 / 125 (0.80%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    CARPAL TUNNEL SYNDROME
         subjects affected / exposed
    1 / 126 (0.79%)
    0 / 126 (0.00%)
    0 / 125 (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
    CEREBRAL HAEMORRHAGE
         subjects affected / exposed
    1 / 126 (0.79%)
    0 / 126 (0.00%)
    0 / 125 (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
    HEMIPARESIS
         subjects affected / exposed
    0 / 126 (0.00%)
    0 / 126 (0.00%)
    1 / 125 (0.80%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    LOSS OF CONSCIOUSNESS
         subjects affected / exposed
    1 / 126 (0.79%)
    0 / 126 (0.00%)
    3 / 125 (2.40%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 3
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    PROGRESSIVE SUPRANUCLEAR PALSY
         subjects affected / exposed
    4 / 126 (3.17%)
    1 / 126 (0.79%)
    2 / 125 (1.60%)
         occurrences causally related to treatment / all
    0 / 4
    0 / 1
    0 / 2
         deaths causally related to treatment / all
    0 / 2
    0 / 0
    0 / 1
    SEIZURE
         subjects affected / exposed
    0 / 126 (0.00%)
    1 / 126 (0.79%)
    0 / 125 (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
    SPINAL STROKE
         subjects affected / exposed
    0 / 126 (0.00%)
    0 / 126 (0.00%)
    1 / 125 (0.80%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    SUBDURAL HYGROMA
         subjects affected / exposed
    0 / 126 (0.00%)
    0 / 126 (0.00%)
    1 / 125 (0.80%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    SYNCOPE
         subjects affected / exposed
    0 / 126 (0.00%)
    2 / 126 (1.59%)
    0 / 125 (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
    Blood and lymphatic system disorders
    LEUKOCYTOSIS
         subjects affected / exposed
    0 / 126 (0.00%)
    0 / 126 (0.00%)
    1 / 125 (0.80%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    Eye disorders
    CATARACT
         subjects affected / exposed
    1 / 126 (0.79%)
    0 / 126 (0.00%)
    1 / 125 (0.80%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    EYE SWELLING
         subjects affected / exposed
    0 / 126 (0.00%)
    0 / 126 (0.00%)
    1 / 125 (0.80%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    OCULAR HYPERAEMIA
         subjects affected / exposed
    0 / 126 (0.00%)
    0 / 126 (0.00%)
    1 / 125 (0.80%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Gastrointestinal disorders
    COLITIS ISCHAEMIC
         subjects affected / exposed
    0 / 126 (0.00%)
    0 / 126 (0.00%)
    1 / 125 (0.80%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    DYSPHAGIA
         subjects affected / exposed
    0 / 126 (0.00%)
    0 / 126 (0.00%)
    2 / 125 (1.60%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    ENTEROVESICAL FISTULA
         subjects affected / exposed
    0 / 126 (0.00%)
    0 / 126 (0.00%)
    1 / 125 (0.80%)
         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
    1 / 126 (0.79%)
    0 / 126 (0.00%)
    0 / 125 (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
    GASTROINTESTINAL HAEMORRHAGE
         subjects affected / exposed
    0 / 126 (0.00%)
    2 / 126 (1.59%)
    1 / 125 (0.80%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 2
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    GASTROINTESTINAL HYPERMOTILITY
         subjects affected / exposed
    1 / 126 (0.79%)
    0 / 126 (0.00%)
    0 / 125 (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
    INTESTINAL OBSTRUCTION
         subjects affected / exposed
    1 / 126 (0.79%)
    1 / 126 (0.79%)
    0 / 125 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    PANCREATITIS
         subjects affected / exposed
    0 / 126 (0.00%)
    1 / 126 (0.79%)
    0 / 125 (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
    VOMITING
         subjects affected / exposed
    0 / 126 (0.00%)
    0 / 126 (0.00%)
    1 / 125 (0.80%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Hepatobiliary disorders
    BILE DUCT STONE
         subjects affected / exposed
    0 / 126 (0.00%)
    1 / 126 (0.79%)
    0 / 125 (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
    Renal and urinary disorders
    ACUTE KIDNEY INJURY
         subjects affected / exposed
    1 / 126 (0.79%)
    0 / 126 (0.00%)
    0 / 125 (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
    BLADDER OBSTRUCTION
         subjects affected / exposed
    0 / 126 (0.00%)
    1 / 126 (0.79%)
    0 / 125 (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
    DYSURIA
         subjects affected / exposed
    0 / 126 (0.00%)
    0 / 126 (0.00%)
    1 / 125 (0.80%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    MICTURITION DISORDER
         subjects affected / exposed
    1 / 126 (0.79%)
    0 / 126 (0.00%)
    0 / 125 (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
    NOCTURIA
         subjects affected / exposed
    0 / 126 (0.00%)
    1 / 126 (0.79%)
    0 / 125 (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
    URETEROLITHIASIS
         subjects affected / exposed
    0 / 126 (0.00%)
    1 / 126 (0.79%)
    0 / 125 (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
    URINARY RETENTION
         subjects affected / exposed
    0 / 126 (0.00%)
    1 / 126 (0.79%)
    0 / 125 (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
    Musculoskeletal and connective tissue disorders
    MUSCLE RIGIDITY
         subjects affected / exposed
    0 / 126 (0.00%)
    0 / 126 (0.00%)
    1 / 125 (0.80%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    MUSCULOSKELETAL CHEST PAIN
         subjects affected / exposed
    1 / 126 (0.79%)
    0 / 126 (0.00%)
    0 / 125 (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
    OSTEOARTHRITIS
         subjects affected / exposed
    0 / 126 (0.00%)
    0 / 126 (0.00%)
    1 / 125 (0.80%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Infections and infestations
    CELLULITIS
         subjects affected / exposed
    0 / 126 (0.00%)
    2 / 126 (1.59%)
    0 / 125 (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
    CHOLECYSTITIS INFECTIVE
         subjects affected / exposed
    0 / 126 (0.00%)
    0 / 126 (0.00%)
    1 / 125 (0.80%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    CYSTITIS
         subjects affected / exposed
    0 / 126 (0.00%)
    0 / 126 (0.00%)
    1 / 125 (0.80%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    INFLUENZA
         subjects affected / exposed
    1 / 126 (0.79%)
    0 / 126 (0.00%)
    0 / 125 (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
    NASOPHARYNGITIS
         subjects affected / exposed
    1 / 126 (0.79%)
    0 / 126 (0.00%)
    0 / 125 (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
    ORCHITIS
         subjects affected / exposed
    0 / 126 (0.00%)
    0 / 126 (0.00%)
    1 / 125 (0.80%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    PNEUMONIA
         subjects affected / exposed
    4 / 126 (3.17%)
    1 / 126 (0.79%)
    3 / 125 (2.40%)
         occurrences causally related to treatment / all
    0 / 4
    0 / 1
    0 / 4
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    PNEUMONIA MYCOPLASMAL
         subjects affected / exposed
    0 / 126 (0.00%)
    1 / 126 (0.79%)
    0 / 125 (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
    SEPSIS
         subjects affected / exposed
    1 / 126 (0.79%)
    1 / 126 (0.79%)
    0 / 125 (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
    URINARY TRACT INFECTION
         subjects affected / exposed
    3 / 126 (2.38%)
    0 / 126 (0.00%)
    1 / 125 (0.80%)
         occurrences causally related to treatment / all
    0 / 3
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Metabolism and nutrition disorders
    DEHYDRATION
         subjects affected / exposed
    1 / 126 (0.79%)
    0 / 126 (0.00%)
    0 / 125 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    HYPOGLYCAEMIA
         subjects affected / exposed
    0 / 126 (0.00%)
    1 / 126 (0.79%)
    1 / 125 (0.80%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    MALNUTRITION
         subjects affected / exposed
    1 / 126 (0.79%)
    0 / 126 (0.00%)
    0 / 125 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    Frequency threshold for reporting non-serious adverse events: 5%
    Non-serious adverse events
    Placebo ABBV-8E12 2000mg ABBV-8E12 4000mg
    Total subjects affected by non serious adverse events
         subjects affected / exposed
    83 / 126 (65.87%)
    75 / 126 (59.52%)
    80 / 125 (64.00%)
    Investigations
    WEIGHT DECREASED
         subjects affected / exposed
    11 / 126 (8.73%)
    10 / 126 (7.94%)
    13 / 125 (10.40%)
         occurrences all number
    12
    12
    15
    Injury, poisoning and procedural complications
    CONTUSION
         subjects affected / exposed
    17 / 126 (13.49%)
    16 / 126 (12.70%)
    23 / 125 (18.40%)
         occurrences all number
    23
    20
    30
    FALL
         subjects affected / exposed
    43 / 126 (34.13%)
    37 / 126 (29.37%)
    48 / 125 (38.40%)
         occurrences all number
    96
    70
    85
    SKIN ABRASION
         subjects affected / exposed
    15 / 126 (11.90%)
    11 / 126 (8.73%)
    8 / 125 (6.40%)
         occurrences all number
    27
    16
    9
    SKIN LACERATION
         subjects affected / exposed
    19 / 126 (15.08%)
    17 / 126 (13.49%)
    21 / 125 (16.80%)
         occurrences all number
    29
    19
    26
    Nervous system disorders
    DIZZINESS
         subjects affected / exposed
    2 / 126 (1.59%)
    8 / 126 (6.35%)
    4 / 125 (3.20%)
         occurrences all number
    2
    9
    4
    HEADACHE
         subjects affected / exposed
    8 / 126 (6.35%)
    9 / 126 (7.14%)
    4 / 125 (3.20%)
         occurrences all number
    13
    11
    4
    General disorders and administration site conditions
    FATIGUE
         subjects affected / exposed
    2 / 126 (1.59%)
    9 / 126 (7.14%)
    4 / 125 (3.20%)
         occurrences all number
    9
    19
    4
    Gastrointestinal disorders
    CONSTIPATION
         subjects affected / exposed
    7 / 126 (5.56%)
    9 / 126 (7.14%)
    6 / 125 (4.80%)
         occurrences all number
    7
    12
    6
    DIARRHOEA
         subjects affected / exposed
    6 / 126 (4.76%)
    10 / 126 (7.94%)
    8 / 125 (6.40%)
         occurrences all number
    6
    10
    10
    Respiratory, thoracic and mediastinal disorders
    COUGH
         subjects affected / exposed
    9 / 126 (7.14%)
    5 / 126 (3.97%)
    5 / 125 (4.00%)
         occurrences all number
    10
    6
    5
    Skin and subcutaneous tissue disorders
    RASH
         subjects affected / exposed
    8 / 126 (6.35%)
    4 / 126 (3.17%)
    3 / 125 (2.40%)
         occurrences all number
    8
    4
    3
    Psychiatric disorders
    ANXIETY
         subjects affected / exposed
    7 / 126 (5.56%)
    2 / 126 (1.59%)
    0 / 125 (0.00%)
         occurrences all number
    8
    2
    0
    DEPRESSION
         subjects affected / exposed
    8 / 126 (6.35%)
    10 / 126 (7.94%)
    3 / 125 (2.40%)
         occurrences all number
    8
    12
    3
    INSOMNIA
         subjects affected / exposed
    5 / 126 (3.97%)
    6 / 126 (4.76%)
    8 / 125 (6.40%)
         occurrences all number
    6
    8
    8
    Musculoskeletal and connective tissue disorders
    MUSCULOSKELETAL PAIN
         subjects affected / exposed
    8 / 126 (6.35%)
    3 / 126 (2.38%)
    8 / 125 (6.40%)
         occurrences all number
    8
    3
    8
    Infections and infestations
    UPPER RESPIRATORY TRACT INFECTION
         subjects affected / exposed
    8 / 126 (6.35%)
    5 / 126 (3.97%)
    6 / 125 (4.80%)
         occurrences all number
    9
    5
    9
    URINARY TRACT INFECTION
         subjects affected / exposed
    14 / 126 (11.11%)
    13 / 126 (10.32%)
    18 / 125 (14.40%)
         occurrences all number
    19
    14
    28

    More information

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    Substantial protocol amendments (globally)

    Were there any global substantial amendments to the protocol? Yes
    Date
    Amendment
    18 Aug 2016
    Amendment 1 ● Updated body weight parameters to infusion times ● Revised reference to 2 DMCs to 1 DMC who will review all clinical trial data of ABBV-8E12 ● Revised Exclusion Criterion 1 to adjust subject weight parameters for the safety of subjects who do not meet the minimum body weight requirement ● Updated the formatting to the Cranial Nerves relative to the assessment of supranuclear gaze palsy and slowing of vertical saccades ● Removed T2 weighted-gradient-echo EPI sequence, rsfMRI to minimize burden on subject and imaging sites ● Updated Table 5, Diagnostic Tools and Scale Order and Duration of Administration, to revise the administration time points of the PGI-C, and order for the CGI-S and CGI-C ● Adjusted Table 5, Legend, Diagnostic Tools and Scale Order and Duration of Administration ● Added an audiotaping component to the SEADL and UPDRS Part II ● Updated volume of blood drawn for Biomarker samples from 10 ml to 11 ml ● Added PK and ADA windows for Cohorts 1 and 2 (Section 5.3.1.2, Collection and Handling of Biomarker and Pharmacogenetic Research Samples). ● Addition of volume for the 0.9% Sodium Chloride Injection/Solution for Infusion ● Revised reference to the Product Complaint eCRF since Product Complaint reporting will be done through a Product Complaint Form (Section 6.2.2, Reporting)
    31 Oct 2016
    Amendment 2 • Updated Inclusion Criterion 1 to add a LAR to the subject informed consent and re-consenting process ● Updated Inclusion Criterion 6 to change the minimum study partner contact from 3 to 10 hours per week ● Modified vital sign parameters to include orthostatic measurements ● Added post-lumbar puncture observation recommendation • Adjusted Table 5, Diagnostic Tools and Scale Order and Duration of Administration to include the NNIPPS-PPS; table was also modified to provide guidance on the order of scale administration at the Screening Visit, to include splitting the screening visit into 2 Screening Visits; and time points for selected scales were shifted to earlier visits ● The addition of an exploratory endpoint scale, NNIPPS-PPS ● The removal of the actigraphy assessments as an exploratory endpoint ● Shifted administration of the Letter Fluency assessment at Week 12/Day 85 and Week 36/Day 253 to Week 8/Day 57 and Week 32/Day 225. Also added the RBANS and Color Trails Test (Parts 1 and 2) at the additional time points
    26 Jan 2018
    Amendment 3 • Updated List of Abbreviations and Definition of Terms, to define Study Drug Infusion Visit and clarify that visit-specified procedures may be conducted over 2 consecutive days • Updated Introduction, Differences Statement, and Selection of Doses in the Study sections to reflect current status of the SAD study • Updated Overall Study Design and Plan: Description section to reflect anticipated number of participating sites due to an increase in the number of study subjects, and to update DMC members and review schedule in-line with the increased number of subjects. • Updated Selection of Study Population section to provide additional definition on screen failures and note that under certain circumstances, re-screening may occur • Updated Study Procedures and Vital Signs sections to remove requirement of obtaining body temperature by oral modality • Updated Section Study Procedures, Central ECG Reading, Cohort 2, Day 1, to remove the post dose ECG collection • Update Study Procedures, Clinical Laboratory Tests section to remove IgG as a required CSF Basic Lab • Updated Study Procedures, Diagnostic Tools and Scale Order and Duration of Administration section, to correct the recommended scale order for the CGI-C, SEADL and UPDRS Part II scales and update the approximate administration duration for the CGIC-S and SEADL scales • Updated Measurement Methods section, to clarify analysis of Serum and CSF Samples • Updated Efficacy Variables section to further include secondary and exploratory variables and include additional variables. • Updated Pharmacokinetic Variables section to clarify the analysis of ABBV-8E12 concentration in CSF • Updated Interim Analyses, to clarify futility interim analyses. ● Updated Determination of Sample size, to reflect new sample size • Updated Preparation/Reconstitution of Dosage Form, Blinding, and Drug Accountability, to provide additional guidance on Investigational Product (IP) blinding and accountability.
    19 Oct 2018
    Amendment 4 • Updated Study Procedures, and Study Activities sections to reflect the current diagnostic tools, scale order and duration and study activities in order to reflect the current diagnostic tools, scale order and duration and study activities for all countries. ● Updated the Treatment Administered section to define the study drug infusion rate during the study in order to reduce study drug infusion time in the 1000 mg/10 mL formulation. Other revisions were made throughout the protocol, including the synopsis, to merge country-specific languages.
    13 Dec 2018
    Amendment 5 • Updated Study Procedures and Study Activities sections to add Progressive Supranuclear Palsy (PSP) clinical features during the Screening Period in order to gather more specific data regarding PSP signs and symptoms prior to enrollment in the trial ● Updated Study Activities section to add telephone contacts at Weeks 12, 24, 36, and 52 for subjects who prematurely discontinue in order to learn about the condition of subjects since their premature discontinuation from the study

    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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