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    Clinical Trial Results:
    A Randomized, Double-Blind, Placebo-Controlled, 52-Week Phase II Study to Evaluate the Efficacy of Intravenous RO7046015 (PRX002) in Participants with Early Parkinson’s Disease with a 6-Year all-Participants-on-Treatment Extension (PASADENA)

    Summary
    EudraCT number
    		 2017-000087-15
    Trial protocol
    		 DE   AT   ES   FR  
    Global end of trial date

    Results information
    Results version number
    		 v1
    This version publication date
    12 Dec 2020
    First version publication date
    12 Dec 2020
    Other versions
    		 v2 , v3

    Trial information

    		 Close Top of page
    Trial identification
    Sponsor protocol code
    BP39529
    Additional study identifiers
    ISRCTN number
    		 -
    US NCT number
    		 NCT03100149
    WHO universal trial number (UTN)
    		 -
    Sponsors
    Sponsor organisation name
    F. Hoffmann-La Roche AG
    Sponsor organisation address
    Grenzacherstrasse 124, Basel, Switzerland, ch-4070
    Public contact
    F. Hoffmann-La Roche AG, F. Hoffmann-La Roche AG, +41 616878333, global.trial_information@roche.com
    Scientific contact
    F. Hoffmann-La Roche AG, F. Hoffmann-La Roche AG, +41 616878333, global.trial_information@roche.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
    Interim
    Date of interim/final analysis
    27 Nov 2019
    Is this the analysis of the primary completion data?
    Yes
    Primary completion date
    27 Nov 2019
    Global end of trial reached?
    No
    General information about the trial
    Main objective of the trial
    To determine the efficacy of prasinezumab versus placebo at Week 52 in participants with early Parkinson's Disease (PD, [H&Y Stages I-II]) who were untreated or treated with MAO-B inhibitors since baseline as measured by change from baseline on the Movement Disorder Society - Unified Parkinson's Disease Rating Scale (MDS-UPDRS) Total Score (sum of Parts I, II and III).
    Protection of trial subjects
    All study subjects were required to read and sign and Informed Consent Form.
    Background therapy
    		 -
    Evidence for comparator
    		 -
    Actual start date of recruitment
    27 Jun 2017
    Long term follow-up planned
    Yes
    Long term follow-up rationale
    		 Safety, Efficacy
    Long term follow-up duration
    		 6 Years
    Independent data monitoring committee (IDMC) involvement?
    Yes
    Population of trial subjects
    Number of subjects enrolled per country
    Country: Number of subjects enrolled
    Austria: 6
    Country: Number of subjects enrolled
    France: 65
    Country: Number of subjects enrolled
    Germany: 35
    Country: Number of subjects enrolled
    Spain: 50
    Country: Number of subjects enrolled
    United States: 160
    Worldwide total number of subjects
    316
    EEA total number of subjects
    156
    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)
    205
    From 65 to 84 years
    111
    85 years and over
    0

    Subject disposition

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    Recruitment
    Recruitment details
    		 -

    Pre-assignment
    Screening details
    		 A total of 316 were randomized with a 1:1:1 allocation between the treatment groups (Placebo, Low-Dose prasinezumab and High-Dose prasinezumab)

    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

    Arms
    Are arms mutually exclusive
    Yes

    Arm title
    		 Part 1: Placebo
    Arm description
    		 Participants received placebo as intravenous (IV) infusion every four weeks (Q4W) up to 52 weeks in Part 1.
    Arm type
    		 Placebo

    Investigational medicinal product name
    Placebo
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Concentrate for solution for infusion
    Routes of administration
    Intravenous use
    Dosage and administration details
    Placebo was administered by intravenous (IV) infusion once every for weeks (Q4W) to all participants in the indicated arm.

    Arm title
    		 Part 1: RO7046015 Low Dose
    Arm description
    		 Participants received RO7046015 at a low dose level (1500 mg; for all body weights) as an IV infusion Q4W up to 52 weeks in Part 1.
    Arm type
    		 Experimental

    Investigational medicinal product name
    RO7046015
    Investigational medicinal product code
    Other name
    PRX002; prasinezumab
    Pharmaceutical forms
    Concentrate for solution for infusion
    Routes of administration
    Intravenous use
    Dosage and administration details
    RO7046015 was administered by IV infusion Q4W at dose of 1500 mg to all participants in the indicated arm.

    Arm title
    		 Part 1: RO7046015 High Dose
    Arm description
    		 Participants received RO7046015 at a high dose level (3500 mg for body weight <65 kilogram (kg) or 4500 mg for body weight >=65 kg) as an IV infusion Q4W up to 52 weeks in Part 1.
    Arm type
    		 Experimental

    Investigational medicinal product name
    RO7046015
    Investigational medicinal product code
    Other name
    PRX002; prasinezumab
    Pharmaceutical forms
    Concentrate for solution for infusion
    Routes of administration
    Intravenous use
    Dosage and administration details
    RO7046015 was administered by IV infusion Q4W at dose of 4500 milligrams (mg) for participants with body-weight greater than or equal to (>/=) 65 kilograms (kg) or 3500 mg for participants with body-weight less than (<) 65 kg.

    Number of subjects in period 1
    		Part 1: Placebo Part 1: RO7046015 Low Dose Part 1: RO7046015 High Dose
    Started
    105
    105
    106
    Completed
    105
    101
    104
    Not completed
    0
    4
    2
         PATIENT MOVING OUT OF THE COUNTRY
    -
    -
    1
         Withdrawal By Subject
    -
    3
    1
         Adverse event, non-fatal
    -
    1
    -

    Baseline characteristics

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    Baseline characteristics reporting groups
    Reporting group title
    Part 1: Placebo
    Reporting group description
    		 Participants received placebo as intravenous (IV) infusion every four weeks (Q4W) up to 52 weeks in Part 1.

    Reporting group title
    Part 1: RO7046015 Low Dose
    Reporting group description
    		 Participants received RO7046015 at a low dose level (1500 mg; for all body weights) as an IV infusion Q4W up to 52 weeks in Part 1.

    Reporting group title
    Part 1: RO7046015 High Dose
    Reporting group description
    		 Participants received RO7046015 at a high dose level (3500 mg for body weight <65 kilogram (kg) or 4500 mg for body weight >=65 kg) as an IV infusion Q4W up to 52 weeks in Part 1.

    Reporting group values
    		 Part 1: Placebo Part 1: RO7046015 Low Dose Part 1: RO7046015 High Dose Total
    Number of subjects
    		 105 105 106 316
    Age Categorical
    Units: Subjects
        Preterm newborn infants(gestational age <37 weeks)
    		 0 0 0 0
        Newborns(0-27 days)
    		 0 0 0 0
        Infants and toddlers (28 days-23 months)
    		 0 0 0 0
        Children (2-11 years)
    		 0 0 0 0
        Adolescents (12-17 years)
    		 0 0 0 0
        Adults (18-64 years)
    		 72 68 65 205
        From 65-84 years
    		 33 37 41 111
        85 years and over
    		 0 0 0 0
    Age Continuous
    Units: years
        arithmetic mean (standard deviation)
    		 59.9 ± 8.7 60.3 ± 8.8 59.4 ± 9.8 -
    Sex: Female, Male
    Units: Subjects
        Male
    		 71 71 71 213
        Female
    		 34 34 35 103
    Race (NIH/OMB)
    Units: Subjects
        Asian
    		 1 0 0 1
        Black or African American
    		 0 2 0 2
        White
    		 91 83 89 263
        Unknown
    		 13 20 17 50

    End points

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    End points reporting groups
    Reporting group title
    Part 1: Placebo
    Reporting group description
    		 Participants received placebo as intravenous (IV) infusion every four weeks (Q4W) up to 52 weeks in Part 1.

    Reporting group title
    Part 1: RO7046015 Low Dose
    Reporting group description
    		 Participants received RO7046015 at a low dose level (1500 mg; for all body weights) as an IV infusion Q4W up to 52 weeks in Part 1.

    Reporting group title
    Part 1: RO7046015 High Dose
    Reporting group description
    		 Participants received RO7046015 at a high dose level (3500 mg for body weight <65 kilogram (kg) or 4500 mg for body weight >=65 kg) as an IV infusion Q4W up to 52 weeks in Part 1.

    Primary: Change From Baseline in Movement Disorder Society-Unified Parkinson's Disease Rating Scale (MDS-UPDRS) Total Score (Sum of Parts I, II, and III) at Week 52

    		 Close Top of page
    End point title
    		 Change From Baseline in Movement Disorder Society-Unified Parkinson's Disease Rating Scale (MDS-UPDRS) Total Score (Sum of Parts I, II, and III) at Week 52
    End point description
    The MDS-UPDRS is a multimodal scale consisting of four subscales. Part I assesses non-motor experiences of daily living. Part IA contains 6 questions and are assessed by the examiner. Part IB contains 7 questions on non-motor experiences of daily living which are a part of the self-administered Patient Questionnaire completed by the participant. Part II assesses motor experiences of daily living. There are 13 questions which are a part of the self-administered Patient Questionnaire completed by the participant. Part III assesses the motor signs of Parkinson's Disease (PD) and is administered by the rater. This part contains 33 scores that are based on 18 items. There are 4 subscores in Part III: Bradykinesia, Rigidity, Resting tremors and Axial symptoms. For each question a numeric score is assigned between 0-4, where 0 = Normal, 1 = Slight, 2 = Mild, 3 = Moderate, 4 = Severe. Composite scores (for each Part and total) were determined by summing the numeric values of each question.
    End point type
    Primary
    End point timeframe
    From baseline to Week 52
    End point values
    		 Part 1: Placebo Part 1: RO7046015 Low Dose Part 1: RO7046015 High Dose
    Number of subjects analysed
    76
    74
    73
    Units: Units on a scale
        least squares mean (standard error)
    9.37 ± 1.221
    7.35 ± 1.225
    8.75 ± 1.234
    Statistical analysis title
    		 MDS-UPDRS Total - Low-Dose group
    Comparison groups
    Part 1: Placebo v Part 1: RO7046015 Low Dose
    Number of subjects included in analysis
    150
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.2385
    Method
    		 Mixed models analysis
    Parameter type
    		 LS Means Difference
    Point estimate
    -2.02
    Confidence interval
         level
    		 80%
         sides
    2-sided
         lower limit
    		 -4.21
         upper limit
    		 0.18
    Variability estimate
    Standard error of the mean
    Dispersion value
    1.71
    Statistical analysis title
    		 MDS-UPDRS Total - High-Dose group
    Comparison groups
    Part 1: Placebo v Part 1: RO7046015 High Dose
    Number of subjects included in analysis
    149
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.7169
    Method
    		 Mixed models analysis
    Parameter type
    		 LS Means Difference
    Point estimate
    -0.62
    Confidence interval
         level
    		 80%
         sides
    2-sided
         lower limit
    		 -2.82
         upper limit
    		 1.58
    Variability estimate
    Standard error of the mean
    Dispersion value
    1.71

    Secondary: Change From Baseline in the MDS-UPDRS Part IA, Part IB, Part I total, Part II total, Part III total and Part III Subscores

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    End point title
    		 Change From Baseline in the MDS-UPDRS Part IA, Part IB, Part I total, Part II total, Part III total and Part III Subscores
    End point description
    The MDS-UPDRS is a multimodal scale consisting of four subscales. Part I assesses non-motor experiences of daily living. Part IA contains 6 questions and are assessed by the examiner. Part IB contains 7 questions on non-motor experiences of daily living which are a part of the self-administered Patient Questionnaire completed by the participant. Part II assesses motor experiences of daily living. There are 13 questions which are a part of the self-administered Patient Questionnaire completed by the participant. Part III assesses the motor signs of PD and is administered by the rater. This part contains 33 scores that are based on 18 items. There are 4 subscores in Part III: Bradykinesia, Rigidity, Resting tremors and Axial symptoms. For each question a numeric score is assigned between 0-4, where 0 = Normal, 1 = Slight, 2 = Mild, 3 = Moderate, 4 = Severe. Composite scores (for each Part and total) were determined by summing the numeric values of each question.
    End point type
    Secondary
    End point timeframe
    From baseline to Week 52
    End point values
    		 Part 1: Placebo Part 1: RO7046015 Low Dose Part 1: RO7046015 High Dose
    Number of subjects analysed
    76
    74
    73
    Units: Units on a scale
    least squares mean (standard error)
        Part IA
    -0.19 ± 0.119
    -0.27 ± 0.119
    -0.10 ± 0.121
        Part IB
    0.94 ± 0.247
    0.90 ± 0.248
    0.96 ± 0.251
        Part I total
    0.77 ± 0.295
    0.59 ± 0.297
    0.89 ± 0.300
        Part II total
    2.75 ± 0.373
    3.09 ± 0.375
    2.69 ± 0.376
        Part III total
    5.57 ± 0.897
    3.69 ± 0.900
    4.55 ± 0.911
        Part III subscore - rigidity
    0.61 ± 0.263
    0.70 ± 0.265
    0.86 ± 0.268
        Part III subscore - bradykinesia
    2.79 ± 0.556
    1.72 ± 0.560
    2.35 ± 0.565
        Part III subscore - resting tremor
    1.20 ± 0.231
    0.59 ± 0.233
    0.79 ± 0.234
        Part III subscore - axial symptoms
    0.19 ± 0.077
    0.11 ± 0.078
    0.18 ± 0.079
    Statistical analysis title
    		 Part IA - Low-Dose Group
    Comparison groups
    Part 1: Placebo v Part 1: RO7046015 Low Dose
    Number of subjects included in analysis
    150
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.6116 [1]
    Method
    		 Mixed models analysis
    Parameter type
    		 LS Means Difference
    Point estimate
    -0.08
    Confidence interval
         level
    		 80%
         sides
    2-sided
         lower limit
    		 -0.3
         upper limit
    		 0.13
    Variability estimate
    Standard error of the mean
    Dispersion value
    0.165
    Notes
    [1] - Nominal p-values are displayed for descriptive purposes only.
    Statistical analysis title
    		 Part IA - High-Dose Group
    Comparison groups
    Part 1: Placebo v Part 1: RO7046015 High Dose
    Number of subjects included in analysis
    149
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.6188 [2]
    Method
    		 Mixed models analysis
    Parameter type
    		 LS Means Difference
    Point estimate
    0.08
    Confidence interval
         level
    		 80%
         sides
    2-sided
         lower limit
    		 -0.13
         upper limit
    		 0.3
    Variability estimate
    Standard error of the mean
    Dispersion value
    0.165
    Notes
    [2] - Nominal p-values are displayed for descriptive purposes only.
    Statistical analysis title
    		 Part IB - Low-Dose Group
    Comparison groups
    Part 1: Placebo v Part 1: RO7046015 Low Dose
    Number of subjects included in analysis
    150
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.9062 [3]
    Method
    		 Mixed models analysis
    Parameter type
    		 LS Means Difference
    Point estimate
    -0.04
    Confidence interval
         level
    		 80%
         sides
    2-sided
         lower limit
    		 -0.48
         upper limit
    		 0.4
    Variability estimate
    Standard error of the mean
    Dispersion value
    0.345
    Notes
    [3] - Nominal p-values are displayed for descriptive purposes only.
    Statistical analysis title
    		 Part IB - High-Dose Group
    Comparison groups
    Part 1: Placebo v Part 1: RO7046015 High Dose
    Number of subjects included in analysis
    149
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.9621 [4]
    Method
    		 Mixed models analysis
    Parameter type
    		 LS Means Difference
    Point estimate
    0.02
    Confidence interval
         level
    		 80%
         sides
    2-sided
         lower limit
    		 -0.43
         upper limit
    		 0.46
    Variability estimate
    Standard error of the mean
    Dispersion value
    0.347
    Notes
    [4] - Nominal p-values are displayed for descriptive purposes only.
    Statistical analysis title
    		 Part I Total - Low-Dose Group
    Comparison groups
    Part 1: Placebo v Part 1: RO7046015 Low Dose
    Number of subjects included in analysis
    150
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.651 [5]
    Method
    		 Mixed models analysis
    Parameter type
    		 LS Means Difference
    Point estimate
    -0.19
    Confidence interval
         level
    		 80%
         sides
    2-sided
         lower limit
    		 -0.71
         upper limit
    		 0.34
    Variability estimate
    Standard error of the mean
    Dispersion value
    0.411
    Notes
    [5] - Nominal p-values are displayed for descriptive purposes only.
    Statistical analysis title
    		 Part I Total - High-Dose Group
    Comparison groups
    Part 1: Placebo v Part 1: RO7046015 High Dose
    Number of subjects included in analysis
    149
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.7709 [6]
    Method
    		 Mixed models analysis
    Parameter type
    		 LS Means Difference
    Point estimate
    0.12
    Confidence interval
         level
    		 80%
         sides
    2-sided
         lower limit
    		 -0.41
         upper limit
    		 0.65
    Variability estimate
    Standard error of the mean
    Dispersion value
    0.413
    Notes
    [6] - Nominal p-values are displayed for descriptive purposes only.
    Statistical analysis title
    		 Part II Total - Low-Dose Group
    Comparison groups
    Part 1: Placebo v Part 1: RO7046015 Low Dose
    Number of subjects included in analysis
    150
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.5177 [7]
    Method
    		 Mixed models analysis
    Parameter type
    		 LS Means Difference
    Point estimate
    0.34
    Confidence interval
         level
    		 80%
         sides
    2-sided
         lower limit
    		 -0.33
         upper limit
    		 1.01
    Variability estimate
    Standard error of the mean
    Dispersion value
    0.523
    Notes
    [7] - Nominal p-values are displayed for descriptive purposes only.
    Statistical analysis title
    		 Part II Total - High-Dose Group
    Comparison groups
    Part 1: Placebo v Part 1: RO7046015 High Dose
    Number of subjects included in analysis
    149
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.9095 [8]
    Method
    		 Mixed models analysis
    Parameter type
    		 LS Means Difference
    Point estimate
    -0.06
    Confidence interval
         level
    		 80%
         sides
    2-sided
         lower limit
    		 -0.73
         upper limit
    		 0.61
    Variability estimate
    Standard error of the mean
    Dispersion value
    0.523
    Notes
    [8] - Nominal p-values are displayed for descriptive purposes only.
    Statistical analysis title
    		 Part III Total - Low-Dose Group
    Comparison groups
    Part 1: Placebo v Part 1: RO7046015 Low Dose
    Number of subjects included in analysis
    150
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.1354 [9]
    Method
    		 Mixed models analysis
    Parameter type
    		 LS Means Difference
    Point estimate
    -1.88
    Confidence interval
         level
    		 80%
         sides
    2-sided
         lower limit
    		 -3.49
         upper limit
    		 -0.27
    Variability estimate
    Standard error of the mean
    Dispersion value
    1.255
    Notes
    [9] - Nominal p-values are displayed for descriptive purposes only.
    Statistical analysis title
    		 Part III Total - High-Dose Group
    Comparison groups
    Part 1: Placebo v Part 1: RO7046015 High Dose
    Number of subjects included in analysis
    149
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.4217 [10]
    Method
    		 Mixed models analysis
    Parameter type
    		 LS Means Difference
    Point estimate
    -1.02
    Confidence interval
         level
    		 80%
         sides
    2-sided
         lower limit
    		 -2.64
         upper limit
    		 0.61
    Variability estimate
    Standard error of the mean
    Dispersion value
    1.262
    Notes
    [10] - Nominal p-values are displayed for descriptive purposes only.
    Statistical analysis title
    		 Part III Subscore: Rigidity Low-Dose Group
    Comparison groups
    Part 1: Placebo v Part 1: RO7046015 Low Dose
    Number of subjects included in analysis
    150
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.8053 [11]
    Method
    		 Mixed models analysis
    Parameter type
    		 LS Means Difference
    Point estimate
    0.09
    Confidence interval
         level
    		 80%
         sides
    2-sided
         lower limit
    		 -0.38
         upper limit
    		 0.56
    Variability estimate
    Standard error of the mean
    Dispersion value
    0.369
    Notes
    [11] - Nominal p-values are displayed for descriptive purposes only.
    Statistical analysis title
    		 Part III Subscore: Rigidity High-Dose Group
    Comparison groups
    Part 1: Placebo v Part 1: RO7046015 High Dose
    Number of subjects included in analysis
    149
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.497 [12]
    Method
    		 Mixed models analysis
    Parameter type
    		 LS Means Difference
    Point estimate
    0.25
    Confidence interval
         level
    		 80%
         sides
    2-sided
         lower limit
    		 -0.22
         upper limit
    		 0.73
    Variability estimate
    Standard error of the mean
    Dispersion value
    0.37
    Notes
    [12] - Nominal p-values are displayed for descriptive purposes only.
    Statistical analysis title
    		 Part III Subscore: Bradykinesia Low-Dose Group
    Comparison groups
    Part 1: Placebo v Part 1: RO7046015 Low Dose
    Number of subjects included in analysis
    150
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.1703 [13]
    Method
    		 Mixed models analysis
    Parameter type
    		 LS Means Difference
    Point estimate
    -1.07
    Confidence interval
         level
    		 80%
         sides
    2-sided
         lower limit
    		 -2.07
         upper limit
    		 -0.07
    Variability estimate
    Standard error of the mean
    Dispersion value
    0.779
    Notes
    [13] - Nominal p-values are displayed for descriptive purposes only.
    Statistical analysis title
    		 Part III Subscore: Bradykinesia High-Dose Group
    Comparison groups
    Part 1: Placebo v Part 1: RO7046015 High Dose
    Number of subjects included in analysis
    149
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.5729 [14]
    Method
    		 Mixed models analysis
    Parameter type
    		 LS Means Difference
    Point estimate
    -0.44
    Confidence interval
         level
    		 80%
         sides
    2-sided
         lower limit
    		 -1.45
         upper limit
    		 0.56
    Variability estimate
    Standard error of the mean
    Dispersion value
    0.782
    Notes
    [14] - Nominal p-values are displayed for descriptive purposes only.
    Statistical analysis title
    		 Part III Subscore: Resting Tremor Low-Dose Group
    Comparison groups
    Part 1: Placebo v Part 1: RO7046015 Low Dose
    Number of subjects included in analysis
    150
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.0628 [15]
    Method
    		 Mixed models analysis
    Parameter type
    		 LS Means Difference
    Point estimate
    -0.61
    Confidence interval
         level
    		 80%
         sides
    2-sided
         lower limit
    		 -1.02
         upper limit
    		 -0.19
    Variability estimate
    Standard error of the mean
    Dispersion value
    0.324
    Notes
    [15] - Nominal p-values are displayed for descriptive purposes only.
    Statistical analysis title
    		 Part III Subscore: Resting Tremor High-Dose Group
    Comparison groups
    Part 1: Placebo v Part 1: RO7046015 High Dose
    Number of subjects included in analysis
    149
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.2125 [16]
    Method
    		 Mixed models analysis
    Parameter type
    		 LS Means Difference
    Point estimate
    -0.41
    Confidence interval
         level
    		 80%
         sides
    2-sided
         lower limit
    		 -0.82
         upper limit
    		 0.01
    Variability estimate
    Standard error of the mean
    Dispersion value
    0.325
    Notes
    [16] - Nominal p-values are displayed for descriptive purposes only.
    Statistical analysis title
    		 Part III Subscore: Axial Symptoms Low-Dose Group
    Comparison groups
    Part 1: Placebo v Part 1: RO7046015 High Dose
    Number of subjects included in analysis
    149
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.4577 [17]
    Method
    		 Mixed models analysis
    Parameter type
    		 LS Means Difference
    Point estimate
    -0.08
    Confidence interval
         level
    		 80%
         sides
    2-sided
         lower limit
    		 -0.22
         upper limit
    		 0.06
    Variability estimate
    Standard error of the mean
    Dispersion value
    0.108
    Notes
    [17] - Nominal p-values are displayed for descriptive purposes only.
    Statistical analysis title
    		 Part III Subscore: Axial Symptoms High-Dose Group
    Comparison groups
    Part 1: Placebo v Part 1: RO7046015 High Dose
    Number of subjects included in analysis
    149
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.9182 [18]
    Method
    		 Mixed models analysis
    Parameter type
    		 LS Means Difference
    Point estimate
    -0.01
    Confidence interval
         level
    		 80%
         sides
    2-sided
         lower limit
    		 -0.15
         upper limit
    		 0.13
    Variability estimate
    Standard error of the mean
    Dispersion value
    0.109
    Notes
    [18] - Nominal p-values are displayed for descriptive purposes only.

    Secondary: Change From Baseline in Dopamine Transporter Imaging With Single Photon Emission Computed Tomography (DaT-SPECT) in the Ipsilateral Putamen

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    End point title
    		 Change From Baseline in Dopamine Transporter Imaging With Single Photon Emission Computed Tomography (DaT-SPECT) in the Ipsilateral Putamen
    End point description
    DaT-SPECT (dopamine transporter imaging with single photon emission computed tomography) is a dopamine transporter SPECT imaging that uses a radioactive agent called 123^I-ioflupane to show the distribution of the dopamine transporters in the striatum. The change in DaT-SPECT uptake values in the ipsilateral putamen to the most clinical affected side, were analyzed.
    End point type
    Secondary
    End point timeframe
    From baseline to Week 52
    End point values
    		 Part 1: Placebo Part 1: RO7046015 Low Dose Part 1: RO7046015 High Dose
    Number of subjects analysed
    102
    100
    104
    Units: Images
        least squares mean (standard error)
    -0.08 ± 0.018
    -0.10 ± 0.018
    -0.11 ± 0.018
    Statistical analysis title
    		 DaT-SPECT - Low-Dose group
    Comparison groups
    Part 1: Placebo v Part 1: RO7046015 Low Dose
    Number of subjects included in analysis
    202
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.3582 [19]
    Method
    		 ANCOVA
    Parameter type
    		 LS Means Difference
    Point estimate
    -0.02
    Confidence interval
         level
    		 80%
         sides
    2-sided
         lower limit
    		 -0.05
         upper limit
    		 0.01
    Variability estimate
    Standard error of the mean
    Dispersion value
    0.02
    Notes
    [19] - Nominal p-values are displayed for descriptive purposes only.
    Statistical analysis title
    		 DaT-SPECT - High-Dose group
    Comparison groups
    Part 1: Placebo v Part 1: RO7046015 High Dose
    Number of subjects included in analysis
    206
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.1955 [20]
    Method
    		 ANCOVA
    Parameter type
    		 LS Means Difference
    Point estimate
    -0.03
    Confidence interval
         level
    		 80%
         sides
    2-sided
         lower limit
    		 -0.06
         upper limit
    		 0
    Variability estimate
    Standard error of the mean
    Dispersion value
    0.02
    Notes
    [20] - Nominal p-values are displayed for descriptive purposes only.

    Secondary: Change from Baseline in Montreal Cognition Assessment (MoCA) Total Score

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    End point title
    		 Change from Baseline in Montreal Cognition Assessment (MoCA) Total Score
    End point description
    The Montreal Cognitive Assessment (MoCA) is a rapid screening that was developed to be more sensitive to participants presenting with mild cognitive complaints. It briefly assesses short term and working memory, visuospatial abilities, executive function, attention, concentration, language and orientation.
    End point type
    Secondary
    End point timeframe
    From baseline to Week 52
    End point values
    		 Part 1: Placebo Part 1: RO7046015 Low Dose Part 1: RO7046015 High Dose
    Number of subjects analysed
    104
    100
    103
    Units: Units on a scale
        least squares mean (standard error)
    0.07 ± 0.177
    0.30 ± 0.181
    0.51 ± 0.178
    Statistical analysis title
    		 MoCA - Low-Dose Group
    Comparison groups
    Part 1: Placebo v Part 1: RO7046015 Low Dose
    Number of subjects included in analysis
    204
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.3611 [21]
    Method
    		 ANCOVA
    Parameter type
    		 LS Means Difference
    Point estimate
    0.22
    Confidence interval
         level
    		 80%
         sides
    2-sided
         lower limit
    		 -0.09
         upper limit
    		 0.54
    Variability estimate
    Standard error of the mean
    Dispersion value
    0.245
    Notes
    [21] - Nominal p-values are displayed for descriptive purposes only.
    Statistical analysis title
    		 MoCA - High-Dose Group
    Comparison groups
    Part 1: Placebo v Part 1: RO7046015 High Dose
    Number of subjects included in analysis
    207
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.0727 [22]
    Method
    		 ANCOVA
    Parameter type
    		 LS Means Difference
    Point estimate
    0.44
    Confidence interval
         level
    		 80%
         sides
    2-sided
         lower limit
    		 0.13
         upper limit
    		 0.75
    Variability estimate
    Standard error of the mean
    Dispersion value
    0.243
    Notes
    [22] - Nominal p-values are displayed for descriptive purposes only.

    Secondary: Change from Baseline in Clinical Global Impression of Improvement (CGI-I) Score

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    End point title
    		 Change from Baseline in Clinical Global Impression of Improvement (CGI-I) Score
    End point description
    The CGI-I is a measure of disease severity at baseline and is rated on a 7-point scale,with the severity (CGI-I) of illness scale using a range of responses from 1 (normal, not at all ill) through to 7 (amongst the most extremely ill patients).
    End point type
    Secondary
    End point timeframe
    From baseline to Week 52
    End point values
    		 Part 1: Placebo Part 1: RO7046015 Low Dose Part 1: RO7046015 High Dose
    Number of subjects analysed
    43
    36
    35
    Units: Percentage of participants
        number (not applicable)
    56.6
    50.0
    48.6
    Statistical analysis title
    		 CGI-I - Low-Dose Group
    Comparison groups
    Part 1: Placebo v Part 1: RO7046015 Low Dose
    Number of subjects included in analysis
    79
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.4265 [23]
    Method
    		 Regression, Logistic
    Parameter type
    		 Odds ratio (OR)
    Point estimate
    0.77
    Confidence interval
         level
    		 80%
         sides
    2-sided
         lower limit
    		 0.5
         upper limit
    		 1.18
    Notes
    [23] - Nominal p-values are displayed for descriptive purposes only.
    Statistical analysis title
    		 CGI-I - High-Dose Group
    Comparison groups
    Part 1: Placebo v Part 1: RO7046015 High Dose
    Number of subjects included in analysis
    78
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.4063 [24]
    Method
    		 Regression, Logistic
    Parameter type
    		 Odds ratio (OR)
    Point estimate
    0.76
    Confidence interval
         level
    		 80%
         sides
    2-sided
         lower limit
    		 0.49
         upper limit
    		 1.16
    Notes
    [24] - Nominal p-values are displayed for descriptive purposes only.

    Secondary: Change from Baseline in Patient Global Impression of Change (PGIC) Score

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    End point title
    		 Change from Baseline in Patient Global Impression of Change (PGIC) Score
    End point description
    The Patient Global Impression of Change (PGIC) is intended as a measure of change in health state from the patient’s perspective. PGIC scores range from 1 (very much improved) through to 7 (very much worse).
    End point type
    Secondary
    End point timeframe
    From baseline to Week 52
    End point values
    		 Part 1: Placebo Part 1: RO7046015 Low Dose Part 1: RO7046015 High Dose
    Number of subjects analysed
    43
    37
    38
    Units: Percentage of participants
        number (not applicable)
    58.1
    50.7
    53.5
    Statistical analysis title
    		 PGIC - Low-Dose Group
    Comparison groups
    Part 1: Placebo v Part 1: RO7046015 Low Dose
    Number of subjects included in analysis
    80
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.3847 [25]
    Method
    		 Regression, Logistic
    Parameter type
    		 Odds ratio (OR)
    Point estimate
    0.75
    Confidence interval
         level
    		 80%
         sides
    2-sided
         lower limit
    		 0.48
         upper limit
    		 1.15
    Notes
    [25] - Nominal p-values are displayed for descriptive purposes only.
    Statistical analysis title
    		 PGIC - High-Dose Group
    Comparison groups
    Part 1: Placebo v Part 1: RO7046015 High Dose
    Number of subjects included in analysis
    81
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.7055 [26]
    Method
    		 Regression, Logistic
    Parameter type
    		 Odds ratio (OR)
    Point estimate
    0.88
    Confidence interval
         level
    		 80%
         sides
    2-sided
         lower limit
    		 0.57
         upper limit
    		 1.36
    Notes
    [26] - Nominal p-values are displayed for descriptive purposes only.

    Secondary: Change from Baseline in Schwab and England Activity of Daily Living (SE-ADL) Score

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    End point title
    		 Change from Baseline in Schwab and England Activity of Daily Living (SE-ADL) Score
    End point description
    The SE-ADL is a single item scale assessing Activities of Daily Living on a scale ranging from 0% (bedridden) to 100% (completely independent), using 10% intervals.
    End point type
    Secondary
    End point timeframe
    From baseline to Week 52
    End point values
    		 Part 1: Placebo Part 1: RO7046015 Low Dose Part 1: RO7046015 High Dose
    Number of subjects analysed
    104
    102
    103
    Units: Units on a scale
        least squares mean (standard error)
    -1.83 ± 0.644
    -2.56 ± 0.650
    -2.50 ± 0.647
    Statistical analysis title
    		 SE-ADL - Low-Dose Group
    Comparison groups
    Part 1: Placebo v Part 1: RO7046015 Low Dose
    Number of subjects included in analysis
    206
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.4142 [27]
    Method
    		 ANCOVA
    Parameter type
    		 LS Means Difference
    Point estimate
    -0.73
    Confidence interval
         level
    		 80%
         sides
    2-sided
         lower limit
    		 -1.87
         upper limit
    		 0.41
    Variability estimate
    Standard error of the mean
    Dispersion value
    0.888
    Notes
    [27] - Nominal p-values are displayed for descriptive purposes only.
    Statistical analysis title
    		 SE-ADL - High-Dose Group
    Comparison groups
    Part 1: Placebo v Part 1: RO7046015 High Dose
    Number of subjects included in analysis
    207
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.4486 [28]
    Method
    		 ANCOVA
    Parameter type
    		 LS Means Difference
    Point estimate
    -0.67
    Confidence interval
         level
    		 80%
         sides
    2-sided
         lower limit
    		 -1.81
         upper limit
    		 0.47
    Variability estimate
    Standard error of the mean
    Dispersion value
    0.885
    Notes
    [28] - Nominal p-values are displayed for descriptive purposes only.

    Secondary: Time to Worsening in Motor or Non-Motor Symptoms

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    End point title
    		 Time to Worsening in Motor or Non-Motor Symptoms
    End point description
    This outcome measure is defined as the time to between first dose of study medication and the date when the patient increase in MDS-UPDRS Part I of 3 or more points, or in MDS-UPDRS Part II of 3 or more points, whichever comes first.
    End point type
    Secondary
    End point timeframe
    From baseline to Week 52
    End point values
    		 Part 1: Placebo Part 1: RO7046015 Low Dose Part 1: RO7046015 High Dose
    Number of subjects analysed
    105
    105
    106
    Units: Days
        median (confidence interval 80%)
    174.0 (168.0 to 225.0)
    169.0 (117.0 to 173.0)
    170.0 (168.0 to 222.0)
    Statistical analysis title
    		 Low-Dose Group
    Comparison groups
    Part 1: Placebo v Part 1: RO7046015 Low Dose
    Number of subjects included in analysis
    210
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.3769 [29]
    Method
    		 Regression, Cox
    Parameter type
    		 Hazard ratio (HR)
    Point estimate
    1.15
    Confidence interval
         level
    		 80%
         sides
    2-sided
         lower limit
    		 0.94
         upper limit
    		 1.42
    Notes
    [29] - Nominal p-values are displayed for descriptive purposes only.
    Statistical analysis title
    		 High-Dose Group
    Comparison groups
    Part 1: Placebo v Part 1: RO7046015 High Dose
    Number of subjects included in analysis
    211
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.1658 [30]
    Method
    		 Regression, Cox
    Parameter type
    		 Hazard ratio (HR)
    Point estimate
    1.25
    Confidence interval
         level
    		 80%
         sides
    2-sided
         lower limit
    		 1.02
         upper limit
    		 1.53
    Notes
    [30] - Nominal p-values are displayed for descriptive purposes only.

    Secondary: Time to Start of Dopaminergic Parkinson's Disease Treatment

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    End point title
    		 Time to Start of Dopaminergic Parkinson's Disease Treatment
    End point description
    This endpoint is defined as the time between first dose of study medication and the date when the participant starts dopaminergic treatment. The median time to start of treatment would be the timepoint when more than 50% of all participants started the treatment. At the end of Week 52, less than 50% of the participants started the treatment, thus the median time to start of treatment was not estimable and is assigned a value of '99999999' in the results table.
    End point type
    Secondary
    End point timeframe
    From baseline to Week 52
    End point values
    		 Part 1: Placebo Part 1: RO7046015 Low Dose Part 1: RO7046015 High Dose
    Number of subjects analysed
    105
    105
    106
    Units: Days
        median (confidence interval 80%)
    99999999 (99999999 to 99999999)
    99999999 (99999999 to 99999999)
    99999999 (99999999 to 99999999)
    Statistical analysis title
    		 Low-Dose Group
    Comparison groups
    Part 1: Placebo v Part 1: RO7046015 Low Dose
    Number of subjects included in analysis
    210
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.9542 [31]
    Method
    		 Regression, Cox
    Parameter type
    		 Hazard ratio (HR)
    Point estimate
    1.01
    Confidence interval
         level
    		 80%
         sides
    2-sided
         lower limit
    		 0.77
         upper limit
    		 1.33
    Notes
    [31] - Nominal p-values are displayed for descriptive purposes only.
    Statistical analysis title
    		 High-Dose Group
    Comparison groups
    Part 1: Placebo v Part 1: RO7046015 High Dose
    Number of subjects included in analysis
    211
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.4567 [32]
    Method
    		 Regression, Cox
    Parameter type
    		 Hazard ratio (HR)
    Point estimate
    0.84
    Confidence interval
         level
    		 80%
         sides
    2-sided
         lower limit
    		 0.63
         upper limit
    		 1.13
    Notes
    [32] - Nominal p-values are displayed for descriptive purposes only.

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

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    End point title
    		 Percentage of Participants With Adverse Events (AEs) and Serious AEs (SAEs)
    End point description
    An AE was any untoward medical occurrence in a participant who received study drug without regard to possibility of causal relationship. An SAE was any AE resulting in any of the following outcomes or deemed significant for any other reason: death; initial or prolonged inpatient hospitalization; life-threatening experience (immediate risk of dying); persistent or significant disability/incapacity; congenital anomaly.
    End point type
    Secondary
    End point timeframe
    From baseline to Week 52
    End point values
    		 Part 1: Placebo Part 1: RO7046015 Low Dose Part 1: RO7046015 High Dose
    Number of subjects analysed
    105
    105
    106
    Units: Percentage of participants
    number (not applicable)
        AEs
    82.9
    93.3
    91.5
        SAEs
    4.8
    6.7
    7.5
    No statistical analyses for this end point

    Secondary: Percentage of Participants With Anti-Drug Antibodies (ADAs) Against RO7046015

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    End point title
    		 Percentage of Participants With Anti-Drug Antibodies (ADAs) Against RO7046015
    End point description
    Samples of the participant's blood was taken to evaluate anti-drug antibodies (ADA). The number of ADA positive participants, Treatment-induced and Treatment-enhanced was reported. Treatment-induced = participants with ADA negative or missing data at baseline but develop an ADA response following exposure to the study drug. Treatment-enhanced = participants with ADA positive at baseline and the titre of one or more post-baseline samples is at least >=4 fold increase greater than the baseline titre sample.
    End point type
    Secondary
    End point timeframe
    Baseline, Pre-dose (0 hours) on Weeks 4, 20, 36, 52, 56, 68, 80, and 104; at early termination (up to Week 104), and follow-up (12 weeks after last dose up to Week 116)
    End point values
    		 Part 1: Placebo Part 1: RO7046015 Low Dose Part 1: RO7046015 High Dose
    Number of subjects analysed
    0 [33]
    104
    105
    Units: Percentage of participants
        number (not applicable)
    1.0
    1.9
    Notes
    [33] - Only participants who received the study drug were analyzed.
    No statistical analyses for this end point

    Secondary: Systemic Clearance (CL) of RO7046015

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    End point title
    		 Systemic Clearance (CL) of RO7046015
    End point description
    Clearance is a measure of the rate at which a drug is removed from the body.
    End point type
    Secondary
    End point timeframe
    Predose (0 hours) and end of infusion (infusion length=2 hours or less) on Baseline, Weeks 4, 20, 36, 52, 56, 68, 80, and 104; at Day 7, Day 14, early termination (up to Week 104), and follow-up (12 weeks after last dose up to Week 116)
    End point values
    		 Part 1: Placebo Part 1: RO7046015 Low Dose Part 1: RO7046015 High Dose
    Number of subjects analysed
    0 [34]
    0 [35]
    0 [36]
    Units: Micrograms per milliliter (ug/mL)
        median (confidence interval 90%)
    ( to )
    ( to )
    ( to )
    Notes
    [34] - Final results for this endpoint will be provided at the time of final results disclosure.
    [35] - Final results for this endpoint will be provided at the time of final results disclosure.
    [36] - Final results for this endpoint will be provided at the time of final results disclosure.
    No statistical analyses for this end point

    Secondary: Apparent Volume of Distribution (Vz/F) of RO7046015

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    End point title
    		 Apparent Volume of Distribution (Vz/F) of RO7046015
    End point description
    Volume of distribution is defined as the theoretical volume which the total amount of drug would need to be uniformly distributed to produce the desired plasma concentration of a drug.
    End point type
    Secondary
    End point timeframe
    Predose (0 hours) and end of infusion (infusion length=2 hours or less) on Baseline, Weeks 4, 20, 36, 52, 56, 68, 80, and 104; at Day 7, Day 14, early termination (up to Week 104), and follow-up (12 weeks after last dose up to Week 116)
    End point values
    		 Part 1: Placebo Part 1: RO7046015 Low Dose Part 1: RO7046015 High Dose
    Number of subjects analysed
    0 [37]
    0 [38]
    0 [39]
    Units: Micrograms per milliliter (ug/mL)
        median (confidence interval 90%)
    ( to )
    ( to )
    ( to )
    Notes
    [37] - Final results for this endpoint will be provided at the time of final results disclosure.
    [38] - Final results for this endpoint will be provided at the time of final results disclosure.
    [39] - Final results for this endpoint will be provided at the time of final results disclosure.
    No statistical analyses for this end point

    Secondary: Area Under the Serum Concentration-Time Curve (AUC) of RO7046015 over the Dosing Interval

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    End point title
    		 Area Under the Serum Concentration-Time Curve (AUC) of RO7046015 over the Dosing Interval [40]
    End point description
    AUC is defined as the measure of RO7046015 plasma concentration over time.
    End point type
    Secondary
    End point timeframe
    Baseline over the duration of the study
    Notes
    [40] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
    Justification: Participants in arms that received the study drug will be analyzed. At the time of these primary results, there is no data available. Final results for this endpoint will be provided at the time of final results disclosure.
    End point values
    		 Part 1: RO7046015 Low Dose Part 1: RO7046015 High Dose
    Number of subjects analysed
    0 [41]
    0 [42]
    Units: Micrograms per milliliter (ug.d/mL)
        median (confidence interval 90%)
    ( to )
    ( to )
    Notes
    [41] - Final results for this endpoint will be provided at the time of final results disclosure.
    [42] - Final results for this endpoint will be provided at the time of final results disclosure.
    No statistical analyses for this end point

    Secondary: Maximum Observed Serum Concentration (Cmax) of RO7046015 at Steady-state

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    End point title
    		 Maximum Observed Serum Concentration (Cmax) of RO7046015 at Steady-state [43]
    End point description
    Cmax is the maximum observed plasma concentration of RO7046015.
    End point type
    Secondary
    End point timeframe
    Baseline over the duration of the study
    Notes
    [43] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
    Justification: Participants in arms that received the study drug will be analyzed. At the time of these primary results, there is no data available. Final results for this endpoint will be provided at the time of final results disclosure.
    End point values
    		 Part 1: RO7046015 Low Dose Part 1: RO7046015 High Dose
    Number of subjects analysed
    0 [44]
    0 [45]
    Units: Micrograms per milliliter (ug/mL)
        median (confidence interval 90%)
    ( to )
    ( to )
    Notes
    [44] - Final results for this endpoint will be provided at the time of final results disclosure.
    [45] - Final results for this endpoint will be provided at the time of final results disclosure.
    No statistical analyses for this end point

    Secondary: Minimum Observed Serum Concentration (Ctrough) of RO7046015 at Steady-state

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    End point title
    		 Minimum Observed Serum Concentration (Ctrough) of RO7046015 at Steady-state [46]
    End point description
    Cmin is the minimum observed plasma concentration of RO7046015.
    End point type
    Secondary
    End point timeframe
    Baseline over the duration of the study
    Notes
    [46] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
    Justification: Participants in arms that received the study drug will be analyzed. At the time of these primary results, there is no data available. Final results for this endpoint will be provided at the time of final results disclosure.
    End point values
    		 Part 1: RO7046015 Low Dose Part 1: RO7046015 High Dose
    Number of subjects analysed
    0 [47]
    0 [48]
    Units: Micrograms per milliliter (ug/mL)
        median (confidence interval 90%)
    ( to )
    ( to )
    Notes
    [47] - Final results for this endpoint will be provided at the time of final results disclosure.
    [48] - Final results for this endpoint will be provided at the time of final results disclosure.
    No statistical analyses for this end point

    Adverse events

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    Adverse events information
    Timeframe for reporting adverse events
    Baseline up to Week 52
    Adverse event reporting additional description
    AEs were graded according to the National Cancer Institute Common Terminology Criteria for Adverse Events (NCI CTCAE) Version 4.0.
    Assessment type
    		 Systematic
    Dictionary used for adverse event reporting
    Dictionary name
    		 MedDRA
    Dictionary version
    22.1
    Reporting groups
    Reporting group title
    Part 1: RO7046015 High Dose
    Reporting group description
    		 Participants received RO7046015 at a high dose level (3500 mg for body weight <65 kilogram (kg) or 4500 mg for body weight >=65 kg) as an IV infusion Q4W up to 52 weeks in Part 1.

    Reporting group title
    Part 1: RO7046015 Low Dose
    Reporting group description
    		 Participants received RO7046015 at a low dose level (1500 mg; for all body weights) as an IV infusion Q4W up to 52 weeks in Part 1.

    Reporting group title
    Part 1: Placebo
    Reporting group description
    		 Participants received placebo as intravenous (IV) infusion every four weeks (Q4W) up to 52 weeks in Part 1.

    Serious adverse events
    		 Part 1: RO7046015 High Dose Part 1: RO7046015 Low Dose Part 1: Placebo
    Total subjects affected by serious adverse events
         subjects affected / exposed
    8 / 106 (7.55%)
    7 / 105 (6.67%)
    5 / 105 (4.76%)
         number of deaths (all causes)
    0
    0
    0
         number of deaths resulting from adverse events
    Neoplasms benign, malignant and unspecified (incl cysts and polyps)
    Basal cell carcinoma
         subjects affected / exposed
    0 / 106 (0.00%)
    1 / 105 (0.95%)
    0 / 105 (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
    Large intestine benign neoplasm
         subjects affected / exposed
    0 / 106 (0.00%)
    0 / 105 (0.00%)
    1 / 105 (0.95%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Malignant melanoma
         subjects affected / exposed
    0 / 106 (0.00%)
    1 / 105 (0.95%)
    0 / 105 (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
    Infusion related reaction
         subjects affected / exposed
    2 / 106 (1.89%)
    0 / 105 (0.00%)
    0 / 105 (0.00%)
         occurrences causally related to treatment / all
    2 / 2
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Limb injury
         subjects affected / exposed
    1 / 106 (0.94%)
    0 / 105 (0.00%)
    0 / 105 (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
    Radius fracture
         subjects affected / exposed
    0 / 106 (0.00%)
    0 / 105 (0.00%)
    1 / 105 (0.95%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Ulna fracture
         subjects affected / exposed
    0 / 106 (0.00%)
    0 / 105 (0.00%)
    1 / 105 (0.95%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Cardiac disorders
    Acute myocardial infarction
         subjects affected / exposed
    0 / 106 (0.00%)
    0 / 105 (0.00%)
    1 / 105 (0.95%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Cardiac failure
         subjects affected / exposed
    0 / 106 (0.00%)
    1 / 105 (0.95%)
    0 / 105 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Nervous system disorders
    Facial paralysis
         subjects affected / exposed
    0 / 106 (0.00%)
    1 / 105 (0.95%)
    0 / 105 (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
    Parkinson's disease
         subjects affected / exposed
    0 / 106 (0.00%)
    1 / 105 (0.95%)
    0 / 105 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Transient ischaemic attack
         subjects affected / exposed
    0 / 106 (0.00%)
    1 / 105 (0.95%)
    0 / 105 (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
    General disorders and administration site conditions
    Influenza like illness
         subjects affected / exposed
    0 / 106 (0.00%)
    1 / 105 (0.95%)
    0 / 105 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Gastrointestinal disorders
    Inguinal hernia
         subjects affected / exposed
    0 / 106 (0.00%)
    0 / 105 (0.00%)
    1 / 105 (0.95%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Psychiatric disorders
    Behaviour disorder
         subjects affected / exposed
    1 / 106 (0.94%)
    0 / 105 (0.00%)
    0 / 105 (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
    1 / 106 (0.94%)
    0 / 105 (0.00%)
    0 / 105 (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
    Renal and urinary disorders
    Nephrolithiasis
         subjects affected / exposed
    1 / 106 (0.94%)
    0 / 105 (0.00%)
    0 / 105 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Musculoskeletal and connective tissue disorders
    Intervertebral disc protrusion
         subjects affected / exposed
    1 / 106 (0.94%)
    1 / 105 (0.95%)
    0 / 105 (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
    Ligament disorder
         subjects affected / exposed
    0 / 106 (0.00%)
    0 / 105 (0.00%)
    1 / 105 (0.95%)
         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
    Anal abscess
         subjects affected / exposed
    1 / 106 (0.94%)
    0 / 105 (0.00%)
    0 / 105 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Frequency threshold for reporting non-serious adverse events: 5%
    Non-serious adverse events
    		 Part 1: RO7046015 High Dose Part 1: RO7046015 Low Dose Part 1: Placebo
    Total subjects affected by non serious adverse events
         subjects affected / exposed
    69 / 106 (65.09%)
    67 / 105 (63.81%)
    57 / 105 (54.29%)
    Injury, poisoning and procedural complications
    Fall
         subjects affected / exposed
    10 / 106 (9.43%)
    5 / 105 (4.76%)
    5 / 105 (4.76%)
         occurrences all number
    15
    9
    7
    Infusion related reaction
         subjects affected / exposed
    35 / 106 (33.02%)
    20 / 105 (19.05%)
    17 / 105 (16.19%)
         occurrences all number
    115
    40
    29
    Nervous system disorders
    Headache
         subjects affected / exposed
    12 / 106 (11.32%)
    10 / 105 (9.52%)
    10 / 105 (9.52%)
         occurrences all number
    15
    19
    12
    Gastrointestinal disorders
    Constipation
         subjects affected / exposed
    10 / 106 (9.43%)
    8 / 105 (7.62%)
    6 / 105 (5.71%)
         occurrences all number
    10
    8
    6
    Nausea
         subjects affected / exposed
    9 / 106 (8.49%)
    5 / 105 (4.76%)
    9 / 105 (8.57%)
         occurrences all number
    16
    6
    10
    Skin and subcutaneous tissue disorders
    Dermatitis contact
         subjects affected / exposed
    3 / 106 (2.83%)
    1 / 105 (0.95%)
    6 / 105 (5.71%)
         occurrences all number
    3
    1
    8
    Psychiatric disorders
    Anxiety
         subjects affected / exposed
    7 / 106 (6.60%)
    2 / 105 (1.90%)
    3 / 105 (2.86%)
         occurrences all number
    7
    2
    3
    Insomnia
         subjects affected / exposed
    8 / 106 (7.55%)
    3 / 105 (2.86%)
    5 / 105 (4.76%)
         occurrences all number
    9
    3
    5
    Musculoskeletal and connective tissue disorders
    Arthralgia
         subjects affected / exposed
    4 / 106 (3.77%)
    7 / 105 (6.67%)
    8 / 105 (7.62%)
         occurrences all number
    4
    8
    9
    Back pain
         subjects affected / exposed
    11 / 106 (10.38%)
    8 / 105 (7.62%)
    8 / 105 (7.62%)
         occurrences all number
    13
    8
    9
    Pain in extremity
         subjects affected / exposed
    5 / 106 (4.72%)
    6 / 105 (5.71%)
    2 / 105 (1.90%)
         occurrences all number
    6
    7
    2
    Infections and infestations
    Nasopharyngitis
         subjects affected / exposed
    13 / 106 (12.26%)
    20 / 105 (19.05%)
    15 / 105 (14.29%)
         occurrences all number
    17
    25
    19
    Upper respiratory tract infection
         subjects affected / exposed
    9 / 106 (8.49%)
    4 / 105 (3.81%)
    9 / 105 (8.57%)
         occurrences all number
    11
    4
    10

    More information

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    Substantial protocol amendments (globally)
    Were there any global substantial amendments to the protocol? Yes
    Date
    Amendment
    13 Nov 2017
    The Safety and Efficacy Monitoring Committee was changed to a single independent Data Monitoring Committee; Sample size was adjusted; Immunogenicity population was corrected; Exclusion criteria was revised; Iodine pretreatment options were clarified; Enrollment criteria allowing participants on stable doses of a selective MAO-B inhibitor and SSRI or SNRI antidepressant was added; The number of study centres increased to help with recruitment; Revisions to the Schedule of Assessments.
    27 Jun 2018
    Exclusion criteria were clarified.
    23 Oct 2019
    Secondary objectives and endpoints were further specified and updated; Analysis population definitions were updated; Additional information on analyses was provided; Clarification of what constitutes a non-investigational medicinal product; Clarification of a medication error was added; Information regarding videotaping participants during administration of the MDS-UPDRS scale.
    20 Mar 2020
    Addition of Part 3 which is a 5-year all participants on treatment extension aiming to assess long-term safety and efficacy effects of RO7046015.

    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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