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    Clinical Trial Results:
    An Open-Label, Phase 3 Study Examining the Long-Term Safety, Tolerability and Efficacy of APL-130277 in Levodopa Responsive Patients with Parkinson’s Disease Complicated by Motor Fluctuations ("OFF" Episodes)

    Summary
    EudraCT number
    		 2016-000637-43
    Trial protocol
    		 GB   ES   AT   IT  
    Global end of trial date
    08 Nov 2022

    Results information
    Results version number
    		 v1(current)
    This version publication date
    15 Jul 2023
    First version publication date
    15 Jul 2023
    Other versions
    Summary report(s)
    		 results

    Trial information

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    Trial identification
    Sponsor protocol code
    CTH-301
    Additional study identifiers
    ISRCTN number
    		 -
    US NCT number
    		 NCT02542696
    WHO universal trial number (UTN)
    		 -
    Sponsors
    Sponsor organisation name
    Sunovion Pharmaceuticals Inc.
    Sponsor organisation address
    84 Waterford Drive, Marlboro, United States, 01752
    Public contact
    CNS Medical Director, CNS Medical Director, 01 18665036351, clinicaltrialdisclosure@sunovion.com
    Scientific contact
    CNS Medical Director, Sunovion Pharmaceuticals Inc., 01 18665036351, clinicaltrialdisclosure@sunovion.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
    08 Nov 2022
    Is this the analysis of the primary completion data?
    Yes
    Primary completion date
    08 Nov 2022
    Global end of trial reached?
    Yes
    Global end of trial date
    08 Nov 2022
    Was the trial ended prematurely?
    No
    General information about the trial
    Main objective of the trial
    The primary objective is to evaluate the long-term safety and tolerability of APL-130277 in Subjects with Parkinson’s disease (PD).
    Protection of trial subjects
    The study was conducted according to the protocol, ICH Good Clinical Practice (GCP), ICH guidelines, and the ethical principles that have their origin in the Declaration of Helsinki
    Background therapy
    		 -
    Evidence for comparator
    		 -
    Actual start date of recruitment
    31 Aug 2015
    Long term follow-up planned
    No
    Independent data monitoring committee (IDMC) involvement?
    No
    Population of trial subjects
    Number of subjects enrolled per country
    Country: Number of subjects enrolled
    Austria: 4
    Country: Number of subjects enrolled
    Canada: 7
    Country: Number of subjects enrolled
    United Kingdom: 41
    Country: Number of subjects enrolled
    Spain: 11
    Country: Number of subjects enrolled
    Italy: 19
    Country: Number of subjects enrolled
    United States: 391
    Country: Number of subjects enrolled
    Germany: 23
    Worldwide total number of subjects
    496
    EEA total number of subjects
    57
    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)
    239
    From 65 to 84 years
    257
    85 years and over
    0

    Subject disposition

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    Recruitment
    Recruitment details
    		 -

    Pre-assignment
    Screening details
    		 informed consent must be obtained at an initial Screening Visit (SV1). If required by the Investigator, and following receipt of subject consent, the Investigator may review the subject’s medical history, BMI, height, weight, vital signs, 12-Lead ECG (in triplicate) and perform a complete physical examination

    Period 1
    Period 1 title
    Overall Study (overall period)
    Is this the baseline period?
    		 Yes
    Allocation method
    Not applicable
    Blinding used
    		 Not blinded

    Arms
    Are arms mutually exclusive
    Yes

    Arm title
    		 Titration
    Arm description
    		 APL-130277 Titration Phase Only
    Arm type
    		 Experimental

    Investigational medicinal product name
    APL-130277
    Investigational medicinal product code
    Other name
    Apomorphine sublingual film
    Pharmaceutical forms
    Sublingual film
    Routes of administration
    Oral use
    Dosage and administration details
    sublingual

    Arm title
    		 Titration+LTS
    Arm description
    		 APL-130277 Titration Phase + Long-Term Safety Phase
    Arm type
    		 experimental

    Investigational medicinal product name
    No investigational medicinal product assigned in this arm
    Arm title
    		 LTS (Long-Term Safety)
    Arm description
    		 APL-130277 Long-Term Safety Phase Only
    Arm type
    		 experimental

    Investigational medicinal product name
    No investigational medicinal product assigned in this arm
    Number of subjects in period 1
    		Titration Titration+LTS LTS (Long-Term Safety)
    Started
    70
    379
    47
    Titration Full Analysis Population
    70
    379
    0 [1]
    LTS Phase Full Analysis Population
    0
    379
    47
    Completed
    0
    114
    6
    Not completed
    70
    265
    41
         Adverse event, serious fatal
    1
    4
    3
         STUDY TERMINATED BY SPONSOR
    -
    22
    14
         SUBJECT DECISION
    -
    2
    -
         DECREASED OFF TIME
    -
    1
    -
         Consent withdrawn by subject
    17
    76
    11
         PROGRESSION OF PARKINSON'S DISEASE
    -
    4
    1
         SITE UNABLE TO COMPLY WITH PROTOCOL
    -
    2
    -
         Adverse event, non-fatal
    28
    128
    11
         MEDICAL HISTORY
    -
    -
    1
         SPONSOR DECISION
    -
    3
    -
         ELIGIBILITY CRITERIA NOT MET
    7
    1
    -
         WITHDRAWN DURING TITRATION
    1
    -
    -
         Lost to follow-up
    -
    6
    -
         DID NOT MEET CRITERIA FOR CONTINUATION
    -
    1
    -
         Lack of efficacy
    14
    12
    -
         Protocol deviation
    2
    3
    -
    Notes
    [1] - The number of subjects at this milestone seems inconsistent with the number of subjects in the arm. It is expected that the number of subjects will be greater than, or equal to the number that completed, minus those who left.
    Justification: there were no subjects in this arm for this analysis

    Baseline characteristics

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    Baseline characteristics reporting groups
    Reporting group title
    Titration
    Reporting group description
    		 APL-130277 Titration Phase Only

    Reporting group title
    Titration+LTS
    Reporting group description
    		 APL-130277 Titration Phase + Long-Term Safety Phase

    Reporting group title
    LTS (Long-Term Safety)
    Reporting group description
    		 APL-130277 Long-Term Safety Phase Only

    Reporting group values
    		 Titration Titration+LTS LTS (Long-Term Safety) Total
    Number of subjects
    		 70 379 47 496
    Age Categorical
    Units: Participants
        Between 18 and 65 years
    		 32 189 18 239
        >=65 years
    		 38 190 29 257
        <=18 years
    		 0 0 0 0
    Age Continuous
    Units: Years
        arithmetic mean (standard deviation)
    		 65.3 ( 9.40 ) 64.1 ( 8.69 ) 65.7 ( 7.79 ) -
    Gender, Male/Female
    Units: Participants
        Female
    		 27 124 12 163
        Male
    		 43 255 35 333
    ON State Modified Hoehn and Yahr Score
    Units: Subjects
        0.0
    		 0 2 0 2
        1.0
    		 2 10 0 12
        1.5
    		 1 8 0 9
        2.0
    		 40 203 0 243
        2.5
    		 8 45 0 53
        3.0
    		 11 31 0 42
        4.0
    		 0 1 0 1
        Missing
    		 8 79 47 134
    Mini-Mental State Examination Total Score
    Units: Subjects
        <26
    		 3 0 0 3
        26
    		 6 24 0 30
        27
    		 6 32 0 38
        28
    		 10 43 0 53
        29
    		 13 101 0 114
        30
    		 30 153 0 183
        Missing
    		 2 26 47 75
    Age, Customized
    Units: Subjects
        <65 years
    		 32 189 18 239
        >=65 years and <75 years
    		 26 147 24 197
        >=75 years
    		 12 43 5 60
    Ethnicity (NIH/OMB)
    Units: Subjects
        Hispanic or Latino
    		 4 33 2 39
        Not Hispanic or Latino
    		 66 346 45 457
        Unknown or Not Reported
    		 0 0 0 0
    Country
    Units: Subjects
        AUT
    		 0 0 4 4
        CAN
    		 1 6 0 7
        DEU
    		 0 0 23 23
        ESP
    		 0 2 9 11
        GBR
    		 6 31 4 41
        ITA
    		 0 12 7 19
        United States
    		 63 328 0 391
    Race/Ethnicity, Customized
    Units: Subjects
        American Indian or Alaska Native
    		 0 1 0 1
        Asian
    		 0 4 0 4
        Black or African American
    		 2 8 0 10
        Native Hawaiian or Other Pacific Islander
    		 0 1 0 1
        Other
    		 1 1 0 2
        White
    		 67 364 47 478
    Baseline Height (cm)
    Units: cm
        arithmetic mean (standard deviation)
    		 170.31 ( 9.849 ) 172.39 ( 9.761 ) 171.48 ( 9.457 ) -
    Baseline Weight (kg)
    Units: kg
        arithmetic mean (standard deviation)
    		 77.62 ( 16.643 ) 82.97 ( 18.760 ) 82.24 ( 20.893 ) -
    Baseline BMI (kg/m^2)
    Units: kg/m^2
        arithmetic mean (standard deviation)
    		 26.506 ( 4.1859 ) 27.851 ( 5.6788 ) 27.781 ( 5.9568 ) -
    Screening MDS-UPDRS Part I Score
    Units: Score
        arithmetic mean (standard deviation)
    		 11.4 ( 5.03 ) 11.0 ( 5.47 ) 10.4 ( 5.65 ) -
    Screening MDS-UPDRS Part II Score
    Units: Score
        arithmetic mean (standard deviation)
    		 14.8 ( 7.16 ) 14.2 ( 7.04 ) 17.4 ( 7.49 ) -
    Baseline MDS-UPDRS Part III Score
    Units: Score
        arithmetic mean (standard deviation)
    		 999999 ( 999999 ) 42.4 ( 15.06 ) 48.0 ( 12.06 ) -
    Screening MDS-UPDRS Part III Score
    Units: Score
        arithmetic mean (standard deviation)
    		 43.4 ( 17.12 ) 41.8 ( 13.96 ) 999999 ( 999999 ) -
    Subject analysis sets

    Subject analysis set title
    APL-130277
    Subject analysis set type
    		 Full analysis
    Subject analysis set description
    APL-130277 Long Term Safety Phase

    Subject analysis set title
    APL-130277
    Subject analysis set type
    		 Full analysis
    Subject analysis set description
    APL-130277 Long Term Safety Phase

    Subject analysis set title
    APL-130277
    Subject analysis set type
    		 Full analysis
    Subject analysis set description
    APL-130277 Long Term Safety Phase

    Subject analysis set title
    APL-130277
    Subject analysis set type
    		 Full analysis
    Subject analysis set description
    APL-130277 Long Term Safety Phase

    Subject analysis set title
    APL-130277
    Subject analysis set type
    		 Full analysis
    Subject analysis set description
    APL-130277 Long Term Safety Phase

    Subject analysis set title
    APL-130277
    Subject analysis set type
    		 Full analysis
    Subject analysis set description
    APL-130277 Long Term Safety Phase

    Subject analysis set title
    APL-130277
    Subject analysis set type
    		 Full analysis
    Subject analysis set description
    APL-130277 Long Term Safety Phase

    Subject analysis set title
    APL-103277
    Subject analysis set type
    		 Full analysis
    Subject analysis set description
    APL-103277 Long Term Safety Phase

    Subject analysis set title
    APL-103277
    Subject analysis set type
    		 Full analysis
    Subject analysis set description
    APL-103277 Long Term Safety Phase

    Subject analysis set title
    APL-103277
    Subject analysis set type
    		 Full analysis
    Subject analysis set description
    APL-103277 Long Term Safety Phase

    Subject analysis set title
    APL-103277
    Subject analysis set type
    		 Full analysis
    Subject analysis set description
    APL-103277 Long Term Safety Phase

    Subject analysis set title
    APL-103277
    Subject analysis set type
    		 Full analysis
    Subject analysis set description
    APL-103277 Long Term Safety Phase

    Subject analysis set title
    APL-103277
    Subject analysis set type
    		 Full analysis
    Subject analysis set description
    APL-103277 Long Term Safety Phase

    Subject analysis set title
    APL-103277
    Subject analysis set type
    		 Full analysis
    Subject analysis set description
    APL-103277 Long Term Safety Phase

    Subject analysis set title
    APL-103277
    Subject analysis set type
    		 Full analysis
    Subject analysis set description
    APL-103277 Long Term Safety Phase

    Subject analysis set title
    APL-103277
    Subject analysis set type
    		 Full analysis
    Subject analysis set description
    APL-103277 Long Term Safety Phase

    Subject analysis sets values
    		 APL-130277 APL-130277 APL-130277 APL-130277 APL-130277 APL-130277 APL-130277 APL-103277 APL-103277 APL-103277 APL-103277 APL-103277 APL-103277 APL-103277 APL-103277 APL-103277
    Number of subjects
    426
    167
    80
    70
    224
    112
    90
    223
    222
    221
    48
    111
    110
    112
    54
    90
    Age Categorical
    Units: Participants
        Between 18 and 65 years
        >=65 years
        <=18 years
    Age Continuous
    Units: Years
        arithmetic mean (standard deviation)
    ( )
    ( )
    ( )
    ( )
    ( )
    ( )
    ( )
    ( )
    ( )
    ( )
    ( )
    ( )
    ( )
    ( )
    ( )
    ( )
    Gender, Male/Female
    Units: Participants
        Female
        Male
    ON State Modified Hoehn and Yahr Score
    Units: Subjects
        0.0
        1.0
        1.5
        2.0
        2.5
        3.0
        4.0
        Missing
    Mini-Mental State Examination Total Score
    Units: Subjects
        <26
        26
        27
        28
        29
        30
        Missing
    Age, Customized
    Units: Subjects
        <65 years
        >=65 years and <75 years
        >=75 years
    Ethnicity (NIH/OMB)
    Units: Subjects
        Hispanic or Latino
        Not Hispanic or Latino
        Unknown or Not Reported
    Country
    Units: Subjects
        AUT
        CAN
        DEU
        ESP
        GBR
        ITA
        United States
    Race/Ethnicity, Customized
    Units: Subjects
        American Indian or Alaska Native
        Asian
        Black or African American
        Native Hawaiian or Other Pacific Islander
        Other
        White
    Baseline Height (cm)
    Units: cm
        arithmetic mean (standard deviation)
    ( )
    ( )
    ( )
    ( )
    ( )
    ( )
    ( )
    ( )
    ( )
    ( )
    ( )
    ( )
    ( )
    ( )
    ( )
    ( )
    Baseline Weight (kg)
    Units: kg
        arithmetic mean (standard deviation)
    ( )
    ( )
    ( )
    ( )
    ( )
    ( )
    ( )
    ( )
    ( )
    ( )
    ( )
    ( )
    ( )
    ( )
    ( )
    ( )
    Baseline BMI (kg/m^2)
    Units: kg/m^2
        arithmetic mean (standard deviation)
    ( )
    ( )
    ( )
    ( )
    ( )
    ( )
    ( )
    ( )
    -22.1 ( )
    ( )
    ( )
    ( )
    ( )
    ( )
    ( )
    ( )
    Screening MDS-UPDRS Part I Score
    Units: Score
        arithmetic mean (standard deviation)
    ( )
    ( )
    ( )
    ( )
    ( )
    ( )
    ( )
    ( )
    ( )
    ( )
    ( )
    ( )
    ( )
    ( )
    ( )
    ( )
    Screening MDS-UPDRS Part II Score
    Units: Score
        arithmetic mean (standard deviation)
    ( )
    ( )
    ( )
    ( )
    ( )
    ( )
    ( )
    ( )
    ( )
    ( )
    ( )
    ( )
    ( )
    ( )
    ( )
    ( )
    Baseline MDS-UPDRS Part III Score
    Units: Score
        arithmetic mean (standard deviation)
    ( )
    ( )
    ( )
    ( )
    ( )
    ( )
    ( )
    ( )
    ( )
    ( )
    ( )
    ( )
    ( )
    ( )
    ( )
    ( )
    Screening MDS-UPDRS Part III Score
    Units: Score
        arithmetic mean (standard deviation)
    ( )
    ( )
    ( )
    ( )
    ( )
    ( )
    ( )
    ( )
    -22.1 ( )
    ( )
    ( )
    ( )
    ( )
    ( )
    ( )
    ( )

    End points

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    End points reporting groups
    Reporting group title
    Titration
    Reporting group description
    		 APL-130277 Titration Phase Only

    Reporting group title
    Titration+LTS
    Reporting group description
    		 APL-130277 Titration Phase + Long-Term Safety Phase

    Reporting group title
    LTS (Long-Term Safety)
    Reporting group description
    		 APL-130277 Long-Term Safety Phase Only

    Subject analysis set title
    APL-130277
    Subject analysis set type
    		 Full analysis
    Subject analysis set description
    APL-130277 Long Term Safety Phase

    Subject analysis set title
    APL-130277
    Subject analysis set type
    		 Full analysis
    Subject analysis set description
    APL-130277 Long Term Safety Phase

    Subject analysis set title
    APL-130277
    Subject analysis set type
    		 Full analysis
    Subject analysis set description
    APL-130277 Long Term Safety Phase

    Subject analysis set title
    APL-130277
    Subject analysis set type
    		 Full analysis
    Subject analysis set description
    APL-130277 Long Term Safety Phase

    Subject analysis set title
    APL-130277
    Subject analysis set type
    		 Full analysis
    Subject analysis set description
    APL-130277 Long Term Safety Phase

    Subject analysis set title
    APL-130277
    Subject analysis set type
    		 Full analysis
    Subject analysis set description
    APL-130277 Long Term Safety Phase

    Subject analysis set title
    APL-130277
    Subject analysis set type
    		 Full analysis
    Subject analysis set description
    APL-130277 Long Term Safety Phase

    Subject analysis set title
    APL-103277
    Subject analysis set type
    		 Full analysis
    Subject analysis set description
    APL-103277 Long Term Safety Phase

    Subject analysis set title
    APL-103277
    Subject analysis set type
    		 Full analysis
    Subject analysis set description
    APL-103277 Long Term Safety Phase

    Subject analysis set title
    APL-103277
    Subject analysis set type
    		 Full analysis
    Subject analysis set description
    APL-103277 Long Term Safety Phase

    Subject analysis set title
    APL-103277
    Subject analysis set type
    		 Full analysis
    Subject analysis set description
    APL-103277 Long Term Safety Phase

    Subject analysis set title
    APL-103277
    Subject analysis set type
    		 Full analysis
    Subject analysis set description
    APL-103277 Long Term Safety Phase

    Subject analysis set title
    APL-103277
    Subject analysis set type
    		 Full analysis
    Subject analysis set description
    APL-103277 Long Term Safety Phase

    Subject analysis set title
    APL-103277
    Subject analysis set type
    		 Full analysis
    Subject analysis set description
    APL-103277 Long Term Safety Phase

    Subject analysis set title
    APL-103277
    Subject analysis set type
    		 Full analysis
    Subject analysis set description
    APL-103277 Long Term Safety Phase

    Subject analysis set title
    APL-103277
    Subject analysis set type
    		 Full analysis
    Subject analysis set description
    APL-103277 Long Term Safety Phase

    Primary: Evaluation of safety and tolerability data collected, based on incidence of adverse events in the LTS phase

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    End point title
    		 Evaluation of safety and tolerability data collected, based on incidence of adverse events in the LTS phase [1]
    End point description
    End point type
    Primary
    End point timeframe
    up to approximately 3 years
    Notes
    [1] - No statistical analyses have been specified for this primary end point. It is expected there is at least one statistical analysis for each primary end point.
    Justification: This outcome measure was not powered for statistical analysis.
    End point values
    		 APL-130277
    Number of subjects analysed
    426
    Units: participants
    365
    No statistical analyses for this end point

    Secondary: The percentage of instances where a full "ON" response was achieved within 30 minutes after self-administration of study medication at Week 24, Week 36, and Week 48 visits (LTS V4, V5, and V6) of the LTS Phase based on the home dosing diary entries.

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    End point title
    		 The percentage of instances where a full "ON" response was achieved within 30 minutes after self-administration of study medication at Week 24, Week 36, and Week 48 visits (LTS V4, V5, and V6) of the LTS Phase based on the home dosing diary entries.
    End point description
    End point type
    Secondary
    End point timeframe
    Week 48
    End point values
    		 APL-130277
    Number of subjects analysed
    70
    Units: mean percentage of instances
        arithmetic mean (standard deviation)
    84.1 ( 30.74 )
    No statistical analyses for this end point

    Secondary: The percentage of instances where a full "ON" response was achieved within 30 minutes after self-administration of study medication at Week 24, Week 36, and Week 48 visits (LTS V4, V5, and V6) of the LTS Phase based on the home dosing diary entries.

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    End point title
    		 The percentage of instances where a full "ON" response was achieved within 30 minutes after self-administration of study medication at Week 24, Week 36, and Week 48 visits (LTS V4, V5, and V6) of the LTS Phase based on the home dosing diary entries.
    End point description
    End point type
    Secondary
    End point timeframe
    Week 36
    End point values
    		 APL-130277
    Number of subjects analysed
    80
    Units: mean percentage of instances
        arithmetic mean (standard deviation)
    87.3 ( 28.70 )
    No statistical analyses for this end point

    Secondary: The percentage of instances where a full "ON" response was achieved within 30 minutes after self-administration of study medication at Week 24, Week 36, and Week 48 visits (LTS V4, V5, and V6) of the LTS Phase based on the home dosing diary entries.

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    End point title
    		 The percentage of instances where a full "ON" response was achieved within 30 minutes after self-administration of study medication at Week 24, Week 36, and Week 48 visits (LTS V4, V5, and V6) of the LTS Phase based on the home dosing diary entries.
    End point description
    End point type
    Secondary
    End point timeframe
    Week 24
    End point values
    		 APL-130277
    Number of subjects analysed
    167
    Units: mean percentage of instances
        arithmetic mean (standard deviation)
    80.7 ( 32.55 )
    No statistical analyses for this end point

    Secondary: Percentage of subjects with a subject-rated full "ON" response within 30 minutes at Week 24, Week 36, and Week 48 visits (LTS V4, V5, and V6) of the LTS Phase.

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    End point title
    		 Percentage of subjects with a subject-rated full "ON" response within 30 minutes at Week 24, Week 36, and Week 48 visits (LTS V4, V5, and V6) of the LTS Phase.
    End point description
    End point type
    Secondary
    End point timeframe
    Week 24
    End point values
    		 APL-130277
    Number of subjects analysed
    224
    Units: percent of participants
        number (not applicable)
    77.2
    No statistical analyses for this end point

    Secondary: Mean change from pre-dose in MDS-UPDRS Part III Motor Examination (MDS UPDRS MOTOR) score at 15, 30, 60, and 90 minutes after dosing at Week 24, Week 36, and Week 48 visits (LTS V4, V5, and V6) of the LTS Phase.

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    End point title
    		 Mean change from pre-dose in MDS-UPDRS Part III Motor Examination (MDS UPDRS MOTOR) score at 15, 30, 60, and 90 minutes after dosing at Week 24, Week 36, and Week 48 visits (LTS V4, V5, and V6) of the LTS Phase.
    End point description
    The Movement Disorders Society Unified Parkinson's Disease Rating Scale (MDS-UPDRS) is a clinimetric assessment of subjective and objective symptoms and signs of Parkinson's disease created by the Movement Disorder Society. Each Part III item has a 0-4 rating, where 0 = normal, 1 = slight, 2 = mild, 3 = moderate, and 4 = severe. Higher MDS-UPDRS scores reflect worse motor function. Score drops over time imply improvement in motor function.
    End point type
    Secondary
    End point timeframe
    Week 24, 30 mins after dosing
    End point values
    		 APL-103277
    Number of subjects analysed
    222
    Units: Units on a scale
        arithmetic mean (standard deviation)
    -22.1 ( 13.04 )
    No statistical analyses for this end point

    Secondary: Mean change from pre-dose in MDS-UPDRS Part III Motor Examination (MDS UPDRS MOTOR) score at 15, 30, 60, and 90 minutes after dosing at Week 24, Week 36, and Week 48 visits (LTS V4, V5, and V6) of the LTS Phase.

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    End point title
    		 Mean change from pre-dose in MDS-UPDRS Part III Motor Examination (MDS UPDRS MOTOR) score at 15, 30, 60, and 90 minutes after dosing at Week 24, Week 36, and Week 48 visits (LTS V4, V5, and V6) of the LTS Phase.
    End point description
    The Movement Disorders Society Unified Parkinson's Disease Rating Scale (MDS-UPDRS) is a clinimetric assessment of subjective and objective symptoms and signs of Parkinson's disease created by the Movement Disorder Society. Each Part III item has a 0-4 rating, where 0 = normal, 1 = slight, 2 = mild, 3 = moderate, and 4 = severe. Higher MDS-UPDRS scores reflect worse motor function. Score drops over time imply improvement in motor function.
    End point type
    Secondary
    End point timeframe
    Week 24, 15 mins after dosing
    End point values
    		 APL-103277
    Number of subjects analysed
    223
    Units: Units on a scale
        arithmetic mean (standard deviation)
    -14.2 ( 11.91 )
    No statistical analyses for this end point

    Secondary: Percentage of subjects with a subject-rated full "ON" response within 30 minutes at Week 24, Week 36, and Week 48 visits (LTS V4, V5, and V6) of the LTS Phase.

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    End point title
    		 Percentage of subjects with a subject-rated full "ON" response within 30 minutes at Week 24, Week 36, and Week 48 visits (LTS V4, V5, and V6) of the LTS Phase.
    End point description
    End point type
    Secondary
    End point timeframe
    Week 48
    End point values
    		 APL-130277
    Number of subjects analysed
    90
    Units: percent of participants
        number (not applicable)
    84.4
    No statistical analyses for this end point

    Secondary: Percentage of subjects with a subject-rated full "ON" response within 30 minutes at Week 24, Week 36, and Week 48 visits (LTS V4, V5, and V6) of the LTS Phase.

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    End point title
    		 Percentage of subjects with a subject-rated full "ON" response within 30 minutes at Week 24, Week 36, and Week 48 visits (LTS V4, V5, and V6) of the LTS Phase.
    End point description
    End point type
    Secondary
    End point timeframe
    Week 36
    End point values
    		 APL-130277
    Number of subjects analysed
    112
    Units: percent of participants
        number (not applicable)
    83.9
    No statistical analyses for this end point

    Secondary: Mean change from pre-dose in MDS-UPDRS Part III Motor Examination (MDS UPDRS MOTOR) score at 15, 30, 60, and 90 minutes after dosing at Week 24, Week 36, and Week 48 visits (LTS V4, V5, and V6) of the LTS Phase.

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    End point title
    		 Mean change from pre-dose in MDS-UPDRS Part III Motor Examination (MDS UPDRS MOTOR) score at 15, 30, 60, and 90 minutes after dosing at Week 24, Week 36, and Week 48 visits (LTS V4, V5, and V6) of the LTS Phase.
    End point description
    The Movement Disorders Society Unified Parkinson's Disease Rating Scale (MDS-UPDRS) is a clinimetric assessment of subjective and objective symptoms and signs of Parkinson's disease created by the Movement Disorder Society. Each Part III item has a 0-4 rating, where 0 = normal, 1 = slight, 2 = mild, 3 = moderate, and 4 = severe. Higher MDS-UPDRS scores reflect worse motor function. Score drops over time imply improvement in motor function.
    End point type
    Secondary
    End point timeframe
    Week 24, 60 mins after dosing
    End point values
    		 APL-103277
    Number of subjects analysed
    221
    Units: Units on a scale
        arithmetic mean (standard deviation)
    -21.0 ( 13.34 )
    No statistical analyses for this end point

    Secondary: Mean change from pre-dose in MDS-UPDRS Part III Motor Examination (MDS UPDRS MOTOR) score at 15, 30, 60, and 90 minutes after dosing at Week 24, Week 36, and Week 48 visits (LTS V4, V5, and V6) of the LTS Phase.

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    End point title
    		 Mean change from pre-dose in MDS-UPDRS Part III Motor Examination (MDS UPDRS MOTOR) score at 15, 30, 60, and 90 minutes after dosing at Week 24, Week 36, and Week 48 visits (LTS V4, V5, and V6) of the LTS Phase.
    End point description
    The Movement Disorders Society Unified Parkinson's Disease Rating Scale (MDS-UPDRS) is a clinimetric assessment of subjective and objective symptoms and signs of Parkinson's disease created by the Movement Disorder Society. Each Part III item has a 0-4 rating, where 0 = normal, 1 = slight, 2 = mild, 3 = moderate, and 4 = severe. Higher MDS-UPDRS scores reflect worse motor function. Score drops over time imply improvement in motor function.
    End point type
    Secondary
    End point timeframe
    Week 36, 30 mins after dosing
    End point values
    		 APL-103277
    Number of subjects analysed
    110
    Units: Units on a scale
        arithmetic mean (standard deviation)
    -22.3 ( 12.22 )
    No statistical analyses for this end point

    Secondary: Mean change from pre-dose in MDS-UPDRS Part III Motor Examination (MDS UPDRS MOTOR) score at 15, 30, 60, and 90 minutes after dosing at Week 24, Week 36, and Week 48 visits (LTS V4, V5, and V6) of the LTS Phase.

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    End point title
    		 Mean change from pre-dose in MDS-UPDRS Part III Motor Examination (MDS UPDRS MOTOR) score at 15, 30, 60, and 90 minutes after dosing at Week 24, Week 36, and Week 48 visits (LTS V4, V5, and V6) of the LTS Phase.
    End point description
    The Movement Disorders Society Unified Parkinson's Disease Rating Scale (MDS-UPDRS) is a clinimetric assessment of subjective and objective symptoms and signs of Parkinson's disease created by the Movement Disorder Society. Each Part III item has a 0-4 rating, where 0 = normal, 1 = slight, 2 = mild, 3 = moderate, and 4 = severe. Higher MDS-UPDRS scores reflect worse motor function. Score drops over time imply improvement in motor function.
    End point type
    Secondary
    End point timeframe
    Week 36, 15 mins after dosing
    End point values
    		 APL-103277
    Number of subjects analysed
    111
    Units: Units on a scale
        arithmetic mean (standard deviation)
    -11.7 ( 10.48 )
    No statistical analyses for this end point

    Secondary: Mean change from pre-dose in MDS-UPDRS Part III Motor Examination (MDS UPDRS MOTOR) score at 15, 30, 60, and 90 minutes after dosing at Week 24, Week 36, and Week 48 visits (LTS V4, V5, and V6) of the LTS Phase.

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    End point title
    		 Mean change from pre-dose in MDS-UPDRS Part III Motor Examination (MDS UPDRS MOTOR) score at 15, 30, 60, and 90 minutes after dosing at Week 24, Week 36, and Week 48 visits (LTS V4, V5, and V6) of the LTS Phase.
    End point description
    The Movement Disorders Society Unified Parkinson's Disease Rating Scale (MDS-UPDRS) is a clinimetric assessment of subjective and objective symptoms and signs of Parkinson's disease created by the Movement Disorder Society. Each Part III item has a 0-4 rating, where 0 = normal, 1 = slight, 2 = mild, 3 = moderate, and 4 = severe. Higher MDS-UPDRS scores reflect worse motor function. Score drops over time imply improvement in motor function.
    End point type
    Secondary
    End point timeframe
    Week 24, 90 mins after dosing
    End point values
    		 APL-103277
    Number of subjects analysed
    48
    Units: Units on a scale
        arithmetic mean (standard deviation)
    -16.9 ( 13.58 )
    No statistical analyses for this end point

    Secondary: Mean change from pre-dose in MDS-UPDRS Part III Motor Examination (MDS UPDRS MOTOR) score at 15, 30, 60, and 90 minutes after dosing at Week 24, Week 36, and Week 48 visits (LTS V4, V5, and V6) of the LTS Phase.

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    End point title
    		 Mean change from pre-dose in MDS-UPDRS Part III Motor Examination (MDS UPDRS MOTOR) score at 15, 30, 60, and 90 minutes after dosing at Week 24, Week 36, and Week 48 visits (LTS V4, V5, and V6) of the LTS Phase.
    End point description
    The Movement Disorders Society Unified Parkinson's Disease Rating Scale (MDS-UPDRS) is a clinimetric assessment of subjective and objective symptoms and signs of Parkinson's disease created by the Movement Disorder Society. Each Part III item has a 0-4 rating, where 0 = normal, 1 = slight, 2 = mild, 3 = moderate, and 4 = severe. Higher MDS-UPDRS scores reflect worse motor function. Score drops over time imply improvement in motor function.
    End point type
    Secondary
    End point timeframe
    Week 36, 60 mins after dosing
    End point values
    		 APL-103277
    Number of subjects analysed
    112
    Units: Units on a scale
        arithmetic mean (standard deviation)
    -21.3 ( 13.54 )
    No statistical analyses for this end point

    Secondary: Mean change from pre-dose in MDS-UPDRS Part III Motor Examination (MDS UPDRS MOTOR) score at 15, 30, 60, and 90 minutes after dosing at Week 24, Week 36, and Week 48 visits (LTS V4, V5, and V6) of the LTS Phase.

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    End point title
    		 Mean change from pre-dose in MDS-UPDRS Part III Motor Examination (MDS UPDRS MOTOR) score at 15, 30, 60, and 90 minutes after dosing at Week 24, Week 36, and Week 48 visits (LTS V4, V5, and V6) of the LTS Phase.
    End point description
    The Movement Disorders Society Unified Parkinson's Disease Rating Scale (MDS-UPDRS) is a clinimetric assessment of subjective and objective symptoms and signs of Parkinson's disease created by the Movement Disorder Society. Each Part III item has a 0-4 rating, where 0 = normal, 1 = slight, 2 = mild, 3 = moderate, and 4 = severe. Higher MDS-UPDRS scores reflect worse motor function. Score drops over time imply improvement in motor function.
    End point type
    Secondary
    End point timeframe
    Week 36, 90 mins after dosing
    End point values
    		 APL-103277
    Number of subjects analysed
    54
    Units: Units on a scale
        arithmetic mean (standard deviation)
    -13.3 ( 13.11 )
    No statistical analyses for this end point

    Secondary: Mean change from pre-dose in MDS-UPDRS Part III Motor Examination (MDS UPDRS MOTOR) score at 15, 30, 60, and 90 minutes after dosing at Week 24, Week 36, and Week 48 visits (LTS V4, V5, and V6) of the LTS Phase.

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    End point title
    		 Mean change from pre-dose in MDS-UPDRS Part III Motor Examination (MDS UPDRS MOTOR) score at 15, 30, 60, and 90 minutes after dosing at Week 24, Week 36, and Week 48 visits (LTS V4, V5, and V6) of the LTS Phase.
    End point description
    The Movement Disorders Society Unified Parkinson's Disease Rating Scale (MDS-UPDRS) is a clinimetric assessment of subjective and objective symptoms and signs of Parkinson's disease created by the Movement Disorder Society. Each Part III item has a 0-4 rating, where 0 = normal, 1 = slight, 2 = mild, 3 = moderate, and 4 = severe. Higher MDS-UPDRS scores reflect worse motor function. Score drops over time imply improvement in motor function.
    End point type
    Secondary
    End point timeframe
    Week 48, 60 mins after dosing
    End point values
    		 APL-103277
    Number of subjects analysed
    90
    Units: Units on a scale
        arithmetic mean (standard deviation)
    -22.3 ( 13.35 )
    No statistical analyses for this end point

    Secondary: Mean change from pre-dose in MDS-UPDRS Part III Motor Examination (MDS UPDRS MOTOR) score at 15, 30, 60, and 90 minutes after dosing at Week 24, Week 36, and Week 48 visits (LTS V4, V5, and V6) of the LTS Phase.

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    End point title
    		 Mean change from pre-dose in MDS-UPDRS Part III Motor Examination (MDS UPDRS MOTOR) score at 15, 30, 60, and 90 minutes after dosing at Week 24, Week 36, and Week 48 visits (LTS V4, V5, and V6) of the LTS Phase.
    End point description
    The Movement Disorders Society Unified Parkinson's Disease Rating Scale (MDS-UPDRS) is a clinimetric assessment of subjective and objective symptoms and signs of Parkinson's disease created by the Movement Disorder Society. Each Part III item has a 0-4 rating, where 0 = normal, 1 = slight, 2 = mild, 3 = moderate, and 4 = severe. Higher MDS-UPDRS scores reflect worse motor function. Score drops over time imply improvement in motor function.
    End point type
    Secondary
    End point timeframe
    Week 48, 30 mins after dosing
    End point values
    		 APL-103277
    Number of subjects analysed
    90
    Units: Units on a scale
        arithmetic mean (standard deviation)
    -23.2 ( 12.44 )
    No statistical analyses for this end point

    Secondary: Mean change from pre-dose in MDS-UPDRS Part III Motor Examination (MDS UPDRS MOTOR) score at 15, 30, 60, and 90 minutes after dosing at Week 24, Week 36, and Week 48 visits (LTS V4, V5, and V6) of the LTS Phase.

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    End point title
    		 Mean change from pre-dose in MDS-UPDRS Part III Motor Examination (MDS UPDRS MOTOR) score at 15, 30, 60, and 90 minutes after dosing at Week 24, Week 36, and Week 48 visits (LTS V4, V5, and V6) of the LTS Phase.
    End point description
    The Movement Disorders Society Unified Parkinson's Disease Rating Scale (MDS-UPDRS) is a clinimetric assessment of subjective and objective symptoms and signs of Parkinson's disease created by the Movement Disorder Society. Each Part III item has a 0-4 rating, where 0 = normal, 1 = slight, 2 = mild, 3 = moderate, and 4 = severe. Higher MDS-UPDRS scores reflect worse motor function. Score drops over time imply improvement in motor function.
    End point type
    Secondary
    End point timeframe
    Week 48, 15 mins after dosing
    End point values
    		 APL-103277
    Number of subjects analysed
    90
    Units: Units on a scale
        arithmetic mean (standard deviation)
    -13.3 ( 10.17 )
    No statistical analyses for this end point

    Secondary: Mean change from pre-dose in MDS-UPDRS Part III Motor Examination (MDS UPDRS MOTOR) score at 15, 30, 60, and 90 minutes after dosing at Week 24, Week 36, and Week 48 visits (LTS V4, V5, and V6) of the LTS Phase.

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    End point title
    		 Mean change from pre-dose in MDS-UPDRS Part III Motor Examination (MDS UPDRS MOTOR) score at 15, 30, 60, and 90 minutes after dosing at Week 24, Week 36, and Week 48 visits (LTS V4, V5, and V6) of the LTS Phase.
    End point description
    The Movement Disorders Society Unified Parkinson's Disease Rating Scale (MDS-UPDRS) is a clinimetric assessment of subjective and objective symptoms and signs of Parkinson's disease created by the Movement Disorder Society. Each Part III item has a 0-4 rating, where 0 = normal, 1 = slight, 2 = mild, 3 = moderate, and 4 = severe. Higher MDS-UPDRS scores reflect worse motor function. Score drops over time imply improvement in motor function.
    End point type
    Secondary
    End point timeframe
    Week 48, 90 mins after dosing
    End point values
    		 APL-103277
    Number of subjects analysed
    48
    Units: Units on a scale
        arithmetic mean (standard deviation)
    -16.6 ( 10.93 )
    No statistical analyses for this end point

    Adverse events

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    Adverse events information
    Timeframe for reporting adverse events
    Up to approximately 22 weeks for titration phase Up to approximately 3 years for Long Term Safety Phase
    Assessment type
    		 Systematic
    Dictionary used for adverse event reporting
    Dictionary name
    		 MedDRA
    Dictionary version
    19.1
    Reporting groups
    Reporting group title
    LTS (Long-Term Safety)
    Reporting group description
    		 APL-130277 Long-Term Safety Phase

    Reporting group title
    Titration
    Reporting group description
    		 APL-130277 Titration Phase

    Serious adverse events
    		 LTS (Long-Term Safety) Titration
    Total subjects affected by serious adverse events
         subjects affected / exposed
    58 / 426 (13.62%)
    6 / 449 (1.34%)
         number of deaths (all causes)
    7
    1
         number of deaths resulting from adverse events
    Neoplasms benign, malignant and unspecified (incl cysts and polyps)
    Basal cell carcinoma
         subjects affected / exposed
    2 / 426 (0.47%)
    0 / 449 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Bone cancer
         subjects affected / exposed
    1 / 426 (0.23%)
    0 / 449 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Glioblastoma
         subjects affected / exposed
    0 / 426 (0.00%)
    1 / 449 (0.22%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Non-Hodgkin's lymphoma
         subjects affected / exposed
    1 / 426 (0.23%)
    0 / 449 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Prostate cancer stage II
         subjects affected / exposed
    1 / 426 (0.23%)
    0 / 449 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Squamous cell carcinoma
         subjects affected / exposed
    2 / 426 (0.47%)
    0 / 449 (0.00%)
         occurrences causally related to treatment / all
    0 / 3
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Vascular disorders
    Deep vein thrombosis
         subjects affected / exposed
    0 / 426 (0.00%)
    1 / 449 (0.22%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Hypotension
         subjects affected / exposed
    1 / 426 (0.23%)
    0 / 449 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    General disorders and administration site conditions
    Chest pain
         subjects affected / exposed
    1 / 426 (0.23%)
    0 / 449 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Drowning
         subjects affected / exposed
    1 / 426 (0.23%)
    1 / 449 (0.22%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 1
    0 / 1
    General physical health deterioration
         subjects affected / exposed
    1 / 426 (0.23%)
    0 / 449 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Respiratory, thoracic and mediastinal disorders
    Chronic obstructive pulmonary disease
         subjects affected / exposed
    1 / 426 (0.23%)
    0 / 449 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Asthma
         subjects affected / exposed
    1 / 426 (0.23%)
    0 / 449 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Acute respiratory failure
         subjects affected / exposed
    1 / 426 (0.23%)
    0 / 449 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pleural thickening
         subjects affected / exposed
    1 / 426 (0.23%)
    0 / 449 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Dyspnoea
         subjects affected / exposed
    1 / 426 (0.23%)
    0 / 449 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pulmonary arterial hypertension
         subjects affected / exposed
    1 / 426 (0.23%)
    0 / 449 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pneumothorax
         subjects affected / exposed
    1 / 426 (0.23%)
    0 / 449 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pneumonia aspiration
         subjects affected / exposed
    2 / 426 (0.47%)
    0 / 449 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pulmonary embolism
         subjects affected / exposed
    1 / 426 (0.23%)
    0 / 449 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Psychiatric disorders
    Adjustment disorder with mixed anxiety and depressed mood
         subjects affected / exposed
    1 / 426 (0.23%)
    0 / 449 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Depression
         subjects affected / exposed
    1 / 426 (0.23%)
    0 / 449 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Dopamine dysregulation syndrome
         subjects affected / exposed
    1 / 426 (0.23%)
    0 / 449 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Mental status changes
         subjects affected / exposed
    1 / 426 (0.23%)
    0 / 449 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Psychotic disorder
         subjects affected / exposed
    1 / 426 (0.23%)
    0 / 449 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Substance-induced psychotic disorder
         subjects affected / exposed
    1 / 426 (0.23%)
    0 / 449 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Investigations
    Carbon dioxide increased
         subjects affected / exposed
    1 / 426 (0.23%)
    0 / 449 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Injury, poisoning and procedural complications
    Clavicle fracture
         subjects affected / exposed
    1 / 426 (0.23%)
    0 / 449 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Adjacent segment degeneration
         subjects affected / exposed
    1 / 426 (0.23%)
    0 / 449 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Contusion
         subjects affected / exposed
    1 / 426 (0.23%)
    0 / 449 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Craniocerebral injury
         subjects affected / exposed
    1 / 426 (0.23%)
    0 / 449 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Fall
         subjects affected / exposed
    5 / 426 (1.17%)
    0 / 449 (0.00%)
         occurrences causally related to treatment / all
    0 / 5
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Femoral neck fracture
         subjects affected / exposed
    1 / 426 (0.23%)
    0 / 449 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Fractured sacrum
         subjects affected / exposed
    1 / 426 (0.23%)
    0 / 449 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Lumbar vertebral fracture
         subjects affected / exposed
    1 / 426 (0.23%)
    0 / 449 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pelvic fracture
         subjects affected / exposed
    1 / 426 (0.23%)
    0 / 449 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Rib fracture
         subjects affected / exposed
    2 / 426 (0.47%)
    0 / 449 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Spinal compression fracture
         subjects affected / exposed
    1 / 426 (0.23%)
    0 / 449 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Sternal fracture
         subjects affected / exposed
    0 / 426 (0.00%)
    1 / 449 (0.22%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Tendon injury
         subjects affected / exposed
    1 / 426 (0.23%)
    0 / 449 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Thoracic vertebral fracture
         subjects affected / exposed
    1 / 426 (0.23%)
    0 / 449 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Wrist fracture
         subjects affected / exposed
    1 / 426 (0.23%)
    0 / 449 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Cardiac disorders
    Arrhythmia
         subjects affected / exposed
    1 / 426 (0.23%)
    0 / 449 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Angina unstable
         subjects affected / exposed
    1 / 426 (0.23%)
    0 / 449 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Acute myocardial infarction
         subjects affected / exposed
    3 / 426 (0.70%)
    0 / 449 (0.00%)
         occurrences causally related to treatment / all
    0 / 3
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Cardiac arrest
         subjects affected / exposed
    1 / 426 (0.23%)
    0 / 449 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Cardiac failure congestive
         subjects affected / exposed
    3 / 426 (0.70%)
    0 / 449 (0.00%)
         occurrences causally related to treatment / all
    0 / 3
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Cardio-respiratory arrest
         subjects affected / exposed
    1 / 426 (0.23%)
    0 / 449 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    Coronary artery stenosis
         subjects affected / exposed
    1 / 426 (0.23%)
    0 / 449 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Myocardial infarction
         subjects affected / exposed
    2 / 426 (0.47%)
    0 / 449 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    Sinus node dysfunction
         subjects affected / exposed
    1 / 426 (0.23%)
    0 / 449 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Bradyarrhythmia
         subjects affected / exposed
    1 / 426 (0.23%)
    0 / 449 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Atrioventricular block second degree
         subjects affected / exposed
    1 / 426 (0.23%)
    0 / 449 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Atrioventricular block complete
         subjects affected / exposed
    1 / 426 (0.23%)
    0 / 449 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Atrial fibrillation
         subjects affected / exposed
    1 / 426 (0.23%)
    1 / 449 (0.22%)
         occurrences causally related to treatment / all
    0 / 1
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Nervous system disorders
    Myelopathy
         subjects affected / exposed
    1 / 426 (0.23%)
    0 / 449 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Autonomic nervous system imbalance
         subjects affected / exposed
    1 / 426 (0.23%)
    0 / 449 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Cerebrovascular accident
         subjects affected / exposed
    2 / 426 (0.47%)
    0 / 449 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Coma
         subjects affected / exposed
    1 / 426 (0.23%)
    0 / 449 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Encephalopathy
         subjects affected / exposed
    1 / 426 (0.23%)
    0 / 449 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Facial paresis
         subjects affected / exposed
    1 / 426 (0.23%)
    0 / 449 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Hypoaesthesia
         subjects affected / exposed
    1 / 426 (0.23%)
    0 / 449 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Syncope
         subjects affected / exposed
    2 / 426 (0.47%)
    0 / 449 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Subarachnoid haematoma
         subjects affected / exposed
    1 / 426 (0.23%)
    0 / 449 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Parkinson's disease
         subjects affected / exposed
    2 / 426 (0.47%)
    0 / 449 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Neuropathy peripheral
         subjects affected / exposed
    1 / 426 (0.23%)
    0 / 449 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Blood and lymphatic system disorders
    Iron deficiency anaemia
         subjects affected / exposed
    1 / 426 (0.23%)
    0 / 449 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Eye disorders
    Retinal artery occlusion
         subjects affected / exposed
    1 / 426 (0.23%)
    0 / 449 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Gastrointestinal disorders
    Constipation
         subjects affected / exposed
    1 / 426 (0.23%)
    0 / 449 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Duodenitis
         subjects affected / exposed
    1 / 426 (0.23%)
    0 / 449 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Dysphagia
         subjects affected / exposed
    1 / 426 (0.23%)
    0 / 449 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Lip blister
         subjects affected / exposed
    1 / 426 (0.23%)
    0 / 449 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Parotid gland enlargement
         subjects affected / exposed
    1 / 426 (0.23%)
    0 / 449 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Small intestinal obstruction
         subjects affected / exposed
    2 / 426 (0.47%)
    0 / 449 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Hepatobiliary disorders
    Hepatitis toxic
         subjects affected / exposed
    1 / 426 (0.23%)
    0 / 449 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Skin and subcutaneous tissue disorders
    Nail fold inflammation
         subjects affected / exposed
    1 / 426 (0.23%)
    0 / 449 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Renal and urinary disorders
    Obstructive uropathy
         subjects affected / exposed
    1 / 426 (0.23%)
    0 / 449 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Nephrolithiasis
         subjects affected / exposed
    1 / 426 (0.23%)
    0 / 449 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Cystitis haemorrhagic
         subjects affected / exposed
    1 / 426 (0.23%)
    0 / 449 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Calculus bladder
         subjects affected / exposed
    1 / 426 (0.23%)
    0 / 449 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Bladder neck obstruction
         subjects affected / exposed
    0 / 426 (0.00%)
    1 / 449 (0.22%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Acute kidney injury
         subjects affected / exposed
    1 / 426 (0.23%)
    0 / 449 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Musculoskeletal and connective tissue disorders
    Arthralgia
         subjects affected / exposed
    1 / 426 (0.23%)
    0 / 449 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Arthropathy
         subjects affected / exposed
    1 / 426 (0.23%)
    0 / 449 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Back pain
         subjects affected / exposed
    3 / 426 (0.70%)
    0 / 449 (0.00%)
         occurrences causally related to treatment / all
    0 / 3
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Osteoarthritis
         subjects affected / exposed
    2 / 426 (0.47%)
    0 / 449 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Lumbar spinal stenosis
         subjects affected / exposed
    1 / 426 (0.23%)
    0 / 449 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Bursitis
         subjects affected / exposed
    1 / 426 (0.23%)
    0 / 449 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Rhabdomyolysis
         subjects affected / exposed
    1 / 426 (0.23%)
    0 / 449 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Musculoskeletal pain
         subjects affected / exposed
    1 / 426 (0.23%)
    0 / 449 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Infections and infestations
    Abscess limb
         subjects affected / exposed
    1 / 426 (0.23%)
    0 / 449 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Cellulitis
         subjects affected / exposed
    2 / 426 (0.47%)
    0 / 449 (0.00%)
         occurrences causally related to treatment / all
    0 / 3
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Corona virus infection
         subjects affected / exposed
    2 / 426 (0.47%)
    0 / 449 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Kidney infection
         subjects affected / exposed
    1 / 426 (0.23%)
    0 / 449 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Oral candidiasis
         subjects affected / exposed
    1 / 426 (0.23%)
    0 / 449 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Osteomyelitis
         subjects affected / exposed
    1 / 426 (0.23%)
    0 / 449 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pneumonia
         subjects affected / exposed
    5 / 426 (1.17%)
    0 / 449 (0.00%)
         occurrences causally related to treatment / all
    0 / 5
    0 / 0
         deaths causally related to treatment / all
    0 / 2
    0 / 0
    Psoas abscess
         subjects affected / exposed
    1 / 426 (0.23%)
    0 / 449 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Sepsis
         subjects affected / exposed
    2 / 426 (0.47%)
    0 / 449 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    Septic shock
         subjects affected / exposed
    1 / 426 (0.23%)
    0 / 449 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Streptococcal sepsis
         subjects affected / exposed
    1 / 426 (0.23%)
    0 / 449 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Urinary tract infection
         subjects affected / exposed
    4 / 426 (0.94%)
    0 / 449 (0.00%)
         occurrences causally related to treatment / all
    0 / 6
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Urosepsis
         subjects affected / exposed
    1 / 426 (0.23%)
    0 / 449 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Wound infection
         subjects affected / exposed
    1 / 426 (0.23%)
    0 / 449 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Metabolism and nutrition disorders
    Dehydration
         subjects affected / exposed
    1 / 426 (0.23%)
    0 / 449 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Frequency threshold for reporting non-serious adverse events: 5%
    Non-serious adverse events
    		 LTS (Long-Term Safety) Titration
    Total subjects affected by non serious adverse events
         subjects affected / exposed
    233 / 426 (54.69%)
    153 / 449 (34.08%)
    Injury, poisoning and procedural complications
    Fall
         subjects affected / exposed
    40 / 426 (9.39%)
    4 / 449 (0.89%)
         occurrences all number
    59
    4
    Nervous system disorders
    Dizziness
         subjects affected / exposed
    27 / 426 (6.34%)
    27 / 449 (6.01%)
         occurrences all number
    35
    35
    Dyskinesia
         subjects affected / exposed
    24 / 426 (5.63%)
    12 / 449 (2.67%)
         occurrences all number
    33
    14
    Headache
         subjects affected / exposed
    14 / 426 (3.29%)
    23 / 449 (5.12%)
         occurrences all number
    15
    28
    Somnolence
         subjects affected / exposed
    32 / 426 (7.51%)
    30 / 449 (6.68%)
         occurrences all number
    34
    47
    General disorders and administration site conditions
    Fatigue
         subjects affected / exposed
    22 / 426 (5.16%)
    18 / 449 (4.01%)
         occurrences all number
    23
    25
    Gastrointestinal disorders
    Lip swelling
         subjects affected / exposed
    27 / 426 (6.34%)
    0 / 449 (0.00%)
         occurrences all number
    36
    0
    Mouth ulceration
         subjects affected / exposed
    25 / 426 (5.87%)
    3 / 449 (0.67%)
         occurrences all number
    34
    3
    Nausea
         subjects affected / exposed
    91 / 426 (21.36%)
    67 / 449 (14.92%)
         occurrences all number
    122
    75
    Oral mucosal erythema
         subjects affected / exposed
    30 / 426 (7.04%)
    17 / 449 (3.79%)
         occurrences all number
    40
    20
    Stomatitis
         subjects affected / exposed
    23 / 426 (5.40%)
    2 / 449 (0.45%)
         occurrences all number
    37
    2
    Respiratory, thoracic and mediastinal disorders
    Yawning
         subjects affected / exposed
    23 / 426 (5.40%)
    43 / 449 (9.58%)
         occurrences all number
    30
    69

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    Substantial protocol amendments (globally)
    Were there any global substantial amendments to the protocol? Yes
    Date
    Amendment
    30 May 2017
    Amendment 3
    25 Feb 2019
    Amendment 4

    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
    For support, Contact us.
    The status and protocol content of GB trials is no longer updated since 1 January 2021. For the UK, as of 31 January 2021, EU Law applies only to the territory of Northern Ireland (NI) to the extent foreseen in the Protocol on Ireland/NI. Legal notice
    As of 31 January 2023, all EU/EEA initial clinical trial applications must be submitted through CTIS . Updated EudraCT trials information and information on PIP/Art 46 trials conducted exclusively in third countries continues to be submitted through EudraCT and published on this website.

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