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    Clinical Trial Results:
    A Multicenter, Multinational, Double-Blind, Placebo-Controlled, 3-Arm, Phase 4 Study To Evaluate The Efficacy Of Rotigotine On Parkinson's Disease-Associated Apathy, Motor Symptoms, And Mood

    Summary
    EudraCT number
    		 2012-002840-26
    Trial protocol
    		 AT   ES   HU   IT   BG   SI   RO   SK  
    Global end of trial date
    04 Mar 2014

    Results information
    Results version number
    		 v1(current)
    This version publication date
    30 Jun 2016
    First version publication date
    25 Jun 2015
    Other versions

    Trial information

    		 Close Top of page
    Trial identification
    Sponsor protocol code
    PD0005
    Additional study identifiers
    ISRCTN number
    		 -
    US NCT number
    		 NCT01782222
    WHO universal trial number (UTN)
    		 -
    Sponsors
    Sponsor organisation name
    UCB BIOSCIENCES GmbH
    Sponsor organisation address
    Alfred-Nobel-Str.10, Monheim, Germany, 40789
    Public contact
    Clinical Trial Registries and Results Disclosure, UCB BIOSCIENCES GmbH, 0049 2173 48 15 15, clinicaltrials@ucb.com
    Scientific contact
    Clinical Trial Registries and Results Disclosure, UCB BIOSCIENCES GmbH, 0049 2173 48 15 15, clinicaltrials@ucb.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 Sep 2014
    Is this the analysis of the primary completion data?
    No
    Global end of trial reached?
    Yes
    Global end of trial date
    04 Mar 2014
    Was the trial ended prematurely?
    No
    General information about the trial
    Main objective of the trial
    The primary objective of this study is to assess the effects of rotigotine over placebo on improvement of apathy and motor symptoms in subjects with early-stage and advanced-stage idiopathic Parkinson’s disease.
    Protection of trial subjects
    Close monitoring of subjects safety status, including checks of mental health e.g. by CSSR-S questionnaire.
    Background therapy
    		 Not applicable
    Evidence for comparator
    		 Not applicable
    Actual start date of recruitment
    05 Feb 2013
    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: 3
    Country: Number of subjects enrolled
    Hungary: 2
    Country: Number of subjects enrolled
    Poland: 21
    Country: Number of subjects enrolled
    Slovakia: 30
    Country: Number of subjects enrolled
    United States: 66
    Worldwide total number of subjects
    122
    EEA total number of subjects
    56
    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)
    43
    From 65 to 84 years
    72
    85 years and over
    7

    Subject disposition

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    Recruitment
    Recruitment details
    		 This study was planned to be conducted globally with 480 subjects (160 subjects per treatment group for the Full Analysis Set). Approx. 600 subjects were planned for enrollment in order to obtain 504 subjects for randomization. Subjects were randomized in a 1:1:1 ratio to either Rotigotine low dose, Rotigotine high dose or Placebo.

    Pre-assignment
    Screening details
    		 The Participant Flow refers to the Randomized Set (RS). The RS included all subjects who were randomized. The outcome of the Interim Analysis was to stop the study, i.e. no more subjects were enrolled into the study and all included subjects completed the study as planned.

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

    Arms
    Are arms mutually exclusive
    Yes

    Arm title
    		 Placebo
    Arm description
    		 Placebo, matching transdermal patches Duration: up to 21 weeks (including de-escalation)
    Arm type
    		 Placebo

    Investigational medicinal product name
    Placebo
    Investigational medicinal product code
    Placebo
    Other name
    Placebo
    Pharmaceutical forms
    Transdermal patch
    Routes of administration
    Transdermal use
    Dosage and administration details
    Matching Placebo to Rotigotine.

    Arm title
    		 Rotigotine, low dose
    Arm description
    		 Rotigotine, transdermal patches, optimal dose, maximal 8 mg / 24 hours for patients with advanced Parkinson’s Disease and 6 mg / 24 hours for those with early Parkinson’s DiseaseRotigotine: Rotigotine, transdermal patches:10 cm^2 (2 mg / 24 hours); 20 cm^2 (4 mg / 24 hours); 30 cm^2 (6 mg / 24 hours);40 cm^2 (8 mg / 24 hours) Optimal dosage:The maximum Rotigotine dose allowed was 8 mg / 24 hours or 16 mg / 24 hours for patients with advanced Parkinson's Disease and 6 mg / 24 hours or 8 mg / 24 hours for those with early Parkinson's Disease Duration: up to 21 weeks (including de-escalation)
    Arm type
    		 Experimental

    Investigational medicinal product name
    Rotigotine
    Investigational medicinal product code
    Neupro
    Other name
    Neupro
    Pharmaceutical forms
    Transdermal patch
    Routes of administration
    Transdermal use
    Dosage and administration details
    Rotigotine, transdermal patches: 10 cm^2 (2 mg / 24 hours); 20 cm^2 (4 mg / 24 hours); 30 cm^2 (6 mg / 24 hours); 40 cm^2 (8 mg / 24 hours) The maximum Rotigotine dose allowed is 8 mg / 24 hours or 16 mg / 24 hours for patients with advanced Parkinson's Disease and 6 mg / 24 hours or 8 mg / 24 hours for those with early Parkinson's Disease Duration: up to 21 weeks (including de-escalation) Other Name: (6S)-6-propyl-[2 (2 thienyl)ethyl]amino-5,6,7,8-tetrahydro-1-naphthalenol

    Arm title
    		 Rotigotine, high dose
    Arm description
    		 Rotigotine, transdermal patches, maximal 16 mg / 24 hours for patients with advanced Parkinson's Disease and 8 mg / 24 hours for those with early Parkinson's DiseaseRotigotine: Rotigotine, transdermal patches:10 cm^2 (2 mg / 24 hours); 20 cm^2 (4 mg / 24 hours); 30 cm^2 (6 mg / 24 hours);40 cm^2 (8 mg / 24 hours) Optimal dosage:The maximum Rotigotine dose allowed was 8 mg / 24 hours or 16 mg / 24 hours for patients with advanced Parkinson's Disease and 6 mg / 24 hours or 8 mg / 24 hours for those with early Parkinson's Disease Duration: up to 21 weeks (including de-escalation)
    Arm type
    		 Experimental

    Investigational medicinal product name
    Rotigotine
    Investigational medicinal product code
    Neupro
    Other name
    Neupro
    Pharmaceutical forms
    Transdermal patch
    Routes of administration
    Transdermal use
    Dosage and administration details
    Rotigotine, transdermal patches: 10 cm^2 (2 mg / 24 hours); 20 cm^2 (4 mg / 24 hours); 30 cm^2 (6 mg / 24 hours); 40 cm^2 (8 mg / 24 hours) The maximum Rotigotine dose allowed is 8 mg / 24 hours or 16 mg / 24 hours for patients with advanced Parkinson's Disease and 6 mg / 24 hours or 8 mg / 24 hours for those with early Parkinson's Disease Duration: up to 21 weeks (including de-escalation) Other Name: (6S)-6-propyl-[2 (2 thienyl)ethyl]amino-5,6,7,8-tetrahydro-1-naphthalenol

    Number of subjects in period 1
    		Placebo Rotigotine, low dose Rotigotine, high dose
    Started
    40
    41
    41
    Completed
    32
    30
    37
    Not completed
    8
    11
    4
         Consent withdrawn by subject
    1
    4
    1
         'Moved to other state '
    -
    1
    -
         AE, non-serious non-fatal
    3
    5
    3
         SAE, non-fatal
    1
    -
    -
         Lack of efficacy
    2
    1
    -
         Protocol deviation
    1
    -
    -

    Baseline characteristics

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    Baseline characteristics reporting groups
    Reporting group title
    Placebo
    Reporting group description
    		 Placebo, matching transdermal patches Duration: up to 21 weeks (including de-escalation)

    Reporting group title
    Rotigotine, low dose
    Reporting group description
    		 Rotigotine, transdermal patches, optimal dose, maximal 8 mg / 24 hours for patients with advanced Parkinson’s Disease and 6 mg / 24 hours for those with early Parkinson’s DiseaseRotigotine: Rotigotine, transdermal patches:10 cm^2 (2 mg / 24 hours); 20 cm^2 (4 mg / 24 hours); 30 cm^2 (6 mg / 24 hours);40 cm^2 (8 mg / 24 hours) Optimal dosage:The maximum Rotigotine dose allowed was 8 mg / 24 hours or 16 mg / 24 hours for patients with advanced Parkinson's Disease and 6 mg / 24 hours or 8 mg / 24 hours for those with early Parkinson's Disease Duration: up to 21 weeks (including de-escalation)

    Reporting group title
    Rotigotine, high dose
    Reporting group description
    		 Rotigotine, transdermal patches, maximal 16 mg / 24 hours for patients with advanced Parkinson's Disease and 8 mg / 24 hours for those with early Parkinson's DiseaseRotigotine: Rotigotine, transdermal patches:10 cm^2 (2 mg / 24 hours); 20 cm^2 (4 mg / 24 hours); 30 cm^2 (6 mg / 24 hours);40 cm^2 (8 mg / 24 hours) Optimal dosage:The maximum Rotigotine dose allowed was 8 mg / 24 hours or 16 mg / 24 hours for patients with advanced Parkinson's Disease and 6 mg / 24 hours or 8 mg / 24 hours for those with early Parkinson's Disease Duration: up to 21 weeks (including de-escalation)

    Reporting group values
    		 Placebo Rotigotine, low dose Rotigotine, high dose Total
    Number of subjects
    		 40 41 41 122
    Age categorical
    Units: Subjects
        >18 - < 65 years
    		 14 17 12 43
        ≥ 65 years
    		 26 24 29 79
    Age Continuous
    Units: years
        arithmetic mean (standard deviation)
    		 69 ± 11.7 68.1 ± 10.5 70.2 ± 8 -
    Gender Categorical
    Units: Subjects
        Female
    		 18 14 14 46
        Male
    		 22 27 27 76
    Race/Ethnicity, Customized
    Units: Subjects
        Black
    		 1 2 1 4
        White
    		 38 39 40 117
        Other/mixed
    		 1 0 0 1
    Weight
    Units: kilograms
        arithmetic mean (standard deviation)
    		 79.59 ± 14.73 77.34 ± 17.93 78.96 ± 15.96 -
    Height
    Units: centimeters
        arithmetic mean (standard deviation)
    		 167.16 ± 10.34 169.25 ± 10.76 170.88 ± 10.94 -
    Body Mass Index (BMI)
    Units: kilogram per square meter
        arithmetic mean (standard deviation)
    		 28.525 ± 4.792 26.859 ± 4.887 26.9 ± 3.859 -

    End points

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    End points reporting groups
    Reporting group title
    Placebo
    Reporting group description
    		 Placebo, matching transdermal patches Duration: up to 21 weeks (including de-escalation)

    Reporting group title
    Rotigotine, low dose
    Reporting group description
    		 Rotigotine, transdermal patches, optimal dose, maximal 8 mg / 24 hours for patients with advanced Parkinson’s Disease and 6 mg / 24 hours for those with early Parkinson’s DiseaseRotigotine: Rotigotine, transdermal patches:10 cm^2 (2 mg / 24 hours); 20 cm^2 (4 mg / 24 hours); 30 cm^2 (6 mg / 24 hours);40 cm^2 (8 mg / 24 hours) Optimal dosage:The maximum Rotigotine dose allowed was 8 mg / 24 hours or 16 mg / 24 hours for patients with advanced Parkinson's Disease and 6 mg / 24 hours or 8 mg / 24 hours for those with early Parkinson's Disease Duration: up to 21 weeks (including de-escalation)

    Reporting group title
    Rotigotine, high dose
    Reporting group description
    		 Rotigotine, transdermal patches, maximal 16 mg / 24 hours for patients with advanced Parkinson's Disease and 8 mg / 24 hours for those with early Parkinson's DiseaseRotigotine: Rotigotine, transdermal patches:10 cm^2 (2 mg / 24 hours); 20 cm^2 (4 mg / 24 hours); 30 cm^2 (6 mg / 24 hours);40 cm^2 (8 mg / 24 hours) Optimal dosage:The maximum Rotigotine dose allowed was 8 mg / 24 hours or 16 mg / 24 hours for patients with advanced Parkinson's Disease and 6 mg / 24 hours or 8 mg / 24 hours for those with early Parkinson's Disease Duration: up to 21 weeks (including de-escalation)

    Primary: Change from Baseline to the End of the Maintenance Period in the score of the Apathy Evaluation Scale (AS) rated by the patient

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    End point title
    		 Change from Baseline to the End of the Maintenance Period in the score of the Apathy Evaluation Scale (AS) rated by the patient
    End point description
    The Apathy Scale (AS) is an abbreviated version of the Apathy Evaluation Scale. The AS (Starkstein et al, 1992) consists of 14 items phrased as questions by the examiner that are to be answered on a 4-point Likert scale. It was developed specifically for subjects with Parkinson’s disease because the Apathy Evaluation Scale was considered too demanding. The questions comprising the AS were answered by the subject. The total scores for Apathy Evaluation Scale ranges from 0 (best possible outcome) to 42 (worst possible outcome).
    End point type
    Primary
    End point timeframe
    Baseline (Visit 2) until End of the Maintenance Period / Early Withdrawal (up to 19 weeks after Baseline)
    End point values
    		 Placebo Rotigotine, low dose Rotigotine, high dose
    Number of subjects analysed
    40
    36
    40
    Units: scores on a scale
    arithmetic mean (standard deviation)
        mean (standard deviation)
    -4.4 ± 4.9
    -4.6 ± 6.7
    -4.9 ± 5.9
    Statistical analysis title
    		 Statistical Analysis 1
    Statistical analysis description
    ANCOVA model for the change from Baseline to End of Maintenance containing treatment and disease stage as factors, and Baseline value as covariate.
    Comparison groups
    Rotigotine, low dose v Placebo
    Number of subjects included in analysis
    76
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.977
    Method
    		 ANCOVA
    Parameter type
    		 Least Square Mean
    Point estimate
    0.04
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -2.42
         upper limit
    		 2.5
    Variability estimate
    Standard error of the mean
    Dispersion value
    1.24
    Statistical analysis title
    		 Statistical Analysis 2
    Statistical analysis description
    ANCOVA model for the change from Baseline to End of Maintenance containing treatment and disease stage as factors, and Baseline value as covariate.
    Comparison groups
    Placebo v Rotigotine, high dose
    Number of subjects included in analysis
    80
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.859
    Method
    		 ANCOVA
    Parameter type
    		 Least Square Mean
    Point estimate
    -0.22
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -2.61
         upper limit
    		 2.18
    Variability estimate
    Standard error of the mean
    Dispersion value
    1.21

    Primary: Change from Baseline to the End of the Maintenance Period in the total score of the Unified Parkinson's Disease Rating Scale (UPDRS) Parts II (activities of daily living) + III (motor symptoms)

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    End point title
    		 Change from Baseline to the End of the Maintenance Period in the total score of the Unified Parkinson's Disease Rating Scale (UPDRS) Parts II (activities of daily living) + III (motor symptoms)
    End point description
    Part II of the Unified Parkinson's Disease Rating Scale (UPDRS) assesses the subject’s activities of daily living. Part III assesses motor function. The UPDRS is completed by questioning the subject about his/her general state in conjunction with any observations made by the investigator (or designee) since the previous visit. Part II is subject-rated and Part III is physician-rated. The UPDRS Part II (Activities of Daily Living) consists of 13 items scored between 0 and 4. The sum score was calculated as the sum of these 13 individual scores. The UPDRS Part III (motor subscale) consists of 27 items and sub items scored between 0 and 4. The sum score was calculated as sum of these 27 individual scores. The sum score of UPDRS Parts II and III is the sum of the corresponding single sum scores. A negative value indicates an improvement.
    End point type
    Primary
    End point timeframe
    Baseline (Visit 2) until End of the Maintenance Period / Early Withdrawal (up to 19 weeks after Baseline)
    End point values
    		 Placebo Rotigotine, low dose Rotigotine, high dose
    Number of subjects analysed
    40
    36
    40
    Units: scores on a scale
    arithmetic mean (standard deviation)
        mean (standard deviation)
    -4.8 ± 10.4
    -12.4 ± 14
    -10.7 ± 8.4
    Statistical analysis title
    		 Statistical Analysis 1
    Statistical analysis description
    ANCOVA model for the change from Baseline to End of Maintenance containing treatment and disease stage as factors, and Baseline value as covariate.
    Comparison groups
    Placebo v Rotigotine, low dose
    Number of subjects included in analysis
    76
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.005
    Method
    		 ANCOVA
    Parameter type
    		 Least Square Mean
    Point estimate
    -7.29
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -12.3
         upper limit
    		 -2.28
    Variability estimate
    Standard error of the mean
    Dispersion value
    2.53
    Statistical analysis title
    		 Statistical Analysis 2
    Statistical analysis description
    ANCOVA model for the change from Baseline to End of Maintenance containing treatment and disease stage as factors, and Baseline value as covariate.
    Comparison groups
    Placebo v Rotigotine, high dose
    Number of subjects included in analysis
    80
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.015
    Method
    		 ANCOVA
    Parameter type
    		 Least Square Mean
    Point estimate
    -6.06
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -10.9
         upper limit
    		 -1.21
    Variability estimate
    Standard error of the mean
    Dispersion value
    2.45

    Secondary: Change from Baseline to the End of the Maintenance Period in the score of the Apathy Evaluation Scale (AS) rated by the caregiver (where available)

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    End point title
    		 Change from Baseline to the End of the Maintenance Period in the score of the Apathy Evaluation Scale (AS) rated by the caregiver (where available)
    End point description
    The Apathy Scale (AS) is an abbreviated version of the Apathy Evaluation Scale. The AS (Starkstein et al, 1992) consists of 14 items phrased as questions by the examiner that are to be answered on a 4-point Likert scale. It was developed specifically for subjects with Parkinson’s disease because the Apathy Evaluation Scale was considered too demanding. The questions comprising the AS were answered by the caregiver. The questions were asked in a structured interview format. The caregiver was interviewed by appropriate medical staff and asked questions about the subject in the third person.The total scores for Apathy Evaluation Scale ranges from 0 (best possible outcome) to 42 (worst possible outcome).
    End point type
    Secondary
    End point timeframe
    Baseline (Visit 2) until End of the Maintenance Period / Early Withdrawal (up to 19 weeks after Baseline)
    End point values
    		 Placebo Rotigotine, low dose Rotigotine, high dose
    Number of subjects analysed
    16
    16
    13
    Units: scores on a scale
    arithmetic mean (standard deviation)
        mean (standard deviation)
    -1.5 ± 7
    -4.8 ± 8
    -5.5 ± 6.1
    Statistical analysis title
    		 Statistical Analysis 1
    Statistical analysis description
    ANCOVA model for the change from Baseline to End of Maintenance containing treatment and disease stage as factors, and Baseline value as covariate.
    Comparison groups
    Placebo v Rotigotine, low dose
    Number of subjects included in analysis
    32
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.2
    Method
    		 ANCOVA
    Parameter type
    		 Least Square Mean
    Point estimate
    -3.2
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -8.17
         upper limit
    		 1.76
    Variability estimate
    Standard error of the mean
    Dispersion value
    2.46
    Statistical analysis title
    		 Statistical Analysis 2
    Statistical analysis description
    ANCOVA model for the change from Baseline to End of Maintenance containing treatment and disease stage as factors, and Baseline value as covariate.
    Comparison groups
    Placebo v Rotigotine, high dose
    Number of subjects included in analysis
    29
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.239
    Method
    		 ANCOVA
    Parameter type
    		 Least Square Mean
    Point estimate
    -3.04
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -8.19
         upper limit
    		 2.1
    Variability estimate
    Standard error of the mean
    Dispersion value
    2.55

    Secondary: Change from Baseline to the End of the Maintenance Period in the sum score of the 8-item Parkinson's Disease Questionnaire (PDQ-8)

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    End point title
    		 Change from Baseline to the End of the Maintenance Period in the sum score of the 8-item Parkinson's Disease Questionnaire (PDQ-8)
    End point description
    The 8-Item Parkinson's Disease Questionnaire (PDQ-8) (Peto et al, 1998) is a self-administered questionnaire that provides a reliable measure of overall health status. The PDQ-8 collects 8 items with 5 categories each (0=never, 1=occasionally, 2=sometimes, 3=often, 4=always or cannot do at all). The total score was calculated by summing the scores of all applicable questions and convert the resulting sum to a summary index score between 0 and 100 by multiplying with 100/32. A negative value indicates an improvement.
    End point type
    Secondary
    End point timeframe
    Baseline (Visit 2) until End of the Maintenance Period / Early Withdrawal (up to 19 weeks after Baseline)
    End point values
    		 Placebo Rotigotine, low dose Rotigotine, high dose
    Number of subjects analysed
    40
    36
    40
    Units: scores on a scale
    arithmetic mean (standard deviation)
        mean (standard deviation)
    -3.8 ± 14
    -5.1 ± 20.4
    -10 ± 15
    Statistical analysis title
    		 Statistical Analysis 1
    Statistical analysis description
    ANCOVA model for the change from Baseline to End of Maintenance containing treatment and disease stage as factors, and Baseline value as covariate.
    Comparison groups
    Placebo v Rotigotine, low dose
    Number of subjects included in analysis
    76
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.519
    Method
    		 ANCOVA
    Parameter type
    		 Least Square Mean
    Point estimate
    -2.09
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -8.48
         upper limit
    		 4.31
    Variability estimate
    Standard error of the mean
    Dispersion value
    3.23
    Statistical analysis title
    		 Statistical Analysis 2
    Statistical analysis description
    ANCOVA model for the change from Baseline to End of Maintenance containing treatment and disease stage as factors, and Baseline value as covariate.
    Comparison groups
    Placebo v Rotigotine, high dose
    Number of subjects included in analysis
    80
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.111
    Method
    		 ANCOVA
    Parameter type
    		 Least Square Mean
    Point estimate
    -5.06
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -11.29
         upper limit
    		 1.17
    Variability estimate
    Standard error of the mean
    Dispersion value
    3.15

    Secondary: Change from Baseline to the End of the Maintenance Period in the sum score of the mood / cognition domain of the Nonmotor Symptom Assessment Scale (NMSS)

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    End point title
    		 Change from Baseline to the End of the Maintenance Period in the sum score of the mood / cognition domain of the Nonmotor Symptom Assessment Scale (NMSS)
    End point description
    Nonmotor performance was assessed via the Nonmotor Symptom Assessment Scale (NMSS), an accepted scale that has been validated in an international study (Naidu et al, 2006; Chaudhuri et al, 2007), at the Baseline Visit as well as at the end of the Maintenance Period. The severity and frequency of the subject’s nonmotor symptoms were assessed by the investigator (or designee) in the following 9 domain categories: cardiovascular, including falls; sleep/fatigue; mood/cognition; perceptual problems/hallucinations; attention/memory; gastrointestinal tract; urinary; sexual function; and miscellaneous. Items are scored for severity (from 0 (none) to 3 (severe)) and frequency (from 1 (rarely) to 4 (very frequent )). The score was calculated as severity x frequency. The theoretical minimum is 0 (best possible outcome) and maximum total score is 360 points (worst possible outcome).
    End point type
    Secondary
    End point timeframe
    Baseline (Visit 2) until End of the Maintenance Period / Early Withdrawal (up to 19 weeks after Baseline)
    End point values
    		 Placebo Rotigotine, low dose Rotigotine, high dose
    Number of subjects analysed
    39
    32
    39
    Units: scores on a scale
    arithmetic mean (standard deviation)
        mean (standard deviation)
    -4.6 ± 7.9
    -9.8 ± 12.1
    -9.8 ± 10.7
    Statistical analysis title
    		 Statistical Analysis 1
    Statistical analysis description
    ANCOVA model for the change from Baseline to End of Treatment containing treatment and disease stage as factors, and Baseline value as covariate.
    Comparison groups
    Placebo v Rotigotine, low dose
    Number of subjects included in analysis
    71
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.06
    Method
    		 ANCOVA
    Parameter type
    		 Least Square Mean
    Point estimate
    -3.62
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -7.39
         upper limit
    		 0.15
    Variability estimate
    Standard error of the mean
    Dispersion value
    1.9
    Statistical analysis title
    		 Statistical Analysis 2
    Statistical analysis description
    ANCOVA model for the change from Baseline to End of Treatment containing treatment and disease stage as factors, and Baseline value as covariate.
    Comparison groups
    Placebo v Rotigotine, high dose
    Number of subjects included in analysis
    78
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.034
    Method
    		 ANCOVA
    Parameter type
    		 Least Square Mean
    Point estimate
    -3.88
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -7.46
         upper limit
    		 -0.3
    Variability estimate
    Standard error of the mean
    Dispersion value
    1.8

    Secondary: Change from Baseline to the End of the Maintenance Period in the sum score of the Snaith Hamilton Pleasure Scale (SHAPS)

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    End point title
    		 Change from Baseline to the End of the Maintenance Period in the sum score of the Snaith Hamilton Pleasure Scale (SHAPS)
    End point description
    The Snaith Hamilton Pleasure Scale (SHAPS) (Snaith et al, 1995) is a self-report instrument developed for the assessment of hedonic capacity. The sum of the 14 items scores range from 0 to 14. A higher score represents more anhedonic symptoms.
    End point type
    Secondary
    End point timeframe
    Baseline (Visit 2) until End of the Maintenance Period / Early Withdrawal (up to 19 weeks after Baseline)
    End point values
    		 Placebo Rotigotine, low dose Rotigotine, high dose
    Number of subjects analysed
    40
    36
    40
    Units: scores on a scale
    arithmetic mean (standard deviation)
        mean (standard deviation)
    -0.5 ± 2.5
    -1.3 ± 2.2
    -0.9 ± 2.8
    Statistical analysis title
    		 Statistical Analysis 1
    Statistical analysis description
    ANCOVA model for the change from Baseline to End of Maintenance containing treatment and disease stage as factors, and Baseline value as covariate.
    Comparison groups
    Placebo v Rotigotine, low dose
    Number of subjects included in analysis
    76
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.334
    Method
    		 ANCOVA
    Parameter type
    		 Least Square Mean
    Point estimate
    -0.38
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -1.16
         upper limit
    		 0.4
    Variability estimate
    Standard error of the mean
    Dispersion value
    0.39
    Statistical analysis title
    		 Statistical Analysis 2
    Statistical analysis description
    ANCOVA model for the change from Baseline to End of Maintenance containing treatment and disease stage as factors, and Baseline value as covariate.
    Comparison groups
    Placebo v Rotigotine, high dose
    Number of subjects included in analysis
    80
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.968
    Method
    		 ANCOVA
    Parameter type
    		 Least Square Mean
    Point estimate
    0.02
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -0.74
         upper limit
    		 0.77
    Variability estimate
    Standard error of the mean
    Dispersion value
    0.38

    Secondary: Change from Baseline to the End of the Maintenance Period in the sum score of the Beck Depression Inventory Second Edition (BDI-II)

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    End point title
    		 Change from Baseline to the End of the Maintenance Period in the sum score of the Beck Depression Inventory Second Edition (BDI-II)
    End point description
    The Beck Depression Inventory (BDI) is a self-report instrument to measure depression symptoms and severity (Beck et al, 1961). The BDI-II is a revised version of the scale in order to be more consistent with the Diagnostic and Statistical Manual of Mental Disorders, Fourth Edition (DSM-IV) criteria for depression (Beck et al, 1996). There are 21 items in the BDI-II, classified as cognitive-affective (Items 1-13) and somatic-performance (Items 14-21) subscales. The degree of severity is indicated on a 4-point scale; items are rated from 0 (not at all) to 3 (extreme form of each symptom). Scores of 0-13 indicate minimal depression, 14-19 indicate mild depression, 20-28 indicate moderate depression, and 29-63 indicate severe depression.
    End point type
    Secondary
    End point timeframe
    Baseline (Visit 2) until End of the Maintenance Period / Early Withdrawal (up to 19 weeks after Baseline)
    End point values
    		 Placebo Rotigotine, low dose Rotigotine, high dose
    Number of subjects analysed
    39
    31
    39
    Units: scores on a scale
    arithmetic mean (standard deviation)
        mean (standard deviation)
    -3.3 ± 7
    -2.9 ± 5.9
    -3.7 ± 5.3
    Statistical analysis title
    		 Statistical Analysis 1
    Statistical analysis description
    ANCOVA model for the change from Baseline to End of Maintenance containing treatment and disease stage as factors, and Baseline value as covariate.
    Comparison groups
    Placebo v Rotigotine, low dose
    Number of subjects included in analysis
    70
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.899
    Method
    		 ANCOVA
    Parameter type
    		 Least Square Mean
    Point estimate
    0.16
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -2.34
         upper limit
    		 2.66
    Variability estimate
    Standard error of the mean
    Dispersion value
    1.26
    Statistical analysis title
    		 Statistical Analysis 2
    Statistical analysis description
    ANCOVA model for the change from Baseline to End of Treatment containing treatment and disease stage as factors, and Baseline value as covariate.
    Comparison groups
    Placebo v Rotigotine, high dose
    Number of subjects included in analysis
    78
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.785
    Method
    		 ANCOVA
    Parameter type
    		 Least Square Mean
    Point estimate
    -0.33
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -2.68
         upper limit
    		 2.03
    Variability estimate
    Standard error of the mean
    Dispersion value
    1.19

    Secondary: Change from Baseline to the End of the Maintenance Period in the sum score of the Unified Parkinson's Disease Rating Scale (UPDRS) Part III (motor subscale) in 'on' state

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    End point title
    		 Change from Baseline to the End of the Maintenance Period in the sum score of the Unified Parkinson's Disease Rating Scale (UPDRS) Part III (motor subscale) in 'on' state
    End point description
    Part III of the Unified Parkinson's Disease Rating Scale (UPDRS) assesses motor function. The UPDRS is completed by questioning the subject about his/her general state in conjunction with any observations made by the investigator (or designee) since the previous visit. The UPDRS Part III (motor subscale) had to be measured in the “on” state and consisted of 27 items and sub items scored between 0 and 4. The sum score ranged between 0 and 108 and was calculated as sum of the 27 individual scores. If 1 or more items were missing and could not be substituted with a previous post-Baseline value, the sum score was also missing. A negative value indicates an improvement.
    End point type
    Secondary
    End point timeframe
    Baseline (Visit 2) until End of the Maintenance Period / Early Withdrawal (up to 19 weeks after Baseline)
    End point values
    		 Placebo Rotigotine, low dose Rotigotine, high dose
    Number of subjects analysed
    40
    36
    40
    Units: scores on a scale
    arithmetic mean (standard deviation)
        mean (standard deviation)
    -3.4 ± 8.2
    -8.9 ± 10.4
    -8.1 ± 7.3
    Statistical analysis title
    		 Statistical Analysis 1
    Statistical analysis description
    ANCOVA model for the change from Baseline to End of Maintenance containing treatment and disease stage as factors, and Baseline value as covariate.
    Comparison groups
    Placebo v Rotigotine, low dose
    Number of subjects included in analysis
    76
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.014
    Method
    		 ANCOVA
    Parameter type
    		 Least Square Mean
    Point estimate
    -4.96
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -8.91
         upper limit
    		 -1.01
    Variability estimate
    Standard error of the mean
    Dispersion value
    1.99
    Statistical analysis title
    		 Statistical Analysis 2
    Statistical analysis description
    ANCOVA model for the change from Baseline to End of Maintenance containing treatment and disease stage as factors, and Baseline value as covariate.
    Comparison groups
    Rotigotine, high dose v Placebo
    Number of subjects included in analysis
    80
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.013
    Method
    		 ANCOVA
    Parameter type
    		 Least Square Mean
    Point estimate
    -4.83
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -8.63
         upper limit
    		 -1.03
    Variability estimate
    Standard error of the mean
    Dispersion value
    1.92

    Secondary: Change from Baseline to the End of the Maintenance Period in the score of the Clinical Global Impression Scale (CGI) Item I (Severity of Illness)

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    End point title
    		 Change from Baseline to the End of the Maintenance Period in the score of the Clinical Global Impression Scale (CGI) Item I (Severity of Illness)
    End point description
    The Clinical Global Impression (CGI) scales (Guy and Bonato, 1970) were initially developed for a risk-benefit estimation within the treatment of mentally ill patients. The 4 global scales (severity of illness, change in severity from Baseline, therapeutic efficacy, and tolerability of treatment) are used as different measures of treatment outcome in different kinds of pharmacological studies. The CGI Item 1 (severity of illness) collected 1 answer out of 8 categories (0-‘Not assessed’, 1-‘Normal, not at all ill’, 2-‘Borderline ill’, 3-‘Mildly ill’, 4-‘Moderately ill’, 5-‘Markedly ill’, 6-‘Severely ill’, and 7-‘Among the most extremely ill patients’) at each assessment. The category 0-‘Not assessed’ was considered as missing and therefore used neither for calculation nor for display purposes.
    End point type
    Secondary
    End point timeframe
    Baseline (Visit 2) until End of the Maintenance Period/Early Withdrawal (up to 19 weeks after Baseline)
    End point values
    		 Placebo Rotigotine, low dose Rotigotine, high dose
    Number of subjects analysed
    40
    36
    40
    Units: participants
    number (not applicable)
        Normal, not ill at all
    1
    1
    2
        Borderline ill
    6
    2
    3
        Mildly ill
    19
    16
    21
        Moderately ill
    9
    10
    12
        Markedly ill
    2
    1
    1
        Severely ill
    1
    1
    0
        Amongst the most extremely ill subjects
    0
    0
    0
        Missing
    2
    5
    1
    No statistical analyses for this end point

    Adverse events

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    Adverse events information
    Timeframe for reporting adverse events
    Treatment Emergent Adverse Events (TEAEs) were reported from Baseline up to the Safety Follow-up Visit (approximately during 19 weeks).
    Adverse event reporting additional description
    The Baseline Analysis Population refers to the Safety Set (SS). The SS includes all randomized subjects who received at least 1 dose of study medication.
    Assessment type
    		 Non-systematic
    Dictionary used for adverse event reporting
    Dictionary name
    		 MedDRA
    Dictionary version
    16.0
    Reporting groups
    Reporting group title
    Placebo
    Reporting group description
    		 Placebo: Placebo, matching transdermal patches Duration: up to 21 weeks (including de-escalation)

    Reporting group title
    Rotigotine, low dose
    Reporting group description
    		 Rotigotine, transdermal patches, optimal dose, maximal 8 mg / 24 hours for patients with advanced Parkinson’s Disease and 6 mg / 24 hours for those with early Parkinson’s Disease Rotigotine: Rotigotine, transdermal patches: 10 cm^2 (2 mg / 24 hours); 20 cm^2 (4 mg / 24 hours); 30 cm^2 (6 mg / 24 hours); 40 cm^2 (8 mg / 24 hours) Optimal dosage: The maximum Rotigotine dose allowed was 8 mg / 24 hours or 16 mg / 24 hours for patients with advanced Parkinson's Disease and 6 mg / 24 hours or 8 mg / 24 hours for those with early Parkinson's Disease Duration: up to 21 weeks (including de-escalation)

    Reporting group title
    Rotigotine, high dose
    Reporting group description
    		 Rotigotine, transdermal patches, maximal 16 mg / 24 hours for patients with advanced Parkinson's Disease and 8 mg / 24 hours for those with early Parkinson's Disease Rotigotine: Rotigotine, transdermal patches: 10 cm^2 (2 mg / 24 hours); 20 cm^2 (4 mg / 24 hours); 30 cm^2 (6 mg / 24 hours); 40 cm^2 (8 mg / 24 hours) Optimal dosage: The maximum Rotigotine dose allowed was 8 mg / 24 hours or 16 mg / 24 hours for patients with advanced Parkinson's Disease and 6 mg / 24 hours or 8 mg / 24 hours for those with early Parkinson's Disease Duration: up to 21 weeks (including de-escalation)

    Serious adverse events
    		 Placebo Rotigotine, low dose Rotigotine, high dose
    Total subjects affected by serious adverse events
         subjects affected / exposed
    4 / 40 (10.00%)
    2 / 41 (4.88%)
    1 / 41 (2.44%)
         number of deaths (all causes)
    0
    0
    0
         number of deaths resulting from adverse events
    0
    0
    0
    Nervous system disorders
    Cerebral haematoma
         subjects affected / exposed
    0 / 40 (0.00%)
    0 / 41 (0.00%)
    1 / 41 (2.44%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Cerebrovascular accident
         subjects affected / exposed
    1 / 40 (2.50%)
    0 / 41 (0.00%)
    0 / 41 (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
    Transient ischaemic attack
         subjects affected / exposed
    1 / 40 (2.50%)
    0 / 41 (0.00%)
    0 / 41 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Gastrointestinal disorders
    Small intestinal obstruction
         subjects affected / exposed
    0 / 40 (0.00%)
    1 / 41 (2.44%)
    0 / 41 (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
    Abdominal pain
         subjects affected / exposed
    1 / 40 (2.50%)
    0 / 41 (0.00%)
    0 / 41 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Ileus
         subjects affected / exposed
    0 / 40 (0.00%)
    1 / 41 (2.44%)
    0 / 41 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Infections and infestations
    Abscess
         subjects affected / exposed
    0 / 40 (0.00%)
    1 / 41 (2.44%)
    0 / 41 (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
    Sepsis
         subjects affected / exposed
    1 / 40 (2.50%)
    0 / 41 (0.00%)
    0 / 41 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Frequency threshold for reporting non-serious adverse events: 5%
    Non-serious adverse events
    		 Placebo Rotigotine, low dose Rotigotine, high dose
    Total subjects affected by non serious adverse events
         subjects affected / exposed
    18 / 40 (45.00%)
    17 / 41 (41.46%)
    15 / 41 (36.59%)
    Injury, poisoning and procedural complications
    Fall
         subjects affected / exposed
    2 / 40 (5.00%)
    3 / 41 (7.32%)
    2 / 41 (4.88%)
         occurrences all number
    3
    3
    2
    Nervous system disorders
    Somnolence
         subjects affected / exposed
    3 / 40 (7.50%)
    2 / 41 (4.88%)
    4 / 41 (9.76%)
         occurrences all number
    3
    2
    5
    Dyskinesia
         subjects affected / exposed
    2 / 40 (5.00%)
    3 / 41 (7.32%)
    1 / 41 (2.44%)
         occurrences all number
    3
    3
    1
    Headache
         subjects affected / exposed
    4 / 40 (10.00%)
    1 / 41 (2.44%)
    3 / 41 (7.32%)
         occurrences all number
    6
    1
    6
    General disorders and administration site conditions
    Application site pruritus
         subjects affected / exposed
    2 / 40 (5.00%)
    4 / 41 (9.76%)
    1 / 41 (2.44%)
         occurrences all number
    2
    4
    2
    Oedema peripheral
         subjects affected / exposed
    1 / 40 (2.50%)
    2 / 41 (4.88%)
    3 / 41 (7.32%)
         occurrences all number
    1
    2
    3
    Gastrointestinal disorders
    Constipation
         subjects affected / exposed
    1 / 40 (2.50%)
    2 / 41 (4.88%)
    3 / 41 (7.32%)
         occurrences all number
    1
    2
    3
    Nausea
         subjects affected / exposed
    4 / 40 (10.00%)
    4 / 41 (9.76%)
    2 / 41 (4.88%)
         occurrences all number
    5
    5
    2
    Dry mouth
         subjects affected / exposed
    0 / 40 (0.00%)
    0 / 41 (0.00%)
    3 / 41 (7.32%)
         occurrences all number
    0
    0
    3
    Psychiatric disorders
    Depression
         subjects affected / exposed
    2 / 40 (5.00%)
    4 / 41 (9.76%)
    1 / 41 (2.44%)
         occurrences all number
    2
    4
    1
    Insomnia
         subjects affected / exposed
    6 / 40 (15.00%)
    1 / 41 (2.44%)
    2 / 41 (4.88%)
         occurrences all number
    6
    1
    2
    Suicidal ideation
         subjects affected / exposed
    3 / 40 (7.50%)
    1 / 41 (2.44%)
    0 / 41 (0.00%)
         occurrences all number
    3
    1
    0

    More information

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    Substantial protocol amendments (globally)
    Were there any global substantial amendments to the protocol? Yes
    Date
    Amendment
    05 Aug 2013
    - A description and rationale of the interim analysis to be performed was added. - The approximate number of participating investigational sites was increased to 120. - Inclusion Criterion 7 was modified to add “200 mg/day” as the minimum allowed stable dose of levodopa for consistency with the concomitant levodopa section. - Tables with the study medication administration schedule and De-Escalation Period for subjects with advanced-stage Parkinson’s disease were corrected. - Wording regarding packaging was updated to remove references to cartons for the de-escalation kits. - Wording regarding the NMSS was updated to indicate that it could also be assessed by an investigator’s designee. - The analysis sets to be used for the analyses of efficacy variables were revised. - The estimated screening failure rate was corrected. - The references list was updated. - The Snaith-Hamilton Pleasure Scale (SHAPS) was updated to reflect the version provided to the subjects. - Additionally, administrative, typographical, and editorial changes were made.

    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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