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    Clinical Trial Results:
    A Multicenter, Multinational, Double-Blind, Placebo-Controlled, 2-Arm Study to Evaluate the Efficacy of Rotigotine on Parkinson's Disease-Associated Pain

    Summary
    EudraCT number
    2012-002608-42
    Trial protocol
    DE   GB   HU   SK  
    Global end of trial date
    30 Jan 2014

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

    Trial information

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    Trial identification
    Sponsor protocol code
    PD0004
    Additional study identifiers
    ISRCTN number
    -
    US NCT number
    NCT01744496
    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
    07 May 2014
    Is this the analysis of the primary completion data?
    No
    Global end of trial reached?
    Yes
    Global end of trial date
    30 Jan 2014
    Was the trial ended prematurely?
    No
    General information about the trial
    Main objective of the trial
    To assess the effects of Rotigotine over placebo on improvement of Parkinson’s disease associated chronic pain in subjects with advanced-stage Parkinson’s disease experiencing Parkinson’s disease associated chronic pain.
    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
    19 Nov 2012
    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
    Germany: 2
    Country: Number of subjects enrolled
    Poland: 19
    Country: Number of subjects enrolled
    United States: 31
    Country: Number of subjects enrolled
    Slovakia: 16
    Worldwide total number of subjects
    68
    EEA total number of subjects
    37
    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)
    27
    From 65 to 84 years
    40
    85 years and over
    1

    Subject disposition

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    Recruitment
    Recruitment details
    The study was conducted in Europe and USA. Recruitment was planned to continue until approximately 64 patients were randomized in the study. Subjects were randomized in a 1:1 ratio to either Rotigotine or Placebo. To achieve this, approximately 28 investigational sites were planned to participate in this hypothesis-generating pilot study.

    Pre-assignment
    Screening details
    The Participant Flow population refers to the Randomized Set (RS). The RS includes all subjects who were randomized.

    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, Assessor

    Arms
    Are arms mutually exclusive
    Yes

    Arm title
    Placebo
    Arm description
    Placebo Transdermal PatchesPlacebo: Placebo patches matched the size of active patches 20 cm^2, 30 cm^2, or 40 cm^2 and contained Placebo. Application of Placebo patches started at the Baseline Visit. Placebo patches were administered once daily starting with the equivalent of 4 mg / 24 h. Doses were then up-titrated in weekly equivalents to 2 mg / 24 h until either optimal dose or maximum dose was reached. The maximum dose was the equivalent to 16 mg / 24 h. The duration of the Titration Period varied from 1 to 7 weeks. The Maintenance Period lasted 12 weeks ± 5 days. During the De-Escalation Period, the dose of Placebo was decreased by the equivalent to 2 mg / 24 h every other day. The De-Escalation Period might have lasted up to 12 days.
    Arm type
    Placebo

    Investigational medicinal product name
    Placebo
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Transdermal patch
    Routes of administration
    Transdermal use
    Dosage and administration details
    Placebo patches matched the size of active patches 20 cm^2, 30 cm^2, or 40 cm^2 and contained Placebo. Application of Placebo patches started at the Baseline Visit. Placebo patches were administered once daily starting with the equivalent of 4 mg / 24 h. Doses were then up-titrated in weekly equivalents to 2 mg / 24 h until either optimal dose or maximum dose was reached. The maximum dose was the equivalent to 16 mg / 24 h. The duration of the Titration Period varied from 1 to 7 weeks. The Maintenance Period lasted 12 weeks ± 5 days. During the De-Escalation Period, the dose of Placebo was decreased by the equivalent to 2 mg / 24 h every other day. The De-Escalation Period might have lasted up to 12 days.

    Arm title
    Rotigotine
    Arm description
    Rotigotine Transdermal PatchesRotigotine: Patches contained 4 mg / 24 h (20 cm^2), 6 mg/ 24 h (30 cm^2), or 8 mg /24 h (40 cm^2) of Rotigotine. Application of study medication started at the Baseline Visit. Rotigotine was administered once daily starting at 4 mg / 24 h. Doses were then up-titrated in weekly increments of 2 mg / 24 h until optimal or maximum dose (16 mg / 24 h) was reached and the Maintenance Period could be started. The duration of the Titration Period varied from 1 to 7 weeks ± 3 days. The Maintenance Period lasted 12 weeks ± 5 days. Thereafter, during the De-Escalation Period, the dose of study medication was decreased by 2 mg / 24 h every other day. The De-Escalation Period might have lasted up to 12 days.
    Arm type
    Experimental

    Investigational medicinal product name
    Rotigotine
    Investigational medicinal product code
    Other name
    Neupro
    Pharmaceutical forms
    Transdermal patch
    Routes of administration
    Transdermal use
    Dosage and administration details
    Patches contained 4 mg / 24 h (20 cm^2), 6 mg/ 24 h (30 cm^2), or 8 mg /24 h (40 cm^2) of Rotigotine. Application of study medication started at the Baseline Visit. Rotigotine was administered once daily starting at 4 mg / 24 h. Doses were then up-titrated in weekly increments of 2 mg / 24 h until optimal or maximum dose (16 mg / 24 h) was reached and the Maintenance Period could be started. The duration of the Titration Period varied from 1 to 7 weeks ± 3 days. The Maintenance Period lasted 12 weeks ± 5 days. Thereafter, during the De-Escalation Period, the dose of study medication was decreased by 2 mg / 24 h every other day. The De-Escalation Period might have lasted up to 12 days.

    Number of subjects in period 1
    Placebo Rotigotine
    Started
    33
    35
    Maintenance Period
    31
    33
    Titration Period
    33
    35
    Completed
    27
    29
    Not completed
    6
    6
         Protocol deviation
    1
    -
         SAE, non-fatal
    1
    1
         Subject left town
    1
    -
         Personal reasons
    -
    1
         Consent withdrawn by subject
    1
    1
         AE, non-serious non-fatal
    2
    3

    Baseline characteristics

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    Baseline characteristics reporting groups
    Reporting group title
    Placebo
    Reporting group description
    Placebo Transdermal PatchesPlacebo: Placebo patches matched the size of active patches 20 cm^2, 30 cm^2, or 40 cm^2 and contained Placebo. Application of Placebo patches started at the Baseline Visit. Placebo patches were administered once daily starting with the equivalent of 4 mg / 24 h. Doses were then up-titrated in weekly equivalents to 2 mg / 24 h until either optimal dose or maximum dose was reached. The maximum dose was the equivalent to 16 mg / 24 h. The duration of the Titration Period varied from 1 to 7 weeks. The Maintenance Period lasted 12 weeks ± 5 days. During the De-Escalation Period, the dose of Placebo was decreased by the equivalent to 2 mg / 24 h every other day. The De-Escalation Period might have lasted up to 12 days.

    Reporting group title
    Rotigotine
    Reporting group description
    Rotigotine Transdermal PatchesRotigotine: Patches contained 4 mg / 24 h (20 cm^2), 6 mg/ 24 h (30 cm^2), or 8 mg /24 h (40 cm^2) of Rotigotine. Application of study medication started at the Baseline Visit. Rotigotine was administered once daily starting at 4 mg / 24 h. Doses were then up-titrated in weekly increments of 2 mg / 24 h until optimal or maximum dose (16 mg / 24 h) was reached and the Maintenance Period could be started. The duration of the Titration Period varied from 1 to 7 weeks ± 3 days. The Maintenance Period lasted 12 weeks ± 5 days. Thereafter, during the De-Escalation Period, the dose of study medication was decreased by 2 mg / 24 h every other day. The De-Escalation Period might have lasted up to 12 days.

    Reporting group values
    Placebo Rotigotine Total
    Number of subjects
    33 35 68
    Age Categorical
    Units: Subjects
        In utero
    0 0 0
        Preterm newborn infants (gestational age < 37 wks)
    0 0 0
        Newborns (0-27 days)
    0 0 0
        Infants and toddlers (28 days-23 months)
    0 0 0
        Children (2-11 years)
    0 0 0
        Adolescents (12-17 years)
    0 0 0
        Adults (18-64 years)
    15 12 27
        From 65-84 years
    17 23 40
        85 years and over
    1 0 1
    Age Continuous
    Units: years
        arithmetic mean (standard deviation)
    65.3 ± 13.8 66.5 ± 11.9 -
    Gender categorical
    Units: Subjects
        Male
    17 19 36
        Female
    16 16 32
    Race/Ethnicity, Customized
    Units: Subjects
        American Indian / Alaskan native
    0 0 0
        Asian
    1 0 1
        Black
    0 0 0
        Native Hawaiian or other Pacific Islander
    0 0 0
        White
    32 35 67
        Other / mixed
    0 0 0
    Weight
    Units: kilograms
        arithmetic mean (standard deviation)
    80.15 ± 20 77.8 ± 13.71 -
    Height
    Units: centimeters
        arithmetic mean (standard deviation)
    167.17 ± 9.92 168.63 ± 9.87 -
    Body Mass Index (BMI)
    Units: kilogram per squaremeter
        arithmetic mean (standard deviation)
    28.54 ± 6.211 27.419 ± 4.743 -

    End points

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    End points reporting groups
    Reporting group title
    Placebo
    Reporting group description
    Placebo Transdermal PatchesPlacebo: Placebo patches matched the size of active patches 20 cm^2, 30 cm^2, or 40 cm^2 and contained Placebo. Application of Placebo patches started at the Baseline Visit. Placebo patches were administered once daily starting with the equivalent of 4 mg / 24 h. Doses were then up-titrated in weekly equivalents to 2 mg / 24 h until either optimal dose or maximum dose was reached. The maximum dose was the equivalent to 16 mg / 24 h. The duration of the Titration Period varied from 1 to 7 weeks. The Maintenance Period lasted 12 weeks ± 5 days. During the De-Escalation Period, the dose of Placebo was decreased by the equivalent to 2 mg / 24 h every other day. The De-Escalation Period might have lasted up to 12 days.

    Reporting group title
    Rotigotine
    Reporting group description
    Rotigotine Transdermal PatchesRotigotine: Patches contained 4 mg / 24 h (20 cm^2), 6 mg/ 24 h (30 cm^2), or 8 mg /24 h (40 cm^2) of Rotigotine. Application of study medication started at the Baseline Visit. Rotigotine was administered once daily starting at 4 mg / 24 h. Doses were then up-titrated in weekly increments of 2 mg / 24 h until optimal or maximum dose (16 mg / 24 h) was reached and the Maintenance Period could be started. The duration of the Titration Period varied from 1 to 7 weeks ± 3 days. The Maintenance Period lasted 12 weeks ± 5 days. Thereafter, during the De-Escalation Period, the dose of study medication was decreased by 2 mg / 24 h every other day. The De-Escalation Period might have lasted up to 12 days.

    Subject analysis set title
    FAS (Placebo treated subjects)
    Subject analysis set type
    Full analysis
    Subject analysis set description
    The Full Analysis Set is a subset of the Safety Set and includes all subjects who were randomized, received at least 1 dose of study medication, and had a valid primary efficacy Baseline measurement and at least 1 valid post-Baseline Maintenance or valid withdrawal primary efficacy measurement.

    Subject analysis set title
    FAS (Rotigotine treated subjects)
    Subject analysis set type
    Full analysis
    Subject analysis set description
    The Full Analysis Set is a subset of the Safety Set and includes all subjects who were randomized, received at least 1 dose of study medication, and had a valid primary efficacy Baseline measurement and at least 1 valid post-Baseline Maintenance or valid withdrawal primary efficacy measurement.

    Primary: Change from Baseline to the End of the Maintenance Period in pain severity assessed using an 11-point Likert Pain Scale

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    End point title
    Change from Baseline to the End of the Maintenance Period in pain severity assessed using an 11-point Likert Pain Scale
    End point description
    An 11-Point Likert Scale was used to assess patients' average daily pain. The subject rated his/her average pain from 0 (no pain) to 10 (worst pain ever experienced). The average pain experienced in the last 7 days was calculated by the mean of the daily Likert Pain Scores within the 7 days prior to the respective visit (ie, Likert Pain Scores with a date of assessment before the date of visit and on or after the date of visit – 7 days). A negative value indicates an improvement.
    End point type
    Primary
    End point timeframe
    Baseline (Visit 2) until End of the Maintenance Period (Maintenance Period lasts 12 weeks ± 5 days after an up to 7 weeks Titration Period)
    End point values
    Placebo Rotigotine
    Number of subjects analysed
    30 [1]
    30 [2]
    Units: scores on a scale
    arithmetic mean (standard deviation)
        arithmetic mean (standard deviation)
    -2.2 ± 2.78
    -2.8 ± 1.84
    Notes
    [1] - Full Analysis Set (FAS)
    [2] - Full Analysis Set (FAS)
    Statistical analysis title
    Statistical Analysis 1
    Statistical analysis description
    ANCOVA model for the change from Baseline to the End of Treatment containing treatment and region as factors and Baseline value as a covariate.
    Comparison groups
    Placebo v Rotigotine
    Number of subjects included in analysis
    60
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    P-value
    = 0.172
    Method
    ANCOVA
    Parameter type
    Least Square Mean
    Point estimate
    -0.76
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    -1.87
         upper limit
    0.34
    Variability estimate
    Standard error of the mean
    Dispersion value
    0.55

    Secondary: Percentage of Responders at the End of the Maintenance Period

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    End point title
    Percentage of Responders at the End of the Maintenance Period
    End point description
    Responders are defined as patients experiencing a 2-Point or more Reduction on an 11-Point Likert Pain Scale from Baseline to the End of the Maintenance Period. An 11-Point Likert Scale was used to assess patients' average daily pain. The patient rated his/her average pain from 0 (no pain) to 10 (worst pain ever experienced).
    End point type
    Secondary
    End point timeframe
    Baseline (Visit 2) until End of the Maintenance Period (Maintenance Period lasts 12 weeks ± 5 days after up to 7 weeks Titration Period)
    End point values
    Placebo Rotigotine
    Number of subjects analysed
    30 [3]
    30 [4]
    Units: percentage of responders
    number (not applicable)
        percentage of responders
    46.7
    60
    Notes
    [3] - Full Analysis Set (FAS)
    [4] - Full Analysis Set (FAS)
    No statistical analyses for this end point

    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 contains 8 items of daily living, with 1 item selected from each of the following 8 scales: mobility, Activities of Daily Living (ADL), emotional well being, stigma, social support, cognitions, communication, and bodily discomfort. The total PDQ-8 score is the sum of all the individual items converted to a summary index score between 0 and 100, with lower scores indicating better health. A negative value indicates an improvement.
    End point type
    Secondary
    End point timeframe
    Baseline (Visit 2) until End of the Maintenance Period (Maintenance Period lasts 12 weeks ± 5 days after up to 7 weeks Titration Period)
    End point values
    Placebo Rotigotine
    Number of subjects analysed
    29 [5]
    30 [6]
    Units: scores on a scale
    arithmetic mean (standard deviation)
        arithmetic mean (standard deviation)
    -3.77 ± 13.93
    -12.4 ± 19.25
    Notes
    [5] - Full Analysis Set (FAS)
    [6] - Full Analysis Set (FAS)
    Statistical analysis title
    Statistical Analysis 1
    Statistical analysis description
    ANCOVA model for the change from Baseline to the End of Treatment containing treatment and region as factors and Baseline value as a covariate.
    Comparison groups
    Placebo v Rotigotine
    Number of subjects included in analysis
    59
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    P-value
    = 0.038
    Method
    ANCOVA
    Parameter type
    Least Square Mean
    Point estimate
    -8.01
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    -15.56
         upper limit
    -0.46
    Variability estimate
    Standard error of the mean
    Dispersion value
    3.77

    Secondary: Change from Baseline to the End of the Maintenance Period in the 7-Item Depression subscore of the Hospital Anxiety and Depression Scale (HADS)

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    End point title
    Change from Baseline to the End of the Maintenance Period in the 7-Item Depression subscore of the Hospital Anxiety and Depression Scale (HADS)
    End point description
    The Hospital Anxiety and Depression Scale (HADS) (Zigmond and Snaith, 1983) is a 14-item self-assessment scale for detecting states of depression and anxiety in the setting of a hospital medical outpatient clinic. It comprises a 7-item anxiety subscale and a 7-item depressive subscale that are also measures of severity of the emotional disorder. The 14 items are scored between 0 and 3. The 7-item depression subscore and 7-item anxiety subscore were calculated as the sum of the 7 corresponding individual scores. A negative value indicates an improvement.
    End point type
    Secondary
    End point timeframe
    Baseline (Visit 2) until End of the Maintenance Period (Maintenance Period lasts 12 weeks ± 5 days after up to 7 weeks Titration Period)
    End point values
    Placebo Rotigotine
    Number of subjects analysed
    28 [7]
    28 [8]
    Units: scores on a scale
    arithmetic mean (standard deviation)
        arithmetic mean (standard deviation)
    -1.7 ± 4.3
    -1.9 ± 4.1
    Notes
    [7] - Full Analysis Set (FAS)
    [8] - Full Analysis Set (FAS)
    Statistical analysis title
    Statistical Analysis 1
    Statistical analysis description
    ANCOVA model for the change from Baseline to the End of Treatment containing treatment and region as factors and Baseline value as a covariate.
    Comparison groups
    Placebo v Rotigotine
    Number of subjects included in analysis
    56
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    P-value
    = 0.247
    Method
    ANCOVA
    Parameter type
    Least Square Mean
    Point estimate
    -1.02
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    -2.76
         upper limit
    0.73
    Variability estimate
    Standard error of the mean
    Dispersion value
    0.87

    Secondary: Change from Baseline to the End of the Maintenance Period in the 7-Item Anxiety subscore of the Hospital Anxiety and Depression Scale (HADS)

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    End point title
    Change from Baseline to the End of the Maintenance Period in the 7-Item Anxiety subscore of the Hospital Anxiety and Depression Scale (HADS)
    End point description
    The Hospital Anxiety and Depression Scale (HADS) (Zigmond and Snaith, 1983) is a 14-item self-assessment scale for detecting states of depression and anxiety in the setting of a hospital medical outpatient clinic. It comprises a 7-item anxiety subscale and a 7-item depressive subscale that are also measures of severity of the emotional disorder. The 14 items are scored between 0 and 3. The 7-item depression subscore and 7-item anxiety subscore were calculated as the sum of the 7 corresponding individual scores. A negative value indicates an improvement.
    End point type
    Secondary
    End point timeframe
    Baseline (Visit 2) until End of the Maintenance Period (Maintenance Period lasts 12 weeks ± 5 days after up to 7 weeks Titration Period)
    End point values
    Placebo Rotigotine
    Number of subjects analysed
    28 [9]
    28 [10]
    Units: scores on a scale
    arithmetic mean (standard deviation)
        arithmetic mean (standard deviation)
    -1 ± 3.2
    -1.8 ± 3.7
    Notes
    [9] - Full Analysis Set (FAS)
    [10] - Full Analysis Set (FAS)
    Statistical analysis title
    Statistical Analysis 1
    Statistical analysis description
    ANCOVA model for the change from Baseline to the End of Treatment containing treatment and region as factors and Baseline value as a covariate.
    Comparison groups
    Placebo v Rotigotine
    Number of subjects included in analysis
    56
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    P-value
    = 0.371
    Method
    ANCOVA
    Parameter type
    Least Square Mean
    Point estimate
    -0.58
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    -1.85
         upper limit
    0.7
    Variability estimate
    Standard error of the mean
    Dispersion value
    0.64

    Secondary: Change from Baseline to the End of the Maintenance Period in the combined score of the Unified Parkinson's Disease Rating Scale (UPDRS) Parts II (Activities of Daily Living [ADL] subscale) and III (motor subscale)

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    End point title
    Change from Baseline to the End of the Maintenance Period in the combined score of the Unified Parkinson's Disease Rating Scale (UPDRS) Parts II (Activities of Daily Living [ADL] subscale) and III (motor subscale)
    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
    Secondary
    End point timeframe
    Baseline (Visit 2) until End of the Maintenance Period (Maintenance Period lasts 12 weeks ± 5 days after up to 7 weeks Titration Period)
    End point values
    Placebo Rotigotine
    Number of subjects analysed
    29 [11]
    30 [12]
    Units: scores on a scale
    arithmetic mean (standard deviation)
        arithmetic mean (standard deviation)
    -5.1 ± 11.7
    -8.3 ± 11.2
    Notes
    [11] - Full Analysis Set (FAS)
    [12] - Full Analysis Set (FAS)
    Statistical analysis title
    Statistical Analysis 1
    Statistical analysis description
    ANCOVA model for the change from Baseline to the End of Treatment containing treatment and region as factors and Baseline value as a covariate.
    Comparison groups
    Placebo v Rotigotine
    Number of subjects included in analysis
    59
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    P-value
    = 0.346
    Method
    ANCOVA
    Parameter type
    Least Square Mean
    Point estimate
    -2.82
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    -8.76
         upper limit
    3.13
    Variability estimate
    Standard error of the mean
    Dispersion value
    2.97

    Secondary: Change from Baseline to the End of the Maintenance Period in the 7 domain scores of Classification of Pain in Parkinson's Disease

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    End point title
    Change from Baseline to the End of the Maintenance Period in the 7 domain scores of Classification of Pain in Parkinson's Disease
    End point description
    The classification of pain in Parkinson’s disease scale classifies pain in the following domains: musculoskeletal pain (item 1), chronic pain (items 2 and 3), fluctuation related pain (items 4, 5 and 6), nocturnal pain (items 7 and 8), oro-facial pain (items 9, 10 and 11), discoloration; edema/swelling (items 12 and 13), and radicular pain (item 14). Severity of the pain is measured on a scale from none (0) to severe (3) and frequency is measured on a scale from never (0) to very frequent (4). A score of a single item was calculated by multiplying severity with frequency. A domain score was calculated as the sum of every individual score related to the respective domain. A negative value indicates an improvement.
    End point type
    Secondary
    End point timeframe
    Baseline (Visit 2) until End of the Maintenance Period (Maintenance Period lasts 12 weeks ± 5 days after up to 7 weeks Titration Period)
    End point values
    Placebo Rotigotine
    Number of subjects analysed
    29 [13]
    30 [14]
    Units: scores on a scale
    arithmetic mean (standard deviation)
        Musculoskeletal Pain
    -1.4 ± 3.6
    -1.5 ± 4.2
        Chronic Pain
    -3.1 ± 5.6
    -0.7 ± 2.9
        Fluctuation-Related Pain
    -2.2 ± 4.6
    -4.2 ± 6.8
        Nocturnal Pain
    -2.9 ± 6.1
    -2.4 ± 5.3
        Oro-Facial Pain
    -0.4 ± 2.5
    -0.6 ± 2.3
        Discoloration; Edema/Swelling
    -1.8 ± 4.9
    -1.7 ± 3.4
        Radicular Pain
    -1.3 ± 3.8
    -1.1 ± 3.7
    Notes
    [13] - Full Analysis Set (FAS)
    [14] - Full Analysis Set (FAS)
    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 were reported from Baseline up to the Safety Follow-up Visit (approximately during 25 weeks).
    Adverse event reporting additional description
    Adverse Events (AEs) refer 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 Transdermal Patches Placebo: Placebo patches matched the size of active patches 20 cm^2, 30 cm^2, or 40 cm^2 and contained Placebo. Application of Placebo patches started at the Baseline Visit. Placebo patches were administered once daily starting with the equivalent of 4 mg / 24 h. Doses were then up-titrated in weekly equivalents to 2 mg / 24 h until either optimal dose or maximum dose was reached. The maximum dose was the equivalent to 16 mg / 24 h. The duration of the Titration Period varied from 1 to 7 weeks. The Maintenance Period lasted 12 weeks ± 5 days. During the De-Escalation Period, the dose of Placebo was decreased by the equivalent to 2 mg / 24 h every other day. The De-Escalation Period might have lasted up to 12 days.

    Reporting group title
    Rotigotine
    Reporting group description
    Rotigotine Transdermal Patches Rotigotine: Patches contained 4 mg / 24 h (20 cm^2), 6 mg/ 24 h (30 cm^2), or 8 mg /24 h (40 cm^2) of Rotigotine. Application of study medication started at the Baseline Visit. Rotigotine was administered once daily starting at 4 mg / 24 h. Doses were then up-titrated in weekly increments of 2 mg / 24 h until optimal or maximum dose (16 mg / 24 h) was reached and the Maintenance Period could be started. The duration of the Titration Period varied from 1 to 7 weeks ± 3 days. The Maintenance Period lasted 12 weeks ± 5 days. Thereafter, during the De-Escalation Period, the dose of study medication was decreased by 2 mg / 24 h every other day. The De-Escalation Period might have lasted up to 12 days.

    Serious adverse events
    Placebo Rotigotine
    Total subjects affected by serious adverse events
         subjects affected / exposed
    1 / 33 (3.03%)
    2 / 35 (5.71%)
         number of deaths (all causes)
    0
    0
         number of deaths resulting from adverse events
    0
    0
    Injury, poisoning and procedural complications
    Hip fracture
         subjects affected / exposed
    1 / 33 (3.03%)
    0 / 35 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Nervous system disorders
    Cerebrovascular accident
         subjects affected / exposed
    0 / 33 (0.00%)
    1 / 35 (2.86%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    General disorders and administration site conditions
    Oedema peripheral
         subjects affected / exposed
    0 / 33 (0.00%)
    1 / 35 (2.86%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Frequency threshold for reporting non-serious adverse events: 5%
    Non-serious adverse events
    Placebo Rotigotine
    Total subjects affected by non serious adverse events
         subjects affected / exposed
    17 / 33 (51.52%)
    20 / 35 (57.14%)
    Injury, poisoning and procedural complications
    Fall
         subjects affected / exposed
    0 / 33 (0.00%)
    2 / 35 (5.71%)
         occurrences all number
    0
    3
    Neoplasms benign, malignant and unspecified (incl cysts and polyps)
    Basal cell carcinoma
         subjects affected / exposed
    2 / 33 (6.06%)
    1 / 35 (2.86%)
         occurrences all number
    2
    1
    Nervous system disorders
    Dyskinesia
         subjects affected / exposed
    2 / 33 (6.06%)
    2 / 35 (5.71%)
         occurrences all number
    2
    2
    Hyperkinesia
         subjects affected / exposed
    2 / 33 (6.06%)
    0 / 35 (0.00%)
         occurrences all number
    2
    0
    Headache
         subjects affected / exposed
    4 / 33 (12.12%)
    6 / 35 (17.14%)
         occurrences all number
    11
    7
    Dizziness
         subjects affected / exposed
    3 / 33 (9.09%)
    3 / 35 (8.57%)
         occurrences all number
    3
    3
    General disorders and administration site conditions
    Fatigue
         subjects affected / exposed
    1 / 33 (3.03%)
    2 / 35 (5.71%)
         occurrences all number
    1
    2
    Application site erythema
         subjects affected / exposed
    0 / 33 (0.00%)
    3 / 35 (8.57%)
         occurrences all number
    0
    3
    Psychiatric disorders
    Insomnia
         subjects affected / exposed
    1 / 33 (3.03%)
    3 / 35 (8.57%)
         occurrences all number
    1
    3
    Gastrointestinal disorders
    Diarrhoea
         subjects affected / exposed
    2 / 33 (6.06%)
    0 / 35 (0.00%)
         occurrences all number
    2
    0
    Nausea
         subjects affected / exposed
    2 / 33 (6.06%)
    8 / 35 (22.86%)
         occurrences all number
    3
    11
    Skin and subcutaneous tissue disorders
    Rash
         subjects affected / exposed
    2 / 33 (6.06%)
    2 / 35 (5.71%)
         occurrences all number
    2
    2
    Infections and infestations
    Upper respiratory tract infection
         subjects affected / exposed
    2 / 33 (6.06%)
    1 / 35 (2.86%)
         occurrences all number
    2
    1
    Urinary tract infection
         subjects affected / exposed
    0 / 33 (0.00%)
    2 / 35 (5.71%)
         occurrences all number
    0
    2

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    Substantial protocol amendments (globally)

    Were there any global substantial amendments to the protocol? Yes
    Date
    Amendment
    22 Jul 2013
    - The study design was changed to a hypothesis-generating pilot study - The number of subjects was reduced. Subject enrollment had to continue until approximately 64 subjects were randomized or until the end of Jul 2013 (whichever occurred first) - The study location was changed from being conducted globally to being conducted in only Europe and the USA - Additionally some administrative information was updated

    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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