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    Clinical Trial Results:
    A fixed dose, dose response study for ropinirole prolonged release (PR) in patients with early stage Parkinson’s Disease.

    Summary
    EudraCT number
    		 2011-002827-17
    Trial protocol
    		 EE   SK  
    Global end of trial date
    30 Apr 2014

    Results information
    Results version number
    		 v1(current)
    This version publication date
    27 Apr 2016
    First version publication date
    10 May 2015
    Other versions

    Trial information

    		 Close Top of page
    Trial identification
    Sponsor protocol code
    ROP111662
    Additional study identifiers
    ISRCTN number
    		 -
    US NCT number
    		 NCT01485172
    WHO universal trial number (UTN)
    		 -
    Sponsors
    Sponsor organisation name
    GlaxoSmithKline
    Sponsor organisation address
    980 Great West Road, Brentford, Middlesex, United Kingdom,
    Public contact
    GSK Response Center, GlaxoSmithKline, +1 8664357343,
    Scientific contact
    GSK Response Center, GlaxoSmithKline, +1 8664357343,
    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
    12 Jan 2015
    Is this the analysis of the primary completion data?
    No
    Global end of trial reached?
    Yes
    Global end of trial date
    30 Apr 2014
    Was the trial ended prematurely?
    No
    General information about the trial
    Main objective of the trial
    To characterize the dose response of fixed doses of ropinirole PR as monotherapy in patients with early stage Parkinson’s disease.
    Protection of trial subjects
    All subjects signed an Informed Consent form to participate in the study. Subjects were allowed to titrate to their randomized dose, and if they experienced AEs, they could remain at a lower dose for the duration of the study.
    Background therapy
    		 -
    Evidence for comparator
    		 -
    Actual start date of recruitment
    31 Jan 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
    Slovakia: 12
    Country: Number of subjects enrolled
    Estonia: 19
    Country: Number of subjects enrolled
    Korea, Republic of: 11
    Country: Number of subjects enrolled
    Russian Federation: 102
    Country: Number of subjects enrolled
    United States: 42
    Worldwide total number of subjects
    186
    EEA total number of subjects
    31
    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)
    118
    From 65 to 84 years
    64
    85 years and over
    4

    Subject disposition

    		 Close Top of page
    Recruitment
    Recruitment details
    		 Eligible participants (par.) were diagnosed with early stage Parkinson’s disease (according to modified Hoehn and Yahr criteria Stages I-III) and randomized at Screening into one of six treatment arms to receive placebo or ropinirole Prolonged Release (PR) tablets.

    Pre-assignment
    Screening details
    		 After Screening, par. underwent a 13 Week Up-Ttitration Period until reaching their target dose then continued on their target dose during a 4 Week Maintenance Period up to Week 17. All par. underwent a 1 Week Down-Titraion Period and then a Follow-Up Visit 1-2 Weeks after receiving the last dose of treatment.

    Period 1
    Period 1 title
    Overall Study (Up to 29 Weeks) (overall period)
    Is this the baseline period?
    		 Yes
    Allocation method
    Randomised - controlled
    Blinding used
    		 Double blind
    Roles blinded
    		 Subject, Investigator, Monitor, Data analyst, Carer, Assessor

    Arms
    Are arms mutually exclusive
    Yes

    Arm title
    		 Treatment Group A: Placebo
    Arm description
    		 Participants (par.) were administered a matching Prolonged Release (PR) placebo tablet Once Daily (OD) for up to 17 weeks. Par. completed a Follow-up visit 2 weeks after receiving the last dose of study medication.
    Arm type
    		 Placebo

    Investigational medicinal product name
    Placebo
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Coated tablet
    Routes of administration
    Oral use
    Dosage and administration details
    For the ropinirole PR tablets and matching placebo the oral prolonged release / extended release tablets are white aqueous film coated capsule shaped tablets, 12.62mm x 6.91mm, with 'SB' debossed on both sides. The Investigational product will be supplied to the clinic in white HDPE 85cc bottles with a 33mm induction heat sealed child resistant cap. Each bottle will contain 18 tablets of either ropinirole PR 2mg, 4mg, 8mg or placebo to match. Subjects will be required to take one tablet per day from each dispensed bottle of medication. Each bottle will be sufficient for 14 days dosing with 4 days overage to allow some flexibility of participant visits. Participants will be instructed to take the medication at the same time every day.

    Arm title
    		 Treatment Group B: 2 mg/day
    Arm description
    		 Par. were administered a ropinirole PR tablet totalling 2 milligrams per day (mg/day), OD up to Study Week 17. Par. reaching their target dose and completing the maintenance period or withdrawing prematurely were switched to placebo for down-titration for 1 week before completing a Follow-up visit 2 weeks after receiving the last dose of study medication.
    Arm type
    		 Experimental

    Investigational medicinal product name
    Ropinirole PR
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Coated tablet
    Routes of administration
    Oral use
    Dosage and administration details
    For the ropinirole PR tablets and matching placebo the oral prolonged release / extended release tablets are white aqueous film coated capsule shaped tablets, 12.62mm x 6.91mm, with 'SB' debossed on both sides. The Investigational product will be supplied to the clinic in white HDPE 85cc bottles with a 33mm induction heat sealed child resistant cap. Each bottle will contain 18 tablets of either ropinirole PR 2mg, 4mg, 8mg or placebo to match. Subjects will be required to take one tablet per day from each dispensed bottle of medication. Each bottle will be sufficient for 14 days dosing with 4 days overage to allow some flexibility of participant visits. Participants will be instructed to take the medication at the same time every day.

    Arm title
    		 Treatment Group C: 4 mg/day
    Arm description
    		 Par. were administered a ropinirole PR tablet totalling 2 mg/day, OD for one week. Par. were up-titrated to 4 mg/day at Week 2 and continued this dose up to Study Week 17. Par. reaching their target dose and completing the maintenance period or withdrawing prematurely were down-titrated to 2 mg for 4 days and then switched to placebo for 3 days for down-titration before completing a Follow-up visit 2 weeks after receiving the last dose of study medication.
    Arm type
    		 Experimental

    Investigational medicinal product name
    Ropinirole PR
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Coated tablet
    Routes of administration
    Oral use
    Dosage and administration details
    For the ropinirole PR tablets and matching placebo the oral prolonged release / extended release tablets are white aqueous film coated capsule shaped tablets, 12.62mm x 6.91mm, with 'SB' debossed on both sides. The Investigational product will be supplied to the clinic in white HDPE 85cc bottles with a 33mm induction heat sealed child resistant cap. Each bottle will contain 18 tablets of either ropinirole PR 2mg, 4mg, 8mg or placebo to match. Subjects will be required to take one tablet per day from each dispensed bottle of medication. Each bottle will be sufficient for 14 days dosing with 4 days overage to allow some flexibility of participant visits. Participants will be instructed to take the medication at the same time every day.

    Arm title
    		 Treatment Group D: 8 mg/day
    Arm description
    		 ar. were administered a ropinirole PR tablet totalling 2 mg/day, OD for one week. Par. were up-titrated to 4 mg/day at Week 2, 6 mg/day at Week 3, and 8 mg/day at Week 4. Par. continued this dose up to Study Week 17. Par. reaching their target dose and completing the maintenance period or withdrawing prematurely were down-titrated for 1 week before completing a Follow-up visit 2 weeks after receiving the last dose of study medication.
    Arm type
    		 Experimental

    Investigational medicinal product name
    Ropinirole PR
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Coated tablet
    Routes of administration
    Oral use
    Dosage and administration details
    For the ropinirole PR tablets and matching placebo the oral prolonged release / extended release tablets are white aqueous film coated capsule shaped tablets, 12.62mm x 6.91mm, with 'SB' debossed on both sides. The Investigational product will be supplied to the clinic in white HDPE 85cc bottles with a 33mm induction heat sealed child resistant cap. Each bottle will contain 18 tablets of either ropinirole PR 2mg, 4mg, 8mg or placebo to match. Subjects will be required to take one tablet per day from each dispensed bottle of medication. Each bottle will be sufficient for 14 days dosing with 4 days overage to allow some flexibility of participant visits. Participants will be instructed to take the medication at the same time every day.

    Arm title
    		 Treatment Group E: 12 mg/day
    Arm description
    		 Par. were administered a ropinirole PR tablet totalling 2 mg/day, OD for one week. Par. were up-titrated to 4 mg/day at Week 2, 6 mg/day at Week 3, 8 mg/day at Week 4, and 12 mg/day at Week 6. Par. continued this dose up to Study Week 17. Par. reaching their target dose and completing the maintenance period or withdrawing prematurely were down-titrated for 1 week before completing a Follow-up visit 2 weeks after receiving the last dose of study medication.
    Arm type
    		 Experimental

    Investigational medicinal product name
    Ropinirole PR
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Coated tablet
    Routes of administration
    Oral use
    Dosage and administration details
    For the ropinirole PR tablets and matching placebo the oral prolonged release / extended release tablets are white aqueous film coated capsule shaped tablets, 12.62mm x 6.91mm, with 'SB' debossed on both sides. The Investigational product will be supplied to the clinic in white HDPE 85cc bottles with a 33mm induction heat sealed child resistant cap. Each bottle will contain 18 tablets of either ropinirole PR 2mg, 4mg, 8mg or placebo to match. Subjects will be required to take one tablet per day from each dispensed bottle of medication. Each bottle will be sufficient for 14 days dosing with 4 days overage to allow some flexibility of participant visits. Participants will be instructed to take the medication at the same time every day.

    Arm title
    		 Treatment Group F: 24 mg/day
    Arm description
    		 Par. were administered a ropinirole PR tablet totalling 2 mg/day, OD for one week. Par. were up-titrated to 4 mg/day at Week 2, 6 mg/day at Week 3, 8 mg/day at Week 4, 12 mg/day at Week 6, 16 mg/day at Week 8, 20 mg/day at Week 10, and 24 mg/day at Week 12. Par. continued this dose up to Study Week 17. Par. reaching their target dose and completing the maintenance or withdrawing prematurely were down-titrated for 1 week before completing a Follow-up visit 2 weeks after receiving the last dose of study medication.
    Arm type
    		 Experimental

    Investigational medicinal product name
    Ropinirole PR
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Coated tablet
    Routes of administration
    Oral use
    Dosage and administration details
    For the ropinirole PR tablets and matching placebo the oral prolonged release / extended release tablets are white aqueous film coated capsule shaped tablets, 12.62mm x 6.91mm, with 'SB' debossed on both sides. The Investigational product will be supplied to the clinic in white HDPE 85cc bottles with a 33mm induction heat sealed child resistant cap. Each bottle will contain 18 tablets of either ropinirole PR 2mg, 4mg, 8mg or placebo to match. Subjects will be required to take one tablet per day from each dispensed bottle of medication. Each bottle will be sufficient for 14 days dosing with 4 days overage to allow some flexibility of participant visits. Participants will be instructed to take the medication at the same time every day.

    Number of subjects in period 1
    		Treatment Group A: Placebo Treatment Group B: 2 mg/day Treatment Group C: 4 mg/day Treatment Group D: 8 mg/day Treatment Group E: 12 mg/day Treatment Group F: 24 mg/day
    Started
    40
    13
    41
    40
    39
    13
    Completed
    33
    12
    34
    32
    34
    9
    Not completed
    7
    1
    7
    8
    5
    4
         Consent withdrawn by subject
    2
    -
    -
    1
    1
    1
         Physician decision
    -
    -
    -
    -
    1
    -
         Adverse event, non-fatal
    2
    1
    2
    2
    1
    2
         Protocol defined stopping criteria
    1
    -
    -
    -
    1
    -
         Lost to follow-up
    -
    -
    1
    -
    -
    1
         Lack of efficacy
    2
    -
    -
    -
    -
    -
         Protocol deviation
    -
    -
    4
    5
    1
    -

    Baseline characteristics

    		 Close Top of page
    Baseline characteristics reporting groups
    Reporting group title
    Treatment Group A: Placebo
    Reporting group description
    		 Participants (par.) were administered a matching Prolonged Release (PR) placebo tablet Once Daily (OD) for up to 17 weeks. Par. completed a Follow-up visit 2 weeks after receiving the last dose of study medication.

    Reporting group title
    Treatment Group B: 2 mg/day
    Reporting group description
    		 Par. were administered a ropinirole PR tablet totalling 2 milligrams per day (mg/day), OD up to Study Week 17. Par. reaching their target dose and completing the maintenance period or withdrawing prematurely were switched to placebo for down-titration for 1 week before completing a Follow-up visit 2 weeks after receiving the last dose of study medication.

    Reporting group title
    Treatment Group C: 4 mg/day
    Reporting group description
    		 Par. were administered a ropinirole PR tablet totalling 2 mg/day, OD for one week. Par. were up-titrated to 4 mg/day at Week 2 and continued this dose up to Study Week 17. Par. reaching their target dose and completing the maintenance period or withdrawing prematurely were down-titrated to 2 mg for 4 days and then switched to placebo for 3 days for down-titration before completing a Follow-up visit 2 weeks after receiving the last dose of study medication.

    Reporting group title
    Treatment Group D: 8 mg/day
    Reporting group description
    		 ar. were administered a ropinirole PR tablet totalling 2 mg/day, OD for one week. Par. were up-titrated to 4 mg/day at Week 2, 6 mg/day at Week 3, and 8 mg/day at Week 4. Par. continued this dose up to Study Week 17. Par. reaching their target dose and completing the maintenance period or withdrawing prematurely were down-titrated for 1 week before completing a Follow-up visit 2 weeks after receiving the last dose of study medication.

    Reporting group title
    Treatment Group E: 12 mg/day
    Reporting group description
    		 Par. were administered a ropinirole PR tablet totalling 2 mg/day, OD for one week. Par. were up-titrated to 4 mg/day at Week 2, 6 mg/day at Week 3, 8 mg/day at Week 4, and 12 mg/day at Week 6. Par. continued this dose up to Study Week 17. Par. reaching their target dose and completing the maintenance period or withdrawing prematurely were down-titrated for 1 week before completing a Follow-up visit 2 weeks after receiving the last dose of study medication.

    Reporting group title
    Treatment Group F: 24 mg/day
    Reporting group description
    		 Par. were administered a ropinirole PR tablet totalling 2 mg/day, OD for one week. Par. were up-titrated to 4 mg/day at Week 2, 6 mg/day at Week 3, 8 mg/day at Week 4, 12 mg/day at Week 6, 16 mg/day at Week 8, 20 mg/day at Week 10, and 24 mg/day at Week 12. Par. continued this dose up to Study Week 17. Par. reaching their target dose and completing the maintenance or withdrawing prematurely were down-titrated for 1 week before completing a Follow-up visit 2 weeks after receiving the last dose of study medication.

    Reporting group values
    		 Treatment Group A: Placebo Treatment Group B: 2 mg/day Treatment Group C: 4 mg/day Treatment Group D: 8 mg/day Treatment Group E: 12 mg/day Treatment Group F: 24 mg/day Total
    Number of subjects
    		 40 13 41 40 39 13 186
    Age categorical
    Units: Subjects
    Age continuous
    Units: years
        arithmetic mean (standard deviation)
    		 63.1 ( 8.82 ) 58.2 ( 11.12 ) 62.1 ( 11.38 ) 60.3 ( 11.72 ) 61.7 ( 10.78 ) 62.5 ( 12.88 ) -
    Gender categorical
    Units: Subjects
        Female
    		 17 5 16 28 19 6 91
        Male
    		 23 8 25 12 20 7 95
    Race, Customized
    Units: Subjects
        African American/African Heritage
    		 2 0 0 0 0 0 2
        Asian - East Asian Heritage
    		 2 0 1 5 2 1 11
        Asian - Japanese Heritage
    		 0 0 1 0 0 0 1
        Asian - South East Asian Heritage
    		 0 0 0 1 0 0 1
        White - White/Caucasian/European Heritage
    		 36 13 39 34 36 12 170
        Missing
    		 0 0 0 0 1 0 1

    End points

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    End points reporting groups
    Reporting group title
    Treatment Group A: Placebo
    Reporting group description
    		 Participants (par.) were administered a matching Prolonged Release (PR) placebo tablet Once Daily (OD) for up to 17 weeks. Par. completed a Follow-up visit 2 weeks after receiving the last dose of study medication.

    Reporting group title
    Treatment Group B: 2 mg/day
    Reporting group description
    		 Par. were administered a ropinirole PR tablet totalling 2 milligrams per day (mg/day), OD up to Study Week 17. Par. reaching their target dose and completing the maintenance period or withdrawing prematurely were switched to placebo for down-titration for 1 week before completing a Follow-up visit 2 weeks after receiving the last dose of study medication.

    Reporting group title
    Treatment Group C: 4 mg/day
    Reporting group description
    		 Par. were administered a ropinirole PR tablet totalling 2 mg/day, OD for one week. Par. were up-titrated to 4 mg/day at Week 2 and continued this dose up to Study Week 17. Par. reaching their target dose and completing the maintenance period or withdrawing prematurely were down-titrated to 2 mg for 4 days and then switched to placebo for 3 days for down-titration before completing a Follow-up visit 2 weeks after receiving the last dose of study medication.

    Reporting group title
    Treatment Group D: 8 mg/day
    Reporting group description
    		 ar. were administered a ropinirole PR tablet totalling 2 mg/day, OD for one week. Par. were up-titrated to 4 mg/day at Week 2, 6 mg/day at Week 3, and 8 mg/day at Week 4. Par. continued this dose up to Study Week 17. Par. reaching their target dose and completing the maintenance period or withdrawing prematurely were down-titrated for 1 week before completing a Follow-up visit 2 weeks after receiving the last dose of study medication.

    Reporting group title
    Treatment Group E: 12 mg/day
    Reporting group description
    		 Par. were administered a ropinirole PR tablet totalling 2 mg/day, OD for one week. Par. were up-titrated to 4 mg/day at Week 2, 6 mg/day at Week 3, 8 mg/day at Week 4, and 12 mg/day at Week 6. Par. continued this dose up to Study Week 17. Par. reaching their target dose and completing the maintenance period or withdrawing prematurely were down-titrated for 1 week before completing a Follow-up visit 2 weeks after receiving the last dose of study medication.

    Reporting group title
    Treatment Group F: 24 mg/day
    Reporting group description
    		 Par. were administered a ropinirole PR tablet totalling 2 mg/day, OD for one week. Par. were up-titrated to 4 mg/day at Week 2, 6 mg/day at Week 3, 8 mg/day at Week 4, 12 mg/day at Week 6, 16 mg/day at Week 8, 20 mg/day at Week 10, and 24 mg/day at Week 12. Par. continued this dose up to Study Week 17. Par. reaching their target dose and completing the maintenance or withdrawing prematurely were down-titrated for 1 week before completing a Follow-up visit 2 weeks after receiving the last dose of study medication.

    Primary: Change From Baseline (BL) in Unified Parkinson Disease (PD) Rating Scale (UPDRS) Motor Score

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    End point title
    		 Change From Baseline (BL) in Unified Parkinson Disease (PD) Rating Scale (UPDRS) Motor Score
    End point description
    The UPDRS is a clinician based rating scale used to measure motor impairments and disability assessing six features of PD impairment. These are evaluated with data collected by interview and examination of the participant. One of the six features include the Part III–Motor Examination where scores range 0-108 and the maximum score indicates the worse condition. BL is defined as the last non-missing value on or before the first dose date. The change from BL was calculated by subtracting the BL values from the individual post-randomization values. The least squares(LS) means were estimated using the mixed model repeated measures(MMRM) adjusting for BL UPDRS motor score and race(white versus other) or by using the non-parametric rank analysis of covariance(ANCOVA). Intent to Treat (ITT) Population: all randomized participants who received at least one dose of study medication, had a BL efficacy assessment for the specific outcome, and at least one respective post-BL efficacy assessment.
    End point type
    Primary
    End point timeframe
    Baseline (BL) and Week 4 of the Maintenance Period (Study Week 17)
    End point values
    		 Treatment Group A: Placebo Treatment Group B: 2 mg/day Treatment Group C: 4 mg/day Treatment Group D: 8 mg/day Treatment Group E: 12 mg/day Treatment Group F: 24 mg/day
    Number of subjects analysed
    33 [1]
    13 [2]
    34 [3]
    33 [4]
    34 [5]
    10 [6]
    Units: Score on a scale
        least squares mean (confidence interval 95%)
    -1.91 (-4.15 to 0.34)
    -1.58 (-5.02 to 1.86)
    -2.76 (-5.04 to -0.49)
    -4.31 (-6.48 to -2.15)
    -4.07 (-6.32 to -1.82)
    -2.83 (-6.61 to 0.95)
    Notes
    [1] - Intent to Treat (ITT) Population
    [2] - Intent to Treat (ITT) Population
    [3] - Intent to Treat (ITT) Population
    [4] - Intent to Treat (ITT) Population
    [5] - Intent to Treat (ITT) Population
    [6] - Intent to Treat (ITT) Population
    Statistical analysis title
    		 Statistical analysis 1
    Statistical analysis description
    LS Mean Difference vs Placebo
    Comparison groups
    Treatment Group A: Placebo v Treatment Group B: 2 mg/day
    Number of subjects included in analysis
    46
    Analysis specification
    Pre-specified
    Analysis type
    		 other
    P-value
    		 = 0.864 [7]
    Method
    		 Mixed models analysis
    Parameter type
    		 Mean difference (final values)
    Point estimate
    0.33
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -3.41
         upper limit
    		 4.05
    Notes
    [7] - P-values are from a Mixed Model Repeated Measures analysis.
    Statistical analysis title
    		 Statistical analysis 2
    Statistical analysis description
    LS Mean Difference vs Placebo
    Comparison groups
    Treatment Group A: Placebo v Treatment Group C: 4 mg/day
    Number of subjects included in analysis
    67
    Analysis specification
    Pre-specified
    Analysis type
    		 other
    P-value
    		 = 0.539 [8]
    Method
    		 Mixed models analysis
    Parameter type
    		 Mean difference (final values)
    Point estimate
    -0.85
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -3.61
         upper limit
    		 1.9
    Notes
    [8] - P-values are from a Mixed Model Repeated Measures analysis.
    Statistical analysis title
    		 Statistical analysis 3
    Statistical analysis description
    LS Mean Difference vs Placebo
    Comparison groups
    Treatment Group A: Placebo v Treatment Group D: 8 mg/day
    Number of subjects included in analysis
    66
    Analysis specification
    Pre-specified
    Analysis type
    		 other
    P-value
    		 = 0.091 [9]
    Method
    		 Mixed models analysis
    Parameter type
    		 Mean difference (final values)
    Point estimate
    -2.4
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -5.21
         upper limit
    		 0.39
    Notes
    [9] - P-values are from a Mixed Model Repeated Measures analysis.
    Statistical analysis title
    		 Statistical analysis 4
    Statistical analysis description
    LS Mean Difference vs Placebo
    Comparison groups
    Treatment Group A: Placebo v Treatment Group E: 12 mg/day
    Number of subjects included in analysis
    67
    Analysis specification
    Pre-specified
    Analysis type
    		 other
    P-value
    		 = 0.124 [10]
    Method
    		 Mixed models analysis
    Parameter type
    		 Mean difference (final values)
    Point estimate
    -2.16
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -4.93
         upper limit
    		 0.6
    Notes
    [10] - P-values are from a Mixed Model Repeated Measures analysis.
    Statistical analysis title
    		 Statistical analysis 5
    Statistical analysis description
    LS Mean Difference vs Placebo
    Comparison groups
    Treatment Group A: Placebo v Treatment Group F: 24 mg/day
    Number of subjects included in analysis
    43
    Analysis specification
    Pre-specified
    Analysis type
    		 other
    P-value
    		 = 0.658 [11]
    Method
    		 Mixed models analysis
    Parameter type
    		 Mean difference (final values)
    Point estimate
    -0.92
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -5.04
         upper limit
    		 3.19
    Notes
    [11] - P-values are from a Mixed Model Repeated Measures analysis.
    Statistical analysis title
    		 Statistical analysis 6
    Comparison groups
    Treatment Group A: Placebo v Treatment Group B: 2 mg/day
    Number of subjects included in analysis
    46
    Analysis specification
    Pre-specified
    Analysis type
    		 other
    P-value
    		 = 0.439 [12]
    Method
    		 ANCOVA
    Confidence interval
    Notes
    [12] - P-values are from nonparametric rank ANCOVA without stratifications.
    Statistical analysis title
    		 Statistical analysis 7
    Comparison groups
    Treatment Group A: Placebo v Treatment Group C: 4 mg/day
    Number of subjects included in analysis
    67
    Analysis specification
    Pre-specified
    Analysis type
    		 other
    P-value
    		 = 0.177 [13]
    Method
    		 ANCOVA
    Confidence interval
    Notes
    [13] - P-values are from nonparametric rank ANCOVA without stratifications.
    Statistical analysis title
    		 Statistical analysis 8
    Comparison groups
    Treatment Group A: Placebo v Treatment Group D: 8 mg/day
    Number of subjects included in analysis
    66
    Analysis specification
    Pre-specified
    Analysis type
    		 other
    P-value
    		 = 0.06 [14]
    Method
    		 ANCOVA
    Confidence interval
    Notes
    [14] - P-values are from nonparametric rank ANCOVA without stratifications.
    Statistical analysis title
    		 Statistical analysis 9
    Comparison groups
    Treatment Group A: Placebo v Treatment Group E: 12 mg/day
    Number of subjects included in analysis
    67
    Analysis specification
    Pre-specified
    Analysis type
    		 other
    P-value
    		 = 0.047 [15]
    Method
    		 ANCOVA
    Confidence interval
    Notes
    [15] - P-values are from nonparametric rank ANCOVA without stratifications.
    Statistical analysis title
    		 Statistical analysis 10
    Comparison groups
    Treatment Group A: Placebo v Treatment Group F: 24 mg/day
    Number of subjects included in analysis
    43
    Analysis specification
    Pre-specified
    Analysis type
    		 other
    P-value
    		 = 0.407 [16]
    Method
    		 ANCOVA
    Confidence interval
    Notes
    [16] - P-values are from nonparametric rank ANCOVA without stratifications.

    Secondary: Number of participants with a >=5 points reduction from Baseline in UPDRS motor score

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    End point title
    		 Number of participants with a >=5 points reduction from Baseline in UPDRS motor score
    End point description
    The UPDRS motor scores can range from 0-108 where the maximum score indicates the worse condition. Baseline is defined as the last non-missing assessment measured on or before the first dose date. The change from Baseline will be calculated by subtracting the Baseline values from the individual post-randomization values. All participants with a non-missing efficacy observation at Baseline and during the maintenance period were analyzed.
    End point type
    Secondary
    End point timeframe
    Baseline and Week 4 of the Maintenance Period (Study Week 17)
    End point values
    		 Treatment Group A: Placebo Treatment Group B: 2 mg/day Treatment Group C: 4 mg/day Treatment Group D: 8 mg/day Treatment Group E: 12 mg/day Treatment Group F: 24 mg/day
    Number of subjects analysed
    35 [17]
    13 [18]
    35 [19]
    33 [20]
    34 [21]
    10 [22]
    Units: Participants
        number (not applicable)
    9
    6
    14
    16
    19
    5
    Notes
    [17] - ITT Population
    [18] - ITT Population
    [19] - ITT Population
    [20] - ITT Population
    [21] - ITT Population
    [22] - ITT Population
    Statistical analysis title
    		 Statistical analysis 1
    Comparison groups
    Treatment Group A: Placebo v Treatment Group B: 2 mg/day
    Number of subjects included in analysis
    48
    Analysis specification
    Pre-specified
    Analysis type
    		 other
    P-value
    		 = 0.397
    Method
    		 Generalized Estimating Equations model
    Parameter type
    		 Odds ratio (OR)
    Point estimate
    2.003
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.4
         upper limit
    		 9.98
    Statistical analysis title
    		 Statistical analysis 2
    Comparison groups
    Treatment Group A: Placebo v Treatment Group C: 4 mg/day
    Number of subjects included in analysis
    70
    Analysis specification
    Pre-specified
    Analysis type
    		 other
    P-value
    		 = 0.131
    Method
    		 Generalized Estimating Equations model
    Parameter type
    		 Odds ratio (OR)
    Point estimate
    2.242
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.79
         upper limit
    		 6.4
    Statistical analysis title
    		 Statistical analysis 3
    Comparison groups
    Treatment Group A: Placebo v Treatment Group D: 8 mg/day
    Number of subjects included in analysis
    68
    Analysis specification
    Pre-specified
    Analysis type
    		 other
    P-value
    		 = 0.018
    Method
    		 Generalized Estimating Equations model
    Parameter type
    		 Odds ratio (OR)
    Point estimate
    3.515
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 1.25
         upper limit
    		 9.92
    Statistical analysis title
    		 Statistical analysis 4
    Comparison groups
    Treatment Group A: Placebo v Treatment Group E: 12 mg/day
    Number of subjects included in analysis
    69
    Analysis specification
    Pre-specified
    Analysis type
    		 other
    P-value
    		 = 0.02
    Method
    		 Generalized Estimating Equations model
    Parameter type
    		 Odds ratio (OR)
    Point estimate
    3.607
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 1.22
         upper limit
    		 10.64
    Statistical analysis title
    		 Statistical analysis 5
    Comparison groups
    Treatment Group A: Placebo v Treatment Group F: 24 mg/day
    Number of subjects included in analysis
    45
    Analysis specification
    Pre-specified
    Analysis type
    		 other
    P-value
    		 = 0.202
    Method
    		 Generalized Estimating Equations model
    Parameter type
    		 Odds ratio (OR)
    Point estimate
    2.679
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.59
         upper limit
    		 12.16

    Secondary: Number of participants with a >=10 points reduction from Baseline in UPDRS motor score

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    End point title
    		 Number of participants with a >=10 points reduction from Baseline in UPDRS motor score
    End point description
    The UPDRS motor scores can range from 0-108 where the maximum score indicates the worse condition. Baseline is defined as the last non-missing assessment measured on or before the first dose date. The change from Baseline will be calculated by subtracting the Baseline values from the individual post-randomization values. All participants with a non-missing efficacy observation at Baseline and during the maintenance period were analyzed
    End point type
    Secondary
    End point timeframe
    Baseline and Week 4 of the Maintenance Period (Study Week 17)
    End point values
    		 Treatment Group A: Placebo Treatment Group B: 2 mg/day Treatment Group C: 4 mg/day Treatment Group D: 8 mg/day Treatment Group E: 12 mg/day Treatment Group F: 24 mg/day
    Number of subjects analysed
    35 [23]
    13 [24]
    35 [25]
    33 [26]
    34 [27]
    10 [28]
    Units: Participants
        number (not applicable)
    5
    3
    7
    7
    9
    2
    Notes
    [23] - ITT Population
    [24] - ITT Population
    [25] - ITT Population
    [26] - ITT Population
    [27] - ITT Population
    [28] - ITT Population
    Statistical analysis title
    		 Statistical analysis 1
    Comparison groups
    Treatment Group A: Placebo v Treatment Group B: 2 mg/day
    Number of subjects included in analysis
    48
    Analysis specification
    Pre-specified
    Analysis type
    		 other
    P-value
    		 = 0.662
    Method
    		 Generalized Estimating Equations model
    Parameter type
    		 Odds ratio (OR)
    Point estimate
    1.544
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.22
         upper limit
    		 10.84
    Statistical analysis title
    		 Statistical analysis 2
    Comparison groups
    Treatment Group A: Placebo v Treatment Group C: 4 mg/day
    Number of subjects included in analysis
    70
    Analysis specification
    Pre-specified
    Analysis type
    		 other
    P-value
    		 = 0.557
    Method
    		 Generalized Estimating Equations model
    Parameter type
    		 Odds ratio (OR)
    Point estimate
    1.485
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.4
         upper limit
    		 5.55
    Statistical analysis title
    		 Statistical analysis 3
    Comparison groups
    Treatment Group A: Placebo v Treatment Group D: 8 mg/day
    Number of subjects included in analysis
    68
    Analysis specification
    Pre-specified
    Analysis type
    		 other
    P-value
    		 = 0.347
    Method
    		 Generalized Estimating Equations model
    Parameter type
    		 Odds ratio (OR)
    Point estimate
    1.855
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.51
         upper limit
    		 6.72
    Statistical analysis title
    		 Statistical analysis 4
    Comparison groups
    Treatment Group A: Placebo v Treatment Group E: 12 mg/day
    Number of subjects included in analysis
    69
    Analysis specification
    Pre-specified
    Analysis type
    		 other
    P-value
    		 = 0.379
    Method
    		 Generalized Estimating Equations model
    Parameter type
    		 Odds ratio (OR)
    Point estimate
    1.776
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.49
         upper limit
    		 6.38
    Statistical analysis title
    		 Statistical analysis 5
    Comparison groups
    Treatment Group A: Placebo v Treatment Group F: 24 mg/day
    Number of subjects included in analysis
    45
    Analysis specification
    Pre-specified
    Analysis type
    		 other
    P-value
    		 = 0.851
    Method
    		 Generalized Estimating Equations model
    Parameter type
    		 Odds ratio (OR)
    Point estimate
    1.194
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.19
         upper limit
    		 7.63

    Secondary: Number of participants with a >=10 points reduction from Baseline in UPDRS Parts II and III combined

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    End point title
    		 Number of participants with a >=10 points reduction from Baseline in UPDRS Parts II and III combined
    End point description
    The UPDRS Part II is the Activities of Daily Living (ADL) score and can range from 0-52 as determined by the physician. The UPDRS Part III is the Motor Examination (Total Motor Score [TMS]) and is defined as the total score, ranging from 0-108 as determined by the physician, of the tests given in the motor examination section. The combined scores of Parts II and III can range from 0-160 with the higher score indicating the worse condition. Tests were performed when the participant is in the "on" state of Parkinson's. Baseline is defined as the last non-missing assessment measured on or before the first dose date. All participants with a non-missing efficacy observation at Baseline and during the maintenance period were analyzed.
    End point type
    Secondary
    End point timeframe
    Baseline and Week 4 of the Maintenance Period (Study Week 17)
    End point values
    		 Treatment Group A: Placebo Treatment Group B: 2 mg/day Treatment Group C: 4 mg/day Treatment Group D: 8 mg/day Treatment Group E: 12 mg/day Treatment Group F: 24 mg/day
    Number of subjects analysed
    35 [29]
    13 [30]
    35 [31]
    33 [32]
    34 [33]
    10 [34]
    Units: Participants
        number (not applicable)
    6
    3
    7
    10
    12
    5
    Notes
    [29] - ITT Population
    [30] - ITT Population
    [31] - ITT Population
    [32] - ITT Population
    [33] - ITT Population
    [34] - ITT Population
    No statistical analyses for this end point

    Secondary: Responder rate defined as participants with a >=30% reduction in Baseline UPDRS motor score

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    End point title
    		 Responder rate defined as participants with a >=30% reduction in Baseline UPDRS motor score
    End point description
    The responder rate is defined as the percentage of participants with a greater than or equal to (>=)30% reduction in their individual Baseline UPDRS motor score at Week 4 of the Maintenance Period (Study Week 17). Baseline is defined as the last non-missing assessment measured on or before the first dose date. The change from Baseline will be calculated by subtracting the Baseline values from the individual post-randomization values. All participants with a non-missing efficacy observation at Baseline and during the maintenance period were analyzed.
    End point type
    Secondary
    End point timeframe
    Baseline and Week 4 of the Maintenance Period (Study Week 17)
    End point values
    		 Treatment Group A: Placebo Treatment Group B: 2 mg/day Treatment Group C: 4 mg/day Treatment Group D: 8 mg/day Treatment Group E: 12 mg/day Treatment Group F: 24 mg/day
    Number of subjects analysed
    35 [35]
    13 [36]
    35 [37]
    33 [38]
    34 [39]
    10 [40]
    Units: Percentage of participants
        number (not applicable)
    18
    31
    23
    30
    38
    31
    Notes
    [35] - ITT Population
    [36] - ITT Population
    [37] - ITT Population
    [38] - ITT Population
    [39] - ITT Population
    [40] - ITT Population
    Statistical analysis title
    		 Statistical analysis 1
    Comparison groups
    Treatment Group B: 2 mg/day v Treatment Group A: Placebo
    Number of subjects included in analysis
    48
    Analysis specification
    Pre-specified
    Analysis type
    		 other
    P-value
    		 = 0.54
    Method
    		 Generalized Estimating Equations model
    Parameter type
    		 Odds ratio (OR)
    Point estimate
    1.591
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.36
         upper limit
    		 7.03
    Statistical analysis title
    		 Statistical analysis 2
    Comparison groups
    Treatment Group A: Placebo v Treatment Group C: 4 mg/day
    Number of subjects included in analysis
    70
    Analysis specification
    Pre-specified
    Analysis type
    		 other
    P-value
    		 = 0.494
    Method
    		 Generalized Estimating Equations model
    Parameter type
    		 Odds ratio (OR)
    Point estimate
    1.473
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.49
         upper limit
    		 4.47
    Statistical analysis title
    		 Statistical analysis 3
    Comparison groups
    Treatment Group A: Placebo v Treatment Group D: 8 mg/day
    Number of subjects included in analysis
    68
    Analysis specification
    Pre-specified
    Analysis type
    		 other
    P-value
    		 = 0.115
    Method
    		 Generalized Estimating Equations model
    Parameter type
    		 Odds ratio (OR)
    Point estimate
    2.391
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.81
         upper limit
    		 7.06
    Statistical analysis title
    		 Statistical analysis 4
    Comparison groups
    Treatment Group A: Placebo v Treatment Group E: 12 mg/day
    Number of subjects included in analysis
    69
    Analysis specification
    Pre-specified
    Analysis type
    		 other
    P-value
    		 = 0.045
    Method
    		 Generalized Estimating Equations model
    Parameter type
    		 Odds ratio (OR)
    Point estimate
    2.96
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 1.02
         upper limit
    		 8.55
    Statistical analysis title
    		 Statistical analysis 5
    Comparison groups
    Treatment Group A: Placebo v Treatment Group F: 24 mg/day
    Number of subjects included in analysis
    45
    Analysis specification
    Pre-specified
    Analysis type
    		 other
    P-value
    		 = 0.221
    Method
    		 Generalized Estimating Equations model
    Parameter type
    		 Odds ratio (OR)
    Point estimate
    2.506
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.58
         upper limit
    		 10.9

    Secondary: Change from Baseline in UPDRS Parts II and III combined

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    End point title
    		 Change from Baseline in UPDRS Parts II and III combined
    End point description
    The UPDRS Part II is the Activities of Daily Living (ADL) score and can range from 0-52 as determined by the physician. The UPDRS Part III is the Motor Examination (Total Motor Score [TMS]) and is defined as the total score, ranging from 0-108 as determined by the physician, of the tests given in the motor examination section. The combined scores of Parts II and III can range from 0-160 with the higher score indicating the worse condition. Tests were performed when the participant is in the "on" state of Parkinson's. Baseline is defined as the last non-missing assessment measured on or before the first dose date. The change from Baseline will be calculated by subtracting the Baseline values from the individual post-randomization values. All participants with a non-missing efficacy observation at Baseline and during the maintenance period were analyzed.
    End point type
    Secondary
    End point timeframe
    Baseline and Week 4 of the Maintenance Period (Study Week 17)
    End point values
    		 Treatment Group A: Placebo Treatment Group B: 2 mg/day Treatment Group C: 4 mg/day Treatment Group D: 8 mg/day Treatment Group E: 12 mg/day Treatment Group F: 24 mg/day
    Number of subjects analysed
    28 [41]
    13 [42]
    32 [43]
    31 [44]
    32 [45]
    10 [46]
    Units: Scores on a scale
        least squares mean (confidence interval 95%)
    -2.88 (-5.87 to 0.1)
    -1.81 (-6.18 to 2.57)
    -3.81 (-6.76 to -0.85)
    -5.63 (-8.44 to -2.81)
    -6.62 (-9.51 to -3.72)
    -3.87 (-8.68 to 0.94)
    Notes
    [41] - ITT Population
    [42] - ITT Population
    [43] - ITT Population
    [44] - ITT Population
    [45] - ITT Population
    [46] - ITT Population
    Statistical analysis title
    		 Statistical analysis 1
    Statistical analysis description
    LS Mean Difference vs Placebo
    Comparison groups
    Treatment Group A: Placebo v Treatment Group B: 2 mg/day
    Number of subjects included in analysis
    41
    Analysis specification
    Pre-specified
    Analysis type
    		 other
    P-value
    		 = 0.662 [47]
    Method
    		 Mixed models analysis
    Parameter type
    		 Mean difference (final values)
    Point estimate
    1.07
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -3.78
         upper limit
    		 5.93
    Notes
    [47] - The P-value was calculated using Mixed Model Repeated Measures analysis
    Statistical analysis title
    		 Statistical analysis 2
    Statistical analysis description
    LS Mean Difference vs Placebo
    Comparison groups
    Treatment Group A: Placebo v Treatment Group C: 4 mg/day
    Number of subjects included in analysis
    60
    Analysis specification
    Pre-specified
    Analysis type
    		 other
    P-value
    		 = 0.621 [48]
    Method
    		 Mixed models analysis
    Parameter type
    		 Mean difference (final values)
    Point estimate
    -0.93
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -4.63
         upper limit
    		 2.77
    Notes
    [48] - The P-value was calculated using Mixed Model Repeated Measures analysis
    Statistical analysis title
    		 Statistical analysis 3
    Statistical analysis description
    LS Mean Difference vs Placebo
    Comparison groups
    Treatment Group A: Placebo v Treatment Group D: 8 mg/day
    Number of subjects included in analysis
    59
    Analysis specification
    Pre-specified
    Analysis type
    		 other
    P-value
    		 = 0.15 [49]
    Method
    		 Mixed models analysis
    Parameter type
    		 Mean difference (final values)
    Point estimate
    -2.75
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -6.5
         upper limit
    		 1.01
    Notes
    [49] - The P-value was calculated using Mixed Model Repeated Measures analysis
    Statistical analysis title
    		 Statistical analysis 4
    Statistical analysis description
    LS Mean Difference vs Placebo
    Comparison groups
    Treatment Group A: Placebo v Treatment Group E: 12 mg/day
    Number of subjects included in analysis
    60
    Analysis specification
    Pre-specified
    Analysis type
    		 other
    P-value
    		 = 0.048 [50]
    Method
    		 Mixed models analysis
    Parameter type
    		 Mean difference (final values)
    Point estimate
    -3.74
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -7.43
         upper limit
    		 -0.04
    Notes
    [50] - The P-value was calculated using Mixed Model Repeated Measures analysis
    Statistical analysis title
    		 Statistical analysis 5
    Statistical analysis description
    LS Mean Difference vs Placebo
    Comparison groups
    Treatment Group A: Placebo v Treatment Group F: 24 mg/day
    Number of subjects included in analysis
    38
    Analysis specification
    Pre-specified
    Analysis type
    		 other
    P-value
    		 = 0.715 [51]
    Method
    		 Mixed models analysis
    Parameter type
    		 Mean difference (final values)
    Point estimate
    -0.99
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -6.32
         upper limit
    		 4.35
    Notes
    [51] - The P-value was calculated using Mixed Model Repeated Measures analysis

    Secondary: Change from Baseline in UPDRS Activities of Daily Living

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    End point title
    		 Change from Baseline in UPDRS Activities of Daily Living
    End point description
    The UPDRS Part II is the Activities of Daily Living (ADL) score and can range from 0-52 as determined by the physician. The higher score indicates the worse condition. Tests were performed when the participant is in the "on" state of Parkinson's. Baseline is defined as the last non-missing assessment measured on or before the first dose date. The change from Baseline will be calculated by subtracting the Baseline values from the individual post-randomization values. All participants with a non-missing efficacy observation at Baseline and during the maintenance period were analyzed.
    End point type
    Secondary
    End point timeframe
    Baseline and Week 4 of the Maintenance Period (Study Week 17)
    End point values
    		 Treatment Group A: Placebo Treatment Group B: 2 mg/day Treatment Group C: 4 mg/day Treatment Group D: 8 mg/day Treatment Group E: 12 mg/day Treatment Group F: 24 mg/day
    Number of subjects analysed
    27 [52]
    11 [53]
    28 [54]
    28 [55]
    25 [56]
    7 [57]
    Units: Score on a scale
        least squares mean (confidence interval 95%)
    -0.26 (-1.23 to 0.72)
    0.91 (-0.58 to 2.41)
    -0.73 (-1.74 to 0.27)
    -1.13 (-2.08 to -0.17)
    -1.27 (-2.32 to -0.22)
    -0.99 (-2.77 to 0.79)
    Notes
    [52] - ITT Population
    [53] - ITT Population
    [54] - ITT Population
    [55] - ITT Population
    [56] - ITT Population
    [57] - ITT Population
    Statistical analysis title
    		 Statistical Analysis 1
    Statistical analysis description
    LS Mean Difference vs Placebo
    Comparison groups
    Treatment Group A: Placebo v Treatment Group B: 2 mg/day
    Number of subjects included in analysis
    38
    Analysis specification
    Pre-specified
    Analysis type
    		 other
    P-value
    		 = 0.158 [58]
    Method
    		 Mixed models analysis
    Parameter type
    		 Mean difference (final values)
    Point estimate
    1.17
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -0.46
         upper limit
    		 2.81
    Notes
    [58] - The P-value was calculated using Mixed Model Repeated Measures analysis
    Statistical analysis title
    		 Statistical Analysis 2
    Statistical analysis description
    LS Mean Difference vs Placebo
    Comparison groups
    Treatment Group A: Placebo v Treatment Group C: 4 mg/day
    Number of subjects included in analysis
    55
    Analysis specification
    Pre-specified
    Analysis type
    		 other
    P-value
    		 = 0.446 [59]
    Method
    		 Mixed models analysis
    Parameter type
    		 Mean difference (final values)
    Point estimate
    -0.47
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -1.71
         upper limit
    		 0.76
    Notes
    [59] - The P-value was calculated using Mixed Model Repeated Measures analysis
    Statistical analysis title
    		 Statistical Analysis 3
    Statistical analysis description
    LS Mean Difference vs Placebo
    Comparison groups
    Treatment Group A: Placebo v Treatment Group D: 8 mg/day
    Number of subjects included in analysis
    55
    Analysis specification
    Pre-specified
    Analysis type
    		 other
    P-value
    		 = 0.163 [60]
    Method
    		 Mixed models analysis
    Parameter type
    		 Mean difference (final values)
    Point estimate
    -0.87
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -2.1
         upper limit
    		 0.36
    Notes
    [60] - The P-value was calculated using Mixed Model Repeated Measures analysis
    Statistical analysis title
    		 Statistical Analysis 4
    Statistical analysis description
    LS Mean Difference vs Placebo
    Comparison groups
    Treatment Group A: Placebo v Treatment Group E: 12 mg/day
    Number of subjects included in analysis
    52
    Analysis specification
    Pre-specified
    Analysis type
    		 other
    P-value
    		 = 0.117 [61]
    Method
    		 Mixed models analysis
    Parameter type
    		 Mean difference (final values)
    Point estimate
    -1.01
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -2.27
         upper limit
    		 0.25
    Notes
    [61] - The P-value was calculated using Mixed Model Repeated Measures analysis
    Statistical analysis title
    		 Statistical Analysis 5
    Statistical analysis description
    LS Mean Difference vs Placebo
    Comparison groups
    Treatment Group A: Placebo v Treatment Group F: 24 mg/day
    Number of subjects included in analysis
    34
    Analysis specification
    Pre-specified
    Analysis type
    		 other
    P-value
    		 = 0.456 [62]
    Method
    		 Mixed models analysis
    Parameter type
    		 Mean difference (final values)
    Point estimate
    -0.73
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -2.67
         upper limit
    		 1.2
    Notes
    [62] - The P-value was calculated using Mixed Model Repeated Measures analysis

    Secondary: Change from Baseline in the total UPDRS score (Parts I-III)

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    End point title
    		 Change from Baseline in the total UPDRS score (Parts I-III)
    End point description
    The total UPDRS score was calculated by the sum of the values for each component (Part I + Part II + Part III) as determined by the physician. The UPDRS Part I scores mentation, behavior and mood and scores can range from 0-16. The UPDRS Part II is the Activities of Daily Living (ADL) score and can range from 0-52. The UPDRS Part III is the Motor Examination (Total Motor Score [TMS]) and scores range from 0-108. The total UPDRS (Part I + II + III) scores can range from 0-176 with the higher score indicating the worse condition. Tests were performed when the participant is in the "on" state of Parkinson's. Baseline is defined as the last non-missing assessment measured on or before the first dose date. The change from Baseline will be calculated by subtracting the Baseline values from the individual postrandomization values. All participants with a non-missing efficacy observation at Baseline and during the maintenance period were analyzed.
    End point type
    Secondary
    End point timeframe
    Baseline and Week 4 of the Maintenance Period (Study Week 17)
    End point values
    		 Treatment Group A: Placebo Treatment Group B: 2 mg/day Treatment Group C: 4 mg/day Treatment Group D: 8 mg/day Treatment Group E: 12 mg/day Treatment Group F: 24 mg/day
    Number of subjects analysed
    28 [63]
    13 [64]
    32 [65]
    31 [66]
    32 [67]
    10 [68]
    Units: Score on a scale
        least squares mean (confidence interval 95%)
    -2.74 (-5.79 to 0.31)
    -2.18 (-6.65 to 2.29)
    -3.83 (-6.85 to -0.81)
    -5.93 (-8.8 to -3.06)
    -6.68 (-9.64 to -3.71)
    -3.4 (-8.3 to 1.5)
    Notes
    [63] - ITT Population
    [64] - ITT Population
    [65] - ITT Population
    [66] - ITT Population
    [67] - ITT Population
    [68] - ITT Population
    Statistical analysis title
    		 Statistical Analysis 1
    Statistical analysis description
    LS Mean Difference vs Placebo
    Comparison groups
    Treatment Group A: Placebo v Treatment Group B: 2 mg/day
    Number of subjects included in analysis
    41
    Analysis specification
    Pre-specified
    Analysis type
    		 other
    P-value
    		 = 0.823 [69]
    Method
    		 Mixed models analysis
    Parameter type
    		 Mean difference (final values)
    Point estimate
    0.56
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -4.38
         upper limit
    		 5.5
    Notes
    [69] - The P-value was calculated using Mixed Model Repeated Measures analysis
    Statistical analysis title
    		 Statistical Analysis 2
    Statistical analysis description
    LS Mean Difference vs Placebo
    Comparison groups
    Treatment Group A: Placebo v Treatment Group C: 4 mg/day
    Number of subjects included in analysis
    60
    Analysis specification
    Pre-specified
    Analysis type
    		 other
    P-value
    		 = 0.568 [70]
    Method
    		 Mixed models analysis
    Parameter type
    		 Mean difference (final values)
    Point estimate
    -1.09
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -4.86
         upper limit
    		 2.68
    Notes
    [70] - The P-value was calculated using Mixed Model Repeated Measures analysis
    Statistical analysis title
    		 Statistical Analysis 3
    Statistical analysis description
    LS Mean Difference vs Placebo
    Comparison groups
    Treatment Group A: Placebo v Treatment Group D: 8 mg/day
    Number of subjects included in analysis
    59
    Analysis specification
    Pre-specified
    Analysis type
    		 other
    P-value
    		 = 0.101 [71]
    Method
    		 Mixed models analysis
    Parameter type
    		 Mean difference (final values)
    Point estimate
    -3.19
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -7.01
         upper limit
    		 0.63
    Notes
    [71] - The P-value was calculated using Mixed Model Repeated Measures analysis
    Statistical analysis title
    		 Statistical Analysis 4
    Statistical analysis description
    LS Mean Difference vs Placebo
    Comparison groups
    Treatment Group A: Placebo v Treatment Group E: 12 mg/day
    Number of subjects included in analysis
    60
    Analysis specification
    Pre-specified
    Analysis type
    		 other
    P-value
    		 = 0.04 [72]
    Method
    		 Mixed models analysis
    Parameter type
    		 Mean difference (final values)
    Point estimate
    -3.94
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -7.7
         upper limit
    		 -0.18
    Notes
    [72] - The P-value was calculated using Mixed Model Repeated Measures analysis
    Statistical analysis title
    		 Statistical Analysis 5
    Statistical analysis description
    LS Mean Difference vs Placebo
    Comparison groups
    Treatment Group A: Placebo v Treatment Group F: 24 mg/day
    Number of subjects included in analysis
    38
    Analysis specification
    Pre-specified
    Analysis type
    		 other
    P-value
    		 = 0.811 [73]
    Method
    		 Mixed models analysis
    Parameter type
    		 Mean difference (final values)
    Point estimate
    -0.66
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -6.08
         upper limit
    		 4.77
    Notes
    [73] - The P-value was calculated using Mixed Model Repeated Measures analysis

    Secondary: Change from Baseline in the UPDRS Part I (mentation)

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    End point title
    		 Change from Baseline in the UPDRS Part I (mentation)
    End point description
    The UPDRS Part I scores mentation, behavior and mood as determined by a physician and participants were tested during the "on" phase of Parkinson's. This component of the UPDRS is the total score for 4 items (the items 1- 4 include intellectual impairment, thought disorder, motivation/initiative, and depression) and may have a value ranging from 0 to 16 as determined by a physician where 16 indicates the maximum score and the worse condition. All 4 items have to be present for a total score to be calculated. If one or more items are missing, the total score for the component will also be missing. Baseline is defined as the last non-missing assessment measured on or before the first dose date. The change from Baseline will be calculated by subtracting the Baseline values from the individual post-randomization values. All participants with a non-missing efficacy observation at Baseline and during the maintenance period were analyzed.
    End point type
    Secondary
    End point timeframe
    Baseline and Week 4 of the Maintenance Period (Study Week 17)
    End point values
    		 Treatment Group A: Placebo Treatment Group B: 2 mg/day Treatment Group C: 4 mg/day Treatment Group D: 8 mg/day Treatment Group E: 12 mg/day Treatment Group F: 24 mg/day
    Number of subjects analysed
    33 [74]
    13 [75]
    34 [76]
    33 [77]
    34 [78]
    10 [79]
    Units: Score on a scale
        least squares mean (confidence interval 95%)
    0.05 (-0.24 to 0.34)
    -0.34 (-0.78 to 0.1)
    -0.01 (-0.31 to 0.28)
    -0.26 (-0.54 to 0.02)
    -0.02 (-0.31 to 0.27)
    0.5 (0.02 to 0.98)
    Notes
    [74] - ITT Population
    [75] - ITT Population
    [76] - ITT Population
    [77] - ITT Population
    [78] - ITT Population
    [79] - ITT Population
    Statistical analysis title
    		 Statistical Analysis 1
    Statistical analysis description
    LS Mean Difference vs. Placebo
    Comparison groups
    Treatment Group A: Placebo v Treatment Group B: 2 mg/day
    Number of subjects included in analysis
    46
    Analysis specification
    Pre-specified
    Analysis type
    		 other
    P-value
    		 = 0.102 [80]
    Method
    		 Mixed models analysis
    Parameter type
    		 Mean difference (final values)
    Point estimate
    -0.39
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -0.86
         upper limit
    		 0.08
    Notes
    [80] - The P-value was calculated using Mixed Model Repeated Measures analysis
    Statistical analysis title
    		 Statistical Analysis 2
    Statistical analysis description
    LS Mean Difference vs. Placebo
    Comparison groups
    Treatment Group A: Placebo v Treatment Group C: 4 mg/day
    Number of subjects included in analysis
    67
    Analysis specification
    Pre-specified
    Analysis type
    		 other
    P-value
    		 = 0.723 [81]
    Method
    		 Mixed models analysis
    Parameter type
    		 Mean difference (final values)
    Point estimate
    -0.06
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -0.41
         upper limit
    		 0.29
    Notes
    [81] - The P-value was calculated using Mixed Model Repeated Measures analysis
    Statistical analysis title
    		 Statistical Analysis 3
    Statistical analysis description
    LS Mean Difference vs. Placebo
    Comparison groups
    Treatment Group A: Placebo v Treatment Group D: 8 mg/day
    Number of subjects included in analysis
    66
    Analysis specification
    Pre-specified
    Analysis type
    		 other
    P-value
    		 = 0.084 [82]
    Method
    		 Mixed models analysis
    Parameter type
    		 Mean difference (final values)
    Point estimate
    -0.31
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -0.66
         upper limit
    		 0.04
    Notes
    [82] - The P-value was calculated using Mixed Model Repeated Measures analysis
    Statistical analysis title
    		 Statistical Analysis 4
    Statistical analysis description
    LS Mean Difference vs Placebo
    Comparison groups
    Treatment Group A: Placebo v Treatment Group E: 12 mg/day
    Number of subjects included in analysis
    67
    Analysis specification
    Pre-specified
    Analysis type
    		 other
    P-value
    		 = 0.697 [83]
    Method
    		 Mixed models analysis
    Parameter type
    		 Mean difference (final values)
    Point estimate
    -0.07
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -0.42
         upper limit
    		 0.28
    Notes
    [83] - The P-value was calculated using Mixed Model Repeated Measures analysis
    Statistical analysis title
    		 Statistical Analysis 5
    Statistical analysis description
    LS Mean Difference vs Placebo
    Comparison groups
    Treatment Group A: Placebo v Treatment Group F: 24 mg/day
    Number of subjects included in analysis
    43
    Analysis specification
    Pre-specified
    Analysis type
    		 other
    P-value
    		 = 0.086 [84]
    Method
    		 Mixed models analysis
    Parameter type
    		 Mean difference (final values)
    Point estimate
    0.45
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -0.06
         upper limit
    		 0.97
    Notes
    [84] - The P-value was calculated using Mixed Model Repeated Measures analysis

    Secondary: Responder rate according to the Clinical Global Impression – Global Improvement (CGI-I) scale

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    End point title
    		 Responder rate according to the Clinical Global Impression – Global Improvement (CGI-I) scale
    End point description
    The CGI-I scale allows the investigator to rate the participant's total improvement since the beginning of treatment (Baseline). Baseline is defined as the last non-missing assessment measured on or before the first dose date. The scale is rated from 1-7 where 1 = "very much improved", 2 = "much improved", 3 = "minimally improved", 4 = "no change", 5 = "minimally worse, 6 = "much worse", and 7 = "very much worse". The responder rate is defined as the percentage of participants with a score of 1 or 2. All participants with a non-missing efficacy observation at Baseline and during the maintenance period were analyzed.
    End point type
    Secondary
    End point timeframe
    Week 4 of the Maintenance Period (Study Week 17)
    End point values
    		 Treatment Group A: Placebo Treatment Group B: 2 mg/day Treatment Group C: 4 mg/day Treatment Group D: 8 mg/day Treatment Group E: 12 mg/day Treatment Group F: 24 mg/day
    Number of subjects analysed
    40 [85]
    13 [86]
    40 [87]
    40 [88]
    39 [89]
    13 [90]
    Units: Percentage of participants
        number (not applicable)
    20
    15
    28
    45
    56
    23
    Notes
    [85] - ITT Population
    [86] - ITT Population
    [87] - ITT Population
    [88] - ITT Population
    [89] - ITT Population
    [90] - ITT Population
    Statistical analysis title
    		 Statistical Analysis 1
    Comparison groups
    Treatment Group A: Placebo v Treatment Group B: 2 mg/day
    Number of subjects included in analysis
    53
    Analysis specification
    Pre-specified
    Analysis type
    		 other
    P-value
    		 = 0.733
    Method
    		 Generalized Estimating Equations model
    Parameter type
    		 Odds ratio (OR)
    Point estimate
    0.769
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.17
         upper limit
    		 3.49
    Statistical analysis title
    		 Statistical Analysis 2
    Comparison groups
    Treatment Group A: Placebo v Treatment Group C: 4 mg/day
    Number of subjects included in analysis
    80
    Analysis specification
    Pre-specified
    Analysis type
    		 other
    P-value
    		 = 0.519
    Method
    		 Generalized Estimating Equations model
    Parameter type
    		 Odds ratio (OR)
    Point estimate
    1.411
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.5
         upper limit
    		 4.02
    Statistical analysis title
    		 Statistical Analysis 3
    Comparison groups
    Treatment Group A: Placebo v Treatment Group D: 8 mg/day
    Number of subjects included in analysis
    80
    Analysis specification
    Pre-specified
    Analysis type
    		 other
    P-value
    		 = 0.008
    Method
    		 Generalized Estimating Equations model
    Parameter type
    		 Odds ratio (OR)
    Point estimate
    4.204
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 1.46
         upper limit
    		 12.07
    Statistical analysis title
    		 Statistical Analysis 4
    Comparison groups
    Treatment Group A: Placebo v Treatment Group E: 12 mg/day
    Number of subjects included in analysis
    79
    Analysis specification
    Pre-specified
    Analysis type
    		 other
    P-value
    		 = 0.001
    Method
    		 Generalized Estimating Equations model
    Parameter type
    		 Odds ratio (OR)
    Point estimate
    5.456
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 1.93
         upper limit
    		 15.46
    Statistical analysis title
    		 Statistical Analysis 5
    Comparison groups
    Treatment Group A: Placebo v Treatment Group F: 24 mg/day
    Number of subjects included in analysis
    53
    Analysis specification
    Pre-specified
    Analysis type
    		 other
    P-value
    		 = 0.752
    Method
    		 Generalized Estimating Equations model
    Parameter type
    		 Odds ratio (OR)
    Point estimate
    1.281
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.27
         upper limit
    		 5.98

    Secondary: Percentage of participants withdrawn from the study due to lack of efficacy

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    End point title
    		 Percentage of participants withdrawn from the study due to lack of efficacy
    End point description
    The percentage of participants who withdrew from the study due to lack of efficacy as defined by either the participant or the investigator is presented here. All participants with a non-missing efficacy observation at Baseline and during the maintenance period were analyzed.
    End point type
    Secondary
    End point timeframe
    Up to Week 4 of the Maintenance Period (Study Week 17)
    End point values
    		 Treatment Group A: Placebo Treatment Group B: 2 mg/day Treatment Group C: 4 mg/day Treatment Group D: 8 mg/day Treatment Group E: 12 mg/day Treatment Group F: 24 mg/day
    Number of subjects analysed
    40 [91]
    13 [92]
    40 [93]
    40 [94]
    39 [95]
    13 [96]
    Units: Percentage of participants
        number (not applicable)
    5
    0
    0
    0
    0
    0
    Notes
    [91] - ITT Population
    [92] - ITT Population
    [93] - ITT Population
    [94] - ITT Population
    [95] - ITT Population
    [96] - ITT Population
    No statistical analyses for this end point

    Adverse events

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    Adverse events information
    Timeframe for reporting adverse events
    Serious adverse events (SAEs) and non-serious AEs were collected from the initial dose of study treatment through the completion of the Follow-up Period
    Adverse event reporting additional description
    An AE is any untoward medical occurrence in a participant temporally associated with the use of a medicinal product, whether or not considered related to the study treatment. A SAE results in death, is life-threatening, requires hospitalization, results in disability or incapacity, or is a congenital anomaly or birth defect.
    Assessment type
    		 Systematic
    Dictionary used for adverse event reporting
    Dictionary name
    		 MedDRA
    Dictionary version
    17.1
    Reporting groups
    Reporting group title
    Treatment Group A: Placebo
    Reporting group description
    		 Participants (par.) were administered a matching Prolonged Release (PR) placebo tablet Once Daily (OD) for up to 17 weeks. Par. completed a Follow-up visit 2 weeks after receiving the last dose of study medication.

    Reporting group title
    Treatment Group B: 2 mg/day
    Reporting group description
    		 Par. were administered a ropinirole PR tablet totalling 2 milligrams per day (mg/day), OD up to Study Week 17. Par. reaching their target dose and completing the maintenance period or withdrawing prematurely were switched to placebo for down-titration for 1 week before completing a Follow-up visit 2 weeks after receiving the last dose of study medication.

    Reporting group title
    Treatment Group C: 4 mg/day
    Reporting group description
    		 Par. were administered a ropinirole PR tablet totalling 2 mg/day, OD for one week. Par. were up-titrated to 4 mg/day at Week 2 and continued this dose up to Study Week 17. Par. reaching their target dose and completing the maintenance period or withdrawing prematurely were down-titrated to 2 mg for 4 days and then switched to placebo for 3 days for down-titration before completing a Follow-up visit 2 weeks after receiving the last dose of study medication.

    Reporting group title
    Treatment Group D: 8 mg/day
    Reporting group description
    		 ar. were administered a ropinirole PR tablet totalling 2 mg/day, OD for one week. Par. were up-titrated to 4 mg/day at Week 2, 6 mg/day at Week 3, and 8 mg/day at Week 4. Par. continued this dose up to Study Week 17. Par. reaching their target dose and completing the maintenance period or withdrawing prematurely were down-titrated for 1 week before completing a Follow-up visit 2 weeks after receiving the last dose of study medication.

    Reporting group title
    Treatment Group E: 12 mg/day
    Reporting group description
    		 Par. were administered a ropinirole PR tablet totalling 2 mg/day, OD for one week. Par. were up-titrated to 4 mg/day at Week 2, 6 mg/day at Week 3, 8 mg/day at Week 4, and 12 mg/day at Week 6. Par. continued this dose up to Study Week 17. Par. reaching their target dose and completing the maintenance period or withdrawing prematurely were down-titrated for 1 week before completing a Follow-up visit 2 weeks after receiving the last dose of study medication.

    Reporting group title
    Treatment Group F: 24 mg/day
    Reporting group description
    		 Par. were administered a ropinirole PR tablet totalling 2 mg/day, OD for one week. Par. were up-titrated to 4 mg/day at Week 2, 6 mg/day at Week 3, 8 mg/day at Week 4, 12 mg/day at Week 6, 16 mg/day at Week 8, 20 mg/day at Week 10, and 24 mg/day at Week 12. Par. continued this dose up to Study Week 17. Par. reaching their target dose and completing the maintenance or withdrawing prematurely were down-titrated for 1 week before completing a Follow-up visit 2 weeks after receiving the last dose of study medication.

    Serious adverse events
    		 Treatment Group A: Placebo Treatment Group B: 2 mg/day Treatment Group C: 4 mg/day Treatment Group D: 8 mg/day Treatment Group E: 12 mg/day Treatment Group F: 24 mg/day
    Total subjects affected by serious adverse events
         subjects affected / exposed
    0 / 40 (0.00%)
    0 / 13 (0.00%)
    1 / 41 (2.44%)
    0 / 40 (0.00%)
    2 / 39 (5.13%)
    0 / 13 (0.00%)
         number of deaths (all causes)
    0
    0
    0
    0
    0
    0
         number of deaths resulting from adverse events
    Cardiac disorders
    Coronary artery disease
         subjects affected / exposed
    0 / 40 (0.00%)
    0 / 13 (0.00%)
    0 / 41 (0.00%)
    0 / 40 (0.00%)
    1 / 39 (2.56%)
    0 / 13 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Nervous system disorders
    Cerebral infarction
         subjects affected / exposed
    0 / 40 (0.00%)
    0 / 13 (0.00%)
    0 / 41 (0.00%)
    0 / 40 (0.00%)
    1 / 39 (2.56%)
    0 / 13 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    General disorders and administration site conditions
    Chest pain
         subjects affected / exposed
    0 / 40 (0.00%)
    0 / 13 (0.00%)
    1 / 41 (2.44%)
    0 / 40 (0.00%)
    0 / 39 (0.00%)
    0 / 13 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Frequency threshold for reporting non-serious adverse events: 0%
    Non-serious adverse events
    		 Treatment Group A: Placebo Treatment Group B: 2 mg/day Treatment Group C: 4 mg/day Treatment Group D: 8 mg/day Treatment Group E: 12 mg/day Treatment Group F: 24 mg/day
    Total subjects affected by non serious adverse events
         subjects affected / exposed
    17 / 40 (42.50%)
    5 / 13 (38.46%)
    18 / 41 (43.90%)
    24 / 40 (60.00%)
    18 / 39 (46.15%)
    7 / 13 (53.85%)
    Neoplasms benign, malignant and unspecified (incl cysts and polyps)
    Basal cell carcinoma
         subjects affected / exposed
    0 / 40 (0.00%)
    0 / 13 (0.00%)
    1 / 41 (2.44%)
    0 / 40 (0.00%)
    0 / 39 (0.00%)
    0 / 13 (0.00%)
         occurrences all number
    0
    0
    1
    0
    0
    0
    Dysplastic naevus
         subjects affected / exposed
    0 / 40 (0.00%)
    1 / 13 (7.69%)
    0 / 41 (0.00%)
    0 / 40 (0.00%)
    0 / 39 (0.00%)
    0 / 13 (0.00%)
         occurrences all number
    0
    1
    0
    0
    0
    0
    Vascular disorders
    Hypertension
         subjects affected / exposed
    0 / 40 (0.00%)
    0 / 13 (0.00%)
    2 / 41 (4.88%)
    2 / 40 (5.00%)
    2 / 39 (5.13%)
    2 / 13 (15.38%)
         occurrences all number
    0
    0
    3
    2
    2
    2
    Hypotension
         subjects affected / exposed
    0 / 40 (0.00%)
    0 / 13 (0.00%)
    0 / 41 (0.00%)
    0 / 40 (0.00%)
    1 / 39 (2.56%)
    0 / 13 (0.00%)
         occurrences all number
    0
    0
    0
    0
    1
    0
    Labile blood pressure
         subjects affected / exposed
    0 / 40 (0.00%)
    0 / 13 (0.00%)
    0 / 41 (0.00%)
    1 / 40 (2.50%)
    1 / 39 (2.56%)
    1 / 13 (7.69%)
         occurrences all number
    0
    0
    0
    1
    1
    1
    Orthostatic hypotension
         subjects affected / exposed
    1 / 40 (2.50%)
    0 / 13 (0.00%)
    0 / 41 (0.00%)
    0 / 40 (0.00%)
    2 / 39 (5.13%)
    0 / 13 (0.00%)
         occurrences all number
    2
    0
    0
    0
    2
    0
    General disorders and administration site conditions
    Asthenia
         subjects affected / exposed
    0 / 40 (0.00%)
    0 / 13 (0.00%)
    0 / 41 (0.00%)
    2 / 40 (5.00%)
    0 / 39 (0.00%)
    1 / 13 (7.69%)
         occurrences all number
    0
    0
    0
    2
    0
    1
    Fatigue
         subjects affected / exposed
    0 / 40 (0.00%)
    0 / 13 (0.00%)
    1 / 41 (2.44%)
    0 / 40 (0.00%)
    1 / 39 (2.56%)
    0 / 13 (0.00%)
         occurrences all number
    0
    0
    1
    0
    1
    0
    Feeling abnormal
         subjects affected / exposed
    0 / 40 (0.00%)
    0 / 13 (0.00%)
    0 / 41 (0.00%)
    0 / 40 (0.00%)
    1 / 39 (2.56%)
    0 / 13 (0.00%)
         occurrences all number
    0
    0
    0
    0
    1
    0
    Ill-defined disorder
         subjects affected / exposed
    0 / 40 (0.00%)
    0 / 13 (0.00%)
    1 / 41 (2.44%)
    0 / 40 (0.00%)
    0 / 39 (0.00%)
    0 / 13 (0.00%)
         occurrences all number
    0
    0
    1
    0
    0
    0
    Local swelling
         subjects affected / exposed
    0 / 40 (0.00%)
    0 / 13 (0.00%)
    0 / 41 (0.00%)
    0 / 40 (0.00%)
    1 / 39 (2.56%)
    0 / 13 (0.00%)
         occurrences all number
    0
    0
    0
    0
    1
    0
    Oedema peripheral
         subjects affected / exposed
    0 / 40 (0.00%)
    0 / 13 (0.00%)
    0 / 41 (0.00%)
    0 / 40 (0.00%)
    1 / 39 (2.56%)
    0 / 13 (0.00%)
         occurrences all number
    0
    0
    0
    0
    1
    0
    Reproductive system and breast disorders
    Peyronie's disease
         subjects affected / exposed
    0 / 40 (0.00%)
    0 / 13 (0.00%)
    1 / 41 (2.44%)
    0 / 40 (0.00%)
    0 / 39 (0.00%)
    0 / 13 (0.00%)
         occurrences all number
    0
    0
    1
    0
    0
    0
    Respiratory, thoracic and mediastinal disorders
    Cough
         subjects affected / exposed
    0 / 40 (0.00%)
    0 / 13 (0.00%)
    0 / 41 (0.00%)
    1 / 40 (2.50%)
    0 / 39 (0.00%)
    0 / 13 (0.00%)
         occurrences all number
    0
    0
    0
    1
    0
    0
    Dyspnoea
         subjects affected / exposed
    0 / 40 (0.00%)
    0 / 13 (0.00%)
    1 / 41 (2.44%)
    0 / 40 (0.00%)
    0 / 39 (0.00%)
    0 / 13 (0.00%)
         occurrences all number
    0
    0
    1
    0
    0
    0
    Hiccups
         subjects affected / exposed
    0 / 40 (0.00%)
    0 / 13 (0.00%)
    0 / 41 (0.00%)
    0 / 40 (0.00%)
    1 / 39 (2.56%)
    0 / 13 (0.00%)
         occurrences all number
    0
    0
    0
    0
    1
    0
    Nasal congestion
         subjects affected / exposed
    1 / 40 (2.50%)
    0 / 13 (0.00%)
    0 / 41 (0.00%)
    0 / 40 (0.00%)
    0 / 39 (0.00%)
    0 / 13 (0.00%)
         occurrences all number
    1
    0
    0
    0
    0
    0
    Upper-airway cough syndrome
         subjects affected / exposed
    0 / 40 (0.00%)
    0 / 13 (0.00%)
    0 / 41 (0.00%)
    0 / 40 (0.00%)
    1 / 39 (2.56%)
    0 / 13 (0.00%)
         occurrences all number
    0
    0
    0
    0
    1
    0
    Yawning
         subjects affected / exposed
    0 / 40 (0.00%)
    0 / 13 (0.00%)
    0 / 41 (0.00%)
    0 / 40 (0.00%)
    1 / 39 (2.56%)
    0 / 13 (0.00%)
         occurrences all number
    0
    0
    0
    0
    1
    0
    Psychiatric disorders
    Abnormal dreams
         subjects affected / exposed
    2 / 40 (5.00%)
    0 / 13 (0.00%)
    0 / 41 (0.00%)
    0 / 40 (0.00%)
    0 / 39 (0.00%)
    0 / 13 (0.00%)
         occurrences all number
    2
    0
    0
    0
    0
    0
    Confusional state
         subjects affected / exposed
    0 / 40 (0.00%)
    0 / 13 (0.00%)
    0 / 41 (0.00%)
    0 / 40 (0.00%)
    0 / 39 (0.00%)
    1 / 13 (7.69%)
         occurrences all number
    0
    0
    0
    0
    0
    1
    Dissociation
         subjects affected / exposed
    0 / 40 (0.00%)
    0 / 13 (0.00%)
    1 / 41 (2.44%)
    0 / 40 (0.00%)
    0 / 39 (0.00%)
    0 / 13 (0.00%)
         occurrences all number
    0
    0
    1
    0
    0
    0
    Hallucination
         subjects affected / exposed
    0 / 40 (0.00%)
    0 / 13 (0.00%)
    1 / 41 (2.44%)
    0 / 40 (0.00%)
    0 / 39 (0.00%)
    0 / 13 (0.00%)
         occurrences all number
    0
    0
    1
    0
    0
    0
    Insomnia
         subjects affected / exposed
    0 / 40 (0.00%)
    0 / 13 (0.00%)
    2 / 41 (4.88%)
    1 / 40 (2.50%)
    0 / 39 (0.00%)
    0 / 13 (0.00%)
         occurrences all number
    0
    0
    3
    1
    0
    0
    Libido increased
         subjects affected / exposed
    0 / 40 (0.00%)
    0 / 13 (0.00%)
    0 / 41 (0.00%)
    0 / 40 (0.00%)
    0 / 39 (0.00%)
    1 / 13 (7.69%)
         occurrences all number
    0
    0
    0
    0
    0
    1
    Rapid eye movements sleep abnormal
         subjects affected / exposed
    0 / 40 (0.00%)
    0 / 13 (0.00%)
    0 / 41 (0.00%)
    0 / 40 (0.00%)
    1 / 39 (2.56%)
    0 / 13 (0.00%)
         occurrences all number
    0
    0
    0
    0
    1
    0
    Investigations
    Alanine aminotransferase increased
         subjects affected / exposed
    0 / 40 (0.00%)
    0 / 13 (0.00%)
    1 / 41 (2.44%)
    0 / 40 (0.00%)
    0 / 39 (0.00%)
    0 / 13 (0.00%)
         occurrences all number
    0
    0
    1
    0
    0
    0
    Blood creatine phosphokinase increased
         subjects affected / exposed
    0 / 40 (0.00%)
    0 / 13 (0.00%)
    1 / 41 (2.44%)
    2 / 40 (5.00%)
    1 / 39 (2.56%)
    1 / 13 (7.69%)
         occurrences all number
    0
    0
    1
    2
    1
    1
    Blood creatinine increased
         subjects affected / exposed
    0 / 40 (0.00%)
    0 / 13 (0.00%)
    0 / 41 (0.00%)
    1 / 40 (2.50%)
    0 / 39 (0.00%)
    0 / 13 (0.00%)
         occurrences all number
    0
    0
    0
    1
    0
    0
    Blood potassium increased
         subjects affected / exposed
    0 / 40 (0.00%)
    0 / 13 (0.00%)
    0 / 41 (0.00%)
    1 / 40 (2.50%)
    0 / 39 (0.00%)
    0 / 13 (0.00%)
         occurrences all number
    0
    0
    0
    1
    0
    0
    Blood pressure increased
         subjects affected / exposed
    0 / 40 (0.00%)
    0 / 13 (0.00%)
    0 / 41 (0.00%)
    1 / 40 (2.50%)
    1 / 39 (2.56%)
    0 / 13 (0.00%)
         occurrences all number
    0
    0
    0
    1
    1
    0
    Electrocardiogram ST segment depression
         subjects affected / exposed
    1 / 40 (2.50%)
    0 / 13 (0.00%)
    0 / 41 (0.00%)
    0 / 40 (0.00%)
    0 / 39 (0.00%)
    0 / 13 (0.00%)
         occurrences all number
    1
    0
    0
    0
    0
    0
    Gamma-glutamyltransferase increased
         subjects affected / exposed
    0 / 40 (0.00%)
    0 / 13 (0.00%)
    1 / 41 (2.44%)
    0 / 40 (0.00%)
    0 / 39 (0.00%)
    0 / 13 (0.00%)
         occurrences all number
    0
    0
    1
    0
    0
    0
    Heart rate increased
         subjects affected / exposed
    0 / 40 (0.00%)
    0 / 13 (0.00%)
    1 / 41 (2.44%)
    0 / 40 (0.00%)
    0 / 39 (0.00%)
    0 / 13 (0.00%)
         occurrences all number
    0
    0
    1
    0
    0
    0
    Injury, poisoning and procedural complications
    Arthropod bite
         subjects affected / exposed
    0 / 40 (0.00%)
    0 / 13 (0.00%)
    0 / 41 (0.00%)
    1 / 40 (2.50%)
    0 / 39 (0.00%)
    0 / 13 (0.00%)
         occurrences all number
    0
    0
    0
    1
    0
    0
    Back injury
         subjects affected / exposed
    0 / 40 (0.00%)
    0 / 13 (0.00%)
    0 / 41 (0.00%)
    0 / 40 (0.00%)
    0 / 39 (0.00%)
    1 / 13 (7.69%)
         occurrences all number
    0
    0
    0
    0
    0
    1
    Skeletal injury
         subjects affected / exposed
    0 / 40 (0.00%)
    0 / 13 (0.00%)
    0 / 41 (0.00%)
    0 / 40 (0.00%)
    0 / 39 (0.00%)
    1 / 13 (7.69%)
         occurrences all number
    0
    0
    0
    0
    0
    1
    Cardiac disorders
    Palpitations
         subjects affected / exposed
    0 / 40 (0.00%)
    0 / 13 (0.00%)
    0 / 41 (0.00%)
    0 / 40 (0.00%)
    0 / 39 (0.00%)
    1 / 13 (7.69%)
         occurrences all number
    0
    0
    0
    0
    0
    1
    Nervous system disorders
    Somnolence
         subjects affected / exposed
    2 / 40 (5.00%)
    2 / 13 (15.38%)
    5 / 41 (12.20%)
    4 / 40 (10.00%)
    3 / 39 (7.69%)
    1 / 13 (7.69%)
         occurrences all number
    2
    2
    6
    5
    3
    1
    Headache
         subjects affected / exposed
    1 / 40 (2.50%)
    1 / 13 (7.69%)
    4 / 41 (9.76%)
    3 / 40 (7.50%)
    2 / 39 (5.13%)
    2 / 13 (15.38%)
         occurrences all number
    1
    1
    4
    7
    2
    3
    Dizziness
         subjects affected / exposed
    2 / 40 (5.00%)
    0 / 13 (0.00%)
    2 / 41 (4.88%)
    4 / 40 (10.00%)
    3 / 39 (7.69%)
    1 / 13 (7.69%)
         occurrences all number
    2
    0
    2
    5
    3
    1
    Sudden onset of sleep
         subjects affected / exposed
    0 / 40 (0.00%)
    0 / 13 (0.00%)
    2 / 41 (4.88%)
    0 / 40 (0.00%)
    5 / 39 (12.82%)
    1 / 13 (7.69%)
         occurrences all number
    0
    0
    2
    0
    8
    1
    Hypoaesthesia
         subjects affected / exposed
    1 / 40 (2.50%)
    0 / 13 (0.00%)
    0 / 41 (0.00%)
    0 / 40 (0.00%)
    0 / 39 (0.00%)
    1 / 13 (7.69%)
         occurrences all number
    1
    0
    0
    0
    0
    1
    Tremor
         subjects affected / exposed
    0 / 40 (0.00%)
    0 / 13 (0.00%)
    0 / 41 (0.00%)
    1 / 40 (2.50%)
    0 / 39 (0.00%)
    1 / 13 (7.69%)
         occurrences all number
    0
    0
    0
    2
    0
    1
    Dizziness postural
         subjects affected / exposed
    0 / 40 (0.00%)
    0 / 13 (0.00%)
    0 / 41 (0.00%)
    0 / 40 (0.00%)
    0 / 39 (0.00%)
    1 / 13 (7.69%)
         occurrences all number
    0
    0
    0
    0
    0
    1
    Syncope
         subjects affected / exposed
    0 / 40 (0.00%)
    0 / 13 (0.00%)
    0 / 41 (0.00%)
    0 / 40 (0.00%)
    0 / 39 (0.00%)
    1 / 13 (7.69%)
         occurrences all number
    0
    0
    0
    0
    0
    1
    Balance disorder
         subjects affected / exposed
    0 / 40 (0.00%)
    0 / 13 (0.00%)
    1 / 41 (2.44%)
    0 / 40 (0.00%)
    1 / 39 (2.56%)
    0 / 13 (0.00%)
         occurrences all number
    0
    0
    1
    0
    1
    0
    Dyskinesia
         subjects affected / exposed
    0 / 40 (0.00%)
    0 / 13 (0.00%)
    0 / 41 (0.00%)
    1 / 40 (2.50%)
    0 / 39 (0.00%)
    0 / 13 (0.00%)
         occurrences all number
    0
    0
    0
    1
    0
    0
    Neuropathy peripheral
         subjects affected / exposed
    0 / 40 (0.00%)
    0 / 13 (0.00%)
    0 / 41 (0.00%)
    0 / 40 (0.00%)
    1 / 39 (2.56%)
    0 / 13 (0.00%)
         occurrences all number
    0
    0
    0
    0
    1
    0
    Nystagmus
         subjects affected / exposed
    0 / 40 (0.00%)
    0 / 13 (0.00%)
    0 / 41 (0.00%)
    0 / 40 (0.00%)
    1 / 39 (2.56%)
    0 / 13 (0.00%)
         occurrences all number
    0
    0
    0
    0
    1
    0
    Parkinson's disease
         subjects affected / exposed
    1 / 40 (2.50%)
    0 / 13 (0.00%)
    1 / 41 (2.44%)
    0 / 40 (0.00%)
    1 / 39 (2.56%)
    0 / 13 (0.00%)
         occurrences all number
    1
    0
    1
    0
    1
    0
    Parosmia
         subjects affected / exposed
    0 / 40 (0.00%)
    0 / 13 (0.00%)
    0 / 41 (0.00%)
    1 / 40 (2.50%)
    0 / 39 (0.00%)
    0 / 13 (0.00%)
         occurrences all number
    0
    0
    0
    1
    0
    0
    Restless legs syndrome
         subjects affected / exposed
    0 / 40 (0.00%)
    0 / 13 (0.00%)
    1 / 41 (2.44%)
    0 / 40 (0.00%)
    0 / 39 (0.00%)
    0 / 13 (0.00%)
         occurrences all number
    0
    0
    1
    0
    0
    0
    Tension headache
         subjects affected / exposed
    0 / 40 (0.00%)
    0 / 13 (0.00%)
    0 / 41 (0.00%)
    0 / 40 (0.00%)
    1 / 39 (2.56%)
    0 / 13 (0.00%)
         occurrences all number
    0
    0
    0
    0
    1
    0
    Blood and lymphatic system disorders
    Iron deficiency anaemia
         subjects affected / exposed
    0 / 40 (0.00%)
    0 / 13 (0.00%)
    0 / 41 (0.00%)
    0 / 40 (0.00%)
    1 / 39 (2.56%)
    0 / 13 (0.00%)
         occurrences all number
    0
    0
    0
    0
    1
    0
    Ear and labyrinth disorders
    Tinnitus
         subjects affected / exposed
    0 / 40 (0.00%)
    0 / 13 (0.00%)
    1 / 41 (2.44%)
    0 / 40 (0.00%)
    0 / 39 (0.00%)
    0 / 13 (0.00%)
         occurrences all number
    0
    0
    1
    0
    0
    0
    Vertigo
         subjects affected / exposed
    0 / 40 (0.00%)
    0 / 13 (0.00%)
    0 / 41 (0.00%)
    0 / 40 (0.00%)
    3 / 39 (7.69%)
    1 / 13 (7.69%)
         occurrences all number
    0
    0
    0
    0
    3
    1
    Vertigo positional
         subjects affected / exposed
    1 / 40 (2.50%)
    0 / 13 (0.00%)
    0 / 41 (0.00%)
    0 / 40 (0.00%)
    0 / 39 (0.00%)
    0 / 13 (0.00%)
         occurrences all number
    1
    0
    0
    0
    0
    0
    Eye disorders
    Photopsia
         subjects affected / exposed
    0 / 40 (0.00%)
    0 / 13 (0.00%)
    1 / 41 (2.44%)
    0 / 40 (0.00%)
    0 / 39 (0.00%)
    0 / 13 (0.00%)
         occurrences all number
    0
    0
    1
    0
    0
    0
    Vision blurred
         subjects affected / exposed
    0 / 40 (0.00%)
    0 / 13 (0.00%)
    2 / 41 (4.88%)
    0 / 40 (0.00%)
    1 / 39 (2.56%)
    0 / 13 (0.00%)
         occurrences all number
    0
    0
    2
    0
    1
    0
    Visual impairment
         subjects affected / exposed
    0 / 40 (0.00%)
    0 / 13 (0.00%)
    1 / 41 (2.44%)
    0 / 40 (0.00%)
    0 / 39 (0.00%)
    0 / 13 (0.00%)
         occurrences all number
    0
    0
    1
    0
    0
    0
    Gastrointestinal disorders
    Nausea
         subjects affected / exposed
    3 / 40 (7.50%)
    1 / 13 (7.69%)
    6 / 41 (14.63%)
    13 / 40 (32.50%)
    4 / 39 (10.26%)
    2 / 13 (15.38%)
         occurrences all number
    3
    1
    8
    16
    4
    3
    Diarrhoea
         subjects affected / exposed
    1 / 40 (2.50%)
    1 / 13 (7.69%)
    0 / 41 (0.00%)
    1 / 40 (2.50%)
    1 / 39 (2.56%)
    0 / 13 (0.00%)
         occurrences all number
    1
    1
    0
    3
    3
    0
    Dyspepsia
         subjects affected / exposed
    2 / 40 (5.00%)
    1 / 13 (7.69%)
    1 / 41 (2.44%)
    3 / 40 (7.50%)
    0 / 39 (0.00%)
    1 / 13 (7.69%)
         occurrences all number
    2
    1
    2
    4
    0
    1
    Vomiting
         subjects affected / exposed
    2 / 40 (5.00%)
    0 / 13 (0.00%)
    2 / 41 (4.88%)
    4 / 40 (10.00%)
    0 / 39 (0.00%)
    0 / 13 (0.00%)
         occurrences all number
    2
    0
    3
    5
    0
    0
    Constipation
         subjects affected / exposed
    0 / 40 (0.00%)
    0 / 13 (0.00%)
    1 / 41 (2.44%)
    2 / 40 (5.00%)
    1 / 39 (2.56%)
    0 / 13 (0.00%)
         occurrences all number
    0
    0
    1
    2
    1
    0
    Abdominal discomfort
         subjects affected / exposed
    0 / 40 (0.00%)
    0 / 13 (0.00%)
    1 / 41 (2.44%)
    0 / 40 (0.00%)
    0 / 39 (0.00%)
    0 / 13 (0.00%)
         occurrences all number
    0
    0
    1
    0
    0
    0
    Abdominal pain
         subjects affected / exposed
    1 / 40 (2.50%)
    0 / 13 (0.00%)
    1 / 41 (2.44%)
    0 / 40 (0.00%)
    0 / 39 (0.00%)
    0 / 13 (0.00%)
         occurrences all number
    1
    0
    1
    0
    0
    0
    Flatulence
         subjects affected / exposed
    0 / 40 (0.00%)
    0 / 13 (0.00%)
    0 / 41 (0.00%)
    1 / 40 (2.50%)
    0 / 39 (0.00%)
    0 / 13 (0.00%)
         occurrences all number
    0
    0
    0
    1
    0
    0
    Gastrooesophageal reflux disease
         subjects affected / exposed
    0 / 40 (0.00%)
    0 / 13 (0.00%)
    1 / 41 (2.44%)
    0 / 40 (0.00%)
    0 / 39 (0.00%)
    0 / 13 (0.00%)
         occurrences all number
    0
    0
    1
    0
    0
    0
    Irritable bowel syndrome
         subjects affected / exposed
    1 / 40 (2.50%)
    0 / 13 (0.00%)
    0 / 41 (0.00%)
    0 / 40 (0.00%)
    0 / 39 (0.00%)
    0 / 13 (0.00%)
         occurrences all number
    1
    0
    0
    0
    0
    0
    Tooth disorder
         subjects affected / exposed
    0 / 40 (0.00%)
    0 / 13 (0.00%)
    1 / 41 (2.44%)
    0 / 40 (0.00%)
    0 / 39 (0.00%)
    0 / 13 (0.00%)
         occurrences all number
    0
    0
    1
    0
    0
    0
    Toothache
         subjects affected / exposed
    0 / 40 (0.00%)
    0 / 13 (0.00%)
    0 / 41 (0.00%)
    1 / 40 (2.50%)
    0 / 39 (0.00%)
    0 / 13 (0.00%)
         occurrences all number
    0
    0
    0
    1
    0
    0
    Skin and subcutaneous tissue disorders
    Dermatitis allergic
         subjects affected / exposed
    0 / 40 (0.00%)
    1 / 13 (7.69%)
    0 / 41 (0.00%)
    0 / 40 (0.00%)
    0 / 39 (0.00%)
    0 / 13 (0.00%)
         occurrences all number
    0
    2
    0
    0
    0
    0
    Dermatitis contact
         subjects affected / exposed
    0 / 40 (0.00%)
    0 / 13 (0.00%)
    1 / 41 (2.44%)
    0 / 40 (0.00%)
    0 / 39 (0.00%)
    0 / 13 (0.00%)
         occurrences all number
    0
    0
    1
    0
    0
    0
    Renal and urinary disorders
    Micturition urgency
         subjects affected / exposed
    0 / 40 (0.00%)
    0 / 13 (0.00%)
    0 / 41 (0.00%)
    0 / 40 (0.00%)
    1 / 39 (2.56%)
    0 / 13 (0.00%)
         occurrences all number
    0
    0
    0
    0
    1
    0
    Musculoskeletal and connective tissue disorders
    Back pain
         subjects affected / exposed
    1 / 40 (2.50%)
    0 / 13 (0.00%)
    2 / 41 (4.88%)
    1 / 40 (2.50%)
    1 / 39 (2.56%)
    2 / 13 (15.38%)
         occurrences all number
    1
    0
    3
    1
    1
    2
    Muscle spasms
         subjects affected / exposed
    0 / 40 (0.00%)
    0 / 13 (0.00%)
    0 / 41 (0.00%)
    0 / 40 (0.00%)
    0 / 39 (0.00%)
    1 / 13 (7.69%)
         occurrences all number
    0
    0
    0
    0
    0
    1
    Arthralgia
         subjects affected / exposed
    0 / 40 (0.00%)
    0 / 13 (0.00%)
    0 / 41 (0.00%)
    1 / 40 (2.50%)
    0 / 39 (0.00%)
    0 / 13 (0.00%)
         occurrences all number
    0
    0
    0
    1
    0
    0
    Arthritis
         subjects affected / exposed
    0 / 40 (0.00%)
    0 / 13 (0.00%)
    1 / 41 (2.44%)
    0 / 40 (0.00%)
    0 / 39 (0.00%)
    0 / 13 (0.00%)
         occurrences all number
    0
    0
    1
    0
    0
    0
    Back disorder
         subjects affected / exposed
    0 / 40 (0.00%)
    0 / 13 (0.00%)
    1 / 41 (2.44%)
    0 / 40 (0.00%)
    0 / 39 (0.00%)
    0 / 13 (0.00%)
         occurrences all number
    0
    0
    1
    0
    0
    0
    Gouty arthritis
         subjects affected / exposed
    1 / 40 (2.50%)
    0 / 13 (0.00%)
    0 / 41 (0.00%)
    0 / 40 (0.00%)
    0 / 39 (0.00%)
    0 / 13 (0.00%)
         occurrences all number
    2
    0
    0
    0
    0
    0
    Musculoskeletal pain
         subjects affected / exposed
    0 / 40 (0.00%)
    0 / 13 (0.00%)
    2 / 41 (4.88%)
    0 / 40 (0.00%)
    0 / 39 (0.00%)
    0 / 13 (0.00%)
         occurrences all number
    0
    0
    2
    0
    0
    0
    Neck pain
         subjects affected / exposed
    0 / 40 (0.00%)
    0 / 13 (0.00%)
    1 / 41 (2.44%)
    0 / 40 (0.00%)
    0 / 39 (0.00%)
    0 / 13 (0.00%)
         occurrences all number
    0
    0
    1
    0
    0
    0
    Osteochondrosis
         subjects affected / exposed
    0 / 40 (0.00%)
    0 / 13 (0.00%)
    0 / 41 (0.00%)
    0 / 40 (0.00%)
    1 / 39 (2.56%)
    0 / 13 (0.00%)
         occurrences all number
    0
    0
    0
    0
    1
    0
    Pain in extremity
         subjects affected / exposed
    0 / 40 (0.00%)
    0 / 13 (0.00%)
    0 / 41 (0.00%)
    1 / 40 (2.50%)
    0 / 39 (0.00%)
    0 / 13 (0.00%)
         occurrences all number
    0
    0
    0
    1
    0
    0
    Infections and infestations
    Nasopharyngitis
         subjects affected / exposed
    3 / 40 (7.50%)
    0 / 13 (0.00%)
    1 / 41 (2.44%)
    2 / 40 (5.00%)
    2 / 39 (5.13%)
    0 / 13 (0.00%)
         occurrences all number
    3
    0
    1
    2
    2
    0
    Pyelonephritis chronic
         subjects affected / exposed
    0 / 40 (0.00%)
    1 / 13 (7.69%)
    0 / 41 (0.00%)
    0 / 40 (0.00%)
    0 / 39 (0.00%)
    0 / 13 (0.00%)
         occurrences all number
    0
    1
    0
    0
    0
    0
    Diverticulitis
         subjects affected / exposed
    0 / 40 (0.00%)
    0 / 13 (0.00%)
    1 / 41 (2.44%)
    0 / 40 (0.00%)
    0 / 39 (0.00%)
    0 / 13 (0.00%)
         occurrences all number
    0
    0
    1
    0
    0
    0
    Influenza
         subjects affected / exposed
    1 / 40 (2.50%)
    0 / 13 (0.00%)
    0 / 41 (0.00%)
    0 / 40 (0.00%)
    0 / 39 (0.00%)
    0 / 13 (0.00%)
         occurrences all number
    1
    0
    0
    0
    0
    0
    Upper respiratory tract infection
         subjects affected / exposed
    0 / 40 (0.00%)
    0 / 13 (0.00%)
    0 / 41 (0.00%)
    1 / 40 (2.50%)
    0 / 39 (0.00%)
    0 / 13 (0.00%)
         occurrences all number
    0
    0
    0
    1
    0
    0
    Urinary tract infection
         subjects affected / exposed
    0 / 40 (0.00%)
    0 / 13 (0.00%)
    1 / 41 (2.44%)
    0 / 40 (0.00%)
    1 / 39 (2.56%)
    0 / 13 (0.00%)
         occurrences all number
    0
    0
    1
    0
    1
    0
    Viral infection
         subjects affected / exposed
    1 / 40 (2.50%)
    0 / 13 (0.00%)
    0 / 41 (0.00%)
    1 / 40 (2.50%)
    0 / 39 (0.00%)
    0 / 13 (0.00%)
         occurrences all number
    1
    0
    0
    1
    0
    0
    Metabolism and nutrition disorders
    Decreased appetite
         subjects affected / exposed
    0 / 40 (0.00%)
    0 / 13 (0.00%)
    1 / 41 (2.44%)
    0 / 40 (0.00%)
    0 / 39 (0.00%)
    0 / 13 (0.00%)
         occurrences all number
    0
    0
    1
    0
    0
    0
    Dyslipidaemia
         subjects affected / exposed
    0 / 40 (0.00%)
    0 / 13 (0.00%)
    0 / 41 (0.00%)
    0 / 40 (0.00%)
    1 / 39 (2.56%)
    0 / 13 (0.00%)
         occurrences all number
    0
    0
    0
    0
    1
    0
    Glucose tolerance impaired
         subjects affected / exposed
    0 / 40 (0.00%)
    0 / 13 (0.00%)
    0 / 41 (0.00%)
    0 / 40 (0.00%)
    1 / 39 (2.56%)
    0 / 13 (0.00%)
         occurrences all number
    0
    0
    0
    0
    1
    0
    Gout
         subjects affected / exposed
    0 / 40 (0.00%)
    0 / 13 (0.00%)
    1 / 41 (2.44%)
    0 / 40 (0.00%)
    0 / 39 (0.00%)
    0 / 13 (0.00%)
         occurrences all number
    0
    0
    1
    0
    0
    0
    Hyperglycaemia
         subjects affected / exposed
    0 / 40 (0.00%)
    1 / 13 (7.69%)
    1 / 41 (2.44%)
    0 / 40 (0.00%)
    1 / 39 (2.56%)
    0 / 13 (0.00%)
         occurrences all number
    0
    1
    1
    0
    1
    0
    Increased appetite
         subjects affected / exposed
    0 / 40 (0.00%)
    0 / 13 (0.00%)
    0 / 41 (0.00%)
    1 / 40 (2.50%)
    0 / 39 (0.00%)
    0 / 13 (0.00%)
         occurrences all number
    0
    0
    0
    1
    0
    0

    More information

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    Substantial protocol amendments (globally)
    Were there any global substantial amendments to the protocol? Yes
    Date
    Amendment
    13 Feb 2012
    Additions of MAO-B inhibitors, apomorphine and Deep Brain Stimulation to the list of prohibited treatments, addition of urinalysis to laboratory assessments, and various administrative corrections.
    18 Feb 2013
    Removed language referring to assessment of UPDRS motor score in the “on” state prior to study treatment, and added language clarifying how the UPDRS is to be administered during the study. A third ammendment, 24Jul2014, added updates and clarifications to the Data Analysis Plan descriptions

    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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    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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