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    Clinical Trial Results:
    Efficacy and safety of BIA 9-1067 in idiopathic Parkinson’s disease patients with “wearing-off” phenomenon treated with levodopa plus a dopa decarboxylase inhibitor (ddci): a double blind, randomised, placebo- and active-controlled, parallel group, multicentre clinical study

    Due to the EudraCT – Results system being out of service between 31 July 2015 and 12 January 2016, these results have been published in compliance with revised timelines.
    Summary
    EudraCT number
    		 2010-021860-13
    Trial protocol
    		 HU   LT   AT   LV   DE   ES   PT   CZ   SK   BG   RO   IT  
    Global end of trial date
    01 Dec 2014

    Results information
    Results version number
    		 v1
    This version publication date
    19 Mar 2016
    First version publication date
    19 Mar 2016
    Other versions
    		 v2

    Trial information

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    Trial identification
    Sponsor protocol code
    BIA-91067-301
    Additional study identifiers
    ISRCTN number
    		 -
    US NCT number
    		 NCT01568073
    WHO universal trial number (UTN)
    		 -
    Sponsors
    Sponsor organisation name
    BIAL - Portela & CA, S.A.
    Sponsor organisation address
    À Av. Siderurgia Nacional, Coronado, Portugal, 4745-457
    Public contact
    André Garrido, BIAL - Portela & Cª, S.A., 0035 229866100, andre.garrido@bial.com
    Scientific contact
    José Francisco Rocha, BIAL - Portela & Cª, S.A., 0035 229866100, jose.rocha@bial.com
    Paediatric regulatory details
    Is trial part of an agreed paediatric investigation plan (PIP)
    No
    Does article 45 of REGULATION (EC) No 1901/2006 apply to this trial?
    No
    Does article 46 of REGULATION (EC) No 1901/2006 apply to this trial?
    No
    Results analysis stage
    Analysis stage
    Final
    Date of interim/final analysis
    21 Apr 2015
    Is this the analysis of the primary completion data?
    Yes
    Primary completion date
    29 Nov 2013
    Global end of trial reached?
    Yes
    Global end of trial date
    01 Dec 2014
    Was the trial ended prematurely?
    No
    General information about the trial
    Main objective of the trial
    Primary: To investigate the efficacy of 3 different doses of BIA 9-1067 (5 mg, 25 mg, and 50 mg) administered once a day, compared with 200 mg of entacapone or placebo, when administered with the existing treatment of L-DOPA plus a DDCI, in patients with PD and end-of-dose motor fluctuations. Secondary: To investigate the safety and tolerability of the combined treatment (L-DOPA/DDCI plus BIA 9-1067, entacapone, or placebo).
    Protection of trial subjects
    The trial was conducted in accordance with the International Conference on Harmonisation (ICH), Good Clinical Practices (GCP), Good Manufacturing Practice (GMP), the ethical principles of the Declaration of Helsinki and with applicable local regulations. This trial was conducted by qualified persons who respected the rights and welfare of the subjects and after the review and approval of the protocol by an EC. Adverse events were collected throughout the trial and subject was followed by 14 days after the completion of the study.
    Background therapy
    		 L-DOPA/DDCI (Carbidopa, Benserazide). Frequency: 3 to 8 daily doses. From V2 to V4 of the DB period, the investigator can decrease the daily dose of L-DOPA and DDCI (keeping the number of daily intakes unchanged), according to subject response. If the investigator finds that the dose reduction was too large, it can be increased again up to the baseline dose level. The dosage of L-DOPA/DDCI must not be changed during the study from V4 through the end of the DB period.
    Evidence for comparator
    		 -
    Actual start date of recruitment
    30 Mar 2011
    Long term follow-up planned
    No
    Independent data monitoring committee (IDMC) involvement?
    Yes
    Population of trial subjects
    Number of subjects enrolled per country
    Country: Number of subjects enrolled
    Slovakia: 19
    Country: Number of subjects enrolled
    Spain: 37
    Country: Number of subjects enrolled
    Ukraine: 79
    Country: Number of subjects enrolled
    Austria: 3
    Country: Number of subjects enrolled
    Bosnia and Herzegovina: 16
    Country: Number of subjects enrolled
    Bulgaria: 50
    Country: Number of subjects enrolled
    Croatia: 14
    Country: Number of subjects enrolled
    Czech Republic: 51
    Country: Number of subjects enrolled
    France: 15
    Country: Number of subjects enrolled
    Germany: 35
    Country: Number of subjects enrolled
    Hungary: 10
    Country: Number of subjects enrolled
    Italy: 14
    Country: Number of subjects enrolled
    Latvia: 7
    Country: Number of subjects enrolled
    Lithuania: 15
    Country: Number of subjects enrolled
    Poland: 90
    Country: Number of subjects enrolled
    Portugal: 22
    Country: Number of subjects enrolled
    Romania: 53
    Country: Number of subjects enrolled
    Russian Federation: 34
    Country: Number of subjects enrolled
    Serbia: 36
    Worldwide total number of subjects
    600
    EEA total number of subjects
    435
    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)
    309
    From 65 to 84 years
    291
    85 years and over
    0

    Subject disposition

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    Recruitment
    Recruitment details
    		 Planned Number of Study Centres: 130 study centres in approximately 20 countries (Austria, Bosnia and Herzegovina, Bulgaria, Croatia, Czech Republic, France, Germany, Hungary, Italy, Latvia, Lithuania, Montenegro, Netherlands, Poland, Portugal, Romania, Russia, Serbia, Slovakia, Spain and Ukraine).

    Pre-assignment
    Screening details
    		 Subjects who met all the inclusion criteria and none of the exclusion criteria. 679 subjects were enrolled to the trial and 79 subjects were screening failures. 1 subject was randomised but not treated.

    Pre-assignment period milestones
    Number of subjects started
    		 679 [1]
    Number of subjects completed
    		 599

    Pre-assignment subject non-completion reasons
    Reason: Number of subjects
    		 Adverse event, non-fatal: 2
    Reason: Number of subjects
    		 Adverse event, serious non-fatal: 2
    Reason: Number of subjects
    		 Consent withdrawn by subject: 29
    Reason: Number of subjects
    		 Physician decision: 3
    Reason: Number of subjects
    		 Protocol deviation: 1
    Reason: Number of subjects
    		 Ineligibility: 38
    Reason: Number of subjects
    		 Subject's non compliance: 1
    Reason: Number of subjects
    		 Sponsor's discretion: 2
    Reason: Number of subjects
    		 Insufficient medication in Germany: 1
    Reason: Number of subjects
    		 Randomised, but not treated: 1
    Notes
    [1] - The number of subjects reported to have started the pre-assignment period are not the same as the worldwide number enrolled in the trial. It is expected that these numbers will be the same.
    Justification: The number of subjects reported to have started the pre-assignment period is the number of enrolled subjects; The worldwide number is number of treated subjects.
    Period 1
    Period 1 title
    Double-blind period
    Is this the baseline period?
    		 Yes
    Allocation method
    Randomised - controlled
    Blinding used
    		 Double blind
    Roles blinded
    		 Subject, Investigator, Assessor

    Arms
    Are arms mutually exclusive
    Yes

    Arm title
    		 Part I - Placebo
    Arm description
    		 All placebo capsules will contain, on average, 1 mg riboflavin to mimic urinary discoloration seen as a harmless side effect of entacapone.
    Arm type
    		 Placebo

    Investigational medicinal product name
    Placebo
    Investigational medicinal product code
    Other name
    PLC
    Pharmaceutical forms
    Tablet
    Routes of administration
    Oral use
    Dosage and administration details
    During the DB period, subjects will take 1 capsule of IMP concomitantly with each daytime L DOPA/DDCI dose (3 to 8 daily doses). An additional IMP bedtime dose will be administered at least 1 hour after the last daily dose of LDOPA/DDCI. For the daytime doses (concomitantly with each L-DOPA/DDCI dose), the IMP administration will be as follows: • placebo. For the bedtime dose (at least 1 hour after the last daily dose of L-DOPA/DDCI), the IMP administration will be as follows: • placebo. The IMP intake (placebo) must start on the day after the Visit 2.

    Arm title
    		 Part I - Entacapone 200mg
    Arm description
    		 Active substance: Entacapone Trade name: Comtan® Strength: Tablets 200 mg Manufacturer: Novartis Pharmaceuticals
    Arm type
    		 Active comparator

    Investigational medicinal product name
    Entacapone
    Investigational medicinal product code
    Other name
    Comtan®
    Pharmaceutical forms
    Tablet
    Routes of administration
    Oral use
    Dosage and administration details
    During the DB period, subjects will take 1 capsule of IMP concomitantly with each daytime L DOPA/DDCI dose (3 to 8 daily doses). An additional IMP bedtime dose will be administered at least 1 hour after the last daily dose of LDOPA/DDCI. For the daytime doses (concomitantly with each L-DOPA/DDCI dose), the IMP administration will be as follows: • 200 mg entacapone. For the bedtime dose (at least 1 hour after the last daily dose of L-DOPA/DDCI), the IMP administration will be as follows: • placebo. The IMP intake (entacapone) must start on the day after the Visit 2.

    Arm title
    		 Part I - OPC 5mg/day
    Arm description
    		 Active substance: BIA 9-1067 Other name: OPC, Opicapone Strength: 5 mg Manufacturer: BIAL – Portela & Cª SA, S. Mamede do Coronado, Portugal
    Arm type
    		 Experimental

    Investigational medicinal product name
    BIA 9-1067
    Investigational medicinal product code
    Other name
    OPC, Opicapone
    Pharmaceutical forms
    Tablet
    Routes of administration
    Oral use
    Dosage and administration details
    During the DB period, subjects will take 1 capsule of IMP concomitantly with each daytime L DOPA/DDCI dose (3 to 8 daily doses). An additional IMP bedtime dose will be administered at least 1 hour after the last daily dose of LDOPA/DDCI. For the daytime doses (concomitantly with each L-DOPA/DDCI dose), the IMP administration will be as follows: • placebo. For the bedtime dose (at least 1 hour after the last daily dose of L-DOPA/DDCI), the IMP administration will be as follows: • 5 mg. The IMP intake (BIA 9-1067) must start on the day after the Visit 2.

    Arm title
    		 Part I - OPC 25mg/day
    Arm description
    		 Active substance: BIA 9-1067 Other name: OPC, Opicapone Strength: 25 mg Manufacturer: BIAL – Portela & Cª SA, S. Mamede do Coronado, Portugal
    Arm type
    		 Experimental

    Investigational medicinal product name
    BIA 9-1067
    Investigational medicinal product code
    Other name
    OPC, Opicapone
    Pharmaceutical forms
    Tablet
    Routes of administration
    Oral use
    Dosage and administration details
    During the DB period, subjects will take 1 capsule of IMP concomitantly with each daytime L DOPA/DDCI dose (3 to 8 daily doses). An additional IMP bedtime dose will be administered at least 1 hour after the last daily dose of LDOPA/DDCI. For the daytime doses (concomitantly with each L-DOPA/DDCI dose), the IMP administration will be as follows: • placebo. For the bedtime dose (at least 1 hour after the last daily dose of L-DOPA/DDCI), the IMP administration will be as follows: • 25 mg. The IMP intake (BIA 9-1067) must start on the day after the Visit 2.

    Arm title
    		 Part I - OPC 50mg/day
    Arm description
    		 Active substance: BIA 9-1067 Other name: OPC, Opicapone Strength: 50 mg Manufacturer: BIAL – Portela & Cª SA, S. Mamede do Coronado, Portugal
    Arm type
    		 Experimental

    Investigational medicinal product name
    BIA 9-1067
    Investigational medicinal product code
    Other name
    OPC, Opicapone
    Pharmaceutical forms
    Tablet
    Routes of administration
    Oral use
    Dosage and administration details
    During the DB period, subjects will take 1 capsule of IMP concomitantly with each daytime L DOPA/DDCI dose (3 to 8 daily doses). An additional IMP bedtime dose will be administered at least 1 hour after the last daily dose of LDOPA/DDCI. For the daytime doses (concomitantly with each L-DOPA/DDCI dose), the IMP administration will be as follows: • placebo. For the bedtime dose (at least 1 hour after the last daily dose of L-DOPA/DDCI), the IMP administration will be as follows: • 50 mg. The IMP intake (BIA 9-1067) must start on the day after the Visit 2.

    Number of subjects in period 1 [2]
    		Part I - Placebo Part I - Entacapone 200mg Part I - OPC 5mg/day Part I - OPC 25mg/day Part I - OPC 50mg/day
    Started
    121
    122
    122
    119
    115
    Completed
    110
    107
    110
    108
    107
    Not completed
    11
    15
    12
    11
    8
         Consent withdrawn by subject
    4
    6
    3
    3
    3
         Physician decision
    -
    -
    1
    1
    -
         Adverse event, non-fatal
    4
    5
    4
    6
    5
         Adverse event, serious non-fatal
    1
    1
    1
    -
    -
         Ineligibility
    1
    2
    -
    -
    -
         Lost to follow-up
    -
    -
    1
    -
    -
         Sponsor's discretion
    -
    -
    1
    -
    -
         Protocol deviation
    1
    -
    -
    -
    -
         Subject's non compliance
    -
    1
    -
    1
    -
         Lack of efficacy
    -
    -
    1
    -
    -
    Notes
    [2] - The number of subjects reported to be in the baseline period are not the same as the worldwide number enrolled in the trial. It is expected that these numbers will be the same.
    Justification: Baseline period does not include 1 subject who was randomised but not treated.
    Period 2
    Period 2 title
    Open-label period
    Is this the baseline period?
    		 No
    Allocation method
    Not applicable
    Blinding used
    		 Not blinded

    Arms
    Arm title
    		 Part II - OPC
    Arm description
    		 Active substance: BIA 9-1067 Other name: OPC, Opicapone Strength: 5 / 25 / 50 mg Manufacturer: BIAL – Portela & Cª SA, S. Mamede do Coronado, Portugal
    Arm type
    		 Experimental

    Investigational medicinal product name
    BIA 9-1067
    Investigational medicinal product code
    Other name
    OPC, Opicapone
    Pharmaceutical forms
    Tablet
    Routes of administration
    Oral use
    Dosage and administration details
    During the OL period, all subjects will take BIA 9-1067. Subjects will begin treatment at a dose of 25 mg BIA 9-1067 once daily at bedtime for the first week (7 days), regardless of their prior treatment in the DB period. If the “wearing-off” is not sufficiently controlled, and tolerability allows, the BIA 9-1067 dose can be adjusted by titrating up to 50 mg. If unacceptable dopaminergic AEs appear, usually reflected in an increased intensity or incidence of dyskinesias, the L-DOPA/DDCI dose should be adjusted first and only then; if not sufficient, the BIA 9-1067 dose can be down titrated as follows: subjects on 50 mg BIA 9-1067 should be down titrated first to 25 mg and if needed to 5 mg afterwards; subjects on 25 mg BIA 9-1067 should be down titrated to 5 mg. Adjustments of doses must be always done titrating upwards or downwards based on individual response and tolerability. From V13 to V14, the dose of L-DOPA/DDCI and BIA 9-1067 should remain stable.

    Number of subjects in period 2 [3]
    		Part II - OPC
    Started
    495
    Completed
    432
    Not completed
    63
         Adverse event, serious fatal
    7
         Consent withdrawn by subject
    23
         Physician decision
    1
         Adverse event, non-fatal
    7
         Subject stopped IMP intake bef scheduled EOS visit
    3
         Adverse event, serious non-fatal
    9
         Lost to follow-up
    1
         Sponsor's discretion
    2
         Subject moved to other place
    4
         Lack of efficacy
    1
         Subject's non compliance
    5
    Notes
    [3] - The number of subjects starting the period is not consistent with the number completing the preceding period. It is expected the number of subjects starting the subsequent period will be the same as the number completing the preceding period.
    Justification: 542 subjects completed double blind part and 47 of them did not start open label part.

    Baseline characteristics

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    Baseline characteristics reporting groups
    Reporting group title
    Part I - Placebo
    Reporting group description
    		 All placebo capsules will contain, on average, 1 mg riboflavin to mimic urinary discoloration seen as a harmless side effect of entacapone.

    Reporting group title
    Part I - Entacapone 200mg
    Reporting group description
    		 Active substance: Entacapone Trade name: Comtan® Strength: Tablets 200 mg Manufacturer: Novartis Pharmaceuticals

    Reporting group title
    Part I - OPC 5mg/day
    Reporting group description
    		 Active substance: BIA 9-1067 Other name: OPC, Opicapone Strength: 5 mg Manufacturer: BIAL – Portela & Cª SA, S. Mamede do Coronado, Portugal

    Reporting group title
    Part I - OPC 25mg/day
    Reporting group description
    		 Active substance: BIA 9-1067 Other name: OPC, Opicapone Strength: 25 mg Manufacturer: BIAL – Portela & Cª SA, S. Mamede do Coronado, Portugal

    Reporting group title
    Part I - OPC 50mg/day
    Reporting group description
    		 Active substance: BIA 9-1067 Other name: OPC, Opicapone Strength: 50 mg Manufacturer: BIAL – Portela & Cª SA, S. Mamede do Coronado, Portugal

    Reporting group values
    		 Part I - Placebo Part I - Entacapone 200mg Part I - OPC 5mg/day Part I - OPC 25mg/day Part I - OPC 50mg/day Total
    Number of subjects
    		 121 122 122 119 115 599
    Age Categorical
    Age Categorical Characteristic
    Units: Subjects
        In Utero
    		 0 0 0 0 0 0
        Preterm newborn- gestational age < 37 wk
    		 0 0 0 0 0 0
        Newborns (0-27days)
    		 0 0 0 0 0 0
        Infants and toddlers (28days – 23months)
    		 0 0 0 0 0 0
        Children (2-11 years)
    		 0 0 0 0 0 0
        Adolescents (12-17 year)
    		 0 0 0 0 0 0
        From 18 - 64 years
    		 60 66 65 59 58 308
        From 65 – 84 years
    		 61 56 57 60 57 291
        Over 85 years
    		 0 0 0 0 0 0
    Age Continuous
    Age Continuous Characteristic
    Units: Years
        arithmetic mean (standard deviation)
    		 64.3 ± 9.25 63.7 ± 8.78 63.6 ± 9.3 64.4 ± 8.98 63.5 ± 9.22 -
    Gender Categorical
    Gender Categorical Characteristic
    Units: Subjects
        Female
    		 71 46 51 52 46 266
        Male
    		 50 76 71 67 69 333

    End points

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    End points reporting groups
    Reporting group title
    Part I - Placebo
    Reporting group description
    		 All placebo capsules will contain, on average, 1 mg riboflavin to mimic urinary discoloration seen as a harmless side effect of entacapone.

    Reporting group title
    Part I - Entacapone 200mg
    Reporting group description
    		 Active substance: Entacapone Trade name: Comtan® Strength: Tablets 200 mg Manufacturer: Novartis Pharmaceuticals

    Reporting group title
    Part I - OPC 5mg/day
    Reporting group description
    		 Active substance: BIA 9-1067 Other name: OPC, Opicapone Strength: 5 mg Manufacturer: BIAL – Portela & Cª SA, S. Mamede do Coronado, Portugal

    Reporting group title
    Part I - OPC 25mg/day
    Reporting group description
    		 Active substance: BIA 9-1067 Other name: OPC, Opicapone Strength: 25 mg Manufacturer: BIAL – Portela & Cª SA, S. Mamede do Coronado, Portugal

    Reporting group title
    Part I - OPC 50mg/day
    Reporting group description
    		 Active substance: BIA 9-1067 Other name: OPC, Opicapone Strength: 50 mg Manufacturer: BIAL – Portela & Cª SA, S. Mamede do Coronado, Portugal
    Reporting group title
    Part II - OPC
    Reporting group description
    		 Active substance: BIA 9-1067 Other name: OPC, Opicapone Strength: 5 / 25 / 50 mg Manufacturer: BIAL – Portela & Cª SA, S. Mamede do Coronado, Portugal

    Subject analysis set title
    Part I - Placebo x Safety set
    Subject analysis set type
    		 Safety analysis
    Subject analysis set description
    All subjects who received at least 1 dose of IMP.

    Subject analysis set title
    Part I - Entacapone x Safety set
    Subject analysis set type
    		 Safety analysis
    Subject analysis set description
    All subjects who received at least 1 dose of IMP.

    Subject analysis set title
    Part I - OPC 5mg/day x Safety set
    Subject analysis set type
    		 Safety analysis
    Subject analysis set description
    All subjects who received at least 1 dose of IMP.

    Subject analysis set title
    Part I - OPC 25mg/day x Safety set
    Subject analysis set type
    		 Safety analysis
    Subject analysis set description
    All subjects who received at least 1 dose of IMP.

    Subject analysis set title
    Part I - OPC 50mg/day x Safety set
    Subject analysis set type
    		 Safety analysis
    Subject analysis set description
    All subjects who received at least 1 dose of IMP.

    Subject analysis set title
    Part II - OPC x Safety set
    Subject analysis set type
    		 Safety analysis
    Subject analysis set description
    All subjects entered OL phase who received at least 1 dose of IMP of the OL phase.

    Subject analysis set title
    Part I - Placebo x Full analysis set
    Subject analysis set type
    		 Full analysis
    Subject analysis set description
    All subjects randomised, treated with at least 1 dose of IMP after randomisation and with at least 1 OFF-time efficacy assessment.

    Subject analysis set title
    Part I - Entacapone x Full analysis set
    Subject analysis set type
    		 Full analysis
    Subject analysis set description
    All subjects randomised, treated with at least 1 dose of IMP after randomisation and with at least 1 OFF-time efficacy assessment.

    Subject analysis set title
    Part I - OPC 5mg/day x Full analysis set
    Subject analysis set type
    		 Full analysis
    Subject analysis set description
    All subjects randomised, treated with at least 1 dose of IMP after randomisation and with at least 1 OFF-time efficacy assessment.

    Subject analysis set title
    Part I - OPC 25mg/day x Full analysis set
    Subject analysis set type
    		 Full analysis
    Subject analysis set description
    All subjects randomised, treated with at least 1 dose of IMP after randomisation and with at least 1 OFF-time efficacy assessment.

    Subject analysis set title
    Part I - OPC 50mg/day x Full analysis set
    Subject analysis set type
    		 Full analysis
    Subject analysis set description
    All subjects randomised, treated with at least 1 dose of IMP after randomisation and with at least 1 OFF-time efficacy assessment.

    Subject analysis set title
    Part I - Placebo x Per protocol set
    Subject analysis set type
    		 Per protocol
    Subject analysis set description
    All subjects of the FAS without any major protocol deviations. Subjects were included into the PP set if they fulfilled all of the following criteria: - Fulfilling all inclusion criteria. - Treated with IMP according to the randomisation plan. - No Intake of prohibited concomitant medication. - Sufficient compliance. - No L-DOPA dose higher than baseline during the study from V4 through the end of the DB period.

    Subject analysis set title
    Part I - Entacapone x Per protocol set
    Subject analysis set type
    		 Per protocol
    Subject analysis set description
    All subjects of the FAS without any major protocol deviations. Subjects were included into the PP set if they fulfilled all of the following criteria: - Fulfilling all inclusion criteria. - Treated with IMP according to the randomisation plan. - No Intake of prohibited concomitant medication. - Sufficient compliance. - No L-DOPA dose higher than baseline during the study from V4 through the end of the DB period.

    Subject analysis set title
    Part I - OPC 5mg/day x Per protocol set
    Subject analysis set type
    		 Per protocol
    Subject analysis set description
    All subjects of the FAS without any major protocol deviations. Subjects were included into the PP set if they fulfilled all of the following criteria: - Fulfilling all inclusion criteria. - Treated with IMP according to the randomisation plan. - No Intake of prohibited concomitant medication. - Sufficient compliance. - No L-DOPA dose higher than baseline during the study from V4 through the end of the DB period.

    Subject analysis set title
    Part I - OPC 25mg/day x Per protocol set
    Subject analysis set type
    		 Per protocol
    Subject analysis set description
    All subjects of the FAS without any major protocol deviations. Subjects were included into the PP set if they fulfilled all of the following criteria: - Fulfilling all inclusion criteria. - Treated with IMP according to the randomisation plan. - No Intake of prohibited concomitant medication. - Sufficient compliance. - No L-DOPA dose higher than baseline during the study from V4 through the end of the DB period.

    Subject analysis set title
    Part I - OPC 50mg/day x Per protocol set
    Subject analysis set type
    		 Per protocol
    Subject analysis set description
    All subjects of the FAS without any major protocol deviations. Subjects were included into the PP set if they fulfilled all of the following criteria: - Fulfilling all inclusion criteria. - Treated with IMP according to the randomisation plan. - No Intake of prohibited concomitant medication. - Sufficient compliance. - No L-DOPA dose higher than baseline during the study from V4 through the end of the DB period.

    Primary: Change from baseline in absolute OFF-time at the end of DB

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    End point title
    		 Change from baseline in absolute OFF-time at the end of DB
    End point description
    The primary efficacy variable will be the change from baseline in absolute OFF-time at the end of the DB period, This results refers when administered with the existing treatment of L-DOPA plus a DDCI, in patients with PD and end-of-dose motor fluctuations.
    End point type
    Primary
    End point timeframe
    From Baseline to End of DB period
    End point values
    		 Part I - Placebo x Full analysis set Part I - Entacapone x Full analysis set Part I - OPC 5mg/day x Full analysis set Part I - OPC 25mg/day x Full analysis set Part I - OPC 50mg/day x Full analysis set Part I - Placebo x Per protocol set Part I - Entacapone x Per protocol set Part I - OPC 5mg/day x Per protocol set Part I - OPC 25mg/day x Per protocol set Part I - OPC 50mg/day x Per protocol set
    Number of subjects analysed
    120
    120
    119
    116
    115
    112
    104
    110
    105
    106
    Units: Minutes
    arithmetic mean (standard deviation)
        Baseline
    370.1 ± 106.72
    387.6 ± 130.47
    403.2 ± 128.1
    411.2 ± 132.29
    372.2 ± 106.95
    374 ± 105.45
    394.7 ± 110.67
    406.1 ± 118.9
    413.6 ± 126.26
    367 ± 106.2
        Endpoint
    325.3 ± 166.17
    294.1 ± 165.64
    307.2 ± 153.88
    316.6 ± 162.21
    265.4 ± 142.54
    328.3 ± 163.48
    304.4 ± 155.66
    307.1 ± 155.36
    312.2 ± 154.89
    263.6 ± 140.77
        Change from Baseline to Endpoint
    -44.8 ± 160.76
    -93.5 ± 155.55
    -96 ± 149.09
    -94.5 ± 162.02
    -106.8 ± 134.2
    -45.7 ± 162.86
    -90.3 ± 136
    -99 ± 146.51
    -101.4 ± 156.96
    -103.4 ± 131.28
    Statistical analysis title
    		 Superiority (Part I): OPC 5mg/day vs Placebo FAS
    Statistical analysis description
    The primary efficacy objective is to demonstrate superiority. Results are based on an ANCOVA model with Treatment and Region as Factors and Baseline OFF-time as Covariate.
    Comparison groups
    Part I - OPC 5mg/day x Full analysis set v Part I - Placebo x Full analysis set
    Number of subjects included in analysis
    239
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.0279
    Method
    		 ANCOVA
    Parameter type
    		 Difference of LS Means
    Point estimate
    -35.2
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -71.4
         upper limit
    		 0.9
    Variability estimate
    Standard error of the mean
    Dispersion value
    18.3846
    Statistical analysis title
    		 Superiority (Part I): OPC 5mg/day vs Placebo PPS
    Statistical analysis description
    The primary efficacy objective is to demonstrate superiority. Results are based on an ANCOVA model with Treatment and Region as Factors and Baseline OFF-time as Covariate.
    Comparison groups
    Part I - OPC 5mg/day x Per protocol set v Part I - Placebo x Per protocol set
    Number of subjects included in analysis
    222
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.0257
    Method
    		 ANCOVA
    Parameter type
    		 Difference of LS Means
    Point estimate
    -36.4
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -73.1
         upper limit
    		 0.2
    Variability estimate
    Standard error of the mean
    Dispersion value
    18.6485
    Statistical analysis title
    		 Superiority (Part I): OPC 25mg/day vs Placebo FAS
    Statistical analysis description
    The primary efficacy objective is to demonstrate superiority. Results are based on an ANCOVA model with Treatment and Region as Factors and Baseline OFF-time as Covariate.
    Comparison groups
    Part I - OPC 25mg/day x Full analysis set v Part I - Placebo x Full analysis set
    Number of subjects included in analysis
    236
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.0536
    Method
    		 ANCOVA
    Parameter type
    		 Difference of LS Means
    Point estimate
    -29.9
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -66.3
         upper limit
    		 6.5
    Variability estimate
    Standard error of the mean
    Dispersion value
    18.5437
    Statistical analysis title
    		 Superiority (Part I): OPC 25mg/day vs Placebo PPS
    Statistical analysis description
    The primary efficacy objective is to demonstrate superiority. Results are based on an ANCOVA model with Treatment and Region as Factors and Baseline OFF-time as Covariate.
    Comparison groups
    Part I - OPC 25mg/day x Per protocol set v Part I - Placebo x Per protocol set
    Number of subjects included in analysis
    217
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.0236
    Method
    		 ANCOVA
    Parameter type
    		 Difference of LS Means
    Point estimate
    -37.6
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -74.7
         upper limit
    		 -0.5
    Variability estimate
    Standard error of the mean
    Dispersion value
    18.8924
    Statistical analysis title
    		 Superiority (Part I): OPC 50mg/day vs Placebo FAS
    Statistical analysis description
    The primary efficacy objective is to demonstrate superiority. Results are based on an ANCOVA model with Treatment and Region as Factors and Baseline OFF-time as Covariate.
    Comparison groups
    Part I - OPC 50mg/day x Full analysis set v Part I - Placebo x Full analysis set
    Number of subjects included in analysis
    235
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.0005
    Method
    		 ANCOVA
    Parameter type
    		 Difference of LS Means
    Point estimate
    -60.8
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -97.2
         upper limit
    		 -24.4
    Variability estimate
    Standard error of the mean
    Dispersion value
    18.5198
    Statistical analysis title
    		 Superiority (Part I): OPC 50mg/day vs Placebo PPS
    Statistical analysis description
    The primary efficacy objective is to demonstrate superiority. Results are based on an ANCOVA model with Treatment and Region as Factors and Baseline OFF-time as Covariate.
    Comparison groups
    Part I - OPC 50mg/day x Per protocol set v Part I - Placebo x Per protocol set
    Number of subjects included in analysis
    218
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.0008
    Method
    		 ANCOVA
    Parameter type
    		 Difference of LS Means
    Point estimate
    -59.4
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -96.3
         upper limit
    		 -22.5
    Variability estimate
    Standard error of the mean
    Dispersion value
    18.7827
    Statistical analysis title
    		 Non-inferiority: OPC 5 mg/day vs Entacapone FAS
    Statistical analysis description
    The primary efficacy objective is to demonstrate non-inferiority. Results are based on an ANCOVA model with Treatment and Region as Factors and Baseline OFF-time as Covariate.
    Comparison groups
    Part I - OPC 5mg/day x Full analysis set v Part I - Entacapone x Full analysis set
    Number of subjects included in analysis
    239
    Analysis specification
    Pre-specified
    Analysis type
    		 non-inferiority
    P-value
    		 = 0.0867
    Method
    		 ANCOVA
    Parameter type
    		 Difference of LS Means
    Point estimate
    5
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -31
         upper limit
    		 41
    Variability estimate
    Standard error of the mean
    Dispersion value
    18.3243
    Statistical analysis title
    		 Non-inferiority: OPC 5 mg/day vs Entacapone PPS
    Statistical analysis description
    The primary efficacy objective is to demonstrate non-inferiority. Results are based on an ANCOVA model with Treatment and Region as Factors and Baseline OFF-time as Covariate.
    Comparison groups
    Part I - OPC 5mg/day x Per protocol set v Part I - Entacapone x Per protocol set
    Number of subjects included in analysis
    214
    Analysis specification
    Pre-specified
    Analysis type
    		 non-inferiority
    P-value
    		 = 0.0398
    Method
    		 ANCOVA
    Parameter type
    		 Difference of LS Means
    Point estimate
    -3.2
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -40.4
         upper limit
    		 33.9
    Variability estimate
    Standard error of the mean
    Dispersion value
    18.9231
    Statistical analysis title
    		 Non-inferiority: OPC 25 mg/day vs Entacapone FAS
    Statistical analysis description
    The primary efficacy objective is to demonstrate non-inferiority. Results are based on an ANCOVA model with Treatment and Region as Factors and Baseline OFF-time as Covariate.
    Comparison groups
    Part I - OPC 25mg/day x Full analysis set v Part I - Entacapone x Full analysis set
    Number of subjects included in analysis
    236
    Analysis specification
    Pre-specified
    Analysis type
    		 non-inferiority
    P-value
    		 = 0.1436
    Method
    		 ANCOVA
    Parameter type
    		 Difference of LS Means
    Point estimate
    10.3
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -25.9
         upper limit
    		 46.6
    Variability estimate
    Standard error of the mean
    Dispersion value
    18.4617
    Statistical analysis title
    		 Non-inferiority: OPC 25 mg/day vs Entacapone PPS
    Statistical analysis description
    The primary efficacy objective is to demonstrate non-inferiority. Results are based on an ANCOVA model with Treatment and Region as Factors and Baseline OFF-time as Covariate.
    Comparison groups
    Part I - OPC 25mg/day x Per protocol set v Part I - Entacapone x Per protocol set
    Number of subjects included in analysis
    209
    Analysis specification
    Pre-specified
    Analysis type
    		 non-inferiority
    P-value
    		 = 0.0366
    Method
    		 ANCOVA
    Parameter type
    		 Difference of LS Means
    Point estimate
    -4.4
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -42
         upper limit
    		 33.2
    Variability estimate
    Standard error of the mean
    Dispersion value
    19.148
    Statistical analysis title
    		 Non-inferiority: OPC 50 mg/day vs Entacapone FAS
    Statistical analysis description
    The primary efficacy objective is to demonstrate non-inferiority. Results are based on an ANCOVA model with Treatment and Region as Factors and Baseline OFF-time as Covariate.
    Comparison groups
    Part I - OPC 50mg/day x Full analysis set v Part I - Entacapone x Full analysis set
    Number of subjects included in analysis
    235
    Analysis specification
    Pre-specified
    Analysis type
    		 non-inferiority
    P-value
    		 = 0.0033
    Method
    		 ANCOVA
    Parameter type
    		 Difference of LS Means
    Point estimate
    -20.5
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -56.9
         upper limit
    		 15.8
    Variability estimate
    Standard error of the mean
    Dispersion value
    18.5075
    Statistical analysis title
    		 Non-inferiority: OPC 50 mg/day vs Entacapone PPS
    Statistical analysis description
    The primary efficacy objective is to demonstrate non-inferiority. Results are based on an ANCOVA with Treatment and Region as Factors and Baseline OFF-time as Covariate.
    Comparison groups
    Part I - OPC 50mg/day x Per protocol set v Part I - Entacapone x Per protocol set
    Number of subjects included in analysis
    210
    Analysis specification
    Pre-specified
    Analysis type
    		 non-inferiority
    P-value
    		 = 0.0017
    Method
    		 ANCOVA
    Parameter type
    		 Difference of LS Means
    Point estimate
    -26.2
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -63.8
         upper limit
    		 11.4
    Variability estimate
    Standard error of the mean
    Dispersion value
    19.1323

    Secondary: Total UPDRS SCORE (I, II (ON), and III)

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    End point title
    		 Total UPDRS SCORE (I, II (ON), and III)
    End point description
    Total UPDRS (Part I, II (ON) and III) •UPDRS I evaluation of mentation, behavior, and mood •UPDRS II self-evaluation of the activities of daily life (ADLs) including speech, swallowing, handwriting, dressing, hygiene, falling, salivating, turning in bed, walking, and cutting food •UPDRS III clinician-scored monitored motor evaluation The UPDRS I, II and III scores and subscores are calculated as the sum of all individual items. If one or two items in a scale are missing, they will be imputed with the mean of the non-missing items of that scale. Subscale has 0-4 ratings, where 0 = normal, 1 = slight, 2 = mild, 3 = moderate, and 4 = severe The final cumulative score will range from 0 (no disability) to 199 (total disability).
    End point type
    Secondary
    End point timeframe
    From Baseline to End of DB period
    End point values
    		 Part I - Placebo x Full analysis set Part I - Entacapone x Full analysis set Part I - OPC 5mg/day x Full analysis set Part I - OPC 25mg/day x Full analysis set Part I - OPC 50mg/day x Full analysis set
    Number of subjects analysed
    120
    120
    119
    116
    115
    Units: UPDRS Score
    arithmetic mean (standard deviation)
        Baseline
    37.6 ± 16.56
    35.4 ± 19.98
    38.2 ± 16.16
    40.1 ± 18.56
    38.8 ± 18.99
        Endpoint
    32.1 ± 14.87
    29.8 ± 18.69
    31 ± 15.98
    32 ± 15.61
    31.5 ± 18.72
        Change from Baseline to Endpoint
    -5.6 ± 10.3
    -6 ± 11.69
    -7.6 ± 9.96
    -7.6 ± 9.76
    -6.5 ± 10.14
    No statistical analyses for this end point

    Secondary: Parkinson's Disease Sleep Scale (PDSS)

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    End point title
    		 Parkinson's Disease Sleep Scale (PDSS)
    End point description
    The Parkinson’s disease Sleep Scale (PDSS) is a specific scale for the assessment of sleep disturbances in subjects with PD. The PDSS score is calculated as the sum of all single items. If one or two items are missing, they will be imputed with the mean of the non-missing items. If three or more items are missing, no imputation will be done and the score will be set to missing. Subscale has 0-10 ratings, where 0 = severe and 10 = normal The PDSS total score is a sum score of all 15 questions and ranges from 0 to 150, with lower scores meaning more disability.
    End point type
    Secondary
    End point timeframe
    From Baseline to End of DB period
    End point values
    		 Part I - Placebo x Full analysis set Part I - Entacapone x Full analysis set Part I - OPC 5mg/day x Full analysis set Part I - OPC 25mg/day x Full analysis set Part I - OPC 50mg/day x Full analysis set
    Number of subjects analysed
    120
    120
    119
    116
    115
    Units: PDS Scale
    arithmetic mean (standard deviation)
        Baseline
    97.5 ± 24.97
    100.7 ± 25.46
    97.8 ± 22.55
    92.7 ± 26.85
    98 ± 22.19
        Endpoint
    98.5 ± 25.81
    102.8 ± 24.98
    102.9 ± 22.61
    100.4 ± 23.75
    100.9 ± 24.05
        Change from Baseline to Endpoint
    1.3 ± 18.27
    2 ± 20.64
    5.4 ± 20.58
    7.3 ± 22.11
    3.1 ± 19.84
    No statistical analyses for this end point

    Secondary: Non-motor Symptoms Scale (NMSS)

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    End point title
    		 Non-motor Symptoms Scale (NMSS)
    End point description
    The Non-motor Symptoms Scale (NMSS) consists of 30 questions, covering 9 dimensions, whereby each item is scored for severity and frequency: Severity None 0 Mild (symptoms present but causes little distress) 1 Moderate (some distress or disturbance to subject) 2 Severe (major source of distress or disturbance to subject) 3 Frequency Rarely (<1/wk) 1 Often (1/wk) 2 Frequent (several times per week) 3 Very Frequent (daily or all the time) 4 The product of frequency and severity is calculated for each item and each dimension score is defined as the sum of the frequency*severity of the respective items. If frequency or severity of a single item is missing, the domain score will not be calculated. The NMSS total score is defined as the sum of all domain scores. The NMSS total score is calculated by adding all domain scores (0–360), and lower scores mean less disability.
    End point type
    Secondary
    End point timeframe
    From Baseline to End of DB period
    End point values
    		 Part I - Placebo x Full analysis set Part I - Entacapone x Full analysis set Part I - OPC 5mg/day x Full analysis set Part I - OPC 25mg/day x Full analysis set Part I - OPC 50mg/day x Full analysis set
    Number of subjects analysed
    118 [1]
    119 [2]
    117 [3]
    115 [4]
    114 [5]
    Units: Score
    arithmetic mean (standard deviation)
        Baseline
    38.8 ± 29.2
    32.1 ± 25.09
    36.1 ± 26.67
    39.8 ± 30.18
    36.4 ± 28.02
        Endpoint
    32 ± 25.71
    27.5 ± 21.82
    29.5 ± 24.3
    34.4 ± 25.32
    33.4 ± 30.23
        Change from Baseline to Endpoint
    -7 ± 15.09
    -4.2 ± 16.52
    -6.2 ± 13.24
    -5.7 ± 20.55
    -2.8 ± 17.82
    Notes
    [1] - Two subjects did not complete questionnaire for baseline visit.
    [2] - One subject did not complete questionnaire for baseline visit.
    [3] - Two subjects did not complete questionnaire for baseline visit.
    [4] - One subject did not complete questionnaire for baseline visit.
    [5] - One subject did not complete questionnaire for baseline visit.
    No statistical analyses for this end point

    Adverse events

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    Adverse events information
    Timeframe for reporting adverse events
    From the first intake of IMP until 2 weeks (14 days) after last intake of IMP in the corresponding part.
    Adverse event reporting additional description
    The investigator monitor AEs and SAEs, at each visit, from V1 on throughout the study, using an unstructured interview. The investigator will inquire generally about the subject’s well-being since the last visit. Details of any reported AEs were recorded at all scheduled and unscheduled visits as well as those reported during any telephone contact.
    Assessment type
    		 Systematic
    Dictionary used for adverse event reporting
    Dictionary name
    		 MedDRA
    Dictionary version
    14.0
    Reporting groups
    Reporting group title
    Part I - Placebo x Safety set
    Reporting group description
    		 -

    Reporting group title
    Part I - Entacapone x Safety set
    Reporting group description
    		 -

    Reporting group title
    Part I - OPC 5mg/day x Safety set
    Reporting group description
    		 -

    Reporting group title
    Part I - OPC 25mg/day x Safety set
    Reporting group description
    		 -

    Reporting group title
    Part I - OPC 50mg/day x Safety set
    Reporting group description
    		 -

    Reporting group title
    Part II - OPC x Safety set
    Reporting group description
    		 -

    Serious adverse events
    		 Part I - Placebo x Safety set Part I - Entacapone x Safety set Part I - OPC 5mg/day x Safety set Part I - OPC 25mg/day x Safety set Part I - OPC 50mg/day x Safety set Part II - OPC x Safety set
    Total subjects affected by serious adverse events
         subjects affected / exposed
    6 / 121 (4.96%)
    8 / 122 (6.56%)
    4 / 122 (3.28%)
    1 / 119 (0.84%)
    4 / 115 (3.48%)
    48 / 495 (9.70%)
         number of deaths (all causes)
    0
    0
    0
    0
    0
    11
         number of deaths resulting from adverse events
    0
    0
    0
    0
    0
    Neoplasms benign, malignant and unspecified (incl cysts and polyps)
    Adrenal adenoma
         subjects affected / exposed
    0 / 121 (0.00%)
    0 / 122 (0.00%)
    0 / 122 (0.00%)
    0 / 119 (0.00%)
    0 / 115 (0.00%)
    1 / 495 (0.20%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Basal cell carcinoma
         subjects affected / exposed
    0 / 121 (0.00%)
    0 / 122 (0.00%)
    1 / 122 (0.82%)
    0 / 119 (0.00%)
    0 / 115 (0.00%)
    2 / 495 (0.40%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    1 / 1
    0 / 0
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Benign ear neoplasm
         subjects affected / exposed
    0 / 121 (0.00%)
    1 / 122 (0.82%)
    0 / 122 (0.00%)
    0 / 119 (0.00%)
    0 / 115 (0.00%)
    0 / 495 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Bowen's disease
         subjects affected / exposed
    0 / 121 (0.00%)
    0 / 122 (0.00%)
    0 / 122 (0.00%)
    1 / 119 (0.84%)
    0 / 115 (0.00%)
    0 / 495 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Brain neoplasm
         subjects affected / exposed
    0 / 121 (0.00%)
    0 / 122 (0.00%)
    0 / 122 (0.00%)
    0 / 119 (0.00%)
    0 / 115 (0.00%)
    1 / 495 (0.20%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Malignant melanoma
         subjects affected / exposed
    0 / 121 (0.00%)
    0 / 122 (0.00%)
    0 / 122 (0.00%)
    0 / 119 (0.00%)
    0 / 115 (0.00%)
    2 / 495 (0.40%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    1 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Malignant melanoma in situ
         subjects affected / exposed
    0 / 121 (0.00%)
    0 / 122 (0.00%)
    0 / 122 (0.00%)
    0 / 119 (0.00%)
    0 / 115 (0.00%)
    1 / 495 (0.20%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Metastases to spine
         subjects affected / exposed
    0 / 121 (0.00%)
    0 / 122 (0.00%)
    0 / 122 (0.00%)
    0 / 119 (0.00%)
    0 / 115 (0.00%)
    1 / 495 (0.20%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    Prostate cancer
         subjects affected / exposed
    0 / 121 (0.00%)
    0 / 122 (0.00%)
    0 / 122 (0.00%)
    0 / 119 (0.00%)
    0 / 115 (0.00%)
    1 / 495 (0.20%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Small cell lung cancer stage unspecified
         subjects affected / exposed
    0 / 121 (0.00%)
    0 / 122 (0.00%)
    0 / 122 (0.00%)
    0 / 119 (0.00%)
    0 / 115 (0.00%)
    1 / 495 (0.20%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    Superficial spreading melanoma stage unspecified
         subjects affected / exposed
    1 / 121 (0.83%)
    0 / 122 (0.00%)
    0 / 122 (0.00%)
    0 / 119 (0.00%)
    0 / 115 (0.00%)
    0 / 495 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Vascular disorders
    Embolism
         subjects affected / exposed
    0 / 121 (0.00%)
    0 / 122 (0.00%)
    0 / 122 (0.00%)
    0 / 119 (0.00%)
    0 / 115 (0.00%)
    1 / 495 (0.20%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    Hypertension
         subjects affected / exposed
    1 / 121 (0.83%)
    0 / 122 (0.00%)
    0 / 122 (0.00%)
    0 / 119 (0.00%)
    0 / 115 (0.00%)
    2 / 495 (0.40%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Hypertensive crisis
         subjects affected / exposed
    0 / 121 (0.00%)
    0 / 122 (0.00%)
    0 / 122 (0.00%)
    0 / 119 (0.00%)
    0 / 115 (0.00%)
    1 / 495 (0.20%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Orthostatic hypotension
         subjects affected / exposed
    0 / 121 (0.00%)
    1 / 122 (0.82%)
    0 / 122 (0.00%)
    0 / 119 (0.00%)
    0 / 115 (0.00%)
    0 / 495 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    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
    Asthenia
         subjects affected / exposed
    0 / 121 (0.00%)
    0 / 122 (0.00%)
    0 / 122 (0.00%)
    0 / 119 (0.00%)
    0 / 115 (0.00%)
    1 / 495 (0.20%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Death
         subjects affected / exposed
    0 / 121 (0.00%)
    0 / 122 (0.00%)
    0 / 122 (0.00%)
    0 / 119 (0.00%)
    0 / 115 (0.00%)
    1 / 495 (0.20%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    Drug effect decreased
         subjects affected / exposed
    0 / 121 (0.00%)
    0 / 122 (0.00%)
    0 / 122 (0.00%)
    0 / 119 (0.00%)
    0 / 115 (0.00%)
    1 / 495 (0.20%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Mucosal inflammation
         subjects affected / exposed
    0 / 121 (0.00%)
    0 / 122 (0.00%)
    0 / 122 (0.00%)
    0 / 119 (0.00%)
    0 / 115 (0.00%)
    1 / 495 (0.20%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Multi-organ failure
         subjects affected / exposed
    0 / 121 (0.00%)
    0 / 122 (0.00%)
    0 / 122 (0.00%)
    0 / 119 (0.00%)
    0 / 115 (0.00%)
    1 / 495 (0.20%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    Sudden death
         subjects affected / exposed
    0 / 121 (0.00%)
    0 / 122 (0.00%)
    0 / 122 (0.00%)
    0 / 119 (0.00%)
    0 / 115 (0.00%)
    1 / 495 (0.20%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    Reproductive system and breast disorders
    Benign prostatic hyperplasia
         subjects affected / exposed
    0 / 121 (0.00%)
    0 / 122 (0.00%)
    0 / 122 (0.00%)
    0 / 119 (0.00%)
    0 / 115 (0.00%)
    2 / 495 (0.40%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Respiratory, thoracic and mediastinal disorders
    Epistaxis
         subjects affected / exposed
    0 / 121 (0.00%)
    0 / 122 (0.00%)
    0 / 122 (0.00%)
    0 / 119 (0.00%)
    0 / 115 (0.00%)
    1 / 495 (0.20%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Hydrothorax
         subjects affected / exposed
    0 / 121 (0.00%)
    0 / 122 (0.00%)
    0 / 122 (0.00%)
    0 / 119 (0.00%)
    0 / 115 (0.00%)
    1 / 495 (0.20%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Lung disorder
         subjects affected / exposed
    0 / 121 (0.00%)
    0 / 122 (0.00%)
    0 / 122 (0.00%)
    0 / 119 (0.00%)
    0 / 115 (0.00%)
    1 / 495 (0.20%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    Pneumonia aspiration
         subjects affected / exposed
    1 / 121 (0.83%)
    0 / 122 (0.00%)
    0 / 122 (0.00%)
    0 / 119 (0.00%)
    0 / 115 (0.00%)
    0 / 495 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Pulmonary embolism
         subjects affected / exposed
    0 / 121 (0.00%)
    1 / 122 (0.82%)
    0 / 122 (0.00%)
    0 / 119 (0.00%)
    0 / 115 (0.00%)
    1 / 495 (0.20%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    Respiratory failure
         subjects affected / exposed
    0 / 121 (0.00%)
    0 / 122 (0.00%)
    0 / 122 (0.00%)
    0 / 119 (0.00%)
    0 / 115 (0.00%)
    1 / 495 (0.20%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Psychiatric disorders
    Aggression
         subjects affected / exposed
    0 / 121 (0.00%)
    0 / 122 (0.00%)
    0 / 122 (0.00%)
    0 / 119 (0.00%)
    0 / 115 (0.00%)
    1 / 495 (0.20%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Anxiety disorder due to a general medical condition
         subjects affected / exposed
    0 / 121 (0.00%)
    0 / 122 (0.00%)
    0 / 122 (0.00%)
    0 / 119 (0.00%)
    0 / 115 (0.00%)
    1 / 495 (0.20%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Jealous delusion
         subjects affected / exposed
    0 / 121 (0.00%)
    0 / 122 (0.00%)
    0 / 122 (0.00%)
    0 / 119 (0.00%)
    0 / 115 (0.00%)
    1 / 495 (0.20%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Investigations
    Cardiac enzymes increased
         subjects affected / exposed
    0 / 121 (0.00%)
    0 / 122 (0.00%)
    0 / 122 (0.00%)
    0 / 119 (0.00%)
    0 / 115 (0.00%)
    1 / 495 (0.20%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Hepatic enzyme increased
         subjects affected / exposed
    1 / 121 (0.83%)
    0 / 122 (0.00%)
    1 / 122 (0.82%)
    0 / 119 (0.00%)
    0 / 115 (0.00%)
    0 / 495 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
    1 / 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
    Occult blood positive
         subjects affected / exposed
    0 / 121 (0.00%)
    0 / 122 (0.00%)
    0 / 122 (0.00%)
    0 / 119 (0.00%)
    0 / 115 (0.00%)
    1 / 495 (0.20%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Weight decreased
         subjects affected / exposed
    0 / 121 (0.00%)
    0 / 122 (0.00%)
    0 / 122 (0.00%)
    0 / 119 (0.00%)
    0 / 115 (0.00%)
    1 / 495 (0.20%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Injury, poisoning and procedural complications
    Ankle fracture
         subjects affected / exposed
    0 / 121 (0.00%)
    0 / 122 (0.00%)
    0 / 122 (0.00%)
    0 / 119 (0.00%)
    0 / 115 (0.00%)
    2 / 495 (0.40%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Contusion
         subjects affected / exposed
    0 / 121 (0.00%)
    1 / 122 (0.82%)
    0 / 122 (0.00%)
    0 / 119 (0.00%)
    0 / 115 (0.00%)
    0 / 495 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Dislocation of vertebra
         subjects affected / exposed
    0 / 121 (0.00%)
    0 / 122 (0.00%)
    0 / 122 (0.00%)
    0 / 119 (0.00%)
    0 / 115 (0.00%)
    1 / 495 (0.20%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Fall
         subjects affected / exposed
    0 / 121 (0.00%)
    2 / 122 (1.64%)
    0 / 122 (0.00%)
    0 / 119 (0.00%)
    0 / 115 (0.00%)
    0 / 495 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 2
    0 / 0
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Femur fracture
         subjects affected / exposed
    0 / 121 (0.00%)
    1 / 122 (0.82%)
    0 / 122 (0.00%)
    0 / 119 (0.00%)
    0 / 115 (0.00%)
    0 / 495 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Near drowning
         subjects affected / exposed
    1 / 121 (0.83%)
    0 / 122 (0.00%)
    0 / 122 (0.00%)
    0 / 119 (0.00%)
    0 / 115 (0.00%)
    0 / 495 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Rib fracture
         subjects affected / exposed
    0 / 121 (0.00%)
    0 / 122 (0.00%)
    0 / 122 (0.00%)
    0 / 119 (0.00%)
    0 / 115 (0.00%)
    1 / 495 (0.20%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Spinal compression fracture
         subjects affected / exposed
    0 / 121 (0.00%)
    0 / 122 (0.00%)
    0 / 122 (0.00%)
    0 / 119 (0.00%)
    0 / 115 (0.00%)
    1 / 495 (0.20%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Wrist fracture
         subjects affected / exposed
    0 / 121 (0.00%)
    0 / 122 (0.00%)
    1 / 122 (0.82%)
    0 / 119 (0.00%)
    0 / 115 (0.00%)
    1 / 495 (0.20%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Cardiac disorders
    Angina pectoris
         subjects affected / exposed
    0 / 121 (0.00%)
    0 / 122 (0.00%)
    0 / 122 (0.00%)
    0 / 119 (0.00%)
    0 / 115 (0.00%)
    1 / 495 (0.20%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Angina unstable
         subjects affected / exposed
    0 / 121 (0.00%)
    1 / 122 (0.82%)
    0 / 122 (0.00%)
    0 / 119 (0.00%)
    0 / 115 (0.00%)
    0 / 495 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Atrial fibrillation
         subjects affected / exposed
    0 / 121 (0.00%)
    0 / 122 (0.00%)
    0 / 122 (0.00%)
    0 / 119 (0.00%)
    0 / 115 (0.00%)
    2 / 495 (0.40%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Cardiac asthma
         subjects affected / exposed
    0 / 121 (0.00%)
    0 / 122 (0.00%)
    0 / 122 (0.00%)
    0 / 119 (0.00%)
    0 / 115 (0.00%)
    1 / 495 (0.20%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Cardiac failure
         subjects affected / exposed
    0 / 121 (0.00%)
    0 / 122 (0.00%)
    0 / 122 (0.00%)
    0 / 119 (0.00%)
    0 / 115 (0.00%)
    1 / 495 (0.20%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Cardiogenic shock
         subjects affected / exposed
    0 / 121 (0.00%)
    0 / 122 (0.00%)
    0 / 122 (0.00%)
    0 / 119 (0.00%)
    0 / 115 (0.00%)
    1 / 495 (0.20%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Cardiovascular insufficiency
         subjects affected / exposed
    0 / 121 (0.00%)
    0 / 122 (0.00%)
    0 / 122 (0.00%)
    0 / 119 (0.00%)
    0 / 115 (0.00%)
    1 / 495 (0.20%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    Cor pulmonale acute
         subjects affected / exposed
    0 / 121 (0.00%)
    1 / 122 (0.82%)
    0 / 122 (0.00%)
    0 / 119 (0.00%)
    0 / 115 (0.00%)
    0 / 495 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Coronary artery disease
         subjects affected / exposed
    0 / 121 (0.00%)
    0 / 122 (0.00%)
    0 / 122 (0.00%)
    0 / 119 (0.00%)
    1 / 115 (0.87%)
    1 / 495 (0.20%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Myocardial infarction
         subjects affected / exposed
    0 / 121 (0.00%)
    0 / 122 (0.00%)
    0 / 122 (0.00%)
    0 / 119 (0.00%)
    0 / 115 (0.00%)
    1 / 495 (0.20%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    Nervous system disorders
    Cauda equina syndrome
         subjects affected / exposed
    0 / 121 (0.00%)
    0 / 122 (0.00%)
    0 / 122 (0.00%)
    0 / 119 (0.00%)
    0 / 115 (0.00%)
    3 / 495 (0.61%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 4
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Dementia
         subjects affected / exposed
    0 / 121 (0.00%)
    0 / 122 (0.00%)
    0 / 122 (0.00%)
    0 / 119 (0.00%)
    0 / 115 (0.00%)
    1 / 495 (0.20%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Dyskinesia
         subjects affected / exposed
    0 / 121 (0.00%)
    0 / 122 (0.00%)
    0 / 122 (0.00%)
    0 / 119 (0.00%)
    1 / 115 (0.87%)
    0 / 495 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Epilepsy
         subjects affected / exposed
    0 / 121 (0.00%)
    0 / 122 (0.00%)
    0 / 122 (0.00%)
    0 / 119 (0.00%)
    0 / 115 (0.00%)
    1 / 495 (0.20%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Haemorrhage intracranial
         subjects affected / exposed
    0 / 121 (0.00%)
    0 / 122 (0.00%)
    0 / 122 (0.00%)
    0 / 119 (0.00%)
    0 / 115 (0.00%)
    1 / 495 (0.20%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Hemiparesis
         subjects affected / exposed
    0 / 121 (0.00%)
    0 / 122 (0.00%)
    0 / 122 (0.00%)
    0 / 119 (0.00%)
    0 / 115 (0.00%)
    1 / 495 (0.20%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Ischaemic stroke
         subjects affected / exposed
    0 / 121 (0.00%)
    0 / 122 (0.00%)
    0 / 122 (0.00%)
    0 / 119 (0.00%)
    0 / 115 (0.00%)
    1 / 495 (0.20%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Radiculitis
         subjects affected / exposed
    0 / 121 (0.00%)
    0 / 122 (0.00%)
    0 / 122 (0.00%)
    0 / 119 (0.00%)
    0 / 115 (0.00%)
    1 / 495 (0.20%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Sciatica
         subjects affected / exposed
    0 / 121 (0.00%)
    0 / 122 (0.00%)
    0 / 122 (0.00%)
    0 / 119 (0.00%)
    0 / 115 (0.00%)
    2 / 495 (0.40%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Spinal cord compression
         subjects affected / exposed
    0 / 121 (0.00%)
    0 / 122 (0.00%)
    0 / 122 (0.00%)
    0 / 119 (0.00%)
    0 / 115 (0.00%)
    1 / 495 (0.20%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Syncope
         subjects affected / exposed
    0 / 121 (0.00%)
    1 / 122 (0.82%)
    0 / 122 (0.00%)
    0 / 119 (0.00%)
    0 / 115 (0.00%)
    1 / 495 (0.20%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Transient ischaemic attack
         subjects affected / exposed
    0 / 121 (0.00%)
    0 / 122 (0.00%)
    0 / 122 (0.00%)
    0 / 119 (0.00%)
    0 / 115 (0.00%)
    1 / 495 (0.20%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Blood and lymphatic system disorders
    Anaemia
         subjects affected / exposed
    0 / 121 (0.00%)
    0 / 122 (0.00%)
    0 / 122 (0.00%)
    0 / 119 (0.00%)
    0 / 115 (0.00%)
    1 / 495 (0.20%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Iron deficiency anaemia
         subjects affected / exposed
    0 / 121 (0.00%)
    0 / 122 (0.00%)
    0 / 122 (0.00%)
    0 / 119 (0.00%)
    0 / 115 (0.00%)
    1 / 495 (0.20%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Eye disorders
    Visual impairment
         subjects affected / exposed
    1 / 121 (0.83%)
    0 / 122 (0.00%)
    0 / 122 (0.00%)
    0 / 119 (0.00%)
    0 / 115 (0.00%)
    0 / 495 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Gastrointestinal disorders
    Abdominal hernia
         subjects affected / exposed
    0 / 121 (0.00%)
    0 / 122 (0.00%)
    0 / 122 (0.00%)
    0 / 119 (0.00%)
    0 / 115 (0.00%)
    1 / 495 (0.20%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Constipation
         subjects affected / exposed
    0 / 121 (0.00%)
    0 / 122 (0.00%)
    0 / 122 (0.00%)
    0 / 119 (0.00%)
    1 / 115 (0.87%)
    0 / 495 (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
    Duodenitis
         subjects affected / exposed
    1 / 121 (0.83%)
    0 / 122 (0.00%)
    0 / 122 (0.00%)
    0 / 119 (0.00%)
    0 / 115 (0.00%)
    0 / 495 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Gastritis
         subjects affected / exposed
    1 / 121 (0.83%)
    0 / 122 (0.00%)
    0 / 122 (0.00%)
    0 / 119 (0.00%)
    0 / 115 (0.00%)
    0 / 495 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Haemorrhoids
         subjects affected / exposed
    0 / 121 (0.00%)
    0 / 122 (0.00%)
    0 / 122 (0.00%)
    0 / 119 (0.00%)
    0 / 115 (0.00%)
    1 / 495 (0.20%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Inguinal hernia
         subjects affected / exposed
    0 / 121 (0.00%)
    0 / 122 (0.00%)
    0 / 122 (0.00%)
    0 / 119 (0.00%)
    1 / 115 (0.87%)
    1 / 495 (0.20%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Intestinal obstruction
         subjects affected / exposed
    0 / 121 (0.00%)
    0 / 122 (0.00%)
    0 / 122 (0.00%)
    0 / 119 (0.00%)
    0 / 115 (0.00%)
    3 / 495 (0.61%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 3
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Pancreatitis
         subjects affected / exposed
    0 / 121 (0.00%)
    0 / 122 (0.00%)
    0 / 122 (0.00%)
    0 / 119 (0.00%)
    0 / 115 (0.00%)
    1 / 495 (0.20%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Pancreatitis acute
         subjects affected / exposed
    1 / 121 (0.83%)
    0 / 122 (0.00%)
    0 / 122 (0.00%)
    0 / 119 (0.00%)
    0 / 115 (0.00%)
    0 / 495 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Pancreatitis chronic
         subjects affected / exposed
    0 / 121 (0.00%)
    0 / 122 (0.00%)
    0 / 122 (0.00%)
    0 / 119 (0.00%)
    0 / 115 (0.00%)
    1 / 495 (0.20%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Hepatobiliary disorders
    Bile duct stone
         subjects affected / exposed
    0 / 121 (0.00%)
    0 / 122 (0.00%)
    0 / 122 (0.00%)
    0 / 119 (0.00%)
    0 / 115 (0.00%)
    1 / 495 (0.20%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Cholecystitis
         subjects affected / exposed
    0 / 121 (0.00%)
    0 / 122 (0.00%)
    0 / 122 (0.00%)
    0 / 119 (0.00%)
    0 / 115 (0.00%)
    1 / 495 (0.20%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Cholelithiasis
         subjects affected / exposed
    0 / 121 (0.00%)
    1 / 122 (0.82%)
    0 / 122 (0.00%)
    0 / 119 (0.00%)
    0 / 115 (0.00%)
    1 / 495 (0.20%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Hepatitis acute
         subjects affected / exposed
    1 / 121 (0.83%)
    0 / 122 (0.00%)
    0 / 122 (0.00%)
    0 / 119 (0.00%)
    0 / 115 (0.00%)
    0 / 495 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Jaundice cholestatic
         subjects affected / exposed
    0 / 121 (0.00%)
    0 / 122 (0.00%)
    0 / 122 (0.00%)
    0 / 119 (0.00%)
    0 / 115 (0.00%)
    1 / 495 (0.20%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Renal and urinary disorders
    Calculus urinary
         subjects affected / exposed
    0 / 121 (0.00%)
    0 / 122 (0.00%)
    0 / 122 (0.00%)
    0 / 119 (0.00%)
    0 / 115 (0.00%)
    1 / 495 (0.20%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Haematuria
         subjects affected / exposed
    0 / 121 (0.00%)
    0 / 122 (0.00%)
    0 / 122 (0.00%)
    0 / 119 (0.00%)
    0 / 115 (0.00%)
    1 / 495 (0.20%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Renal colic
         subjects affected / exposed
    0 / 121 (0.00%)
    0 / 122 (0.00%)
    0 / 122 (0.00%)
    0 / 119 (0.00%)
    0 / 115 (0.00%)
    1 / 495 (0.20%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Renal failure acute
         subjects affected / exposed
    0 / 121 (0.00%)
    0 / 122 (0.00%)
    0 / 122 (0.00%)
    0 / 119 (0.00%)
    0 / 115 (0.00%)
    1 / 495 (0.20%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Stress urinary incontinence
         subjects affected / exposed
    0 / 121 (0.00%)
    0 / 122 (0.00%)
    0 / 122 (0.00%)
    0 / 119 (0.00%)
    0 / 115 (0.00%)
    1 / 495 (0.20%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Urinary retention
         subjects affected / exposed
    0 / 121 (0.00%)
    0 / 122 (0.00%)
    0 / 122 (0.00%)
    0 / 119 (0.00%)
    0 / 115 (0.00%)
    1 / 495 (0.20%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 3
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Urinary tract inflammation
         subjects affected / exposed
    0 / 121 (0.00%)
    1 / 122 (0.82%)
    0 / 122 (0.00%)
    0 / 119 (0.00%)
    0 / 115 (0.00%)
    0 / 495 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Endocrine disorders
    Hyperthyroidism
         subjects affected / exposed
    0 / 121 (0.00%)
    0 / 122 (0.00%)
    0 / 122 (0.00%)
    0 / 119 (0.00%)
    0 / 115 (0.00%)
    1 / 495 (0.20%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Musculoskeletal and connective tissue disorders
    Arthritis
         subjects affected / exposed
    0 / 121 (0.00%)
    0 / 122 (0.00%)
    0 / 122 (0.00%)
    0 / 119 (0.00%)
    0 / 115 (0.00%)
    1 / 495 (0.20%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Back pain
         subjects affected / exposed
    1 / 121 (0.83%)
    0 / 122 (0.00%)
    0 / 122 (0.00%)
    0 / 119 (0.00%)
    0 / 115 (0.00%)
    0 / 495 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Lumbar spinal stenosis
         subjects affected / exposed
    0 / 121 (0.00%)
    0 / 122 (0.00%)
    0 / 122 (0.00%)
    0 / 119 (0.00%)
    0 / 115 (0.00%)
    1 / 495 (0.20%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Pain in extremity
         subjects affected / exposed
    0 / 121 (0.00%)
    0 / 122 (0.00%)
    1 / 122 (0.82%)
    0 / 119 (0.00%)
    0 / 115 (0.00%)
    0 / 495 (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
    Rotator cuff syndrome
         subjects affected / exposed
    0 / 121 (0.00%)
    0 / 122 (0.00%)
    0 / 122 (0.00%)
    0 / 119 (0.00%)
    0 / 115 (0.00%)
    1 / 495 (0.20%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Infections and infestations
    Appendicitis
         subjects affected / exposed
    0 / 121 (0.00%)
    0 / 122 (0.00%)
    0 / 122 (0.00%)
    0 / 119 (0.00%)
    0 / 115 (0.00%)
    1 / 495 (0.20%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Bronchitis
         subjects affected / exposed
    0 / 121 (0.00%)
    0 / 122 (0.00%)
    0 / 122 (0.00%)
    0 / 119 (0.00%)
    0 / 115 (0.00%)
    2 / 495 (0.40%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Bronchopneumonia
         subjects affected / exposed
    0 / 121 (0.00%)
    0 / 122 (0.00%)
    0 / 122 (0.00%)
    0 / 119 (0.00%)
    0 / 115 (0.00%)
    1 / 495 (0.20%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Cholecystitis infective
         subjects affected / exposed
    0 / 121 (0.00%)
    1 / 122 (0.82%)
    0 / 122 (0.00%)
    0 / 119 (0.00%)
    0 / 115 (0.00%)
    1 / 495 (0.20%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Erysipelas
         subjects affected / exposed
    0 / 121 (0.00%)
    1 / 122 (0.82%)
    0 / 122 (0.00%)
    0 / 119 (0.00%)
    0 / 115 (0.00%)
    0 / 495 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Influenza
         subjects affected / exposed
    0 / 121 (0.00%)
    0 / 122 (0.00%)
    0 / 122 (0.00%)
    0 / 119 (0.00%)
    0 / 115 (0.00%)
    1 / 495 (0.20%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Pneumonia
         subjects affected / exposed
    0 / 121 (0.00%)
    0 / 122 (0.00%)
    0 / 122 (0.00%)
    0 / 119 (0.00%)
    0 / 115 (0.00%)
    2 / 495 (0.40%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    Urosepsis
         subjects affected / exposed
    0 / 121 (0.00%)
    0 / 122 (0.00%)
    0 / 122 (0.00%)
    0 / 119 (0.00%)
    0 / 115 (0.00%)
    1 / 495 (0.20%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Metabolism and nutrition disorders
    Dehydration
         subjects affected / exposed
    0 / 121 (0.00%)
    0 / 122 (0.00%)
    0 / 122 (0.00%)
    0 / 119 (0.00%)
    0 / 115 (0.00%)
    1 / 495 (0.20%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 1
         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
    		 Part I - Placebo x Safety set Part I - Entacapone x Safety set Part I - OPC 5mg/day x Safety set Part I - OPC 25mg/day x Safety set Part I - OPC 50mg/day x Safety set Part II - OPC x Safety set
    Total subjects affected by non serious adverse events
         subjects affected / exposed
    59 / 121 (48.76%)
    67 / 122 (54.92%)
    62 / 122 (50.82%)
    65 / 119 (54.62%)
    60 / 115 (52.17%)
    332 / 495 (67.07%)
    Neoplasms benign, malignant and unspecified (incl cysts and polyps)
    Basal cell carcinoma
         subjects affected / exposed
    1 / 121 (0.83%)
    0 / 122 (0.00%)
    0 / 122 (0.00%)
    0 / 119 (0.00%)
    0 / 115 (0.00%)
    2 / 495 (0.40%)
         occurrences all number
    1
    0
    0
    0
    0
    4
    Benign bone neoplasm
         subjects affected / exposed
    0 / 121 (0.00%)
    0 / 122 (0.00%)
    0 / 122 (0.00%)
    0 / 119 (0.00%)
    0 / 115 (0.00%)
    1 / 495 (0.20%)
         occurrences all number
    0
    0
    0
    0
    0
    1
    Fibrous histiocytoma
         subjects affected / exposed
    0 / 121 (0.00%)
    0 / 122 (0.00%)
    0 / 122 (0.00%)
    1 / 119 (0.84%)
    0 / 115 (0.00%)
    1 / 495 (0.20%)
         occurrences all number
    0
    0
    0
    1
    0
    1
    Haemangioma
         subjects affected / exposed
    0 / 121 (0.00%)
    0 / 122 (0.00%)
    0 / 122 (0.00%)
    0 / 119 (0.00%)
    0 / 115 (0.00%)
    1 / 495 (0.20%)
         occurrences all number
    0
    0
    0
    0
    0
    1
    Lipoma
         subjects affected / exposed
    0 / 121 (0.00%)
    0 / 122 (0.00%)
    1 / 122 (0.82%)
    0 / 119 (0.00%)
    0 / 115 (0.00%)
    1 / 495 (0.20%)
         occurrences all number
    0
    0
    1
    0
    0
    1
    Melanocytic naevus
         subjects affected / exposed
    0 / 121 (0.00%)
    0 / 122 (0.00%)
    0 / 122 (0.00%)
    1 / 119 (0.84%)
    0 / 115 (0.00%)
    4 / 495 (0.81%)
         occurrences all number
    0
    0
    0
    1
    0
    4
    Prostatic adenoma
         subjects affected / exposed
    0 / 121 (0.00%)
    0 / 122 (0.00%)
    0 / 122 (0.00%)
    0 / 119 (0.00%)
    0 / 115 (0.00%)
    1 / 495 (0.20%)
         occurrences all number
    0
    0
    0
    0
    0
    1
    Seborrhoeic keratosis
         subjects affected / exposed
    0 / 121 (0.00%)
    0 / 122 (0.00%)
    0 / 122 (0.00%)
    2 / 119 (1.68%)
    0 / 115 (0.00%)
    4 / 495 (0.81%)
         occurrences all number
    0
    0
    0
    2
    0
    4
    Skin papilloma
         subjects affected / exposed
    0 / 121 (0.00%)
    0 / 122 (0.00%)
    0 / 122 (0.00%)
    0 / 119 (0.00%)
    0 / 115 (0.00%)
    1 / 495 (0.20%)
         occurrences all number
    0
    0
    0
    0
    0
    1
    Vascular disorders
    Aortic stenosis
         subjects affected / exposed
    1 / 121 (0.83%)
    0 / 122 (0.00%)
    0 / 122 (0.00%)
    0 / 119 (0.00%)
    0 / 115 (0.00%)
    0 / 495 (0.00%)
         occurrences all number
    1
    0
    0
    0
    0
    0
    Arteriosclerosis
         subjects affected / exposed
    0 / 121 (0.00%)
    0 / 122 (0.00%)
    0 / 122 (0.00%)
    0 / 119 (0.00%)
    0 / 115 (0.00%)
    1 / 495 (0.20%)
         occurrences all number
    0
    0
    0
    0
    0
    1
    Deep vein thrombosis
         subjects affected / exposed
    0 / 121 (0.00%)
    0 / 122 (0.00%)
    0 / 122 (0.00%)
    1 / 119 (0.84%)
    0 / 115 (0.00%)
    0 / 495 (0.00%)
         occurrences all number
    0
    0
    0
    1
    0
    0
    Haematoma
         subjects affected / exposed
    0 / 121 (0.00%)
    0 / 122 (0.00%)
    0 / 122 (0.00%)
    1 / 119 (0.84%)
    0 / 115 (0.00%)
    1 / 495 (0.20%)
         occurrences all number
    0
    0
    0
    1
    0
    1
    Hypertension
         subjects affected / exposed
    2 / 121 (1.65%)
    2 / 122 (1.64%)
    4 / 122 (3.28%)
    2 / 119 (1.68%)
    2 / 115 (1.74%)
    12 / 495 (2.42%)
         occurrences all number
    2
    2
    4
    2
    2
    12
    Hypertensive crisis
         subjects affected / exposed
    0 / 121 (0.00%)
    0 / 122 (0.00%)
    0 / 122 (0.00%)
    0 / 119 (0.00%)
    0 / 115 (0.00%)
    2 / 495 (0.40%)
         occurrences all number
    0
    0
    0
    0
    0
    2
    Hypotension
         subjects affected / exposed
    0 / 121 (0.00%)
    3 / 122 (2.46%)
    2 / 122 (1.64%)
    2 / 119 (1.68%)
    0 / 115 (0.00%)
    6 / 495 (1.21%)
         occurrences all number
    0
    3
    2
    2
    0
    6
    Orthostatic hypertension
         subjects affected / exposed
    0 / 121 (0.00%)
    2 / 122 (1.64%)
    0 / 122 (0.00%)
    0 / 119 (0.00%)
    0 / 115 (0.00%)
    2 / 495 (0.40%)
         occurrences all number
    0
    2
    0
    0
    0
    4
    Orthostatic hypotension
         subjects affected / exposed
    0 / 121 (0.00%)
    2 / 122 (1.64%)
    0 / 122 (0.00%)
    0 / 119 (0.00%)
    1 / 115 (0.87%)
    16 / 495 (3.23%)
         occurrences all number
    0
    2
    0
    0
    1
    18
    Phlebitis
         subjects affected / exposed
    0 / 121 (0.00%)
    0 / 122 (0.00%)
    0 / 122 (0.00%)
    0 / 119 (0.00%)
    1 / 115 (0.87%)
    0 / 495 (0.00%)
         occurrences all number
    0
    0
    0
    0
    1
    0
    Post thrombotic syndrome
         subjects affected / exposed
    0 / 121 (0.00%)
    0 / 122 (0.00%)
    0 / 122 (0.00%)
    0 / 119 (0.00%)
    0 / 115 (0.00%)
    1 / 495 (0.20%)
         occurrences all number
    0
    0
    0
    0
    0
    1
    Varicose vein
         subjects affected / exposed
    0 / 121 (0.00%)
    0 / 122 (0.00%)
    0 / 122 (0.00%)
    0 / 119 (0.00%)
    0 / 115 (0.00%)
    2 / 495 (0.40%)
         occurrences all number
    0
    0
    0
    0
    0
    2
    Vein disorder
         subjects affected / exposed
    1 / 121 (0.83%)
    0 / 122 (0.00%)
    0 / 122 (0.00%)
    0 / 119 (0.00%)
    0 / 115 (0.00%)
    0 / 495 (0.00%)
         occurrences all number
    1
    0
    0
    0
    0
    0
    Venous insufficiency
         subjects affected / exposed
    0 / 121 (0.00%)
    0 / 122 (0.00%)
    0 / 122 (0.00%)
    1 / 119 (0.84%)
    0 / 115 (0.00%)
    2 / 495 (0.40%)
         occurrences all number
    0
    0
    0
    1
    0
    2
    Surgical and medical procedures
    Facial operation
         subjects affected / exposed
    0 / 121 (0.00%)
    0 / 122 (0.00%)
    0 / 122 (0.00%)
    0 / 119 (0.00%)
    1 / 115 (0.87%)
    0 / 495 (0.00%)
         occurrences all number
    0
    0
    0
    0
    1
    0
    Nasal septal operation
         subjects affected / exposed
    0 / 121 (0.00%)
    0 / 122 (0.00%)
    0 / 122 (0.00%)
    0 / 119 (0.00%)
    1 / 115 (0.87%)
    0 / 495 (0.00%)
         occurrences all number
    0
    0
    0
    0
    1
    0
    Ureteral meatotomy
         subjects affected / exposed
    0 / 121 (0.00%)
    0 / 122 (0.00%)
    0 / 122 (0.00%)
    0 / 119 (0.00%)
    1 / 115 (0.87%)
    0 / 495 (0.00%)
         occurrences all number
    0
    0
    0
    0
    1
    0
    General disorders and administration site conditions
    Asthenia
         subjects affected / exposed
    0 / 121 (0.00%)
    1 / 122 (0.82%)
    3 / 122 (2.46%)
    0 / 119 (0.00%)
    0 / 115 (0.00%)
    4 / 495 (0.81%)
         occurrences all number
    0
    1
    3
    0
    0
    4
    Chest discomfort
         subjects affected / exposed
    0 / 121 (0.00%)
    0 / 122 (0.00%)
    0 / 122 (0.00%)
    1 / 119 (0.84%)
    0 / 115 (0.00%)
    0 / 495 (0.00%)
         occurrences all number
    0
    0
    0
    1
    0
    0
    Chest pain
         subjects affected / exposed
    0 / 121 (0.00%)
    0 / 122 (0.00%)
    0 / 122 (0.00%)
    0 / 119 (0.00%)
    0 / 115 (0.00%)
    1 / 495 (0.20%)
         occurrences all number
    0
    0
    0
    0
    0
    1
    Discomfort
         subjects affected / exposed
    0 / 121 (0.00%)
    0 / 122 (0.00%)
    0 / 122 (0.00%)
    1 / 119 (0.84%)
    0 / 115 (0.00%)
    0 / 495 (0.00%)
         occurrences all number
    0
    0
    0
    1
    0
    0
    Drug effect decreased
         subjects affected / exposed
    3 / 121 (2.48%)
    3 / 122 (2.46%)
    1 / 122 (0.82%)
    1 / 119 (0.84%)
    2 / 115 (1.74%)
    59 / 495 (11.92%)
         occurrences all number
    3
    3
    2
    1
    2
    67
    Fatigue
         subjects affected / exposed
    2 / 121 (1.65%)
    3 / 122 (2.46%)
    3 / 122 (2.46%)
    3 / 119 (2.52%)
    1 / 115 (0.87%)
    2 / 495 (0.40%)
         occurrences all number
    2
    3
    3
    4
    1
    2
    Gait disturbance
         subjects affected / exposed
    0 / 121 (0.00%)
    0 / 122 (0.00%)
    0 / 122 (0.00%)
    0 / 119 (0.00%)
    0 / 115 (0.00%)
    6 / 495 (1.21%)
         occurrences all number
    0
    0
    0
    0
    0
    6
    Influenza like illness
         subjects affected / exposed
    1 / 121 (0.83%)
    0 / 122 (0.00%)
    0 / 122 (0.00%)
    0 / 119 (0.00%)
    0 / 115 (0.00%)
    0 / 495 (0.00%)
         occurrences all number
    1
    0
    0
    0
    0
    0
    Oedema
         subjects affected / exposed
    0 / 121 (0.00%)
    1 / 122 (0.82%)
    0 / 122 (0.00%)
    0 / 119 (0.00%)
    0 / 115 (0.00%)
    0 / 495 (0.00%)
         occurrences all number
    0
    1
    0
    0
    0
    0
    Oedema peripheral
         subjects affected / exposed
    0 / 121 (0.00%)
    2 / 122 (1.64%)
    2 / 122 (1.64%)
    1 / 119 (0.84%)
    1 / 115 (0.87%)
    2 / 495 (0.40%)
         occurrences all number
    0
    3
    2
    1
    1
    2
    Pyrexia
         subjects affected / exposed
    1 / 121 (0.83%)
    0 / 122 (0.00%)
    0 / 122 (0.00%)
    0 / 119 (0.00%)
    0 / 115 (0.00%)
    1 / 495 (0.20%)
         occurrences all number
    1
    0
    0
    0
    0
    1
    Sense of oppression
         subjects affected / exposed
    0 / 121 (0.00%)
    0 / 122 (0.00%)
    0 / 122 (0.00%)
    0 / 119 (0.00%)
    0 / 115 (0.00%)
    1 / 495 (0.20%)
         occurrences all number
    0
    0
    0
    0
    0
    1
    Xerosis
         subjects affected / exposed
    0 / 121 (0.00%)
    0 / 122 (0.00%)
    0 / 122 (0.00%)
    0 / 119 (0.00%)
    1 / 115 (0.87%)
    0 / 495 (0.00%)
         occurrences all number
    0
    0
    0
    0
    1
    0
    Immune system disorders
    Drug hypersensitivity
         subjects affected / exposed
    0 / 121 (0.00%)
    0 / 122 (0.00%)
    1 / 122 (0.82%)
    0 / 119 (0.00%)
    0 / 115 (0.00%)
    0 / 495 (0.00%)
         occurrences all number
    0
    0
    1
    0
    0
    0
    Hypersensitivity
         subjects affected / exposed
    0 / 121 (0.00%)
    0 / 122 (0.00%)
    0 / 122 (0.00%)
    1 / 119 (0.84%)
    1 / 115 (0.87%)
    0 / 495 (0.00%)
         occurrences all number
    0
    0
    0
    1
    1
    0
    Social circumstances
    Gambling
         subjects affected / exposed
    0 / 121 (0.00%)
    0 / 122 (0.00%)
    0 / 122 (0.00%)
    0 / 119 (0.00%)
    0 / 115 (0.00%)
    1 / 495 (0.20%)
         occurrences all number
    0
    0
    0
    0
    0
    1
    Social problem
         subjects affected / exposed
    0 / 121 (0.00%)
    1 / 122 (0.82%)
    0 / 122 (0.00%)
    0 / 119 (0.00%)
    0 / 115 (0.00%)
    0 / 495 (0.00%)
         occurrences all number
    0
    1
    0
    0
    0
    0
    Reproductive system and breast disorders
    Benign prostatic hyperplasia
         subjects affected / exposed
    0 / 121 (0.00%)
    0 / 122 (0.00%)
    0 / 122 (0.00%)
    0 / 119 (0.00%)
    1 / 115 (0.87%)
    2 / 495 (0.40%)
         occurrences all number
    0
    0
    0
    0
    1
    4
    Erectile dysfunction
         subjects affected / exposed
    0 / 121 (0.00%)
    0 / 122 (0.00%)
    0 / 122 (0.00%)
    0 / 119 (0.00%)
    0 / 115 (0.00%)
    1 / 495 (0.20%)
         occurrences all number
    0
    0
    0
    0
    0
    1
    Polycystic ovaries
         subjects affected / exposed
    0 / 121 (0.00%)
    0 / 122 (0.00%)
    0 / 122 (0.00%)
    0 / 119 (0.00%)
    0 / 115 (0.00%)
    1 / 495 (0.20%)
         occurrences all number
    0
    0
    0
    0
    0
    1
    Prostatitis
         subjects affected / exposed
    1 / 121 (0.83%)
    0 / 122 (0.00%)
    0 / 122 (0.00%)
    0 / 119 (0.00%)
    0 / 115 (0.00%)
    0 / 495 (0.00%)
         occurrences all number
    1
    0
    0
    0
    0
    0
    Uterine polyp
         subjects affected / exposed
    0 / 121 (0.00%)
    0 / 122 (0.00%)
    0 / 122 (0.00%)
    0 / 119 (0.00%)
    0 / 115 (0.00%)
    1 / 495 (0.20%)
         occurrences all number
    0
    0
    0
    0
    0
    1
    Respiratory, thoracic and mediastinal disorders
    Asphyxia
         subjects affected / exposed
    0 / 121 (0.00%)
    0 / 122 (0.00%)
    0 / 122 (0.00%)
    1 / 119 (0.84%)
    0 / 115 (0.00%)
    0 / 495 (0.00%)
         occurrences all number
    0
    0
    0
    1
    0
    0
    Asthma
         subjects affected / exposed
    0 / 121 (0.00%)
    0 / 122 (0.00%)
    1 / 122 (0.82%)
    0 / 119 (0.00%)
    0 / 115 (0.00%)
    0 / 495 (0.00%)
         occurrences all number
    0
    0
    1
    0
    0
    0
    Bronchospasm
         subjects affected / exposed
    1 / 121 (0.83%)
    0 / 122 (0.00%)
    0 / 122 (0.00%)
    0 / 119 (0.00%)
    0 / 115 (0.00%)
    0 / 495 (0.00%)
         occurrences all number
    1
    0
    0
    0
    0
    0
    Choking
         subjects affected / exposed
    0 / 121 (0.00%)
    0 / 122 (0.00%)
    0 / 122 (0.00%)
    0 / 119 (0.00%)
    0 / 115 (0.00%)
    1 / 495 (0.20%)
         occurrences all number
    0
    0
    0
    0
    0
    1
    Cough
         subjects affected / exposed
    1 / 121 (0.83%)
    0 / 122 (0.00%)
    0 / 122 (0.00%)
    0 / 119 (0.00%)
    0 / 115 (0.00%)
    4 / 495 (0.81%)
         occurrences all number
    1
    0
    0
    0
    0
    4
    Dyspnoea
         subjects affected / exposed
    0 / 121 (0.00%)
    0 / 122 (0.00%)
    2 / 122 (1.64%)
    0 / 119 (0.00%)
    1 / 115 (0.87%)
    1 / 495 (0.20%)
         occurrences all number
    0
    0
    2
    0
    1
    1
    Epistaxis
         subjects affected / exposed
    0 / 121 (0.00%)
    1 / 122 (0.82%)
    1 / 122 (0.82%)
    0 / 119 (0.00%)
    0 / 115 (0.00%)
    0 / 495 (0.00%)
         occurrences all number
    0
    1
    1
    0
    0
    0
    Oropharyngeal pain
         subjects affected / exposed
    0 / 121 (0.00%)
    0 / 122 (0.00%)
    0 / 122 (0.00%)
    0 / 119 (0.00%)
    0 / 115 (0.00%)
    1 / 495 (0.20%)
         occurrences all number
    0
    0
    0
    0
    0
    2
    Pulmonary oedema
         subjects affected / exposed
    0 / 121 (0.00%)
    0 / 122 (0.00%)
    1 / 122 (0.82%)
    0 / 119 (0.00%)
    0 / 115 (0.00%)
    0 / 495 (0.00%)
         occurrences all number
    0
    0
    1
    0
    0
    0
    Psychiatric disorders
    Abnormal behaviour
         subjects affected / exposed
    0 / 121 (0.00%)
    0 / 122 (0.00%)
    0 / 122 (0.00%)
    0 / 119 (0.00%)
    0 / 115 (0.00%)
    1 / 495 (0.20%)
         occurrences all number
    0
    0
    0
    0
    0
    1
    Abnormal dreams
         subjects affected / exposed
    2 / 121 (1.65%)
    0 / 122 (0.00%)
    0 / 122 (0.00%)
    1 / 119 (0.84%)
    0 / 115 (0.00%)
    4 / 495 (0.81%)
         occurrences all number
    2
    0
    0
    1
    0
    5
    Agitation
         subjects affected / exposed
    0 / 121 (0.00%)
    0 / 122 (0.00%)
    0 / 122 (0.00%)
    0 / 119 (0.00%)
    1 / 115 (0.87%)
    2 / 495 (0.40%)
         occurrences all number
    0
    0
    0
    0
    1
    3
    Anxiety
         subjects affected / exposed
    4 / 121 (3.31%)
    2 / 122 (1.64%)
    1 / 122 (0.82%)
    2 / 119 (1.68%)
    2 / 115 (1.74%)
    11 / 495 (2.22%)
         occurrences all number
    4
    2
    1
    2
    2
    12
    Apathy
         subjects affected / exposed
    0 / 121 (0.00%)
    0 / 122 (0.00%)
    0 / 122 (0.00%)
    0 / 119 (0.00%)
    2 / 115 (1.74%)
    0 / 495 (0.00%)
         occurrences all number
    0
    0
    0
    0
    2
    0
    Binge eating
         subjects affected / exposed
    0 / 121 (0.00%)
    0 / 122 (0.00%)
    0 / 122 (0.00%)
    1 / 119 (0.84%)
    0 / 115 (0.00%)
    2 / 495 (0.40%)
         occurrences all number
    0
    0
    0
    1
    0
    2
    Bradyphrenia
         subjects affected / exposed
    0 / 121 (0.00%)
    0 / 122 (0.00%)
    0 / 122 (0.00%)
    0 / 119 (0.00%)
    0 / 115 (0.00%)
    1 / 495 (0.20%)
         occurrences all number
    0
    0
    0
    0
    0
    1
    Compulsive shopping
         subjects affected / exposed
    0 / 121 (0.00%)
    0 / 122 (0.00%)
    0 / 122 (0.00%)
    0 / 119 (0.00%)
    0 / 115 (0.00%)
    1 / 495 (0.20%)
         occurrences all number
    0
    0
    0
    0
    0
    1
    Confusional state
         subjects affected / exposed
    0 / 121 (0.00%)
    0 / 122 (0.00%)
    0 / 122 (0.00%)
    1 / 119 (0.84%)
    0 / 115 (0.00%)
    3 / 495 (0.61%)
         occurrences all number
    0
    0
    0
    1
    0
    3
    Delirium
         subjects affected / exposed
    0 / 121 (0.00%)
    0 / 122 (0.00%)
    0 / 122 (0.00%)
    0 / 119 (0.00%)
    0 / 115 (0.00%)
    1 / 495 (0.20%)
         occurrences all number
    0
    0
    0
    0
    0
    1
    Delusion
         subjects affected / exposed
    0 / 121 (0.00%)
    0 / 122 (0.00%)
    0 / 122 (0.00%)
    0 / 119 (0.00%)
    1 / 115 (0.87%)
    1 / 495 (0.20%)
         occurrences all number
    0
    0
    0
    0
    2
    3
    Depressed mood
         subjects affected / exposed
    0 / 121 (0.00%)
    0 / 122 (0.00%)
    0 / 122 (0.00%)
    1 / 119 (0.84%)
    1 / 115 (0.87%)
    1 / 495 (0.20%)
         occurrences all number
    0
    0
    0
    1
    1
    1
    Depression
         subjects affected / exposed
    1 / 121 (0.83%)
    1 / 122 (0.82%)
    1 / 122 (0.82%)
    1 / 119 (0.84%)
    2 / 115 (1.74%)
    11 / 495 (2.22%)
         occurrences all number
    1
    1
    1
    1
    2
    11
    Depressive symptom
         subjects affected / exposed
    0 / 121 (0.00%)
    0 / 122 (0.00%)
    0 / 122 (0.00%)
    1 / 119 (0.84%)
    0 / 115 (0.00%)
    1 / 495 (0.20%)
         occurrences all number
    0
    0
    0
    1
    0
    1
    Disorientation
         subjects affected / exposed
    0 / 121 (0.00%)
    0 / 122 (0.00%)
    0 / 122 (0.00%)
    0 / 119 (0.00%)
    1 / 115 (0.87%)
    0 / 495 (0.00%)
         occurrences all number
    0
    0
    0
    0
    1
    0
    Distractibility
         subjects affected / exposed
    0 / 121 (0.00%)
    0 / 122 (0.00%)
    0 / 122 (0.00%)
    0 / 119 (0.00%)
    0 / 115 (0.00%)
    1 / 495 (0.20%)
         occurrences all number
    0
    0
    0
    0
    0
    4
    Disturbance in sexual arousal
         subjects affected / exposed
    0 / 121 (0.00%)
    0 / 122 (0.00%)
    0 / 122 (0.00%)
    0 / 119 (0.00%)
    1 / 115 (0.87%)
    0 / 495 (0.00%)
         occurrences all number
    0
    0
    0
    0
    1
    0
    Dopamine dysregulation syndrome
         subjects affected / exposed
    0 / 121 (0.00%)
    0 / 122 (0.00%)
    0 / 122 (0.00%)
    0 / 119 (0.00%)
    1 / 115 (0.87%)
    0 / 495 (0.00%)
         occurrences all number
    0
    0
    0
    0
    1
    0
    Emotional distress
         subjects affected / exposed
    0 / 121 (0.00%)
    0 / 122 (0.00%)
    0 / 122 (0.00%)
    1 / 119 (0.84%)
    0 / 115 (0.00%)
    0 / 495 (0.00%)
         occurrences all number
    0
    0
    0
    1
    0
    0
    Hallucination
         subjects affected / exposed
    1 / 121 (0.83%)
    1 / 122 (0.82%)
    1 / 122 (0.82%)
    6 / 119 (5.04%)
    1 / 115 (0.87%)
    8 / 495 (1.62%)
         occurrences all number
    1
    1
    3
    6
    1
    9
    Hallucination, auditory
         subjects affected / exposed
    0 / 121 (0.00%)
    0 / 122 (0.00%)
    0 / 122 (0.00%)
    2 / 119 (1.68%)
    1 / 115 (0.87%)
    2 / 495 (0.40%)
         occurrences all number
    0
    0
    0
    2
    1
    2
    Hallucination, visual
         subjects affected / exposed
    1 / 121 (0.83%)
    0 / 122 (0.00%)
    1 / 122 (0.82%)
    1 / 119 (0.84%)
    3 / 115 (2.61%)
    4 / 495 (0.81%)
         occurrences all number
    1
    0
    1
    1
    3
    5
    Hallucinations, mixed
         subjects affected / exposed
    0 / 121 (0.00%)
    0 / 122 (0.00%)
    0 / 122 (0.00%)
    0 / 119 (0.00%)
    1 / 115 (0.87%)
    0 / 495 (0.00%)
         occurrences all number
    0
    0
    0
    0
    2
    0
    Hypersexuality
         subjects affected / exposed
    0 / 121 (0.00%)
    0 / 122 (0.00%)
    1 / 122 (0.82%)
    0 / 119 (0.00%)
    0 / 115 (0.00%)
    0 / 495 (0.00%)
         occurrences all number
    0
    0
    1
    0
    0
    0
    Hypochondriasis
         subjects affected / exposed
    0 / 121 (0.00%)
    0 / 122 (0.00%)
    0 / 122 (0.00%)
    0 / 119 (0.00%)
    0 / 115 (0.00%)
    1 / 495 (0.20%)
         occurrences all number
    0
    0
    0
    0
    0
    1
    Illogical thinking
         subjects affected / exposed
    0 / 121 (0.00%)
    0 / 122 (0.00%)
    0 / 122 (0.00%)
    0 / 119 (0.00%)
    0 / 115 (0.00%)
    1 / 495 (0.20%)
         occurrences all number
    0
    0
    0
    0
    0
    1
    Illusion
         subjects affected / exposed
    0 / 121 (0.00%)
    0 / 122 (0.00%)
    1 / 122 (0.82%)
    0 / 119 (0.00%)
    0 / 115 (0.00%)
    1 / 495 (0.20%)
         occurrences all number
    0
    0
    1
    0
    0
    1
    Impulse-control disorder
         subjects affected / exposed
    0 / 121 (0.00%)
    0 / 122 (0.00%)
    0 / 122 (0.00%)
    0 / 119 (0.00%)
    0 / 115 (0.00%)
    2 / 495 (0.40%)
         occurrences all number
    0
    0
    0
    0
    0
    2
    Impulsive behaviour
         subjects affected / exposed
    0 / 121 (0.00%)
    0 / 122 (0.00%)
    0 / 122 (0.00%)
    0 / 119 (0.00%)
    0 / 115 (0.00%)
    1 / 495 (0.20%)
         occurrences all number
    0
    0
    0
    0
    0
    1
    Insomnia
         subjects affected / exposed
    1 / 121 (0.83%)
    7 / 122 (5.74%)
    2 / 122 (1.64%)
    7 / 119 (5.88%)
    7 / 115 (6.09%)
    23 / 495 (4.65%)
         occurrences all number
    1
    8
    2
    7
    8
    29
    Jealous delusion
         subjects affected / exposed
    0 / 121 (0.00%)
    0 / 122 (0.00%)
    0 / 122 (0.00%)
    0 / 119 (0.00%)
    0 / 115 (0.00%)
    1 / 495 (0.20%)
         occurrences all number
    0
    0
    0
    0
    0
    1
    Libido decreased
         subjects affected / exposed
    0 / 121 (0.00%)
    0 / 122 (0.00%)
    1 / 122 (0.82%)
    0 / 119 (0.00%)
    1 / 115 (0.87%)
    0 / 495 (0.00%)
         occurrences all number
    0
    0
    1
    0
    1
    0
    Nervousness
         subjects affected / exposed
    0 / 121 (0.00%)
    0 / 122 (0.00%)
    0 / 122 (0.00%)
    0 / 119 (0.00%)
    1 / 115 (0.87%)
    0 / 495 (0.00%)
         occurrences all number
    0
    0
    0
    0
    1
    0
    Nightmare
         subjects affected / exposed
    1 / 121 (0.83%)
    0 / 122 (0.00%)
    0 / 122 (0.00%)
    0 / 119 (0.00%)
    0 / 115 (0.00%)
    9 / 495 (1.82%)
         occurrences all number
    1
    0
    0
    0
    0
    10
    Panic attack
         subjects affected / exposed
    0 / 121 (0.00%)
    0 / 122 (0.00%)
    0 / 122 (0.00%)
    1 / 119 (0.84%)
    1 / 115 (0.87%)
    0 / 495 (0.00%)
         occurrences all number
    0
    0
    0
    1
    1
    0
    Pathological gambling
         subjects affected / exposed
    0 / 121 (0.00%)
    0 / 122 (0.00%)
    0 / 122 (0.00%)
    0 / 119 (0.00%)
    0 / 115 (0.00%)
    1 / 495 (0.20%)
         occurrences all number
    0
    0
    0
    0
    0
    1
    Persecutory delusion
         subjects affected / exposed
    0 / 121 (0.00%)
    0 / 122 (0.00%)
    0 / 122 (0.00%)
    0 / 119 (0.00%)
    0 / 115 (0.00%)
    1 / 495 (0.20%)
         occurrences all number
    0
    0
    0
    0
    0
    1
    Rapid eye movements sleep abnormal
         subjects affected / exposed
    0 / 121 (0.00%)
    0 / 122 (0.00%)
    0 / 122 (0.00%)
    0 / 119 (0.00%)
    0 / 115 (0.00%)
    1 / 495 (0.20%)
         occurrences all number
    0
    0
    0
    0
    0
    1
    Restlessness
         subjects affected / exposed
    1 / 121 (0.83%)
    0 / 122 (0.00%)
    0 / 122 (0.00%)
    0 / 119 (0.00%)
    0 / 115 (0.00%)
    0 / 495 (0.00%)
         occurrences all number
    1
    0
    0
    0
    0
    0
    Sleep attacks
         subjects affected / exposed
    2 / 121 (1.65%)
    0 / 122 (0.00%)
    0 / 122 (0.00%)
    1 / 119 (0.84%)
    0 / 115 (0.00%)
    1 / 495 (0.20%)
         occurrences all number
    2
    0
    0
    1
    0
    1
    Sleep disorder
         subjects affected / exposed
    1 / 121 (0.83%)
    0 / 122 (0.00%)
    1 / 122 (0.82%)
    1 / 119 (0.84%)
    3 / 115 (2.61%)
    9 / 495 (1.82%)
         occurrences all number
    1
    0
    1
    1
    3
    11
    Somnambulism
         subjects affected / exposed
    0 / 121 (0.00%)
    0 / 122 (0.00%)
    0 / 122 (0.00%)
    0 / 119 (0.00%)
    0 / 115 (0.00%)
    1 / 495 (0.20%)
         occurrences all number
    0
    0
    0
    0
    0
    3
    Suicidal ideation
         subjects affected / exposed
    0 / 121 (0.00%)
    0 / 122 (0.00%)
    0 / 122 (0.00%)
    0 / 119 (0.00%)
    0 / 115 (0.00%)
    3 / 495 (0.61%)
         occurrences all number
    0
    0
    0
    0
    0
    3
    Investigations
    Activated partial thromboplastin time prolonged
         subjects affected / exposed
    0 / 121 (0.00%)
    0 / 122 (0.00%)
    0 / 122 (0.00%)
    0 / 119 (0.00%)
    0 / 115 (0.00%)
    1 / 495 (0.20%)
         occurrences all number
    0
    0
    0
    0
    0
    1
    Alanine aminotransferase decreased
         subjects affected / exposed
    0 / 121 (0.00%)
    0 / 122 (0.00%)
    0 / 122 (0.00%)
    0 / 119 (0.00%)
    0 / 115 (0.00%)
    1 / 495 (0.20%)
         occurrences all number
    0
    0
    0
    0
    0
    1
    Alanine aminotransferase increased
         subjects affected / exposed
    0 / 121 (0.00%)
    0 / 122 (0.00%)
    0 / 122 (0.00%)
    2 / 119 (1.68%)
    1 / 115 (0.87%)
    2 / 495 (0.40%)
         occurrences all number
    0
    0
    0
    2
    1
    2
    Aspartate aminotransferase increased
         subjects affected / exposed
    0 / 121 (0.00%)
    1 / 122 (0.82%)
    0 / 122 (0.00%)
    1 / 119 (0.84%)
    1 / 115 (0.87%)
    4 / 495 (0.81%)
         occurrences all number
    0
    1
    0
    1
    1
    5
    Bilirubin conjugated increased
         subjects affected / exposed
    0 / 121 (0.00%)
    0 / 122 (0.00%)
    0 / 122 (0.00%)
    0 / 119 (0.00%)
    0 / 115 (0.00%)
    1 / 495 (0.20%)
         occurrences all number
    0
    0
    0
    0
    0
    1
    Blood alkaline phosphatase increased
         subjects affected / exposed
    0 / 121 (0.00%)
    0 / 122 (0.00%)
    0 / 122 (0.00%)
    0 / 119 (0.00%)
    0 / 115 (0.00%)
    1 / 495 (0.20%)
         occurrences all number
    0
    0
    0
    0
    0
    2
    Blood bilirubin increased
         subjects affected / exposed
    1 / 121 (0.83%)
    0 / 122 (0.00%)
    0 / 122 (0.00%)
    0 / 119 (0.00%)
    0 / 115 (0.00%)
    1 / 495 (0.20%)
         occurrences all number
    1
    0
    0
    0
    0
    1
    Blood bilirubin unconjugated increased
         subjects affected / exposed
    0 / 121 (0.00%)
    1 / 122 (0.82%)
    0 / 122 (0.00%)
    0 / 119 (0.00%)
    0 / 115 (0.00%)
    0 / 495 (0.00%)
         occurrences all number
    0
    1
    0
    0
    0
    0
    Blood creatine phosphokinase increased
         subjects affected / exposed
    0 / 121 (0.00%)
    1 / 122 (0.82%)
    2 / 122 (1.64%)
    2 / 119 (1.68%)
    1 / 115 (0.87%)
    12 / 495 (2.42%)
         occurrences all number
    0
    1
    2
    2
    1
    13
    Blood creatinine decreased
         subjects affected / exposed
    0 / 121 (0.00%)
    0 / 122 (0.00%)
    0 / 122 (0.00%)
    0 / 119 (0.00%)
    0 / 115 (0.00%)
    1 / 495 (0.20%)
         occurrences all number
    0
    0
    0
    0
    0
    1
    Blood creatinine increased
         subjects affected / exposed
    0 / 121 (0.00%)
    1 / 122 (0.82%)
    0 / 122 (0.00%)
    0 / 119 (0.00%)
    1 / 115 (0.87%)
    2 / 495 (0.40%)
         occurrences all number
    0
    1
    0
    0
    1
    3
    Blood glucose abnormal
         subjects affected / exposed
    1 / 121 (0.83%)
    0 / 122 (0.00%)
    0 / 122 (0.00%)
    0 / 119 (0.00%)
    0 / 115 (0.00%)
    0 / 495 (0.00%)
         occurrences all number
    1
    0
    0
    0
    0
    0
    Blood glucose increased
         subjects affected / exposed
    0 / 121 (0.00%)
    0 / 122 (0.00%)
    0 / 122 (0.00%)
    1 / 119 (0.84%)
    0 / 115 (0.00%)
    4 / 495 (0.81%)
         occurrences all number
    0
    0
    0
    1
    0
    6
    Blood lactate dehydrogenase increased
         subjects affected / exposed
    0 / 121 (0.00%)
    0 / 122 (0.00%)
    0 / 122 (0.00%)
    0 / 119 (0.00%)
    0 / 115 (0.00%)
    1 / 495 (0.20%)
         occurrences all number
    0
    0
    0
    0
    0
    1
    Blood potassium increased
         subjects affected / exposed
    0 / 121 (0.00%)
    0 / 122 (0.00%)
    0 / 122 (0.00%)
    0 / 119 (0.00%)
    0 / 115 (0.00%)
    3 / 495 (0.61%)
         occurrences all number
    0
    0
    0
    0
    0
    3
    Blood pressure decreased
         subjects affected / exposed
    0 / 121 (0.00%)
    0 / 122 (0.00%)
    0 / 122 (0.00%)
    1 / 119 (0.84%)
    0 / 115 (0.00%)
    1 / 495 (0.20%)
         occurrences all number
    0
    0
    0
    1
    0
    1
    Blood pressure increased
         subjects affected / exposed
    0 / 121 (0.00%)
    0 / 122 (0.00%)
    0 / 122 (0.00%)
    0 / 119 (0.00%)
    0 / 115 (0.00%)
    1 / 495 (0.20%)
         occurrences all number
    0
    0
    0
    0
    0
    1
    Blood pressure systolic decreased
         subjects affected / exposed
    0 / 121 (0.00%)
    1 / 122 (0.82%)
    0 / 122 (0.00%)
    0 / 119 (0.00%)
    0 / 115 (0.00%)
    0 / 495 (0.00%)
         occurrences all number
    0
    1
    0
    0
    0
    0
    Blood triglycerides increased
         subjects affected / exposed
    0 / 121 (0.00%)
    1 / 122 (0.82%)
    0 / 122 (0.00%)
    0 / 119 (0.00%)
    0 / 115 (0.00%)
    3 / 495 (0.61%)
         occurrences all number
    0
    1
    0
    0
    0
    4
    Blood urea increased
         subjects affected / exposed
    0 / 121 (0.00%)
    1 / 122 (0.82%)
    0 / 122 (0.00%)
    1 / 119 (0.84%)
    1 / 115 (0.87%)
    2 / 495 (0.40%)
         occurrences all number
    0
    1
    0
    1
    1
    2
    Body mass index increased
         subjects affected / exposed
    0 / 121 (0.00%)
    0 / 122 (0.00%)
    0 / 122 (0.00%)
    0 / 119 (0.00%)
    0 / 115 (0.00%)
    1 / 495 (0.20%)
         occurrences all number
    0
    0
    0
    0
    0
    1
    Cardiac murmur
         subjects affected / exposed
    0 / 121 (0.00%)
    0 / 122 (0.00%)
    0 / 122 (0.00%)
    0 / 119 (0.00%)
    0 / 115 (0.00%)
    1 / 495 (0.20%)
         occurrences all number
    0
    0
    0
    0
    0
    1
    Electrocardiogram qt prolonged
         subjects affected / exposed
    0 / 121 (0.00%)
    0 / 122 (0.00%)
    0 / 122 (0.00%)
    0 / 119 (0.00%)
    0 / 115 (0.00%)
    1 / 495 (0.20%)
         occurrences all number
    0
    0
    0
    0
    0
    1
    Electrocardiogram repolarisation abnormality
         subjects affected / exposed
    0 / 121 (0.00%)
    0 / 122 (0.00%)
    0 / 122 (0.00%)
    1 / 119 (0.84%)
    0 / 115 (0.00%)
    0 / 495 (0.00%)
         occurrences all number
    0
    0
    0
    1
    0
    0
    Eosinophil count increased
         subjects affected / exposed
    0 / 121 (0.00%)
    1 / 122 (0.82%)
    0 / 122 (0.00%)
    0 / 119 (0.00%)
    0 / 115 (0.00%)
    0 / 495 (0.00%)
         occurrences all number
    0
    1
    0
    0
    0
    0
    Gamma-glutamyltransferase increased
         subjects affected / exposed
    2 / 121 (1.65%)
    1 / 122 (0.82%)
    0 / 122 (0.00%)
    1 / 119 (0.84%)
    0 / 115 (0.00%)
    7 / 495 (1.41%)
         occurrences all number
    2
    1
    0
    1
    0
    8
    Glucose tolerance decreased
         subjects affected / exposed
    1 / 121 (0.83%)
    0 / 122 (0.00%)
    0 / 122 (0.00%)
    1 / 119 (0.84%)
    0 / 115 (0.00%)
    2 / 495 (0.40%)
         occurrences all number
    1
    0
    0
    1
    0
    2
    Haemoglobin decreased
         subjects affected / exposed
    0 / 121 (0.00%)
    0 / 122 (0.00%)
    0 / 122 (0.00%)
    0 / 119 (0.00%)
    0 / 115 (0.00%)
    1 / 495 (0.20%)
         occurrences all number
    0
    0
    0
    0
    0
    1
    Heart rate irregular
         subjects affected / exposed
    0 / 121 (0.00%)
    0 / 122 (0.00%)
    0 / 122 (0.00%)
    0 / 119 (0.00%)
    0 / 115 (0.00%)
    1 / 495 (0.20%)
         occurrences all number
    0
    0
    0
    0
    0
    1
    Hepatic enzyme increased
         subjects affected / exposed
    0 / 121 (0.00%)
    0 / 122 (0.00%)
    1 / 122 (0.82%)
    0 / 119 (0.00%)
    0 / 115 (0.00%)
    1 / 495 (0.20%)
         occurrences all number
    0
    0
    1
    0
    0
    2
    International normalised ratio increased
         subjects affected / exposed
    0 / 121 (0.00%)
    0 / 122 (0.00%)
    0 / 122 (0.00%)
    0 / 119 (0.00%)
    0 / 115 (0.00%)
    2 / 495 (0.40%)
         occurrences all number
    0
    0
    0
    0
    0
    2
    Lymphocyte count decreased
         subjects affected / exposed
    0 / 121 (0.00%)
    1 / 122 (0.82%)
    0 / 122 (0.00%)
    2 / 119 (1.68%)
    0 / 115 (0.00%)
    0 / 495 (0.00%)
         occurrences all number
    0
    1
    0
    2
    0
    0
    Monocyte count increased
         subjects affected / exposed
    0 / 121 (0.00%)
    0 / 122 (0.00%)
    0 / 122 (0.00%)
    0 / 119 (0.00%)
    0 / 115 (0.00%)
    1 / 495 (0.20%)
         occurrences all number
    0
    0
    0
    0
    0
    1
    Neutrophil count increased
         subjects affected / exposed
    0 / 121 (0.00%)
    1 / 122 (0.82%)
    0 / 122 (0.00%)
    1 / 119 (0.84%)
    0 / 115 (0.00%)
    0 / 495 (0.00%)
         occurrences all number
    0
    1
    0
    1
    0
    0
    Weight decreased
         subjects affected / exposed
    0 / 121 (0.00%)
    2 / 122 (1.64%)
    1 / 122 (0.82%)
    0 / 119 (0.00%)
    4 / 115 (3.48%)
    12 / 495 (2.42%)
         occurrences all number
    0
    2
    1
    0
    5
    12
    Weight increased
         subjects affected / exposed
    1 / 121 (0.83%)
    0 / 122 (0.00%)
    0 / 122 (0.00%)
    0 / 119 (0.00%)
    1 / 115 (0.87%)
    2 / 495 (0.40%)
         occurrences all number
    1
    0
    0
    0
    1
    2
    White blood cell count decreased
         subjects affected / exposed
    0 / 121 (0.00%)
    0 / 122 (0.00%)
    0 / 122 (0.00%)
    0 / 119 (0.00%)
    0 / 115 (0.00%)
    1 / 495 (0.20%)
         occurrences all number
    0
    0
    0
    0
    0
    1
    Injury, poisoning and procedural complications
    Arthropod bite
         subjects affected / exposed
    0 / 121 (0.00%)
    0 / 122 (0.00%)
    0 / 122 (0.00%)
    1 / 119 (0.84%)
    0 / 115 (0.00%)
    0 / 495 (0.00%)
         occurrences all number
    0
    0
    0
    1
    0
    0
    Bone fissure
         subjects affected / exposed
    0 / 121 (0.00%)
    0 / 122 (0.00%)
    0 / 122 (0.00%)
    0 / 119 (0.00%)
    0 / 115 (0.00%)
    1 / 495 (0.20%)
         occurrences all number
    0
    0
    0
    0
    0
    1
    Chest injury
         subjects affected / exposed
    0 / 121 (0.00%)
    0 / 122 (0.00%)
    0 / 122 (0.00%)
    1 / 119 (0.84%)
    0 / 115 (0.00%)
    0 / 495 (0.00%)
         occurrences all number
    0
    0
    0
    1
    0
    0
    Contusion
         subjects affected / exposed
    0 / 121 (0.00%)
    0 / 122 (0.00%)
    0 / 122 (0.00%)
    1 / 119 (0.84%)
    0 / 115 (0.00%)
    3 / 495 (0.61%)
         occurrences all number
    0
    0
    0
    1
    0
    3
    Eye penetration
         subjects affected / exposed
    0 / 121 (0.00%)
    0 / 122 (0.00%)
    0 / 122 (0.00%)
    0 / 119 (0.00%)
    0 / 115 (0.00%)
    1 / 495 (0.20%)
         occurrences all number
    0
    0
    0
    0
    0
    1
    Face injury
         subjects affected / exposed
    0 / 121 (0.00%)
    0 / 122 (0.00%)
    0 / 122 (0.00%)
    0 / 119 (0.00%)
    0 / 115 (0.00%)
    1 / 495 (0.20%)
         occurrences all number
    0
    0
    0
    0
    0
    1
    Fall
         subjects affected / exposed
    3 / 121 (2.48%)
    3 / 122 (2.46%)
    2 / 122 (1.64%)
    4 / 119 (3.36%)
    1 / 115 (0.87%)
    13 / 495 (2.63%)
         occurrences all number
    3
    4
    3
    4
    1
    17
    Hand fracture
         subjects affected / exposed
    0 / 121 (0.00%)
    0 / 122 (0.00%)
    0 / 122 (0.00%)
    0 / 119 (0.00%)
    1 / 115 (0.87%)
    0 / 495 (0.00%)
         occurrences all number
    0
    0
    0
    0
    1
    0
    Head injury
         subjects affected / exposed
    1 / 121 (0.83%)
    0 / 122 (0.00%)
    0 / 122 (0.00%)
    1 / 119 (0.84%)
    0 / 115 (0.00%)
    1 / 495 (0.20%)
         occurrences all number
    1
    0
    0
    1
    0
    1
    Humerus fracture
         subjects affected / exposed
    0 / 121 (0.00%)
    0 / 122 (0.00%)
    0 / 122 (0.00%)
    0 / 119 (0.00%)
    0 / 115 (0.00%)
    1 / 495 (0.20%)
         occurrences all number
    0
    0
    0
    0
    0
    1
    Injury
         subjects affected / exposed
    0 / 121 (0.00%)
    1 / 122 (0.82%)
    0 / 122 (0.00%)
    0 / 119 (0.00%)
    0 / 115 (0.00%)
    0 / 495 (0.00%)
         occurrences all number
    0
    1
    0
    0
    0
    0
    Joint injury
         subjects affected / exposed
    0 / 121 (0.00%)
    0 / 122 (0.00%)
    0 / 122 (0.00%)
    0 / 119 (0.00%)
    0 / 115 (0.00%)
    1 / 495 (0.20%)
         occurrences all number
    0
    0
    0
    0
    0
    1
    Laceration
         subjects affected / exposed
    0 / 121 (0.00%)
    0 / 122 (0.00%)
    0 / 122 (0.00%)
    0 / 119 (0.00%)
    0 / 115 (0.00%)
    1 / 495 (0.20%)
         occurrences all number
    0
    0
    0
    0
    0
    1
    Limb injury
         subjects affected / exposed
    1 / 121 (0.83%)
    0 / 122 (0.00%)
    1 / 122 (0.82%)
    0 / 119 (0.00%)
    0 / 115 (0.00%)
    0 / 495 (0.00%)
         occurrences all number
    1
    0
    1
    0
    0
    0
    Lumbar vertebral fracture
         subjects affected / exposed
    0 / 121 (0.00%)
    0 / 122 (0.00%)
    0 / 122 (0.00%)
    0 / 119 (0.00%)
    1 / 115 (0.87%)
    0 / 495 (0.00%)
         occurrences all number
    0
    0
    0
    0
    1
    0
    Post-traumatic pain
         subjects affected / exposed
    0 / 121 (0.00%)
    0 / 122 (0.00%)
    0 / 122 (0.00%)
    0 / 119 (0.00%)
    0 / 115 (0.00%)
    1 / 495 (0.20%)
         occurrences all number
    0
    0
    0
    0
    0
    1
    Skin injury
         subjects affected / exposed
    0 / 121 (0.00%)
    0 / 122 (0.00%)
    0 / 122 (0.00%)
    0 / 119 (0.00%)
    0 / 115 (0.00%)
    1 / 495 (0.20%)
         occurrences all number
    0
    0
    0
    0
    0
    1
    Suture related complication
         subjects affected / exposed
    0 / 121 (0.00%)
    0 / 122 (0.00%)
    0 / 122 (0.00%)
    0 / 119 (0.00%)
    0 / 115 (0.00%)
    1 / 495 (0.20%)
         occurrences all number
    0
    0
    0
    0
    0
    1
    Thermal burn
         subjects affected / exposed
    0 / 121 (0.00%)
    0 / 122 (0.00%)
    1 / 122 (0.82%)
    0 / 119 (0.00%)
    0 / 115 (0.00%)
    0 / 495 (0.00%)
         occurrences all number
    0
    0
    1
    0
    0
    0
    Tooth injury
         subjects affected / exposed
    0 / 121 (0.00%)
    0 / 122 (0.00%)
    0 / 122 (0.00%)
    0 / 119 (0.00%)
    0 / 115 (0.00%)
    1 / 495 (0.20%)
         occurrences all number
    0
    0
    0
    0
    0
    1
    Cardiac disorders
    Aortic valve incompetence
         subjects affected / exposed
    1 / 121 (0.83%)
    0 / 122 (0.00%)
    0 / 122 (0.00%)
    0 / 119 (0.00%)
    0 / 115 (0.00%)
    0 / 495 (0.00%)
         occurrences all number
    1
    0
    0
    0
    0
    0
    Arrhythmia
         subjects affected / exposed
    0 / 121 (0.00%)
    0 / 122 (0.00%)
    0 / 122 (0.00%)
    0 / 119 (0.00%)
    0 / 115 (0.00%)
    1 / 495 (0.20%)
         occurrences all number
    0
    0
    0
    0
    0
    1
    Atrial fibrillation
         subjects affected / exposed
    0 / 121 (0.00%)
    0 / 122 (0.00%)
    0 / 122 (0.00%)
    0 / 119 (0.00%)
    0 / 115 (0.00%)
    3 / 495 (0.61%)
         occurrences all number
    0
    0
    0
    0
    0
    3
    Atrioventricular block first degree
         subjects affected / exposed
    0 / 121 (0.00%)
    0 / 122 (0.00%)
    0 / 122 (0.00%)
    0 / 119 (0.00%)
    1 / 115 (0.87%)
    3 / 495 (0.61%)
         occurrences all number
    0
    0
    0
    0
    1
    3
    Bradycardia
         subjects affected / exposed
    0 / 121 (0.00%)
    0 / 122 (0.00%)
    0 / 122 (0.00%)
    1 / 119 (0.84%)
    1 / 115 (0.87%)
    1 / 495 (0.20%)
         occurrences all number
    0
    0
    0
    1
    1
    1
    Bundle branch block right
         subjects affected / exposed
    0 / 121 (0.00%)
    1 / 122 (0.82%)
    1 / 122 (0.82%)
    0 / 119 (0.00%)
    0 / 115 (0.00%)
    2 / 495 (0.40%)
         occurrences all number
    0
    1
    1
    0
    0
    2
    Cardiac failure
         subjects affected / exposed
    0 / 121 (0.00%)
    0 / 122 (0.00%)
    0 / 122 (0.00%)
    0 / 119 (0.00%)
    1 / 115 (0.87%)
    3 / 495 (0.61%)
         occurrences all number
    0
    0
    0
    0
    1
    3
    Cardiomyopathy
         subjects affected / exposed
    0 / 121 (0.00%)
    0 / 122 (0.00%)
    0 / 122 (0.00%)
    0 / 119 (0.00%)
    0 / 115 (0.00%)
    1 / 495 (0.20%)
         occurrences all number
    0
    0
    0
    0
    0
    1
    Coronary artery disease
         subjects affected / exposed
    0 / 121 (0.00%)
    0 / 122 (0.00%)
    0 / 122 (0.00%)
    0 / 119 (0.00%)
    0 / 115 (0.00%)
    1 / 495 (0.20%)
         occurrences all number
    0
    0
    0
    0
    0
    1
    Extrasystoles
         subjects affected / exposed
    0 / 121 (0.00%)
    0 / 122 (0.00%)
    0 / 122 (0.00%)
    0 / 119 (0.00%)
    0 / 115 (0.00%)
    1 / 495 (0.20%)
         occurrences all number
    0
    0
    0
    0
    0
    1
    Mitral valve incompetence
         subjects affected / exposed
    1 / 121 (0.83%)
    0 / 122 (0.00%)
    0 / 122 (0.00%)
    0 / 119 (0.00%)
    0 / 115 (0.00%)
    1 / 495 (0.20%)
         occurrences all number
    1
    0
    0
    0
    0
    1
    Myocardial ischaemia
         subjects affected / exposed
    1 / 121 (0.83%)
    1 / 122 (0.82%)
    0 / 122 (0.00%)
    0 / 119 (0.00%)
    0 / 115 (0.00%)
    4 / 495 (0.81%)
         occurrences all number
    1
    1
    0
    0
    0
    4
    Palpitations
         subjects affected / exposed
    0 / 121 (0.00%)
    0 / 122 (0.00%)
    0 / 122 (0.00%)
    0 / 119 (0.00%)
    1 / 115 (0.87%)
    2 / 495 (0.40%)
         occurrences all number
    0
    0
    0
    0
    1
    2
    Sinus bradycardia
         subjects affected / exposed
    0 / 121 (0.00%)
    1 / 122 (0.82%)
    0 / 122 (0.00%)
    0 / 119 (0.00%)
    0 / 115 (0.00%)
    2 / 495 (0.40%)
         occurrences all number
    0
    1
    0
    0
    0
    2
    Sinus tachycardia
         subjects affected / exposed
    0 / 121 (0.00%)
    1 / 122 (0.82%)
    0 / 122 (0.00%)
    0 / 119 (0.00%)
    0 / 115 (0.00%)
    3 / 495 (0.61%)
         occurrences all number
    0
    1
    0
    0
    0
    3
    Supraventricular extrasystoles
         subjects affected / exposed
    0 / 121 (0.00%)
    0 / 122 (0.00%)
    0 / 122 (0.00%)
    0 / 119 (0.00%)
    0 / 115 (0.00%)
    1 / 495 (0.20%)
         occurrences all number
    0
    0
    0
    0
    0
    1
    Tachycardia
         subjects affected / exposed
    1 / 121 (0.83%)
    0 / 122 (0.00%)
    0 / 122 (0.00%)
    1 / 119 (0.84%)
    1 / 115 (0.87%)
    3 / 495 (0.61%)
         occurrences all number
    1
    0
    0
    1
    1
    4
    Tricuspid valve incompetence
         subjects affected / exposed
    0 / 121 (0.00%)
    0 / 122 (0.00%)
    0 / 122 (0.00%)
    0 / 119 (0.00%)
    0 / 115 (0.00%)
    1 / 495 (0.20%)
         occurrences all number
    0
    0
    0
    0
    0
    1
    Ventricular extrasystoles
         subjects affected / exposed
    0 / 121 (0.00%)
    0 / 122 (0.00%)
    0 / 122 (0.00%)
    0 / 119 (0.00%)
    1 / 115 (0.87%)
    1 / 495 (0.20%)
         occurrences all number
    0
    0
    0
    0
    1
    1
    Nervous system disorders
    Akinesia
         subjects affected / exposed
    1 / 121 (0.83%)
    1 / 122 (0.82%)
    0 / 122 (0.00%)
    0 / 119 (0.00%)
    0 / 115 (0.00%)
    0 / 495 (0.00%)
         occurrences all number
    1
    1
    0
    0
    0
    0
    Aphonia
         subjects affected / exposed
    0 / 121 (0.00%)
    0 / 122 (0.00%)
    0 / 122 (0.00%)
    1 / 119 (0.84%)
    0 / 115 (0.00%)
    0 / 495 (0.00%)
         occurrences all number
    0
    0
    0
    1
    0
    0
    Bradykinesia
         subjects affected / exposed
    0 / 121 (0.00%)
    0 / 122 (0.00%)
    0 / 122 (0.00%)
    0 / 119 (0.00%)
    0 / 115 (0.00%)
    2 / 495 (0.40%)
         occurrences all number
    0
    0
    0
    0
    0
    3
    Burning sensation
         subjects affected / exposed
    0 / 121 (0.00%)
    0 / 122 (0.00%)
    1 / 122 (0.82%)
    0 / 119 (0.00%)
    0 / 115 (0.00%)
    0 / 495 (0.00%)
         occurrences all number
    0
    0
    1
    0
    0
    0
    Cauda equina syndrome
         subjects affected / exposed
    0 / 121 (0.00%)
    0 / 122 (0.00%)
    0 / 122 (0.00%)
    0 / 119 (0.00%)
    0 / 115 (0.00%)
    1 / 495 (0.20%)
         occurrences all number
    0
    0
    0
    0
    0
    1
    Cervicobrachial syndrome
         subjects affected / exposed
    0 / 121 (0.00%)
    0 / 122 (0.00%)
    0 / 122 (0.00%)
    0 / 119 (0.00%)
    1 / 115 (0.87%)
    0 / 495 (0.00%)
         occurrences all number
    0
    0
    0
    0
    1
    0
    Chorea
         subjects affected / exposed
    0 / 121 (0.00%)
    0 / 122 (0.00%)
    0 / 122 (0.00%)
    0 / 119 (0.00%)
    1 / 115 (0.87%)
    1 / 495 (0.20%)
         occurrences all number
    0
    0
    0
    0
    2
    1
    Cognitive disorder
         subjects affected / exposed
    0 / 121 (0.00%)
    0 / 122 (0.00%)
    0 / 122 (0.00%)
    0 / 119 (0.00%)
    0 / 115 (0.00%)
    2 / 495 (0.40%)
         occurrences all number
    0
    0
    0
    0
    0
    2
    Disturbance in attention
         subjects affected / exposed
    0 / 121 (0.00%)
    0 / 122 (0.00%)
    0 / 122 (0.00%)
    2 / 119 (1.68%)
    1 / 115 (0.87%)
    0 / 495 (0.00%)
         occurrences all number
    0
    0
    0
    2
    1
    0
    Dizziness
         subjects affected / exposed
    1 / 121 (0.83%)
    5 / 122 (4.10%)
    2 / 122 (1.64%)
    6 / 119 (5.04%)
    3 / 115 (2.61%)
    8 / 495 (1.62%)
         occurrences all number
    1
    5
    2
    7
    3
    10
    Dizziness postural
         subjects affected / exposed
    0 / 121 (0.00%)
    0 / 122 (0.00%)
    0 / 122 (0.00%)
    1 / 119 (0.84%)
    0 / 115 (0.00%)
    0 / 495 (0.00%)
         occurrences all number
    0
    0
    0
    1
    0
    0
    Dysgeusia
         subjects affected / exposed
    0 / 121 (0.00%)
    0 / 122 (0.00%)
    1 / 122 (0.82%)
    0 / 119 (0.00%)
    2 / 115 (1.74%)
    1 / 495 (0.20%)
         occurrences all number
    0
    0
    1
    0
    2
    1
    Dyskinesia
         subjects affected / exposed
    5 / 121 (4.13%)
    10 / 122 (8.20%)
    17 / 122 (13.93%)
    9 / 119 (7.56%)
    18 / 115 (15.65%)
    72 / 495 (14.55%)
         occurrences all number
    5
    12
    17
    13
    19
    88
    Dystonia
         subjects affected / exposed
    1 / 121 (0.83%)
    0 / 122 (0.00%)
    0 / 122 (0.00%)
    0 / 119 (0.00%)
    0 / 115 (0.00%)
    9 / 495 (1.82%)
         occurrences all number
    1
    0
    0
    0
    0
    11
    Epilepsy
         subjects affected / exposed
    0 / 121 (0.00%)
    0 / 122 (0.00%)
    0 / 122 (0.00%)
    1 / 119 (0.84%)
    0 / 115 (0.00%)
    2 / 495 (0.40%)
         occurrences all number
    0
    0
    0
    1
    0
    2
    Formication
         subjects affected / exposed
    0 / 121 (0.00%)
    1 / 122 (0.82%)
    0 / 122 (0.00%)
    0 / 119 (0.00%)
    0 / 115 (0.00%)
    0 / 495 (0.00%)
         occurrences all number
    0
    1
    0
    0
    0
    0
    Freezing phenomenon
         subjects affected / exposed
    1 / 121 (0.83%)
    0 / 122 (0.00%)
    2 / 122 (1.64%)
    0 / 119 (0.00%)
    0 / 115 (0.00%)
    2 / 495 (0.40%)
         occurrences all number
    1
    0
    2
    0
    0
    2
    Headache
         subjects affected / exposed
    3 / 121 (2.48%)
    3 / 122 (2.46%)
    1 / 122 (0.82%)
    2 / 119 (1.68%)
    4 / 115 (3.48%)
    8 / 495 (1.62%)
         occurrences all number
    3
    4
    1
    2
    4
    11
    Hyperkinesia
         subjects affected / exposed
    0 / 121 (0.00%)
    1 / 122 (0.82%)
    0 / 122 (0.00%)
    1 / 119 (0.84%)
    0 / 115 (0.00%)
    1 / 495 (0.20%)
         occurrences all number
    0
    1
    0
    1
    0
    1
    Hypersomnia
         subjects affected / exposed
    2 / 121 (1.65%)
    0 / 122 (0.00%)
    0 / 122 (0.00%)
    0 / 119 (0.00%)
    0 / 115 (0.00%)
    0 / 495 (0.00%)
         occurrences all number
    2
    0
    0
    0
    0
    0
    Hypoaesthesia
         subjects affected / exposed
    0 / 121 (0.00%)
    0 / 122 (0.00%)
    1 / 122 (0.82%)
    0 / 119 (0.00%)
    0 / 115 (0.00%)
    0 / 495 (0.00%)
         occurrences all number
    0
    0
    1
    0
    0
    0
    Hypokinesia
         subjects affected / exposed
    1 / 121 (0.83%)
    1 / 122 (0.82%)
    1 / 122 (0.82%)
    0 / 119 (0.00%)
    0 / 115 (0.00%)
    6 / 495 (1.21%)
         occurrences all number
    1
    1
    2
    0
    0
    7
    Hyporeflexia
         subjects affected / exposed
    0 / 121 (0.00%)
    0 / 122 (0.00%)
    0 / 122 (0.00%)
    0 / 119 (0.00%)
    1 / 115 (0.87%)
    0 / 495 (0.00%)
         occurrences all number
    0
    0
    0
    0
    1
    0
    Hypotonia
         subjects affected / exposed
    1 / 121 (0.83%)
    0 / 122 (0.00%)
    0 / 122 (0.00%)
    0 / 119 (0.00%)
    0 / 115 (0.00%)
    0 / 495 (0.00%)
         occurrences all number
    1
    0
    0
    0
    0
    0
    Intercostal neuralgia
         subjects affected / exposed
    0 / 121 (0.00%)
    0 / 122 (0.00%)
    0 / 122 (0.00%)
    0 / 119 (0.00%)
    0 / 115 (0.00%)
    1 / 495 (0.20%)
         occurrences all number
    0
    0
    0
    0
    0
    1
    Lumbar radiculopathy
         subjects affected / exposed
    0 / 121 (0.00%)
    0 / 122 (0.00%)
    0 / 122 (0.00%)
    0 / 119 (0.00%)
    1 / 115 (0.87%)
    0 / 495 (0.00%)
         occurrences all number
    0
    0
    0
    0
    1
    0
    Memory impairment
         subjects affected / exposed
    0 / 121 (0.00%)
    0 / 122 (0.00%)
    0 / 122 (0.00%)
    0 / 119 (0.00%)
    2 / 115 (1.74%)
    2 / 495 (0.40%)
         occurrences all number
    0
    0
    0
    0
    2
    3
    Mental impairment
         subjects affected / exposed
    0 / 121 (0.00%)
    0 / 122 (0.00%)
    0 / 122 (0.00%)
    0 / 119 (0.00%)
    0 / 115 (0.00%)
    1 / 495 (0.20%)
         occurrences all number
    0
    0
    0
    0
    0
    1
    Migraine
         subjects affected / exposed
    0 / 121 (0.00%)
    1 / 122 (0.82%)
    0 / 122 (0.00%)
    0 / 119 (0.00%)
    0 / 115 (0.00%)
    0 / 495 (0.00%)
         occurrences all number
    0
    1
    0
    0
    0
    0
    Motor dysfunction
         subjects affected / exposed
    2 / 121 (1.65%)
    1 / 122 (0.82%)
    0 / 122 (0.00%)
    0 / 119 (0.00%)
    0 / 115 (0.00%)
    4 / 495 (0.81%)
         occurrences all number
    2
    1
    0
    0
    0
    6
    Movement disorder
         subjects affected / exposed
    0 / 121 (0.00%)
    2 / 122 (1.64%)
    0 / 122 (0.00%)
    0 / 119 (0.00%)
    0 / 115 (0.00%)
    3 / 495 (0.61%)
         occurrences all number
    0
    2
    0
    0
    0
    3
    Neuralgia
         subjects affected / exposed
    0 / 121 (0.00%)
    0 / 122 (0.00%)
    0 / 122 (0.00%)
    0 / 119 (0.00%)
    0 / 115 (0.00%)
    2 / 495 (0.40%)
         occurrences all number
    0
    0
    0
    0
    0
    2
    Paraesthesia
         subjects affected / exposed
    2 / 121 (1.65%)
    1 / 122 (0.82%)
    1 / 122 (0.82%)
    0 / 119 (0.00%)
    0 / 115 (0.00%)
    1 / 495 (0.20%)
         occurrences all number
    2
    1
    1
    0
    0
    1
    Parkinson's disease
         subjects affected / exposed
    1 / 121 (0.83%)
    0 / 122 (0.00%)
    1 / 122 (0.82%)
    2 / 119 (1.68%)
    0 / 115 (0.00%)
    33 / 495 (6.67%)
         occurrences all number
    1
    0
    1
    2
    0
    41
    Parkinsonian gait
         subjects affected / exposed
    0 / 121 (0.00%)
    0 / 122 (0.00%)
    0 / 122 (0.00%)
    0 / 119 (0.00%)
    0 / 115 (0.00%)
    1 / 495 (0.20%)
         occurrences all number
    0
    0
    0
    0
    0
    1
    Parkinsonian rest tremor
         subjects affected / exposed
    0 / 121 (0.00%)
    0 / 122 (0.00%)
    0 / 122 (0.00%)
    0 / 119 (0.00%)
    0 / 115 (0.00%)
    2 / 495 (0.40%)
         occurrences all number
    0
    0
    0
    0
    0
    2
    Presyncope
         subjects affected / exposed
    0 / 121 (0.00%)
    1 / 122 (0.82%)
    0 / 122 (0.00%)
    0 / 119 (0.00%)
    0 / 115 (0.00%)
    1 / 495 (0.20%)
         occurrences all number
    0
    1
    0
    0
    0
    1
    Psychomotor hyperactivity
         subjects affected / exposed
    0 / 121 (0.00%)
    0 / 122 (0.00%)
    0 / 122 (0.00%)
    0 / 119 (0.00%)
    1 / 115 (0.87%)
    1 / 495 (0.20%)
         occurrences all number
    0
    0
    0
    0
    1
    1
    Restless legs syndrome
         subjects affected / exposed
    1 / 121 (0.83%)
    0 / 122 (0.00%)
    0 / 122 (0.00%)
    1 / 119 (0.84%)
    0 / 115 (0.00%)
    2 / 495 (0.40%)
         occurrences all number
    2
    0
    0
    2
    0
    2
    Sciatica
         subjects affected / exposed
    2 / 121 (1.65%)
    0 / 122 (0.00%)
    1 / 122 (0.82%)
    1 / 119 (0.84%)
    0 / 115 (0.00%)
    4 / 495 (0.81%)
         occurrences all number
    2
    0
    1
    1
    0
    4
    Somnolence
         subjects affected / exposed
    2 / 121 (1.65%)
    0 / 122 (0.00%)
    1 / 122 (0.82%)
    4 / 119 (3.36%)
    2 / 115 (1.74%)
    7 / 495 (1.41%)
         occurrences all number
    2
    0
    1
    4
    2
    7
    Sudden onset of sleep