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    Clinical Trial Results:
    A Randomized Controlled Study to Compare the Safety and Efficacy of IPX203 with Immediate-Release Carbidopa-Levodopa in Parkinson's Disease Patients with Motor Fluctuations

    Summary
    EudraCT number
    		 2018-002233-37
    Trial protocol
    		 CZ   DE   GB   PL   IT  
    Global end of trial date
    15 Jun 2021

    Results information
    Results version number
    		 v1(current)
    This version publication date
    30 Dec 2022
    First version publication date
    30 Dec 2022
    Other versions

    Trial information

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    Trial identification
    Sponsor protocol code
    IPX203-B16-02
    Additional study identifiers
    ISRCTN number
    		 -
    US NCT number
    		 NCT03670953
    WHO universal trial number (UTN)
    		 -
    Sponsors
    Sponsor organisation name
    Impax Laboratories, LLC
    Sponsor organisation address
    400 Crossing Boulevard , Bridgewater, United States, NJ 08807
    Public contact
    Pfitz Patrick, Impax Laboratories, LLC, +1 631-633-2104, pfitzpatrick@amneal.com
    Scientific contact
    Pfitz Patrick, Impax Laboratories, LLC, +1 631-633-2104, pfitzpatrick@amneal.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
    15 Jun 2021
    Is this the analysis of the primary completion data?
    No
    Global end of trial reached?
    Yes
    Global end of trial date
    15 Jun 2021
    Was the trial ended prematurely?
    No
    General information about the trial
    Main objective of the trial
    The main objective of this study is to evaluate the safety and efficacy of IPX203 in comparison to immediate-release carbidopa-levodopa (IR CD-LD) in the treatment of CD-LD-experienced subjects with Parkinson’s disease who have motor fluctuations.
    Protection of trial subjects
    This study was conducted in accordance with the ethical principles that have their origin in the Declaration of Helsinki and that are consistent with the International Conference on Harmonisation (ICH) guidelines for Good Clinical Practice (GCP) and applicable regulatory requirements.
    Background therapy
    		 -
    Evidence for comparator
    		 -
    Actual start date of recruitment
    06 Nov 2018
    Long term follow-up planned
    No
    Independent data monitoring committee (IDMC) involvement?
    No
    Population of trial subjects
    Number of subjects enrolled per country
    Country: Number of subjects enrolled
    Poland: 78
    Country: Number of subjects enrolled
    Spain: 71
    Country: Number of subjects enrolled
    United Kingdom: 12
    Country: Number of subjects enrolled
    Czechia: 45
    Country: Number of subjects enrolled
    France: 13
    Country: Number of subjects enrolled
    Germany: 48
    Country: Number of subjects enrolled
    Italy: 36
    Country: Number of subjects enrolled
    United States: 327
    Worldwide total number of subjects
    630
    EEA total number of subjects
    291
    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)
    236
    From 65 to 84 years
    388
    85 years and over
    6

    Subject disposition

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    Recruitment
    Recruitment details
    		 This study was conducted at 105 sites in the United States, Italy, Spain, France, the United Kingdom, the Czech Republic, Poland, and Germany. A total of 770 subjects were screened, of which 140 subjects were screen failures, and 630 subjects were enrolled in this study.

    Pre-assignment
    Screening details
    		 Study consisted of 4-week Screening period, 3 week open-label IR CD-LD dose adjustment period, 4 week open-label period for conversion to IPX203 and 13 week double-blind treatment period (DBP). Subjects were randomized in 1:1 ratio to receive either IPX203 (with matching IR CD-LD placebo) or IR CD-LD (with matching IPX203 placebo) in DBP.

    Period 1
    Period 1 title
    IR CD-LD dose adjustment period(3 weeks)
    Is this the baseline period?
    		 Yes
    Allocation method
    Not applicable
    Blinding used
    		 Not blinded

    Arms
    Arm title
    		 IR CD-LD Dose Adjustment
    Arm description
    		 Subjects who were previously treated on a stable regimen with CD-LD for at least 4 weeks entered a 3-week, open-label IR CD-LD treatment period allowing for dose adjustment. During the IR CD-LD dose adjustment period, the initial dosing regimen of IR CD-LD was to be the same as the subject’s stable pre-study regimen unless the subject was taking a single daily bedtime dose of controlled releases (CR) CD-LD. In such a case, the CR CD-LD dose was discontinued and substituted with a 1:1 milligram (mg)-equivalent dose of IR CD-LD.
    Arm type
    		 Active comparator

    Investigational medicinal product name
    IR CD-LD
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Tablet
    Routes of administration
    Oral use
    Dosage and administration details
    Subjects received multiple doses of IR CD-LD oral tablets containing 25 mg CD and 100 mg LD.

    Number of subjects in period 1
    		IR CD-LD Dose Adjustment
    Started
    630
    Completed
    589
    Not completed
    41
         Consent withdrawn by subject
    9
         Adverse event, non-fatal
    4
         Unspecified
    21
         Lack of efficacy
    1
         Protocol deviation
    6
    Period 2
    Period 2 title
    Open-label Conversion Period to IPX203
    Is this the baseline period?
    		 No
    Allocation method
    Not applicable
    Blinding used
    		 Not blinded

    Arms
    Arm title
    		 IPX203 Dose Conversion period
    Arm description
    		 Subjects who completed IR CD-LD dose adjustment period entered a 4-week open-label dose conversion period for conversion from IR CD-LD to IPX203. The initial dosing regimen of IPX203 was based on the most frequent dose of the subject’s stable dosing regimen of IR CD-LD at the end of the dose adjustment period.
    Arm type
    		 Experimental

    Investigational medicinal product name
    IPX203 ER CD-LD
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Capsule
    Routes of administration
    Oral use
    Dosage and administration details
    Subjects received multiple doses of IPX203 extended-release (ER) CD-LD oral capsules, containing 35 mg CD and 140 mg LD.

    Number of subjects in period 2
    		IPX203 Dose Conversion period
    Started
    589
    Completed
    506
    Not completed
    83
         Consent withdrawn by subject
    32
         Adverse event, non-fatal
    35
         Non-compliance with study drug
    2
         Unspecified
    2
         Lost to follow-up
    1
         Lack of efficacy
    10
         Protocol deviation
    1
    Period 3
    Period 3 title
    Double-Blind Maintenance Period
    Is this the baseline period?
    		 No
    Allocation method
    Randomised - controlled
    Blinding used
    		 Double blind
    Roles blinded
    		 Subject, Investigator, Carer, Assessor

    Arms
    Are arms mutually exclusive
    Yes

    Arm title
    		 IPX203 Double-Blind Period
    Arm description
    		 Subjects who successfully completed the IPX203 dose conversion period were randomized to receive multiple doses IPX203 35 mg CD and 140 mg LD ER oral capsules (with matching IR CD-LD placebo or multiple doses of IR CD-LD [with matching IPX203]) for up to 13 weeks of double-blind, double-dummy maintenance therapy with the stable dosing regimen established at the end of Week 7 for IPX203.
    Arm type
    		 Experimental

    Investigational medicinal product name
    IPX203
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Capsule
    Routes of administration
    Oral use
    Dosage and administration details
    Subjects received multiple doses of IPX203 CD-LD ER oral capsules, containing 35 mg CD and 140 mg LD.

    Investigational medicinal product name
    IR CD-LD
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Tablet
    Routes of administration
    Oral use
    Dosage and administration details
    Subjects received IR CD-LD oral tablets.

    Arm title
    		 IR CD-LD Double-Blind Period
    Arm description
    		 Subjects who successfully completed the IPX203 dose conversion period were randomized to receive multiple doses of IR CD-LD 25 mg CD and 100 mg LD oral tablets (with matching IPX203 placebo) for up to 13 weeks of double-blind, double-dummy maintenance therapy with the stable dosing regimen established at the end of Week 3 for IR CD-LD.
    Arm type
    		 Active comparator

    Investigational medicinal product name
    IR CD-LD
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Tablet
    Routes of administration
    Oral use
    Dosage and administration details
    Subjects received multiple doses of IR CD-LD oral tablets containing 25 mg CD and 100 mg LD.

    Investigational medicinal product name
    Placebo matched to IPX203
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Capsule
    Routes of administration
    Oral use
    Dosage and administration details
    Subjects received placebo matched to IPX203 ER oral capsules.

    Number of subjects in period 3
    		IPX203 Double-Blind Period IR CD-LD Double-Blind Period
    Started
    256
    250
    Completed
    222
    227
    Not completed
    34
    23
         Consent withdrawn by subject
    10
    11
         Adverse event, non-fatal
    14
    3
         Non-compliance with study drug
    1
    -
         Unspecified
    1
    -
         Protocol deviation
    3
    1
         Lack of efficacy
    5
    8

    Baseline characteristics

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    Baseline characteristics reporting groups
    Reporting group title
    IR CD-LD Dose Adjustment
    Reporting group description
    		 Subjects who were previously treated on a stable regimen with CD-LD for at least 4 weeks entered a 3-week, open-label IR CD-LD treatment period allowing for dose adjustment. During the IR CD-LD dose adjustment period, the initial dosing regimen of IR CD-LD was to be the same as the subject’s stable pre-study regimen unless the subject was taking a single daily bedtime dose of controlled releases (CR) CD-LD. In such a case, the CR CD-LD dose was discontinued and substituted with a 1:1 milligram (mg)-equivalent dose of IR CD-LD.

    Reporting group values
    		 IR CD-LD Dose Adjustment Total
    Number of subjects
    		 630 630
    Age categorical
    Units: Subjects
    Age continuous
    Units: years
        arithmetic mean (standard deviation)
    		 66.5 ± 8.95 -
    Gender categorical
    Units: Subjects
        Female
    		 234 234
        Male
    		 396 396
    Race
    Units: Subjects
        American Indian/Alaska Native
    		 3 3
        Asian
    		 10 10
        Black/African American
    		 6 6
        Native Hawaiian/Other Pacific Islander
    		 0 0
        White
    		 606 606
        Mixed
    		 0 0
        Other
    		 0 0
        Unknown or Not Reported
    		 5 5
    Ethnicity
    Units: Subjects
        Not Hispanic or Latino
    		 544 544
        Hispanic or Latino
    		 77 77
        Not reported
    		 9 9
        Unknown
    		 0 0

    End points

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    End points reporting groups
    Reporting group title
    IR CD-LD Dose Adjustment
    Reporting group description
    		 Subjects who were previously treated on a stable regimen with CD-LD for at least 4 weeks entered a 3-week, open-label IR CD-LD treatment period allowing for dose adjustment. During the IR CD-LD dose adjustment period, the initial dosing regimen of IR CD-LD was to be the same as the subject’s stable pre-study regimen unless the subject was taking a single daily bedtime dose of controlled releases (CR) CD-LD. In such a case, the CR CD-LD dose was discontinued and substituted with a 1:1 milligram (mg)-equivalent dose of IR CD-LD.
    Reporting group title
    IPX203 Dose Conversion period
    Reporting group description
    		 Subjects who completed IR CD-LD dose adjustment period entered a 4-week open-label dose conversion period for conversion from IR CD-LD to IPX203. The initial dosing regimen of IPX203 was based on the most frequent dose of the subject’s stable dosing regimen of IR CD-LD at the end of the dose adjustment period.
    Reporting group title
    IPX203 Double-Blind Period
    Reporting group description
    		 Subjects who successfully completed the IPX203 dose conversion period were randomized to receive multiple doses IPX203 35 mg CD and 140 mg LD ER oral capsules (with matching IR CD-LD placebo or multiple doses of IR CD-LD [with matching IPX203]) for up to 13 weeks of double-blind, double-dummy maintenance therapy with the stable dosing regimen established at the end of Week 7 for IPX203.

    Reporting group title
    IR CD-LD Double-Blind Period
    Reporting group description
    		 Subjects who successfully completed the IPX203 dose conversion period were randomized to receive multiple doses of IR CD-LD 25 mg CD and 100 mg LD oral tablets (with matching IPX203 placebo) for up to 13 weeks of double-blind, double-dummy maintenance therapy with the stable dosing regimen established at the end of Week 3 for IR CD-LD.

    Primary: Mean Change from Baseline in “Good on” Time in Hours per day, Averaged Over the Parkinson’s disease (PD) Diary Days at the End of the Double-blind Treatment Period

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    End point title
    		 Mean Change from Baseline in “Good on” Time in Hours per day, Averaged Over the Parkinson’s disease (PD) Diary Days at the End of the Double-blind Treatment Period
    End point description
    “Good on” time was derived from the 3-day PD Diaries and was defined as the sum of “On time without dyskinesia” and “On time with non-troublesome dyskinesia”. The Modified Intent-to-treat (mITT) Analysis Set included all subjects who were randomized and treated and have a valid baseline PD Diary and at least one valid post-randomization PD Diary (using double-blind PD Diary baseline). Baseline was defined as data obtained from PD Diary collected over 3 days prior to Visit 4/Randomization (Week 7).
    End point type
    Primary
    End point timeframe
    Baseline up to end of double-blind treatment period (Week 20)
    End point values
    		 IPX203 Double-Blind Period IR CD-LD Double-Blind Period
    Number of subjects analysed
    249
    246
    Units: hours per day
        least squares mean (standard error)
    -0.50 ± 0.183
    -1.03 ± 0.183
    Statistical analysis title
    		 IPX203 vs IR CD-LD
    Comparison groups
    IR CD-LD Double-Blind Period v IPX203 Double-Blind Period
    Number of subjects included in analysis
    495
    Analysis specification
    Pre-specified
    Analysis type
    		 other
    P-value
    		 = 0.0194 [1]
    Method
    		 MMRM model
    Parameter type
    		 Least square mean difference
    Point estimate
    0.53
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.09
         upper limit
    		 0.97
    Notes
    [1] - P-value was analyzed using a mixed model for repeated measures (MMRM) which included baseline "Good on" time as a covariate, treatment and visit (5, 6 or 7/ET) as fixed effects, pooled center as random effect and a treatment-by-visit interaction.

    Secondary: Change from Baseline in “Off” Time in Hours per day, Averaged Over the PD Diary Days at the End of the Double-blind Treatment Period

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    End point title
    		 Change from Baseline in “Off” Time in Hours per day, Averaged Over the PD Diary Days at the End of the Double-blind Treatment Period
    End point description
    “Off” time was calculated by adding the number of half-hour intervals in which an “Off” was checked. The mITT analysis set included all subjects who were randomized and treated and have a valid baseline PD Diary and at least one valid post-randomization PD Diary (using double-blind PD Diary baseline). Baseline was defined as data obtained from PD Diary collected over 3 days prior to Visit 4/Randomization (Week 7).
    End point type
    Secondary
    End point timeframe
    Baseline up to end of double-blind treatment period (Week 20)
    End point values
    		 IPX203 Double-Blind Period IR CD-LD Double-Blind Period
    Number of subjects analysed
    249
    246
    Units: hours per day
        least squares mean (standard error)
    0.38 ± 0.172
    0.86 ± 0.171
    Statistical analysis title
    		 IPX203 vs IR CD-LD
    Comparison groups
    IPX203 Double-Blind Period v IR CD-LD Double-Blind Period
    Number of subjects included in analysis
    495
    Analysis specification
    Pre-specified
    Analysis type
    		 other
    P-value
    		 = 0.0252 [2]
    Method
    		 MMRM model
    Parameter type
    		 LS Mean difference
    Point estimate
    -0.48
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -0.9
         upper limit
    		 -0.06
    Notes
    [2] - P-value was analyzed using a MMRM which included baseline "Off" time as a covariate, treatment and visit (5, 6 or 7/ET) as fixed effects, pooled center as random effect and a treatment-by-visit interaction.

    Secondary: Percentage of Subjects with Either “Much Improved” or “Very Much Improved” in Patient Global Impression of Change (PGI-C) Scores at the End of the Double-blind Treatment Period

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    End point title
    		 Percentage of Subjects with Either “Much Improved” or “Very Much Improved” in Patient Global Impression of Change (PGI-C) Scores at the End of the Double-blind Treatment Period
    End point description
    PGI-C was a single, subject-reported item reflecting the subject’s impression of change in his/her disease status since the start of the study (that is, in relation to activity limitations, symptoms, emotions, and overall quality of life). Subjects rated their impression of change in disease status on a 7-point scale:1-very much improved; 2-much improved; 3-minimally improved; 4-no change; 5-minimally worse; 6-much worse; 7-very much worse where a higher score indicated worsening. Score ranges from 1 (Very Much Improved) to 7 (Very Much Worse). Lower scores indicate better health status. Percentage of subjects with either “Much Improved” or “Very Much Improved” PGI-C scores were reported. Intent-to-treat (ITT) Analysis Set included all subjects who were randomized and treated with any study drug and have a baseline and at least one post-baseline efficacy assessment (using double-blind baseline). “Number of subjects analyzed” signifies subjects who were evaluable for this endpoint.
    End point type
    Secondary
    End point timeframe
    At the end of the double-blind treatment period (Week 20)
    End point values
    		 IPX203 Double-Blind Period IR CD-LD Double-Blind Period
    Number of subjects analysed
    255
    248
    Units: Percentage of subjects
    number (not applicable)
        Much Improved
    26.7
    18.5
        Very much Improved
    3.1
    0.4
    Statistical analysis title
    		 IPX203 vs IR CD-LD
    Comparison groups
    IPX203 Double-Blind Period v IR CD-LD Double-Blind Period
    Number of subjects included in analysis
    503
    Analysis specification
    Pre-specified
    Analysis type
    P-value
    		 = 0.0015 [3]
    Method
    		 Cochran-Mantel-Haenszel
    Parameter type
    		 Percent difference
    Point estimate
    10.9
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 3.5
         upper limit
    		 18.3
    Notes
    [3] - P-value from the Cochran-Mantel-Haenszel (CMH) test stratified by pooled center compared the percent of Much or Very Much Improved subjects between the treatment groups.

    Secondary: Change from Baseline in the Movement Disorders Society - Unified Parkinson’s Disease Rating Scale (MDS-UPDRS) Part III at the End of the Double-blind Treatment Period

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    End point title
    		 Change from Baseline in the Movement Disorders Society - Unified Parkinson’s Disease Rating Scale (MDS-UPDRS) Part III at the End of the Double-blind Treatment Period
    End point description
    The MDS-UPDRS evaluates motor and non-motor symptoms in persons with Parkinson's and consists of 4 parts with various questions and evaluations. Part I (13 items; Score 0 to 52) examines non-motor experiences, Part II (13 items; Score 0 to 52) examines motor experiences, Part III (33 items; Score 0 to 132) examines the cardinal motor disabilities and Part IV (6 items; Score 0 to 24) examines motor complications. Each Part has 0 to 4 ratings, where 0 (no problems) to 4 (severe problems). Higher scores indicate a greater impact of Parkinson's disease symptoms (that is worse symptoms). The ITT analysis set included all subjects who were randomized and treated with any study drug and have a baseline and at least one post-baseline efficacy assessment (double-blind baseline). Baseline was defined as the last assessment obtained prior to the first dose of the randomized study drug.
    End point type
    Secondary
    End point timeframe
    Baseline to the end of the double-blind treatment period (Week 20)
    End point values
    		 IPX203 Double-Blind Period IR CD-LD Double-Blind Period
    Number of subjects analysed
    256
    250
    Units: Score on a scale
        least squares mean (standard error)
    0.8 ± 0.71
    0.8 ± 0.72
    Statistical analysis title
    		 IPX203 vs IR CD-LD
    Comparison groups
    IPX203 Double-Blind Period v IR CD-LD Double-Blind Period
    Number of subjects included in analysis
    506
    Analysis specification
    Pre-specified
    Analysis type
    		 other
    P-value
    		 = 0.9587 [4]
    Method
    		 MMRM model
    Parameter type
    		 LS Mean difference
    Point estimate
    0
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -1.8
         upper limit
    		 1.7
    Variability estimate
    Standard error of the mean
    Dispersion value
    0.89
    Notes
    [4] - P-value was analyzed using a MMRM which included baseline MDS as a covariate, treatment and visit (5, 6 or 7/ET) as fixed effects, pooled center as random effect and a treatment-by-visit interaction.

    Secondary: Change from Baseline in the Sum of MDS-UPDRS Part II and III at the End of the Double-blind Treatment Period

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    End point title
    		 Change from Baseline in the Sum of MDS-UPDRS Part II and III at the End of the Double-blind Treatment Period
    End point description
    The MDS-UPDRS evaluates motor and non-motor symptoms in persons with Parkinson's and consists of 4 parts with various questions and evaluations. Part I (13 items; Score 0 to 52) examines non-motor experiences, Part II (13 items; Score 0 to 52) examines motor experiences, Part III (33 items; Score 0 to 132) examines the cardinal motor disabilities and Part IV (6 items; Score 0-24) examines motor complications. Each Part has 0 to 4 ratings, where 0 (no problems) to 4 (severe problems). Higher scores indicate a greater impact of Parkinson's disease symptoms (that is worse symptoms). Data was collected and analyzed as the sum of all answers in Parts II and III of the MDS-UPDRS questionnaire. ITT analysis set included all subjects who were randomized and treated with any study drug and have a baseline and at least one post-baseline efficacy assessment (double-blind baseline). Baseline was defined as the last assessment obtained prior to the first dose of the randomized study drug.
    End point type
    Secondary
    End point timeframe
    Baseline to the end of the double-blind treatment period (Week 20)
    End point values
    		 IPX203 Double-Blind Period IR CD-LD Double-Blind Period
    Number of subjects analysed
    256
    250
    Units: Score on a scale
        least squares mean (standard error)
    1.7 ± 0.87
    1.8 ± 0.87
    Statistical analysis title
    		 IPX203 vs IR CD-LD
    Comparison groups
    IPX203 Double-Blind Period v IR CD-LD Double-Blind Period
    Number of subjects included in analysis
    506
    Analysis specification
    Pre-specified
    Analysis type
    		 other
    P-value
    		 = 0.9668 [5]
    Method
    		 MMRM model
    Parameter type
    		 LS Mean difference
    Point estimate
    0
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -2.2
         upper limit
    		 2.1
    Variability estimate
    Standard error of the mean
    Dispersion value
    1.11
    Notes
    [5] - P-value was analyzed using a MMRM which included baseline MDS as a covariate, treatment and visit (5, 6 or 7/ET) as fixed effects, pooled center as random effect and a treatment-by-visit interaction.

    Adverse events

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    Adverse events information
    Timeframe for reporting adverse events
    From Baseline up to end of the double-blind treatment period (Week 20)
    Adverse event reporting additional description
    The Safety Analysis Set included all subjects who were treated with any study drug (IPX203 or IR CD-LD).
    Assessment type
    		 Non-systematic
    Dictionary used for adverse event reporting
    Dictionary name
    		 MedDRA
    Dictionary version
    22.0
    Reporting groups
    Reporting group title
    IR CD-LD Dose Adjustment Period
    Reporting group description
    		 Subjects who were previously treated on a stable regimen with CD-LD for at least 4 weeks entered a 3-week, open-label IR CD-LD treatment period allowing for dose adjustment. During the IR CD-LD dose adjustment period, the initial dosing regimen of IR CD-LD was to be the same as the subject’s stable pre-study regimen unless the subject was taking a single daily bedtime dose of CR CD-LD. In such a case, the CR CD-LD dose was discontinued and substituted with a 1:1 mg-equivalent dose of IR CD-LD.

    Reporting group title
    IPX203 Conversion Period
    Reporting group description
    		 Subjects who completed IR CD-LD dose adjustment period entered a 4-week open-label dose conversion period for conversion from IR CD-LD to IPX203. The initial dosing regimen of IPX203 was based on the most frequent dose of the subject’s stable dosing regimen of IR CD-LD at the end of the dose adjustment period.

    Reporting group title
    IPX203 Double-Blind Period
    Reporting group description
    		 Subjects who successfully completed the IPX203 dose conversion period were randomized to receive multiple doses of IPX203 35 mg CD and 140 mg LD ER oral capsules (with matching IR CD-LD placebo or multiple doses of IR CD-LD [with matching IPX203]) for up to 13 weeks of double-blind, double-dummy maintenance therapy with the stable dosing regimen established at the end of Week 7 for IPX203.

    Reporting group title
    IR CD-LD Double-Blind Period
    Reporting group description
    		 Subjects who successfully completed the IPX203 dose conversion period were randomized to receive multiple doses of IR CD-LD 25 mg CD and 100 mg LD oral tablets (with matching IPX203 placebo) for up to 13 weeks of double-blind, double-dummy maintenance therapy with the stable dosing regimen established at the end of Week 3 for IR CD-LD.

    Serious adverse events
    		 IR CD-LD Dose Adjustment Period IPX203 Conversion Period IPX203 Double-Blind Period IR CD-LD Double-Blind Period
    Total subjects affected by serious adverse events
         subjects affected / exposed
    7 / 630 (1.11%)
    12 / 589 (2.04%)
    8 / 256 (3.13%)
    4 / 250 (1.60%)
         number of deaths (all causes)
    0
    0
    0
    0
         number of deaths resulting from adverse events
    0
    0
    0
    0
    Neoplasms benign, malignant and unspecified (incl cysts and polyps)
    Bladder transitional cell carcinoma
         subjects affected / exposed
    0 / 630 (0.00%)
    1 / 589 (0.17%)
    0 / 256 (0.00%)
    0 / 250 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Surgical and medical procedures
    Inguinal hernia repair
         subjects affected / exposed
    0 / 630 (0.00%)
    1 / 589 (0.17%)
    0 / 256 (0.00%)
    0 / 250 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    General disorders and administration site conditions
    Asthenia
         subjects affected / exposed
    0 / 630 (0.00%)
    0 / 589 (0.00%)
    1 / 256 (0.39%)
    0 / 250 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Chest pain
         subjects affected / exposed
    0 / 630 (0.00%)
    1 / 589 (0.17%)
    0 / 256 (0.00%)
    0 / 250 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Fatigue
         subjects affected / exposed
    0 / 630 (0.00%)
    0 / 589 (0.00%)
    1 / 256 (0.39%)
    0 / 250 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Reproductive system and breast disorders
    Benign prostatic hyperplasia
         subjects affected / exposed
    0 / 630 (0.00%)
    0 / 589 (0.00%)
    0 / 256 (0.00%)
    1 / 250 (0.40%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Respiratory, thoracic and mediastinal disorders
    Chronic obstructive pulmonary disease
         subjects affected / exposed
    0 / 630 (0.00%)
    1 / 589 (0.17%)
    0 / 256 (0.00%)
    0 / 250 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Psychiatric disorders
    Hallucinations, mixed
         subjects affected / exposed
    0 / 630 (0.00%)
    0 / 589 (0.00%)
    1 / 256 (0.39%)
    0 / 250 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Investigations
    Ejection fraction decreased
         subjects affected / exposed
    0 / 630 (0.00%)
    0 / 589 (0.00%)
    1 / 256 (0.39%)
    0 / 250 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Injury, poisoning and procedural complications
    Contusion
         subjects affected / exposed
    0 / 630 (0.00%)
    1 / 589 (0.17%)
    0 / 256 (0.00%)
    0 / 250 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Hip fracture
         subjects affected / exposed
    0 / 630 (0.00%)
    1 / 589 (0.17%)
    0 / 256 (0.00%)
    0 / 250 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Radiation neuropathy
         subjects affected / exposed
    1 / 630 (0.16%)
    0 / 589 (0.00%)
    0 / 256 (0.00%)
    0 / 250 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Skin laceration
         subjects affected / exposed
    0 / 630 (0.00%)
    1 / 589 (0.17%)
    0 / 256 (0.00%)
    0 / 250 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Subdural haematoma
         subjects affected / exposed
    0 / 630 (0.00%)
    1 / 589 (0.17%)
    0 / 256 (0.00%)
    0 / 250 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Cardiac disorders
    Atrioventricular block complete
         subjects affected / exposed
    0 / 630 (0.00%)
    0 / 589 (0.00%)
    0 / 256 (0.00%)
    1 / 250 (0.40%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Bradycardia
         subjects affected / exposed
    0 / 630 (0.00%)
    0 / 589 (0.00%)
    1 / 256 (0.39%)
    0 / 250 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Cardiac failure
         subjects affected / exposed
    0 / 630 (0.00%)
    0 / 589 (0.00%)
    0 / 256 (0.00%)
    1 / 250 (0.40%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Nervous system disorders
    Cognitive disorder
         subjects affected / exposed
    1 / 630 (0.16%)
    0 / 589 (0.00%)
    0 / 256 (0.00%)
    0 / 250 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Dyskinesia
         subjects affected / exposed
    1 / 630 (0.16%)
    0 / 589 (0.00%)
    0 / 256 (0.00%)
    0 / 250 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Epilepsy
         subjects affected / exposed
    0 / 630 (0.00%)
    0 / 589 (0.00%)
    1 / 256 (0.39%)
    0 / 250 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Neuralgia
         subjects affected / exposed
    1 / 630 (0.16%)
    0 / 589 (0.00%)
    0 / 256 (0.00%)
    0 / 250 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    On and off phenomenon
         subjects affected / exposed
    1 / 630 (0.16%)
    0 / 589 (0.00%)
    0 / 256 (0.00%)
    0 / 250 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Syncope
         subjects affected / exposed
    0 / 630 (0.00%)
    0 / 589 (0.00%)
    1 / 256 (0.39%)
    0 / 250 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Transient ischaemic attack
         subjects affected / exposed
    0 / 630 (0.00%)
    2 / 589 (0.34%)
    0 / 256 (0.00%)
    0 / 250 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 2
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Vertebral artery aneurysm
         subjects affected / exposed
    0 / 630 (0.00%)
    0 / 589 (0.00%)
    1 / 256 (0.39%)
    0 / 250 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Blood and lymphatic system disorders
    Anaemia
         subjects affected / exposed
    0 / 630 (0.00%)
    1 / 589 (0.17%)
    0 / 256 (0.00%)
    0 / 250 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Gastrointestinal disorders
    Duodenitis
         subjects affected / exposed
    1 / 630 (0.16%)
    0 / 589 (0.00%)
    0 / 256 (0.00%)
    0 / 250 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Inguinal hernia
         subjects affected / exposed
    1 / 630 (0.16%)
    0 / 589 (0.00%)
    0 / 256 (0.00%)
    0 / 250 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Renal and urinary disorders
    Acute kidney injury
         subjects affected / exposed
    1 / 630 (0.16%)
    0 / 589 (0.00%)
    0 / 256 (0.00%)
    0 / 250 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Nephrolithiasis
         subjects affected / exposed
    0 / 630 (0.00%)
    1 / 589 (0.17%)
    0 / 256 (0.00%)
    0 / 250 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Urinary retention
         subjects affected / exposed
    0 / 630 (0.00%)
    1 / 589 (0.17%)
    0 / 256 (0.00%)
    0 / 250 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Urinary tract obstruction
         subjects affected / exposed
    1 / 630 (0.16%)
    0 / 589 (0.00%)
    0 / 256 (0.00%)
    0 / 250 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Musculoskeletal and connective tissue disorders
    Back pain
         subjects affected / exposed
    0 / 630 (0.00%)
    0 / 589 (0.00%)
    0 / 256 (0.00%)
    1 / 250 (0.40%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Osteoarthritis
         subjects affected / exposed
    1 / 630 (0.16%)
    0 / 589 (0.00%)
    0 / 256 (0.00%)
    0 / 250 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Infections and infestations
    Cystitis
         subjects affected / exposed
    0 / 630 (0.00%)
    1 / 589 (0.17%)
    0 / 256 (0.00%)
    0 / 250 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Epididymitis
         subjects affected / exposed
    1 / 630 (0.16%)
    0 / 589 (0.00%)
    0 / 256 (0.00%)
    0 / 250 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Influenza
         subjects affected / exposed
    0 / 630 (0.00%)
    1 / 589 (0.17%)
    0 / 256 (0.00%)
    0 / 250 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Pneumonia
         subjects affected / exposed
    0 / 630 (0.00%)
    1 / 589 (0.17%)
    0 / 256 (0.00%)
    0 / 250 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Pyelonephritis
         subjects affected / exposed
    0 / 630 (0.00%)
    0 / 589 (0.00%)
    1 / 256 (0.39%)
    0 / 250 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Sepsis
         subjects affected / exposed
    0 / 630 (0.00%)
    1 / 589 (0.17%)
    0 / 256 (0.00%)
    0 / 250 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Urinary tract infection
         subjects affected / exposed
    0 / 630 (0.00%)
    1 / 589 (0.17%)
    0 / 256 (0.00%)
    1 / 250 (0.40%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Metabolism and nutrition disorders
    Hypokalaemia
         subjects affected / exposed
    0 / 630 (0.00%)
    1 / 589 (0.17%)
    0 / 256 (0.00%)
    0 / 250 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Hyponatraemia
         subjects affected / exposed
    1 / 630 (0.16%)
    0 / 589 (0.00%)
    0 / 256 (0.00%)
    0 / 250 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Frequency threshold for reporting non-serious adverse events: 0%
    Non-serious adverse events
    		 IR CD-LD Dose Adjustment Period IPX203 Conversion Period IPX203 Double-Blind Period IR CD-LD Double-Blind Period
    Total subjects affected by non serious adverse events
         subjects affected / exposed
    118 / 630 (18.73%)
    229 / 589 (38.88%)
    108 / 256 (42.19%)
    79 / 250 (31.60%)
    Neoplasms benign, malignant and unspecified (incl cysts and polyps)
    Basal cell carcinoma
         subjects affected / exposed
    1 / 630 (0.16%)
    0 / 589 (0.00%)
    0 / 256 (0.00%)
    0 / 250 (0.00%)
         occurrences all number
    1
    0
    0
    0
    Extranodal marginal zone B-cell lymphoma (MALT type)
         subjects affected / exposed
    0 / 630 (0.00%)
    0 / 589 (0.00%)
    0 / 256 (0.00%)
    1 / 250 (0.40%)
         occurrences all number
    0
    0
    0
    1
    Squamous cell carcinoma
         subjects affected / exposed
    0 / 630 (0.00%)
    0 / 589 (0.00%)
    0 / 256 (0.00%)
    1 / 250 (0.40%)
         occurrences all number
    0
    0
    0
    1
    Vascular disorders
    Blood pressure inadequately controlled
         subjects affected / exposed
    0 / 630 (0.00%)
    0 / 589 (0.00%)
    1 / 256 (0.39%)
    0 / 250 (0.00%)
         occurrences all number
    0
    0
    1
    0
    Flushing
         subjects affected / exposed
    0 / 630 (0.00%)
    2 / 589 (0.34%)
    0 / 256 (0.00%)
    0 / 250 (0.00%)
         occurrences all number
    0
    2
    0
    0
    Hypertension
         subjects affected / exposed
    7 / 630 (1.11%)
    4 / 589 (0.68%)
    2 / 256 (0.78%)
    3 / 250 (1.20%)
         occurrences all number
    7
    4
    2
    3
    Hypertensive crisis
         subjects affected / exposed
    0 / 630 (0.00%)
    1 / 589 (0.17%)
    0 / 256 (0.00%)
    0 / 250 (0.00%)
         occurrences all number
    0
    1
    0
    0
    Hypertensive urgency
         subjects affected / exposed
    0 / 630 (0.00%)
    1 / 589 (0.17%)
    0 / 256 (0.00%)
    0 / 250 (0.00%)
         occurrences all number
    0
    1
    0
    0
    Hypotension
         subjects affected / exposed
    0 / 630 (0.00%)
    3 / 589 (0.51%)
    1 / 256 (0.39%)
    0 / 250 (0.00%)
         occurrences all number
    0
    3
    1
    0
    Labile hypertension
         subjects affected / exposed
    0 / 630 (0.00%)
    0 / 589 (0.00%)
    1 / 256 (0.39%)
    0 / 250 (0.00%)
         occurrences all number
    0
    0
    1
    0
    Orthostatic hypotension
         subjects affected / exposed
    5 / 630 (0.79%)
    8 / 589 (1.36%)
    2 / 256 (0.78%)
    1 / 250 (0.40%)
         occurrences all number
    5
    8
    2
    1
    Peripheral venous disease
         subjects affected / exposed
    0 / 630 (0.00%)
    1 / 589 (0.17%)
    0 / 256 (0.00%)
    0 / 250 (0.00%)
         occurrences all number
    0
    1
    0
    0
    Thrombosis
         subjects affected / exposed
    1 / 630 (0.16%)
    0 / 589 (0.00%)
    0 / 256 (0.00%)
    0 / 250 (0.00%)
         occurrences all number
    1
    0
    0
    0
    Varicophlebitis
         subjects affected / exposed
    0 / 630 (0.00%)
    1 / 589 (0.17%)
    0 / 256 (0.00%)
    0 / 250 (0.00%)
         occurrences all number
    0
    1
    0
    0
    Surgical and medical procedures
    Tooth extraction
         subjects affected / exposed
    0 / 630 (0.00%)
    0 / 589 (0.00%)
    2 / 256 (0.78%)
    0 / 250 (0.00%)
         occurrences all number
    0
    0
    2
    0
    General disorders and administration site conditions
    Balance disorder
         subjects affected / exposed
    0 / 630 (0.00%)
    0 / 589 (0.00%)
    0 / 256 (0.00%)
    1 / 250 (0.40%)
         occurrences all number
    0
    0
    0
    1
    Chest discomfort
         subjects affected / exposed
    0 / 630 (0.00%)
    1 / 589 (0.17%)
    0 / 256 (0.00%)
    0 / 250 (0.00%)
         occurrences all number
    0
    1
    0
    0
    Feeling abnormal
         subjects affected / exposed
    0 / 630 (0.00%)
    3 / 589 (0.51%)
    3 / 256 (1.17%)
    0 / 250 (0.00%)
         occurrences all number
    0
    3
    3
    0
    Gait disturbance
         subjects affected / exposed
    2 / 630 (0.32%)
    0 / 589 (0.00%)
    1 / 256 (0.39%)
    1 / 250 (0.40%)
         occurrences all number
    2
    0
    1
    1
    Hernia
         subjects affected / exposed
    0 / 630 (0.00%)
    0 / 589 (0.00%)
    0 / 256 (0.00%)
    1 / 250 (0.40%)
         occurrences all number
    0
    0
    0
    1
    Influenza like illness
         subjects affected / exposed
    0 / 630 (0.00%)
    1 / 589 (0.17%)
    0 / 256 (0.00%)
    1 / 250 (0.40%)
         occurrences all number
    0
    1
    0
    1
    Mass
         subjects affected / exposed
    0 / 630 (0.00%)
    0 / 589 (0.00%)
    0 / 256 (0.00%)
    1 / 250 (0.40%)
         occurrences all number
    0
    0
    0
    1
    Non-cardiac chest pain
         subjects affected / exposed
    0 / 630 (0.00%)
    1 / 589 (0.17%)
    0 / 256 (0.00%)
    0 / 250 (0.00%)
         occurrences all number
    0
    1
    0
    0
    Oedema
         subjects affected / exposed
    2 / 630 (0.32%)
    0 / 589 (0.00%)
    0 / 256 (0.00%)
    0 / 250 (0.00%)
         occurrences all number
    2
    0
    0
    0
    Oedema peripheral
         subjects affected / exposed
    0 / 630 (0.00%)
    0 / 589 (0.00%)
    3 / 256 (1.17%)
    1 / 250 (0.40%)
         occurrences all number
    0
    0
    3
    1
    Pain
         subjects affected / exposed
    0 / 630 (0.00%)
    1 / 589 (0.17%)
    0 / 256 (0.00%)
    1 / 250 (0.40%)
         occurrences all number
    0
    1
    0
    1
    Peripheral swelling
         subjects affected / exposed
    1 / 630 (0.16%)
    0 / 589 (0.00%)
    0 / 256 (0.00%)
    0 / 250 (0.00%)
         occurrences all number
    1
    0
    0
    0
    Pyrexia
         subjects affected / exposed
    2 / 630 (0.32%)
    2 / 589 (0.34%)
    0 / 256 (0.00%)
    0 / 250 (0.00%)
         occurrences all number
    2
    2
    0
    0
    Reproductive system and breast disorders
    Benign prostatic hyperplasia
         subjects affected / exposed
    0 / 630 (0.00%)
    0 / 589 (0.00%)
    0 / 256 (0.00%)
    1 / 250 (0.40%)
         occurrences all number
    0
    0
    0
    1
    Erectile dysfunction
         subjects affected / exposed
    1 / 630 (0.16%)
    0 / 589 (0.00%)
    0 / 256 (0.00%)
    0 / 250 (0.00%)
         occurrences all number
    1
    0
    0
    0
    Prostatitis
         subjects affected / exposed
    0 / 630 (0.00%)
    0 / 589 (0.00%)
    1 / 256 (0.39%)
    0 / 250 (0.00%)
         occurrences all number
    0
    0
    1
    0
    Vaginal prolapse
         subjects affected / exposed
    0 / 630 (0.00%)
    0 / 589 (0.00%)
    1 / 256 (0.39%)
    0 / 250 (0.00%)
         occurrences all number
    0
    0
    1
    0
    Respiratory, thoracic and mediastinal disorders
    Asthma
         subjects affected / exposed
    0 / 630 (0.00%)
    1 / 589 (0.17%)
    2 / 256 (0.78%)
    0 / 250 (0.00%)
         occurrences all number
    0
    1
    2
    0
    Chronic obstructive pulmonary disease
         subjects affected / exposed
    1 / 630 (0.16%)
    2 / 589 (0.34%)
    0 / 256 (0.00%)
    0 / 250 (0.00%)
         occurrences all number
    1
    2
    0
    0
    Cough
         subjects affected / exposed
    3 / 630 (0.48%)
    1 / 589 (0.17%)
    1 / 256 (0.39%)
    1 / 250 (0.40%)
         occurrences all number
    3
    1
    1
    1
    Dry throat
         subjects affected / exposed
    1 / 630 (0.16%)
    0 / 589 (0.00%)
    0 / 256 (0.00%)
    0 / 250 (0.00%)
         occurrences all number
    1
    0
    0
    0
    Dysphonia
         subjects affected / exposed
    0 / 630 (0.00%)
    1 / 589 (0.17%)
    0 / 256 (0.00%)
    0 / 250 (0.00%)
         occurrences all number
    0
    1
    0
    0
    Dyspnoea
         subjects affected / exposed
    1 / 630 (0.16%)
    1 / 589 (0.17%)
    3 / 256 (1.17%)
    0 / 250 (0.00%)
         occurrences all number
    1
    1
    3
    0
    Oropharyngeal pain
         subjects affected / exposed
    1 / 630 (0.16%)
    0 / 589 (0.00%)
    0 / 256 (0.00%)
    1 / 250 (0.40%)
         occurrences all number
    1
    0
    0
    1
    Pulmonary mass
         subjects affected / exposed
    0 / 630 (0.00%)
    1 / 589 (0.17%)
    0 / 256 (0.00%)
    0 / 250 (0.00%)
         occurrences all number
    0
    1
    0
    0
    Rhinorrhoea
         subjects affected / exposed
    0 / 630 (0.00%)
    2 / 589 (0.34%)
    0 / 256 (0.00%)
    0 / 250 (0.00%)
         occurrences all number
    0
    2
    0
    0
    Sinus congestion
         subjects affected / exposed
    0 / 630 (0.00%)
    0 / 589 (0.00%)
    0 / 256 (0.00%)
    1 / 250 (0.40%)
         occurrences all number
    0
    0
    0
    1
    Upper-airway cough syndrome
         subjects affected / exposed
    0 / 630 (0.00%)
    1 / 589 (0.17%)
    0 / 256 (0.00%)
    0 / 250 (0.00%)
         occurrences all number
    0
    1
    0
    0
    Wheezing
         subjects affected / exposed
    0 / 630 (0.00%)
    0 / 589 (0.00%)
    1 / 256 (0.39%)
    0 / 250 (0.00%)
         occurrences all number
    0
    0
    1
    0
    Psychiatric disorders
    Abnormal dreams
         subjects affected / exposed
    1 / 630 (0.16%)
    5 / 589 (0.85%)
    0 / 256 (0.00%)
    0 / 250 (0.00%)
         occurrences all number
    1
    5
    0
    0
    Affect lability
         subjects affected / exposed
    0 / 630 (0.00%)
    3 / 589 (0.51%)
    0 / 256 (0.00%)
    0 / 250 (0.00%)
         occurrences all number
    0
    3
    0
    0
    Agitation
         subjects affected / exposed
    0 / 630 (0.00%)
    0 / 589 (0.00%)
    1 / 256 (0.39%)
    0 / 250 (0.00%)
         occurrences all number
    0
    0
    1
    0
    Anxiety
         subjects affected / exposed
    1 / 630 (0.16%)
    9 / 589 (1.53%)
    7 / 256 (2.73%)
    0 / 250 (0.00%)
         occurrences all number
    1
    9
    7
    0
    Apathy
         subjects affected / exposed
    0 / 630 (0.00%)
    0 / 589 (0.00%)
    0 / 256 (0.00%)
    1 / 250 (0.40%)
         occurrences all number
    0
    0
    0
    1
    Behaviour disorder
         subjects affected / exposed
    1 / 630 (0.16%)
    1 / 589 (0.17%)
    0 / 256 (0.00%)
    0 / 250 (0.00%)
         occurrences all number
    1
    1
    0
    0
    Binge eating
         subjects affected / exposed
    0 / 630 (0.00%)
    0 / 589 (0.00%)
    0 / 256 (0.00%)
    1 / 250 (0.40%)
         occurrences all number
    0
    0
    0
    1
    Bruxism
         subjects affected / exposed
    1 / 630 (0.16%)
    1 / 589 (0.17%)
    0 / 256 (0.00%)
    0 / 250 (0.00%)
         occurrences all number
    1
    1
    0
    0
    Confusional state
         subjects affected / exposed
    1 / 630 (0.16%)
    4 / 589 (0.68%)
    1 / 256 (0.39%)
    0 / 250 (0.00%)
         occurrences all number
    1
    4
    1
    0
    Depressed mood
         subjects affected / exposed
    0 / 630 (0.00%)
    1 / 589 (0.17%)
    1 / 256 (0.39%)
    0 / 250 (0.00%)
         occurrences all number
    0
    1
    1
    0
    Depression
         subjects affected / exposed
    0 / 630 (0.00%)
    7 / 589 (1.19%)
    4 / 256 (1.56%)
    2 / 250 (0.80%)
         occurrences all number
    0
    7
    4
    2
    Fear
         subjects affected / exposed
    0 / 630 (0.00%)
    0 / 589 (0.00%)
    1 / 256 (0.39%)
    0 / 250 (0.00%)
         occurrences all number
    0
    0
    1
    0
    Hallucination
         subjects affected / exposed
    1 / 630 (0.16%)
    6 / 589 (1.02%)
    2 / 256 (0.78%)
    0 / 250 (0.00%)
         occurrences all number
    1
    6
    2
    0
    Hallucination, auditory
         subjects affected / exposed
    0 / 630 (0.00%)
    0 / 589 (0.00%)
    1 / 256 (0.39%)
    0 / 250 (0.00%)
         occurrences all number
    0
    0
    1
    0
    Hallucination, visual
         subjects affected / exposed
    0 / 630 (0.00%)
    3 / 589 (0.51%)
    4 / 256 (1.56%)
    1 / 250 (0.40%)
         occurrences all number
    0
    3
    4
    1
    Illusion
         subjects affected / exposed
    0 / 630 (0.00%)
    0 / 589 (0.00%)
    1 / 256 (0.39%)
    0 / 250 (0.00%)
         occurrences all number
    0
    0
    1
    0
    Impulse-control disorder
         subjects affected / exposed
    0 / 630 (0.00%)
    1 / 589 (0.17%)
    0 / 256 (0.00%)
    0 / 250 (0.00%)
         occurrences all number
    0
    1
    0
    0
    Initial insomnia
         subjects affected / exposed
    1 / 630 (0.16%)
    1 / 589 (0.17%)
    1 / 256 (0.39%)
    0 / 250 (0.00%)
         occurrences all number
    1
    1
    1
    0
    Insomnia
         subjects affected / exposed
    6 / 630 (0.95%)
    13 / 589 (2.21%)
    2 / 256 (0.78%)
    1 / 250 (0.40%)
         occurrences all number
    6
    13
    2
    1
    Irritability
         subjects affected / exposed
    0 / 630 (0.00%)
    2 / 589 (0.34%)
    1 / 256 (0.39%)
    0 / 250 (0.00%)
         occurrences all number
    0
    2
    1
    0
    Libido increased
         subjects affected / exposed
    0 / 630 (0.00%)
    0 / 589 (0.00%)
    0 / 256 (0.00%)
    1 / 250 (0.40%)
         occurrences all number
    0
    0
    0
    1
    Mania
         subjects affected / exposed
    0 / 630 (0.00%)
    2 / 589 (0.34%)
    0 / 256 (0.00%)
    0 / 250 (0.00%)
         occurrences all number
    0
    2
    0
    0
    Mood altered
         subjects affected / exposed
    0 / 630 (0.00%)
    1 / 589 (0.17%)
    0 / 256 (0.00%)
    0 / 250 (0.00%)
         occurrences all number
    0
    1
    0
    0
    Mood swings
         subjects affected / exposed
    0 / 630 (0.00%)
    1 / 589 (0.17%)
    0 / 256 (0.00%)
    0 / 250 (0.00%)
         occurrences all number
    0
    1
    0
    0
    Nervousness
         subjects affected / exposed
    0 / 630 (0.00%)
    2 / 589 (0.34%)
    0 / 256 (0.00%)
    0 / 250 (0.00%)
         occurrences all number
    0
    2
    0
    0
    Nightmare
         subjects affected / exposed
    1 / 630 (0.16%)
    0 / 589 (0.00%)
    0 / 256 (0.00%)
    1 / 250 (0.40%)
         occurrences all number
    1
    0
    0
    1
    Obsessive-compulsive disorder
         subjects affected / exposed
    0 / 630 (0.00%)
    0 / 589 (0.00%)
    1 / 256 (0.39%)
    0 / 250 (0.00%)
         occurrences all number
    0
    0
    1
    0
    Panic attack
         subjects affected / exposed
    0 / 630 (0.00%)
    1 / 589 (0.17%)
    0 / 256 (0.00%)
    0 / 250 (0.00%)
         occurrences all number
    0
    1
    0
    0
    Panic disorder
         subjects affected / exposed
    0 / 630 (0.00%)
    1 / 589 (0.17%)
    0 / 256 (0.00%)
    0 / 250 (0.00%)
         occurrences all number
    0
    1
    0
    0
    Rapid eye movement sleep behaviour disorder
         subjects affected / exposed
    0 / 630 (0.00%)
    1 / 589 (0.17%)
    0 / 256 (0.00%)
    1 / 250 (0.40%)
         occurrences all number
    0
    1
    0
    1
    Rapid eye movements sleep abnormal
         subjects affected / exposed
    0 / 630 (0.00%)
    1 / 589 (0.17%)
    0 / 256 (0.00%)
    0 / 250 (0.00%)
         occurrences all number
    0
    1
    0
    0
    Restlessness
         subjects affected / exposed
    0 / 630 (0.00%)
    4 / 589 (0.68%)
    0 / 256 (0.00%)
    1 / 250 (0.40%)
         occurrences all number
    0
    4
    0
    1
    Sleep disorder
         subjects affected / exposed
    2 / 630 (0.32%)
    5 / 589 (0.85%)
    0 / 256 (0.00%)
    1 / 250 (0.40%)
         occurrences all number
    2
    5
    0
    1
    Stereotypy
         subjects affected / exposed
    0 / 630 (0.00%)
    1 / 589 (0.17%)
    0 / 256 (0.00%)
    0 / 250 (0.00%)
         occurrences all number
    0
    1
    0
    0
    Tearfulness
         subjects affected / exposed
    0 / 630 (0.00%)
    0 / 589 (0.00%)
    1 / 256 (0.39%)
    0 / 250 (0.00%)
         occurrences all number
    0
    0
    1
    0
    Thinking abnormal
         subjects affected / exposed
    0 / 630 (0.00%)
    1 / 589 (0.17%)
    0 / 256 (0.00%)
    0 / 250 (0.00%)
         occurrences all number
    0
    1
    0
    0
    Investigations
    Biopsy skin
         subjects affected / exposed
    0 / 630 (0.00%)
    0 / 589 (0.00%)
    1 / 256 (0.39%)
    0 / 250 (0.00%)
         occurrences all number
    0
    0
    1
    0
    Blood alkaline phosphatase increased
         subjects affected / exposed
    0 / 630 (0.00%)
    0 / 589 (0.00%)
    1 / 256 (0.39%)
    0 / 250 (0.00%)
         occurrences all number
    0
    0
    1
    0
    Blood bilirubin increased
         subjects affected / exposed
    0 / 630 (0.00%)
    0 / 589 (0.00%)
    0 / 256 (0.00%)
    1 / 250 (0.40%)
         occurrences all number
    0
    0
    0
    1
    Blood creatine phosphokinase increased
         subjects affected / exposed
    0 / 630 (0.00%)
    0 / 589 (0.00%)
    1 / 256 (0.39%)
    0 / 250 (0.00%)
         occurrences all number
    0
    0
    1
    0
    Blood creatinine increased
         subjects affected / exposed
    1 / 630 (0.16%)
    1 / 589 (0.17%)
    0 / 256 (0.00%)
    1 / 250 (0.40%)
         occurrences all number
    1
    1
    0
    1
    Blood glucose increased
         subjects affected / exposed
    0 / 630 (0.00%)
    0 / 589 (0.00%)
    1 / 256 (0.39%)
    1 / 250 (0.40%)
         occurrences all number
    0
    0
    1
    1
    Blood pressure increased
         subjects affected / exposed
    1 / 630 (0.16%)
    6 / 589 (1.02%)
    2 / 256 (0.78%)
    0 / 250 (0.00%)
         occurrences all number
    1
    6
    2
    0
    Blood sodium decreased
         subjects affected / exposed
    0 / 630 (0.00%)
    0 / 589 (0.00%)
    1 / 256 (0.39%)
    0 / 250 (0.00%)
         occurrences all number
    0
    0
    1
    0
    Blood urea increased
         subjects affected / exposed
    0 / 630 (0.00%)
    0 / 589 (0.00%)
    0 / 256 (0.00%)
    1 / 250 (0.40%)
         occurrences all number
    0
    0
    0
    1
    Computerised tomogram abnormal
         subjects affected / exposed
    0 / 630 (0.00%)
    0 / 589 (0.00%)
    1 / 256 (0.39%)
    0 / 250 (0.00%)
         occurrences all number
    0
    0
    1
    0
    Coronavirus test positive
         subjects affected / exposed
    0 / 630 (0.00%)
    1 / 589 (0.17%)
    0 / 256 (0.00%)
    0 / 250 (0.00%)
         occurrences all number
    0
    1
    0
    0
    Ejection fraction decreased
         subjects affected / exposed
    0 / 630 (0.00%)
    0 / 589 (0.00%)
    1 / 256 (0.39%)
    0 / 250 (0.00%)
         occurrences all number
    0
    0
    1
    0
    Electrocardiogram abnormal
         subjects affected / exposed
    0 / 630 (0.00%)
    0 / 589 (0.00%)
    1 / 256 (0.39%)
    0 / 250 (0.00%)
         occurrences all number
    0
    0
    1
    0
    Electrocardiogram low voltage
         subjects affected / exposed
    0 / 630 (0.00%)
    0 / 589 (0.00%)
    0 / 256 (0.00%)
    1 / 250 (0.40%)
         occurrences all number
    0
    0
    0
    1
    Electrocardiogram QT prolonged
         subjects affected / exposed
    0 / 630 (0.00%)
    0 / 589 (0.00%)
    0 / 256 (0.00%)
    1 / 250 (0.40%)
         occurrences all number
    0
    0
    0
    1
    Electrocardiogram repolarisation abnormality
         subjects affected / exposed
    0 / 630 (0.00%)
    0 / 589 (0.00%)
    1 / 256 (0.39%)
    0 / 250 (0.00%)
         occurrences all number
    0
    0
    1
    0
    Lymphocyte count decreased
         subjects affected / exposed
    0 / 630 (0.00%)
    0 / 589 (0.00%)
    1 / 256 (0.39%)
    0 / 250 (0.00%)
         occurrences all number
    0
    0
    1
    0
    Oxygen saturation decreased
         subjects affected / exposed
    0 / 630 (0.00%)
    0 / 589 (0.00%)
    1 / 256 (0.39%)
    0 / 250 (0.00%)
         occurrences all number
    0
    0
    1
    0
    QRS axis abnormal
         subjects affected / exposed
    0 / 630 (0.00%)
    0 / 589 (0.00%)
    0 / 256 (0.00%)
    1 / 250 (0.40%)
         occurrences all number
    0
    0
    0
    1
    Viral test negative
         subjects affected / exposed
    0 / 630 (0.00%)
    1 / 589 (0.17%)
    0 / 256 (0.00%)
    0 / 250 (0.00%)
         occurrences all number
    0
    1
    0
    0
    Weight decreased
         subjects affected / exposed
    1 / 630 (0.16%)
    2 / 589 (0.34%)
    0 / 256 (0.00%)
    1 / 250 (0.40%)
         occurrences all number
    1
    2
    0
    1
    White blood cells urine positive
         subjects affected / exposed
    0 / 630 (0.00%)
    1 / 589 (0.17%)
    0 / 256 (0.00%)
    0 / 250 (0.00%)
         occurrences all number
    0
    1
    0
    0
    Injury, poisoning and procedural complications
    Exposure to toxic agent
         subjects affected / exposed
    0 / 630 (0.00%)
    1 / 589 (0.17%)
    0 / 256 (0.00%)
    0 / 250 (0.00%)
         occurrences all number
    0
    1
    0
    0
    Fall
         subjects affected / exposed
    6 / 630 (0.95%)
    13 / 589 (2.21%)
    5 / 256 (1.95%)
    9 / 250 (3.60%)
         occurrences all number
    6
    13
    5
    9
    Foot fracture
         subjects affected / exposed
    0 / 630 (0.00%)
    1 / 589 (0.17%)
    0 / 256 (0.00%)
    0 / 250 (0.00%)
         occurrences all number
    0
    1
    0
    0
    Hand fracture
         subjects affected / exposed
    0 / 630 (0.00%)
    0 / 589 (0.00%)
    1 / 256 (0.39%)
    0 / 250 (0.00%)
         occurrences all number
    0
    0
    1
    0
    Head injury
         subjects affected / exposed
    0 / 630 (0.00%)
    0 / 589 (0.00%)
    0 / 256 (0.00%)
    2 / 250 (0.80%)
         occurrences all number
    0
    0
    0
    2
    Joint dislocation
         subjects affected / exposed
    0 / 630 (0.00%)
    2 / 589 (0.34%)
    1 / 256 (0.39%)
    0 / 250 (0.00%)
         occurrences all number
    0
    2
    1
    0
    Joint injury
         subjects affected / exposed
    1 / 630 (0.16%)
    2 / 589 (0.34%)
    0 / 256 (0.00%)
    0 / 250 (0.00%)
         occurrences all number
    1
    2
    0
    0
    Ligament sprain
         subjects affected / exposed
    0 / 630 (0.00%)
    1 / 589 (0.17%)
    0 / 256 (0.00%)
    0 / 250 (0.00%)
         occurrences all number
    0
    1
    0
    0
    Limb injury
         subjects affected / exposed
    0 / 630 (0.00%)
    0 / 589 (0.00%)
    0 / 256 (0.00%)
    1 / 250 (0.40%)
         occurrences all number
    0
    0
    0
    1
    Meniscus injury
         subjects affected / exposed
    0 / 630 (0.00%)
    0 / 589 (0.00%)
    1 / 256 (0.39%)
    0 / 250 (0.00%)
         occurrences all number
    0
    0
    1
    0
    Muscle strain
         subjects affected / exposed
    0 / 630 (0.00%)
    0 / 589 (0.00%)
    1 / 256 (0.39%)
    0 / 250 (0.00%)
         occurrences all number
    0
    0
    1
    0
    Neck injury
         subjects affected / exposed
    0 / 630 (0.00%)
    1 / 589 (0.17%)
    0 / 256 (0.00%)
    0 / 250 (0.00%)
         occurrences all number
    0
    1
    0
    0
    Post vaccination syndrome
         subjects affected / exposed
    0 / 630 (0.00%)
    0 / 589 (0.00%)
    1 / 256 (0.39%)
    0 / 250 (0.00%)
         occurrences all number
    0
    0
    1
    0
    Procedural nausea
         subjects affected / exposed
    0 / 630 (0.00%)
    0 / 589 (0.00%)
    1 / 256 (0.39%)
    0 / 250 (0.00%)
         occurrences all number
    0
    0
    1
    0
    Procedural pain
         subjects affected / exposed
    1 / 630 (0.16%)
    0 / 589 (0.00%)
    0 / 256 (0.00%)
    0 / 250 (0.00%)
         occurrences all number
    1
    0
    0
    0
    Product administration error
         subjects affected / exposed
    0 / 630 (0.00%)
    1 / 589 (0.17%)
    0 / 256 (0.00%)
    0 / 250 (0.00%)
         occurrences all number
    0
    1
    0
    0
    Radius fracture
         subjects affected / exposed
    1 / 630 (0.16%)
    0 / 589 (0.00%)
    1 / 256 (0.39%)
    0 / 250 (0.00%)
         occurrences all number
    1
    0
    1
    0
    Road traffic accident
         subjects affected / exposed
    0 / 630 (0.00%)
    0 / 589 (0.00%)
    1 / 256 (0.39%)
    0 / 250 (0.00%)
         occurrences all number
    0
    0
    1
    0
    Skin abrasion
         subjects affected / exposed
    1 / 630 (0.16%)
    0 / 589 (0.00%)
    0 / 256 (0.00%)
    0 / 250 (0.00%)
         occurrences all number
    1
    0
    0
    0
    Spinal compression fracture
         subjects affected / exposed
    0 / 630 (0.00%)
    1 / 589 (0.17%)
    0 / 256 (0.00%)
    0 / 250 (0.00%)
         occurrences all number
    0
    1
    0
    0
    Tooth fracture
         subjects affected / exposed
    0 / 630 (0.00%)
    0 / 589 (0.00%)
    1 / 256 (0.39%)
    0 / 250 (0.00%)
         occurrences all number
    0
    0
    1
    0
    Upper limb fracture
         subjects affected / exposed
    0 / 630 (0.00%)
    1 / 589 (0.17%)
    0 / 256 (0.00%)
    0 / 250 (0.00%)
         occurrences all number
    0
    1
    0
    0
    Wrist fracture
         subjects affected / exposed
    0 / 630 (0.00%)
    0 / 589 (0.00%)
    0 / 256 (0.00%)
    1 / 250 (0.40%)
         occurrences all number
    0
    0
    0
    1
    Cardiac disorders
    Atrial fibrillation
         subjects affected / exposed
    0 / 630 (0.00%)
    0 / 589 (0.00%)
    2 / 256 (0.78%)
    0 / 250 (0.00%)
         occurrences all number
    0
    0
    2
    0
    Atrioventricular block first degree
         subjects affected / exposed
    0 / 630 (0.00%)
    0 / 589 (0.00%)
    0 / 256 (0.00%)
    1 / 250 (0.40%)
         occurrences all number
    0
    0
    0
    1
    Atrioventricular block second degree
         subjects affected / exposed
    1 / 630 (0.16%)
    0 / 589 (0.00%)
    0 / 256 (0.00%)
    0 / 250 (0.00%)
         occurrences all number
    1
    0
    0
    0
    Bundle branch block left
         subjects affected / exposed
    0 / 630 (0.00%)
    0 / 589 (0.00%)
    0 / 256 (0.00%)
    1 / 250 (0.40%)
         occurrences all number
    0
    0
    0
    1
    Palpitations
         subjects affected / exposed
    0 / 630 (0.00%)
    1 / 589 (0.17%)
    0 / 256 (0.00%)
    1 / 250 (0.40%)
         occurrences all number
    0
    1
    0
    1
    Tachycardia
         subjects affected / exposed
    1 / 630 (0.16%)
    0 / 589 (0.00%)
    0 / 256 (0.00%)
    0 / 250 (0.00%)
         occurrences all number
    1
    0
    0
    0
    Nervous system disorders
    Ageusia
         subjects affected / exposed
    0 / 630 (0.00%)
    1 / 589 (0.17%)
    0 / 256 (0.00%)
    0 / 250 (0.00%)
         occurrences all number
    0
    1
    0
    0
    Akinesia
         subjects affected / exposed
    1 / 630 (0.16%)
    0 / 589 (0.00%)
    0 / 256 (0.00%)
    0 / 250 (0.00%)
         occurrences all number
    1
    0
    0
    0
    Anosognosia
         subjects affected / exposed
    0 / 630 (0.00%)
    0 / 589 (0.00%)
    1 / 256 (0.39%)
    0 / 250 (0.00%)
         occurrences all number
    0
    0
    1
    0
    Carpal tunnel syndrome
         subjects affected / exposed
    0 / 630 (0.00%)
    1 / 589 (0.17%)
    1 / 256 (0.39%)
    1 / 250 (0.40%)
         occurrences all number
    0
    1
    1
    1
    Cervicobrachial syndrome
         subjects affected / exposed
    0 / 630 (0.00%)
    1 / 589 (0.17%)
    0 / 256 (0.00%)
    0 / 250 (0.00%)
         occurrences all number
    0
    1
    0
    0
    Depressed level of consciousness
         subjects affected / exposed
    0 / 630 (0.00%)
    1 / 589 (0.17%)
    0 / 256 (0.00%)
    0 / 250 (0.00%)
         occurrences all number
    0
    1
    0
    0
    Disturbance in attention
         subjects affected / exposed
    0 / 630 (0.00%)
    0 / 589 (0.00%)
    0 / 256 (0.00%)
    1 / 250 (0.40%)
         occurrences all number
    0
    0
    0
    1
    Dizziness
         subjects affected / exposed
    3 / 630 (0.48%)
    17 / 589 (2.89%)
    6 / 256 (2.34%)
    2 / 250 (0.80%)
         occurrences all number
    3
    17
    6
    2
    Dizziness postural
         subjects affected / exposed
    0 / 630 (0.00%)
    0 / 589 (0.00%)
    1 / 256 (0.39%)
    0 / 250 (0.00%)
         occurrences all number
    0
    0
    1
    0
    Drooling
         subjects affected / exposed
    0 / 630 (0.00%)
    0 / 589 (0.00%)
    1 / 256 (0.39%)
    0 / 250 (0.00%)
         occurrences all number
    0
    0
    1
    0
    Dysaesthesia
         subjects affected / exposed
    0 / 630 (0.00%)
    0 / 589 (0.00%)
    1 / 256 (0.39%)
    0 / 250 (0.00%)
         occurrences all number
    0
    0
    1
    0
    Dysarthria
         subjects affected / exposed
    0 / 630 (0.00%)
    1 / 589 (0.17%)
    0 / 256 (0.00%)
    0 / 250 (0.00%)
         occurrences all number
    0
    1
    0
    0
    Dystonia
         subjects affected / exposed
    2 / 630 (0.32%)
    3 / 589 (0.51%)
    2 / 256 (0.78%)
    0 / 250 (0.00%)
         occurrences all number
    2
    3
    2
    0
    Freezing phenomenon
         subjects affected / exposed
    0 / 630 (0.00%)
    3 / 589 (0.51%)
    2 / 256 (0.78%)
    2 / 250 (0.80%)
         occurrences all number
    0
    3
    2
    2
    Headache
         subjects affected / exposed
    8 / 630 (1.27%)
    9 / 589 (1.53%)
    3 / 256 (1.17%)
    0 / 250 (0.00%)
         occurrences all number
    8
    9
    3
    0
    Hyperkinesia
         subjects affected / exposed
    0 / 630 (0.00%)
    1 / 589 (0.17%)
    0 / 256 (0.00%)
    0 / 250 (0.00%)
         occurrences all number
    0
    1
    0
    0
    Hypersomnia
         subjects affected / exposed
    2 / 630 (0.32%)
    1 / 589 (0.17%)
    1 / 256 (0.39%)
    0 / 250 (0.00%)
         occurrences all number
    2
    1
    1
    0
    Hypoaesthesia
         subjects affected / exposed
    0 / 630 (0.00%)
    2 / 589 (0.34%)
    2 / 256 (0.78%)
    0 / 250 (0.00%)
         occurrences all number
    0
    2
    2
    0
    Judgement impaired
         subjects affected / exposed
    0 / 630 (0.00%)
    0 / 589 (0.00%)
    1 / 256 (0.39%)
    0 / 250 (0.00%)
         occurrences all number
    0
    0
    1
    0
    Lethargy
         subjects affected / exposed
    0 / 630 (0.00%)
    2 / 589 (0.34%)
    0 / 256 (0.00%)
    0 / 250 (0.00%)
         occurrences all number
    0
    2
    0
    0
    Memory impairment
         subjects affected / exposed
    0 / 630 (0.00%)
    2 / 589 (0.34%)
    0 / 256 (0.00%)
    0 / 250 (0.00%)
         occurrences all number
    0
    2
    0
    0
    Migraine
         subjects affected / exposed
    1 / 630 (0.16%)
    1 / 589 (0.17%)
    0 / 256 (0.00%)
    0 / 250 (0.00%)
         occurrences all number
    1
    1
    0
    0
    Migraine with aura
         subjects affected / exposed
    0 / 630 (0.00%)
    1 / 589 (0.17%)
    0 / 256 (0.00%)
    0 / 250 (0.00%)
         occurrences all number
    0
    1
    0
    0
    Movement disorder
         subjects affected / exposed
    0 / 630 (0.00%)
    1 / 589 (0.17%)
    1 / 256 (0.39%)
    0 / 250 (0.00%)
         occurrences all number
    0
    1
    1
    0
    Muscle contractions involuntary
         subjects affected / exposed
    0 / 630 (0.00%)
    1 / 589 (0.17%)
    0 / 256 (0.00%)
    0 / 250 (0.00%)
         occurrences all number
    0
    1
    0
    0
    Myoclonus
         subjects affected / exposed
    0 / 630 (0.00%)
    0 / 589 (0.00%)
    0 / 256 (0.00%)
    1 / 250 (0.40%)
         occurrences all number
    0
    0
    0
    1
    Neuropathy peripheral
         subjects affected / exposed
    0 / 630 (0.00%)
    0 / 589 (0.00%)
    1 / 256 (0.39%)
    0 / 250 (0.00%)
         occurrences all number
    0
    0
    1
    0
    Paraesthesia
         subjects affected / exposed
    0 / 630 (0.00%)
    2 / 589 (0.34%)
    0 / 256 (0.00%)
    1 / 250 (0.40%)
         occurrences all number
    0
    2
    0
    1
    Parkinson's disease
         subjects affected / exposed
    1 / 630 (0.16%)
    3 / 589 (0.51%)
    2 / 256 (0.78%)
    2 / 250 (0.80%)
         occurrences all number
    1
    3
    2
    2
    Parkinsonian rest tremor
         subjects affected / exposed
    0 / 630 (0.00%)
    1 / 589 (0.17%)
    0 / 256 (0.00%)
    0 / 250 (0.00%)
         occurrences all number
    0
    1
    0
    0
    Parkinsonism
         subjects affected / exposed
    0 / 630 (0.00%)
    0 / 589 (0.00%)
    0 / 256 (0.00%)
    1 / 250 (0.40%)
         occurrences all number
    0
    0
    0
    1
    Poor quality sleep
         subjects affected / exposed
    0 / 630 (0.00%)
    1 / 589 (0.17%)
    0 / 256 (0.00%)
    0 / 250 (0.00%)
         occurrences all number
    0
    1
    0
    0
    Presyncope
         subjects affected / exposed
    0 / 630 (0.00%)
    0 / 589 (0.00%)
    0 / 256 (0.00%)
    1 / 250 (0.40%)
         occurrences all number
    0
    0
    0
    1
    Restless legs syndrome
         subjects affected / exposed
    3 / 630 (0.48%)
    0 / 589 (0.00%)
    1 / 256 (0.39%)
    0 / 250 (0.00%)
         occurrences all number
    3
    0
    1
    0
    Sciatica
         subjects affected / exposed
    2 / 630 (0.32%)
    0 / 589 (0.00%)
    1 / 256 (0.39%)
    1 / 250 (0.40%)
         occurrences all number
    2
    0
    1
    1
    Somnolence
         subjects affected / exposed
    1 / 630 (0.16%)
    5 / 589 (0.85%)
    4 / 256 (1.56%)
    2 / 250 (0.80%)
         occurrences all number
    1
    5
    4
    2
    Taste disorder
         subjects affected / exposed
    0 / 630 (0.00%)
    1 / 589 (0.17%)
    0 / 256 (0.00%)
    0 / 250 (0.00%)
         occurrences all number
    0
    1
    0
    0
    Tremor
         subjects affected / exposed
    2 / 630 (0.32%)
    3 / 589 (0.51%)
    1 / 256 (0.39%)
    2 / 250 (0.80%)
         occurrences all number
    2
    3
    1
    2
    Balance disorder
         subjects affected / exposed
    1 / 630 (0.16%)
    6 / 589 (1.02%)
    2 / 256 (0.78%)
    0 / 250 (0.00%)
         occurrences all number
    1
    6
    2
    0
    Dysphonia
         subjects affected / exposed
    0 / 630 (0.00%)
    1 / 589 (0.17%)
    0 / 256 (0.00%)
    0 / 250 (0.00%)
         occurrences all number
    0
    1
    0
    0
    Epilepsy
         subjects affected / exposed
    1 / 630 (0.16%)
    0 / 589 (0.00%)
    2 / 256 (0.78%)
    0 / 250 (0.00%)
         occurrences all number
    1
    0
    2
    0
    Syncope
         subjects affected / exposed
    1 / 630 (0.16%)
    3 / 589 (0.51%)
    1 / 256 (0.39%)
    0 / 250 (0.00%)
         occurrences all number
    1
    3
    1
    0
    Blood and lymphatic system disorders
    Microcytic anaemia
         subjects affected / exposed
    0 / 630 (0.00%)
    0 / 589 (0.00%)
    0 / 256 (0.00%)
    1 / 250 (0.40%)
         occurrences all number
    0
    0
    0
    1
    Ear and labyrinth disorders
    Tinnitus
         subjects affected / exposed
    0 / 630 (0.00%)
    1 / 589 (0.17%)
    0 / 256 (0.00%)
    0 / 250 (0.00%)
         occurrences all number
    0
    1
    0
    0
    Vertigo
         subjects affected / exposed
    1 / 630 (0.16%)
    0 / 589 (0.00%)
    1 / 256 (0.39%)
    1 / 250 (0.40%)
         occurrences all number
    1
    0
    1
    1
    Vertigo positional
         subjects affected / exposed
    0 / 630 (0.00%)
    1 / 589 (0.17%)
    1 / 256 (0.39%)
    0 / 250 (0.00%)
         occurrences all number
    0
    1
    1
    0
    Eye disorders
    Accommodation disorder
         subjects affected / exposed
    0 / 630 (0.00%)
    1 / 589 (0.17%)
    0 / 256 (0.00%)
    0 / 250 (0.00%)
         occurrences all number
    0
    1
    0
    0
    Cataract
         subjects affected / exposed
    0 / 630 (0.00%)
    1 / 589 (0.17%)
    0 / 256 (0.00%)
    2 / 250 (0.80%)
         occurrences all number
    0
    1
    0
    2
    Dry eye
         subjects affected / exposed
    0 / 630 (0.00%)
    0 / 589 (0.00%)
    0 / 256 (0.00%)
    1 / 250 (0.40%)
         occurrences all number
    0
    0
    0
    1
    Eyelid ptosis
         subjects affected / exposed
    0 / 630 (0.00%)
    0 / 589 (0.00%)
    1 / 256 (0.39%)
    0 / 250 (0.00%)
         occurrences all number
    0
    0
    1
    0
    Vision blurred
         subjects affected / exposed
    0 / 630 (0.00%)
    3 / 589 (0.51%)
    1 / 256 (0.39%)
    1 / 250 (0.40%)
         occurrences all number
    0
    3
    1
    1
    Visual impairment
         subjects affected / exposed
    1 / 630 (0.16%)
    1 / 589 (0.17%)
    1 / 256 (0.39%)
    0 / 250 (0.00%)
         occurrences all number
    1
    1
    1
    0
    Gastrointestinal disorders
    Abdominal discomfort
         subjects affected / exposed
    0 / 630 (0.00%)
    1 / 589 (0.17%)
    0 / 256 (0.00%)
    0 / 250 (0.00%)
         occurrences all number
    0
    1
    0
    0
    Abdominal distension
         subjects affected / exposed
    0 / 630 (0.00%)
    2 / 589 (0.34%)
    0 / 256 (0.00%)
    1 / 250 (0.40%)
         occurrences all number
    0
    2
    0
    1
    Abdominal pain
         subjects affected / exposed
    0 / 630 (0.00%)
    2 / 589 (0.34%)
    2 / 256 (0.78%)
    0 / 250 (0.00%)
         occurrences all number
    0
    2
    2
    0
    Abdominal pain upper
         subjects affected / exposed
    0 / 630 (0.00%)
    4 / 589 (0.68%)
    0 / 256 (0.00%)
    1 / 250 (0.40%)
         occurrences all number
    0
    4
    0
    1
    Aptyalism
         subjects affected / exposed
    1 / 630 (0.16%)
    0 / 589 (0.00%)
    0 / 256 (0.00%)
    0 / 250 (0.00%)
         occurrences all number
    1
    0
    0
    0
    Breath odour
         subjects affected / exposed
    0 / 630 (0.00%)
    1 / 589 (0.17%)
    0 / 256 (0.00%)
    0 / 250 (0.00%)
         occurrences all number
    0
    1
    0
    0
    Chapped lips
         subjects affected / exposed
    0 / 630 (0.00%)
    1 / 589 (0.17%)
    0 / 256 (0.00%)
    0 / 250 (0.00%)
         occurrences all number
    0
    1
    0
    0
    Constipation
         subjects affected / exposed
    7 / 630 (1.11%)
    12 / 589 (2.04%)
    4 / 256 (1.56%)
    1 / 250 (0.40%)
         occurrences all number
    7
    12
    4
    1
    Diarrhoea
         subjects affected / exposed
    4 / 630 (0.63%)
    5 / 589 (0.85%)
    0 / 256 (0.00%)
    0 / 250 (0.00%)
         occurrences all number
    4
    5
    0
    0
    Dry mouth
         subjects affected / exposed
    2 / 630 (0.32%)
    25 / 589 (4.24%)
    3 / 256 (1.17%)
    2 / 250 (0.80%)
         occurrences all number
    2
    25
    3
    2
    Dyspepsia
         subjects affected / exposed
    2 / 630 (0.32%)
    3 / 589 (0.51%)
    1 / 256 (0.39%)
    0 / 250 (0.00%)
         occurrences all number
    2
    3
    1
    0
    Dysphagia
         subjects affected / exposed
    0 / 630 (0.00%)
    1 / 589 (0.17%)
    0 / 256 (0.00%)
    0 / 250 (0.00%)
         occurrences all number
    0
    1
    0
    0
    Flatulence
         subjects affected / exposed
    0 / 630 (0.00%)
    2 / 589 (0.34%)
    0 / 256 (0.00%)
    0 / 250 (0.00%)
         occurrences all number
    0
    2
    0
    0
    Gastritis
         subjects affected / exposed
    0 / 630 (0.00%)
    1 / 589 (0.17%)
    1 / 256 (0.39%)
    0 / 250 (0.00%)
         occurrences all number
    0
    1
    1
    0
    Hiatus hernia
         subjects affected / exposed
    0 / 630 (0.00%)
    0 / 589 (0.00%)
    1 / 256 (0.39%)
    0 / 250 (0.00%)
         occurrences all number
    0
    0
    1
    0
    Impaired gastric emptying
         subjects affected / exposed
    0 / 630 (0.00%)
    0 / 589 (0.00%)
    0 / 256 (0.00%)
    1 / 250 (0.40%)
         occurrences all number
    0
    0
    0
    1
    Nausea
         subjects affected / exposed
    7 / 630 (1.11%)
    29 / 589 (4.92%)
    11 / 256 (4.30%)
    2 / 250 (0.80%)
         occurrences all number
    7
    29
    11
    2
    Oesophagitis
         subjects affected / exposed
    0 / 630 (0.00%)
    0 / 589 (0.00%)
    1 / 256 (0.39%)
    0 / 250 (0.00%)
         occurrences all number
    0
    0
    1
    0
    Oral dysaesthesia
         subjects affected / exposed
    0 / 630 (0.00%)
    1 / 589 (0.17%)
    0 / 256 (0.00%)
    0 / 250 (0.00%)
         occurrences all number
    0
    1
    0
    0
    Post-tussive vomiting
         subjects affected / exposed
    0 / 630 (0.00%)
    0 / 589 (0.00%)
    1 / 256 (0.39%)
    0 / 250 (0.00%)
         occurrences all number
    0
    0
    1
    0
    Retching
         subjects affected / exposed
    0 / 630 (0.00%)
    1 / 589 (0.17%)
    0 / 256 (0.00%)
    0 / 250 (0.00%)
         occurrences all number
    0
    1
    0
    0
    Tooth loss
         subjects affected / exposed
    0 / 630 (0.00%)
    1 / 589 (0.17%)
    0 / 256 (0.00%)
    0 / 250 (0.00%)
         occurrences all number
    0
    1
    0
    0
    Toothache
         subjects affected / exposed
    1 / 630 (0.16%)
    0 / 589 (0.00%)
    1 / 256 (0.39%)
    0 / 250 (0.00%)
         occurrences all number
    1
    0
    1
    0
    Vomiting
         subjects affected / exposed
    3 / 630 (0.48%)
    13 / 589 (2.21%)
    3 / 256 (1.17%)
    0 / 250 (0.00%)
         occurrences all number
    3
    13
    3
    0
    Skin and subcutaneous tissue disorders
    Blister
         subjects affected / exposed
    0 / 630 (0.00%)
    0 / 589 (0.00%)
    1 / 256 (0.39%)
    0 / 250 (0.00%)
         occurrences all number
    0
    0
    1
    0
    Cold sweat
         subjects affected / exposed
    0 / 630 (0.00%)
    0 / 589 (0.00%)
    1 / 256 (0.39%)
    0 / 250 (0.00%)
         occurrences all number
    0
    0
    1
    0
    Dermatitis
         subjects affected / exposed
    0 / 630 (0.00%)
    0 / 589 (0.00%)
    0 / 256 (0.00%)
    1 / 250 (0.40%)
         occurrences all number
    0
    0
    0
    1
    Dry skin
         subjects affected / exposed
    0 / 630 (0.00%)
    1 / 589 (0.17%)
    0 / 256 (0.00%)
    0 / 250 (0.00%)
         occurrences all number
    0
    1
    0
    0
    Erythema
         subjects affected / exposed
    0 / 630 (0.00%)
    0 / 589 (0.00%)
    1 / 256 (0.39%)
    1 / 250 (0.40%)
         occurrences all number
    0
    0
    1
    1
    Hyperhidrosis
         subjects affected / exposed
    0 / 630 (0.00%)
    2 / 589 (0.34%)
    0 / 256 (0.00%)
    0 / 250 (0.00%)
         occurrences all number
    0
    2
    0
    0
    Pruritus
         subjects affected / exposed
    0 / 630 (0.00%)
    0 / 589 (0.00%)
    1 / 256 (0.39%)
    0 / 250 (0.00%)
         occurrences all number
    0
    0
    1
    0
    Rash
         subjects affected / exposed
    0 / 630 (0.00%)
    2 / 589 (0.34%)
    2 / 256 (0.78%)
    2 / 250 (0.80%)
         occurrences all number
    0
    2
    2
    2
    Rash generalised
         subjects affected / exposed
    0 / 630 (0.00%)
    1 / 589 (0.17%)
    0 / 256 (0.00%)
    0 / 250 (0.00%)
         occurrences all number
    0
    1
    0
    0
    Rash papular
         subjects affected / exposed
    1 / 630 (0.16%)
    0 / 589 (0.00%)
    0 / 256 (0.00%)
    0 / 250 (0.00%)
         occurrences all number
    1
    0
    0
    0
    Skin ulcer
         subjects affected / exposed
    0 / 630 (0.00%)
    1 / 589 (0.17%)
    0 / 256 (0.00%)
    0 / 250 (0.00%)
         occurrences all number
    0
    1
    0
    0
    Renal and urinary disorders
    Dysuria
         subjects affected / exposed
    1 / 630 (0.16%)
    0 / 589 (0.00%)
    0 / 256 (0.00%)
    0 / 250 (0.00%)
         occurrences all number
    1
    0
    0
    0
    Haematuria
         subjects affected / exposed
    1 / 630 (0.16%)
    1 / 589 (0.17%)
    0 / 256 (0.00%)
    0 / 250 (0.00%)
         occurrences all number
    1
    1
    0
    0
    Hydronephrosis
         subjects affected / exposed
    0 / 630 (0.00%)
    0 / 589 (0.00%)
    0 / 256 (0.00%)
    1 / 250 (0.40%)
         occurrences all number
    0
    0
    0
    1
    Incontinence
         subjects affected / exposed
    0 / 630 (0.00%)
    0 / 589 (0.00%)
    1 / 256 (0.39%)
    0 / 250 (0.00%)
         occurrences all number
    0
    0
    1
    0
    Micturition urgency
         subjects affected / exposed
    1 / 630 (0.16%)
    1 / 589 (0.17%)
    0 / 256 (0.00%)
    1 / 250 (0.40%)
         occurrences all number
    1
    1
    0
    1
    Nocturia
         subjects affected / exposed
    1 / 630 (0.16%)
    0 / 589 (0.00%)
    0 / 256 (0.00%)
    0 / 250 (0.00%)
         occurrences all number
    1
    0
    0
    0
    Pollakiuria
         subjects affected / exposed
    1 / 630 (0.16%)
    1 / 589 (0.17%)
    0 / 256 (0.00%)
    0 / 250 (0.00%)
         occurrences all number
    1
    1
    0
    0
    Polyuria
         subjects affected / exposed
    0 / 630 (0.00%)
    0 / 589 (0.00%)
    1 / 256 (0.39%)
    0 / 250 (0.00%)
         occurrences all number
    0
    0
    1
    0
    Renal cyst
         subjects affected / exposed
    0 / 630 (0.00%)
    0 / 589 (0.00%)
    1 / 256 (0.39%)
    0 / 250 (0.00%)
         occurrences all number
    0
    0
    1
    0
    Renal impairment
         subjects affected / exposed
    0 / 630 (0.00%)
    1 / 589 (0.17%)
    0 / 256 (0.00%)
    0 / 250 (0.00%)
         occurrences all number
    0
    1
    0
    0
    Urge incontinence
         subjects affected / exposed
    0 / 630 (0.00%)
    1 / 589 (0.17%)
    0 / 256 (0.00%)
    0 / 250 (0.00%)
         occurrences all number
    0
    1
    0
    0
    Urinary incontinence
         subjects affected / exposed
    0 / 630 (0.00%)
    1 / 589 (0.17%)
    1 / 256 (0.39%)
    0 / 250 (0.00%)
         occurrences all number
    0
    1
    1
    0
    Urinary tract inflammation
         subjects affected / exposed
    0 / 630 (0.00%)
    0 / 589 (0.00%)
    0 / 256 (0.00%)
    1 / 250 (0.40%)
         occurrences all number
    0
    0
    0
    1
    Endocrine disorders
    Goitre
         subjects affected / exposed
    0 / 630 (0.00%)
    0 / 589 (0.00%)
    1 / 256 (0.39%)
    0 / 250 (0.00%)
         occurrences all number
    0
    0
    1
    0
    Hypothyroidism
         subjects affected / exposed
    0 / 630 (0.00%)
    1 / 589 (0.17%)
    0 / 256 (0.00%)
    0 / 250 (0.00%)
         occurrences all number
    0
    1
    0
    0
    Thyroid mass
         subjects affected / exposed
    0 / 630 (0.00%)
    1 / 589 (0.17%)
    0 / 256 (0.00%)
    0 / 250 (0.00%)
         occurrences all number
    0
    1
    0
    0
    Musculoskeletal and connective tissue disorders
    Arthralgia
         subjects affected / exposed
    0 / 630 (0.00%)
    1 / 589 (0.17%)
    4 / 256 (1.56%)
    0 / 250 (0.00%)
         occurrences all number
    0
    1
    4
    0
    Arthritis
         subjects affected / exposed
    1 / 630 (0.16%)
    1 / 589 (0.17%)
    1 / 256 (0.39%)
    0 / 250 (0.00%)
         occurrences all number
    1
    1
    1
    0
    Bursitis
         subjects affected / exposed
    0 / 630 (0.00%)
    0 / 589 (0.00%)
    2 / 256 (0.78%)
    0 / 250 (0.00%)
         occurrences all number
    0
    0
    2
    0
    Dupuytren's contracture
         subjects affected / exposed
    1 / 630 (0.16%)
    0 / 589 (0.00%)
    0 / 256 (0.00%)
    0 / 250 (0.00%)
         occurrences all number
    1
    0
    0
    0
    Gouty arthritis
         subjects affected / exposed
    1 / 630 (0.16%)
    0 / 589 (0.00%)
    0 / 256 (0.00%)
    0 / 250 (0.00%)
         occurrences all number
    1
    0
    0
    0
    Intervertebral disc compression
         subjects affected / exposed
    1 / 630 (0.16%)
    0 / 589 (0.00%)
    0 / 256 (0.00%)
    0 / 250 (0.00%)
         occurrences all number
    1
    0
    0
    0
    Intervertebral disc disorder
         subjects affected / exposed
    1 / 630 (0.16%)
    0 / 589 (0.00%)
    0 / 256 (0.00%)
    0 / 250 (0.00%)
         occurrences all number
    1
    0
    0
    0
    Muscle rigidity
         subjects affected / exposed
    0 / 630 (0.00%)
    1 / 589 (0.17%)
    0 / 256 (0.00%)
    0 / 250 (0.00%)
         occurrences all number
    0
    1
    0
    0
    Muscle spasms
         subjects affected / exposed
    0 / 630 (0.00%)
    5 / 589 (0.85%)
    1 / 256 (0.39%)
    1 / 250 (0.40%)
         occurrences all number
    0
    5
    1
    1
    Muscle twitching
         subjects affected / exposed
    0 / 630 (0.00%)
    0 / 589 (0.00%)
    0 / 256 (0.00%)
    1 / 250 (0.40%)
         occurrences all number
    0
    0
    0
    1
    Muscular weakness
         subjects affected / exposed
    0 / 630 (0.00%)
    0 / 589 (0.00%)
    2 / 256 (0.78%)
    0 / 250 (0.00%)
         occurrences all number
    0
    0
    2
    0
    Musculoskeletal chest pain
         subjects affected / exposed
    0 / 630 (0.00%)
    1 / 589 (0.17%)
    0 / 256 (0.00%)
    0 / 250 (0.00%)
         occurrences all number
    0
    1
    0
    0
    Musculoskeletal discomfort
         subjects affected / exposed
    0 / 630 (0.00%)
    0 / 589 (0.00%)
    1 / 256 (0.39%)
    0 / 250 (0.00%)
         occurrences all number
    0
    0
    1
    0
    Musculoskeletal pain
         subjects affected / exposed
    0 / 630 (0.00%)
    2 / 589 (0.34%)
    1 / 256 (0.39%)
    0 / 250 (0.00%)
         occurrences all number
    0
    2
    1
    0
    Musculoskeletal stiffness
         subjects affected / exposed
    0 / 630 (0.00%)
    1 / 589 (0.17%)
    0 / 256 (0.00%)
    0 / 250 (0.00%)
         occurrences all number
    0
    1
    0
    0
    Myalgia
         subjects affected / exposed
    2 / 630 (0.32%)
    1 / 589 (0.17%)
    0 / 256 (0.00%)
    1 / 250 (0.40%)
         occurrences all number
    2
    1
    0
    1
    Neck pain
         subjects affected / exposed
    1 / 630 (0.16%)
    1 / 589 (0.17%)
    2 / 256 (0.78%)
    1 / 250 (0.40%)
         occurrences all number
    1
    1
    2
    1
    Pain in extremity
         subjects affected / exposed
    1 / 630 (0.16%)
    3 / 589 (0.51%)
    3 / 256 (1.17%)
    0 / 250 (0.00%)
         occurrences all number
    1
    3
    3
    0
    Plantar fasciitis
         subjects affected / exposed
    1 / 630 (0.16%)
    0 / 589 (0.00%)
    0 / 256 (0.00%)
    0 / 250 (0.00%)
         occurrences all number
    1
    0
    0
    0
    Spinal pain
         subjects affected / exposed
    0 / 630 (0.00%)
    0 / 589 (0.00%)
    0 / 256 (0.00%)
    1 / 250 (0.40%)
         occurrences all number
    0
    0
    0
    1
    Spinal stenosis
         subjects affected / exposed
    0 / 630 (0.00%)
    1 / 589 (0.17%)
    0 / 256 (0.00%)
    0 / 250 (0.00%)
         occurrences all number
    0
    1
    0
    0
    Synovial cyst
         subjects affected / exposed
    0 / 630 (0.00%)
    0 / 589 (0.00%)
    0 / 256 (0.00%)
    1 / 250 (0.40%)
         occurrences all number
    0
    0
    0
    1
    Trismus
         subjects affected / exposed
    0 / 630 (0.00%)
    1 / 589 (0.17%)
    0 / 256 (0.00%)
    0 / 250 (0.00%)
         occurrences all number
    0
    1
    0
    0
    Infections and infestations
    Appendicitis
         subjects affected / exposed
    1 / 630 (0.16%)
    0 / 589 (0.00%)
    0 / 256 (0.00%)
    0 / 250 (0.00%)
         occurrences all number
    1
    0
    0
    0
    Arthritis infective
         subjects affected / exposed
    0 / 630 (0.00%)
    1 / 589 (0.17%)
    0 / 256 (0.00%)
    0 / 250 (0.00%)
         occurrences all number
    0
    1
    0
    0
    Balanitis candida
         subjects affected / exposed
    0 / 630 (0.00%)
    0 / 589 (0.00%)
    0 / 256 (0.00%)
    1 / 250 (0.40%)
         occurrences all number
    0
    0
    0
    1
    Bronchitis
         subjects affected / exposed
    1 / 630 (0.16%)
    0 / 589 (0.00%)
    1 / 256 (0.39%)
    1 / 250 (0.40%)
         occurrences all number
    1
    0
    1
    1
    Cellulitis
         subjects affected / exposed
    0 / 630 (0.00%)
    0 / 589 (0.00%)
    1 / 256 (0.39%)
    1 / 250 (0.40%)
         occurrences all number
    0
    0
    1
    1
    Conjunctivitis
         subjects affected / exposed
    0 / 630 (0.00%)
    0 / 589 (0.00%)
    1 / 256 (0.39%)
    0 / 250 (0.00%)
         occurrences all number
    0
    0
    1
    0
    Conjunctivitis bacterial
         subjects affected / exposed
    1 / 630 (0.16%)
    0 / 589 (0.00%)
    0 / 256 (0.00%)
    0 / 250 (0.00%)
         occurrences all number
    1
    0
    0
    0
    Corona virus infection
         subjects affected / exposed
    0 / 630 (0.00%)
    1 / 589 (0.17%)
    3 / 256 (1.17%)
    1 / 250 (0.40%)
         occurrences all number
    0
    1
    3
    1
    Folliculitis
         subjects affected / exposed
    0 / 630 (0.00%)
    0 / 589 (0.00%)
    1 / 256 (0.39%)
    0 / 250 (0.00%)
         occurrences all number
    0
    0
    1
    0
    Gastroenteritis
         subjects affected / exposed
    0 / 630 (0.00%)
    1 / 589 (0.17%)
    0 / 256 (0.00%)
    0 / 250 (0.00%)
         occurrences all number
    0
    1
    0
    0
    Gastroenteritis viral
         subjects affected / exposed
    0 / 630 (0.00%)
    0 / 589 (0.00%)
    1 / 256 (0.39%)
    0 / 250 (0.00%)
         occurrences all number
    0
    0
    1
    0
    Herpes zoster
         subjects affected / exposed
    0 / 630 (0.00%)
    0 / 589 (0.00%)
    1 / 256 (0.39%)
    0 / 250 (0.00%)
         occurrences all number
    0
    0
    1
    0
    Hordeolum
         subjects affected / exposed
    0 / 630 (0.00%)
    0 / 589 (0.00%)
    1 / 256 (0.39%)
    0 / 250 (0.00%)
         occurrences all number
    0
    0
    1
    0
    Localised infection
         subjects affected / exposed
    1 / 630 (0.16%)
    0 / 589 (0.00%)
    0 / 256 (0.00%)
    0 / 250 (0.00%)
         occurrences all number
    1
    0
    0
    0
    Nasopharyngitis
         subjects affected / exposed
    3 / 630 (0.48%)
    7 / 589 (1.19%)
    2 / 256 (0.78%)
    2 / 250 (0.80%)
         occurrences all number
    3
    7
    2
    2
    Onychomycosis
         subjects affected / exposed
    1 / 630 (0.16%)
    0 / 589 (0.00%)
    1 / 256 (0.39%)
    0 / 250 (0.00%)
         occurrences all number
    1
    0
    1
    0
    Oral herpes
         subjects affected / exposed
    0 / 630 (0.00%)
    1 / 589 (0.17%)
    0 / 256 (0.00%)
    0 / 250 (0.00%)
         occurrences all number
    0
    1
    0
    0
    Pharyngitis
         subjects affected / exposed
    0 / 630 (0.00%)
    1 / 589 (0.17%)
    0 / 256 (0.00%)
    0 / 250 (0.00%)
         occurrences all number
    0
    1
    0
    0
    Rhinitis
         subjects affected / exposed
    0 / 630 (0.00%)
    0 / 589 (0.00%)
    0 / 256 (0.00%)
    1 / 250 (0.40%)
         occurrences all number
    0
    0
    0
    1
    Rhinovirus infection
         subjects affected / exposed
    1 / 630 (0.16%)
    0 / 589 (0.00%)
    0 / 256 (0.00%)
    0 / 250 (0.00%)
         occurrences all number
    1
    0
    0
    0
    Severe acute respiratory syndrome
         subjects affected / exposed
    0 / 630 (0.00%)
    1 / 589 (0.17%)
    0 / 256 (0.00%)
    0 / 250 (0.00%)
         occurrences all number
    0
    1
    0
    0
    Tooth abscess
         subjects affected / exposed
    1 / 630 (0.16%)
    0 / 589 (0.00%)
    0 / 256 (0.00%)
    1 / 250 (0.40%)
         occurrences all number
    1
    0
    0
    1
    Tooth infection
         subjects affected / exposed
    1 / 630 (0.16%)
    1 / 589 (0.17%)
    0 / 256 (0.00%)
    0 / 250 (0.00%)
         occurrences all number
    1
    1
    0
    0
    Upper respiratory tract infection
         subjects affected / exposed
    2 / 630 (0.32%)
    2 / 589 (0.34%)
    2 / 256 (0.78%)
    3 / 250 (1.20%)
         occurrences all number
    2
    2
    2
    3
    Urinary tract infection
         subjects affected / exposed
    1 / 630 (0.16%)
    7 / 589 (1.19%)
    4 / 256 (1.56%)
    8 / 250 (3.20%)
         occurrences all number
    1
    7
    4
    8
    Viral upper respiratory tract infection
         subjects affected / exposed
    0 / 630 (0.00%)
    1 / 589 (0.17%)
    1 / 256 (0.39%)
    0 / 250 (0.00%)
         occurrences all number
    0
    1
    1
    0
    Metabolism and nutrition disorders
    Appetite disorder
         subjects affected / exposed
    0 / 630 (0.00%)
    1 / 589 (0.17%)
    0 / 256 (0.00%)
    0 / 250 (0.00%)
         occurrences all number
    0
    1
    0
    0
    Decreased appetite
         subjects affected / exposed
    2 / 630 (0.32%)
    6 / 589 (1.02%)
    0 / 256 (0.00%)
    0 / 250 (0.00%)
         occurrences all number
    2
    6
    0
    0
    Dehydration
         subjects affected / exposed
    0 / 630 (0.00%)
    1 / 589 (0.17%)
    0 / 256 (0.00%)
    0 / 250 (0.00%)
         occurrences all number
    0
    1
    0
    0
    Diabetes mellitus
         subjects affected / exposed
    0 / 630 (0.00%)
    1 / 589 (0.17%)
    0 / 256 (0.00%)
    0 / 250 (0.00%)
         occurrences all number
    0
    1
    0
    0
    Gout
         subjects affected / exposed
    0 / 630 (0.00%)
    1 / 589 (0.17%)
    0 / 256 (0.00%)
    0 / 250 (0.00%)
         occurrences all number
    0
    1
    0
    0
    Hypercholesterolaemia
         subjects affected / exposed
    1 / 630 (0.16%)
    0 / 589 (0.00%)
    0 / 256 (0.00%)
    0 / 250 (0.00%)
         occurrences all number
    1
    0
    0
    0

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    Substantial protocol amendments (globally)
    Were there any global substantial amendments to the protocol? Yes
    Date
    Amendment
    30 Aug 2017
    Protocol amendment 1: • Changed the IR CD-LD package insert provided in Appendix A from carbidopa and levodopa tablets (Mylan Pharmaceuticals Inc.) to Sinemet® (carbidopa-levodopa) tablets (Merck & Co., Inc.). • Added the following statement to the IR CD-LD dose adjustment period, Section 6.4.1 ‘Subjects who were receiving IR CD-LD as a 1:10 CD-LD formulation will be started on IR CD-LD with a 1:4 ratio at the same frequency and LD dose.’ • Added a new section on Rescue Medications as follows: Subjects who need rescue medications or need to change treatment will be discontinued from the study. Rescue with additional or modified doses of concomitant PD medications or use of CD-LD products other than the dispensed study medication are not permitted and will trigger discontinuation from the study. Rescue medications are not allowed during the dose adjustment, dose conversion or double-blind treatment periods. • Updated the third key secondary endpoint as follows: Change from baseline in the MDS-UPDRS Part III at end of double-blind treatment period (Visit 7 or early termination).
    23 Oct 2017
    Protocol amendment 2: • To clarify the dose adjustments made during the dose adjustment period: Following Visit 1, qualified subjects will enter a 3-week, open-label IR CD-LD treatment period allowing for dose adjustment. ‘The dosing regimen of IR CD-LD may be adjusted during the dose adjustment period to minimize “Off” time without causing troublesome dyskinesia. The doses and regimens of the subject’s other non-CD-LD PD medications (dopamine agonists, MAO-B inhibitors, amantadine, anticholinergics) should remain stable throughout this study.’ • To clarify the dose conversion made during the dose conversion period: Following completion of the IR CD-LD dose adjustment period…… It is recommended that IPX203 should be dosed approximately every 8 hours with the exception that subjects who are currently receiving a total daily dose of less than 125-500 mg IR CD-LD at the end of the dose adjustment period will be initially administered every 12 hours. The dosing interval may be reduced to approximately every 8 hours if the subject does not achieve an acceptable duration of effect. The dosing regimen of IPX203 may be adjusted during the dose conversion period to achieve the optimal balance of efficacy and tolerability (minimize “Off” time without causing troublesome dyskinesia or other dopaminergic side effects). The doses and regimens of the subject’s other non-CD-LD PD medications should remain stable throughout this study. The subject must be on a stable dosing regimen of IPX203 (no change in dose or in dosing frequency) for at least 5 days prior to returning for Visit 4. • During the dose conversion to IPX203, the Investigator or site staff are advised to be in frequent contact (every 1 to 3 days) with the subject especially during the initial dose conversion to assess the need for dosage adjustment with the goal of minimizing “Off” time without causing troublesome dyskinesia.
    07 Dec 2017
    Protocol amendment 3: • Included the maximum recommended daily dose of IPX203 in Dose Conversion Period as 600 to 2400 mg CD-LD.
    28 Sep 2018
    Protocol amendment 4: • Updated the measures and/or instruments such as MDS-UPDRS, PDQ-39, GCSI, PDSS-2, PAS, PD Diary to the most current versions available for licensing.

    Interruptions (globally)
    Were there any global interruptions to the trial? No

    Limitations and caveats
    Limitations of the trial such as small numbers of subjects analysed or technical problems leading to unreliable data.
    None reported
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