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    Clinical Trial Results:
    An open-label treatment study to evaluate the safety, tolerability and efficacy of AFQ056 in Parkinson’s patients with L-dopa induced dyskinesias

    Summary
    EudraCT number
    2010-019418-25
    Trial protocol
    IT   FR   DE   FI  
    Global end of trial date
    15 Oct 2013

    Results information
    Results version number
    v1(current)
    This version publication date
    13 Jul 2016
    First version publication date
    03 Aug 2015
    Other versions

    Trial information

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    Trial identification
    Sponsor protocol code
    CAFQ056A2217
    Additional study identifiers
    ISRCTN number
    -
    US NCT number
    NCT01173731
    WHO universal trial number (UTN)
    -
    Sponsors
    Sponsor organisation name
    Novartis Pharma AG
    Sponsor organisation address
    CH-4002 , Basel, Switzerland,
    Public contact
    Clinical Disclosure Office, Novartis Pharma AG, +41 613241111 ,
    Scientific contact
    Clinical Disclosure Office, Novartis Pharma AG, +41 613241111 ,
    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 Oct 2013
    Is this the analysis of the primary completion data?
    No
    Global end of trial reached?
    Yes
    Global end of trial date
    15 Oct 2013
    Was the trial ended prematurely?
    Yes
    General information about the trial
    Main objective of the trial
    Primary objectives: To evaluate the safety and tolerability of AFQ056 in patients with PD-LID as assessed by: • Incidence and severity of adverse events and serious adverse events • Changes in vital signs, laboratory assessments, and ECGs • Changes in cognitive function as measured by the MMSE • Changes in psychiatric symptoms as measured by the SCOPA-PC • Changes in underlying symptoms of PD as measured by the UPDRS part III and the PD symptom items in the Clinical Global Impression of Change (CGIC) and Patient Global Impression of Change (PGIC), and by AEs potentially related to an exacerbation of movement disorder of PD • Occurrence of rebound symptoms upon discontinuation of study drug
    Protection of trial subjects
    The study was in compliance with the ethical principles derived from the Declaration of Helsinki and the International Conference on Harmonization (ICH) Good Clinical Practice (GCP) Guidelines. All the local regulatory requirements pertinent to safety of trial subjects were also followed during the conduct of the trial.
    Background therapy
    -
    Evidence for comparator
    -
    Actual start date of recruitment
    13 Oct 2010
    Long term follow-up planned
    No
    Independent data monitoring committee (IDMC) involvement?
    Yes
    Population of trial subjects
    Number of subjects enrolled per country
    Country: Number of subjects enrolled
    Germany: 26
    Country: Number of subjects enrolled
    Italy: 14
    Country: Number of subjects enrolled
    Australia: 7
    Country: Number of subjects enrolled
    Canada: 6
    Country: Number of subjects enrolled
    United States: 8
    Country: Number of subjects enrolled
    France: 5
    Worldwide total number of subjects
    66
    EEA total number of subjects
    45
    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)
    31
    From 65 to 84 years
    35
    85 years and over
    0

    Subject disposition

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    Recruitment
    Recruitment details
    -

    Pre-assignment
    Screening details
    The study population consisted of male or female patients with PD-LID who have completed selected double-blind studies with AFQ056 or placebo.

    Period 1
    Period 1 title
    Open-label Treatment Period (overall period)
    Is this the baseline period?
    Yes
    Allocation method
    Not applicable
    Blinding used
    Not blinded

    Arms
    Are arms mutually exclusive
    Yes

    Arm title
    AFQ056 10 mg b.i.d.
    Arm description
    The investigational drug, AFQ056, was provided as hard gelatin capsules.
    Arm type
    Experimental

    Investigational medicinal product name
    AFQ056
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Capsule
    Routes of administration
    Oral use
    Dosage and administration details
    Patients were asked to take the number of capsules in the morning and in the evening as indicated. The morning and evening doses were taken at approximately 12-hour intervals. If a patient missed a dose of study drug for any reason, the patient was instructed to not make up the missed dose with the next scheduled dose. Study drug was administered with a glass of water. Patients were instructed to not chew the medication, but swallow it whole. Patients were asked to avoid drinking grapefruit juice during the study.

    Arm title
    AFQ056 25 mg b.i.d
    Arm description
    The investigational drug, AFQ056, was provided as hard gelatin capsules.
    Arm type
    Experimental

    Investigational medicinal product name
    AFQ056
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Capsule
    Routes of administration
    Oral use
    Dosage and administration details
    Patients were asked to take the number of capsules in the morning and in the evening as indicated. The morning and evening doses were taken at approximately 12-hour intervals. If a patient missed a dose of study drug for any reason, the patient was instructed to not make up the missed dose with the next scheduled dose. Study drug was administered with a glass of water. Patients were instructed to not chew the medication, but swallow it whole. Patients were asked to avoid drinking grapefruit juice during the study.

    Arm title
    AFQ056 50 mg b.i.d.
    Arm description
    The investigational drug, AFQ056, was provided as hard gelatin capsules.
    Arm type
    Experimental

    Investigational medicinal product name
    AFQ056
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Capsule
    Routes of administration
    Oral use
    Dosage and administration details
    Patients were asked to take the number of capsules in the morning and in the evening as indicated. The morning and evening doses were taken at approximately 12-hour intervals. If a patient missed a dose of study drug for any reason, the patient was instructed to not make up the missed dose with the next scheduled dose. Study drug was administered with a glass of water. Patients were instructed to not chew the medication, but swallow it whole. Patients were asked to avoid drinking grapefruit juice during the study.

    Arm title
    AFQ056 75 mg b.i.d.
    Arm description
    The investigational drug, AFQ056, was provided as hard gelatin capsules.
    Arm type
    Experimental

    Investigational medicinal product name
    AFQ056
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Capsule
    Routes of administration
    Oral use
    Dosage and administration details
    Patients were asked to take the number of capsules in the morning and in the evening as indicated. The morning and evening doses were taken at approximately 12-hour intervals. If a patient missed a dose of study drug for any reason, the patient was instructed to not make up the missed dose with the next scheduled dose. Study drug was administered with a glass of water. Patients were instructed to not chew the medication, but swallow it whole. Patients were asked to avoid drinking grapefruit juice during the study.

    Arm title
    AFQ056 100 mg b.i.d
    Arm description
    The investigational drug, AFQ056, was provided as hard gelatin capsules.
    Arm type
    Experimental

    Investigational medicinal product name
    AFQ056
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Capsule
    Routes of administration
    Oral use
    Dosage and administration details
    Patients were asked to take the number of capsules in the morning and in the evening as indicated. The morning and evening doses were taken at approximately 12-hour intervals. If a patient missed a dose of study drug for any reason, the patient was instructed to not make up the missed dose with the next scheduled dose. Study drug was administered with a glass of water. Patients were instructed to not chew the medication, but swallow it whole. Patients were asked to avoid drinking grapefruit juice during the study.

    Number of subjects in period 1
    AFQ056 10 mg b.i.d. AFQ056 25 mg b.i.d AFQ056 50 mg b.i.d. AFQ056 75 mg b.i.d. AFQ056 100 mg b.i.d
    Started
    3
    16
    13
    15
    19
    Completed
    0
    0
    0
    0
    0
    Not completed
    3
    16
    13
    15
    19
         Unsatisfactory therapeutic effect
    1
    1
    4
    2
    5
         Adverse Event(s)
    1
    8
    3
    8
    5
         Adverse event, serious fatal
    -
    1
    -
    1
    -
         Administrative problems
    -
    5
    3
    3
    5
         Consent withdrawn by subject
    1
    -
    3
    1
    4
         Lost to follow-up
    -
    1
    -
    -
    -

    Baseline characteristics

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    Baseline characteristics reporting groups
    Reporting group title
    AFQ056 10 mg b.i.d.
    Reporting group description
    The investigational drug, AFQ056, was provided as hard gelatin capsules.

    Reporting group title
    AFQ056 25 mg b.i.d
    Reporting group description
    The investigational drug, AFQ056, was provided as hard gelatin capsules.

    Reporting group title
    AFQ056 50 mg b.i.d.
    Reporting group description
    The investigational drug, AFQ056, was provided as hard gelatin capsules.

    Reporting group title
    AFQ056 75 mg b.i.d.
    Reporting group description
    The investigational drug, AFQ056, was provided as hard gelatin capsules.

    Reporting group title
    AFQ056 100 mg b.i.d
    Reporting group description
    The investigational drug, AFQ056, was provided as hard gelatin capsules.

    Reporting group values
    AFQ056 10 mg b.i.d. AFQ056 25 mg b.i.d AFQ056 50 mg b.i.d. AFQ056 75 mg b.i.d. AFQ056 100 mg b.i.d Total
    Number of subjects
    3 16 13 15 19 66
    Age categorical
    Units: Subjects
        Adults (18-64 years)
    1 9 4 7 10 31
        From 65-84 years
    2 7 9 8 9 35
    Age continuous
    Units: years
        arithmetic mean (standard deviation)
    64.7 ± 14.5 63.3 ± 6.82 65.5 ± 6.42 62.6 ± 9.09 64.2 ± 6.88 -
    Gender categorical
    Units: Subjects
        Female
    1 13 6 5 9 34
        Male
    2 3 7 10 10 32
    Subject analysis sets

    Subject analysis set title
    Full Analysis Set (FAS)
    Subject analysis set type
    Full analysis
    Subject analysis set description
    The FAS included all patients who received at least one dose of open-label study medication during this open-label study.

    Subject analysis set title
    Safety Set (SS)
    Subject analysis set type
    Safety analysis
    Subject analysis set description
    The SS consisted of all patients who received at least one dose of open-label study medication during this open-label study and who had at least one post-baseline safety assessment.

    Subject analysis sets values
    Full Analysis Set (FAS) Safety Set (SS)
    Number of subjects
    66
    66
    Age categorical
    Units: Subjects
        Adults (18-64 years)
    31
    31
        From 65-84 years
    35
    35
    Age continuous
    Units: years
        arithmetic mean (standard deviation)
    ±
    ±
    Gender categorical
    Units: Subjects
        Female
        Male

    End points

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    End points reporting groups
    Reporting group title
    AFQ056 10 mg b.i.d.
    Reporting group description
    The investigational drug, AFQ056, was provided as hard gelatin capsules.

    Reporting group title
    AFQ056 25 mg b.i.d
    Reporting group description
    The investigational drug, AFQ056, was provided as hard gelatin capsules.

    Reporting group title
    AFQ056 50 mg b.i.d.
    Reporting group description
    The investigational drug, AFQ056, was provided as hard gelatin capsules.

    Reporting group title
    AFQ056 75 mg b.i.d.
    Reporting group description
    The investigational drug, AFQ056, was provided as hard gelatin capsules.

    Reporting group title
    AFQ056 100 mg b.i.d
    Reporting group description
    The investigational drug, AFQ056, was provided as hard gelatin capsules.

    Subject analysis set title
    Full Analysis Set (FAS)
    Subject analysis set type
    Full analysis
    Subject analysis set description
    The FAS included all patients who received at least one dose of open-label study medication during this open-label study.

    Subject analysis set title
    Safety Set (SS)
    Subject analysis set type
    Safety analysis
    Subject analysis set description
    The SS consisted of all patients who received at least one dose of open-label study medication during this open-label study and who had at least one post-baseline safety assessment.

    Primary: Changes from baseline in cognitive function as measured by the Mini-Mental State Examination (MMSE) total score

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    End point title
    Changes from baseline in cognitive function as measured by the Mini-Mental State Examination (MMSE) total score [1]
    End point description
    The study was terminated based on the results of studies CAFQ056A2222 and CAFQ056A2223 (due to lack of efficacy) and the sponsor’s decision to terminate the program.
    End point type
    Primary
    End point timeframe
    Baseline through Month 36
    Notes
    [1] - No statistical analyses have been specified for this primary end point. It is expected there is at least one statistical analysis for each primary end point.
    Justification: No statistical analyses have been performed for this primary end point.
    End point values
    Safety Set (SS)
    Number of subjects analysed
    0 [2]
    Units: units on a scale
    arithmetic mean (standard deviation)
        Month 6 baseline
    ±
        Month 6 change from baseline
    ±
        Month 12 baseline
    ±
        Month 12 change from baseline
    ±
        Month 18 baseline
    ±
        Month 18 change from baseline
    ±
        Month 24 baseline
    ±
        Month 24 change from baseline
    ±
        Month 30 baseline
    ±
        Month 30 change from baseline
    ±
        Month 36 baseline
    ±
        Month 36 change from baseline
    ±
    Notes
    [2] - The study was terminated based on the results of studies CAFQ056A2222 and CAFQ056A2223 (due to lack
    No statistical analyses for this end point

    Adverse events

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    Adverse events information
    Timeframe for reporting adverse events
    Adverse Events are collected from First Patient First Visit (FPFV) until Last Patient Last Visit (LPLV).  All Adverse events are reported in this record from First Patient First Treatment until Last Patient Last Visit.
    Adverse event reporting additional description
    Consistent with EudraCT disclosure specifications, Novartis has reported under the Serious adverse events field “number of deaths resulting from adverse events” all those deaths, resulting from serious adverse events that are deemed to be causally related to treatment by the investigator.
    Assessment type
    Systematic
    Dictionary used for adverse event reporting
    Dictionary name
    MedDRA
    Dictionary version
    16.1
    Reporting groups
    Reporting group title
    AFQ056 10mg
    Reporting group description
    AFQ056 10mg

    Reporting group title
    AFQ056 25mg
    Reporting group description
    AFQ056 25mg

    Reporting group title
    AFQ056 100mg
    Reporting group description
    AFQ056 100mg

    Reporting group title
    AFQ056 75mg
    Reporting group description
    AFQ056 75mg

    Reporting group title
    AFQ056 50mg
    Reporting group description
    AFQ056 50mg

    Serious adverse events
    AFQ056 10mg AFQ056 25mg AFQ056 100mg AFQ056 75mg AFQ056 50mg
    Total subjects affected by serious adverse events
         subjects affected / exposed
    1 / 3 (33.33%)
    4 / 16 (25.00%)
    8 / 19 (42.11%)
    8 / 15 (53.33%)
    4 / 13 (30.77%)
         number of deaths (all causes)
    0
    1
    0
    1
    0
         number of deaths resulting from adverse events
    0
    0
    0
    0
    0
    Vascular disorders
    Haematoma
         subjects affected / exposed
    0 / 3 (0.00%)
    0 / 16 (0.00%)
    0 / 19 (0.00%)
    1 / 15 (6.67%)
    0 / 13 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Neoplasms benign, malignant and unspecified (incl cysts and polyps)
    Prostate cancer
         subjects affected / exposed
    0 / 3 (0.00%)
    0 / 16 (0.00%)
    1 / 19 (5.26%)
    0 / 15 (0.00%)
    1 / 13 (7.69%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Meningioma
         subjects affected / exposed
    0 / 3 (0.00%)
    0 / 16 (0.00%)
    0 / 19 (0.00%)
    0 / 15 (0.00%)
    1 / 13 (7.69%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    General disorders and administration site conditions
    Non-cardiac chest pain
         subjects affected / exposed
    0 / 3 (0.00%)
    0 / 16 (0.00%)
    1 / 19 (5.26%)
    0 / 15 (0.00%)
    0 / 13 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Psychiatric disorders
    Delusion
         subjects affected / exposed
    0 / 3 (0.00%)
    0 / 16 (0.00%)
    0 / 19 (0.00%)
    1 / 15 (6.67%)
    0 / 13 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Hallucination, visual
         subjects affected / exposed
    0 / 3 (0.00%)
    1 / 16 (6.25%)
    0 / 19 (0.00%)
    1 / 15 (6.67%)
    0 / 13 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Injury, poisoning and procedural complications
    Fall
         subjects affected / exposed
    0 / 3 (0.00%)
    1 / 16 (6.25%)
    0 / 19 (0.00%)
    0 / 15 (0.00%)
    2 / 13 (15.38%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Laceration
         subjects affected / exposed
    0 / 3 (0.00%)
    0 / 16 (0.00%)
    0 / 19 (0.00%)
    1 / 15 (6.67%)
    0 / 13 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Limb injury
         subjects affected / exposed
    0 / 3 (0.00%)
    0 / 16 (0.00%)
    1 / 19 (5.26%)
    0 / 15 (0.00%)
    0 / 13 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Meniscus injury
         subjects affected / exposed
    0 / 3 (0.00%)
    0 / 16 (0.00%)
    0 / 19 (0.00%)
    0 / 15 (0.00%)
    1 / 13 (7.69%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Lower limb fracture
         subjects affected / exposed
    0 / 3 (0.00%)
    1 / 16 (6.25%)
    0 / 19 (0.00%)
    0 / 15 (0.00%)
    0 / 13 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Road traffic accident
         subjects affected / exposed
    0 / 3 (0.00%)
    0 / 16 (0.00%)
    1 / 19 (5.26%)
    1 / 15 (6.67%)
    0 / 13 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    1 / 1
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Radius fracture
         subjects affected / exposed
    0 / 3 (0.00%)
    0 / 16 (0.00%)
    0 / 19 (0.00%)
    1 / 15 (6.67%)
    0 / 13 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Sternal fracture
         subjects affected / exposed
    0 / 3 (0.00%)
    0 / 16 (0.00%)
    0 / 19 (0.00%)
    1 / 15 (6.67%)
    0 / 13 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Toxicity to various agents
         subjects affected / exposed
    0 / 3 (0.00%)
    0 / 16 (0.00%)
    0 / 19 (0.00%)
    1 / 15 (6.67%)
    0 / 13 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Ulna fracture
         subjects affected / exposed
    0 / 3 (0.00%)
    0 / 16 (0.00%)
    1 / 19 (5.26%)
    0 / 15 (0.00%)
    0 / 13 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Investigations
    Alanine aminotransferase increased
         subjects affected / exposed
    0 / 3 (0.00%)
    0 / 16 (0.00%)
    0 / 19 (0.00%)
    0 / 15 (0.00%)
    1 / 13 (7.69%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Aspartate aminotransferase increased
         subjects affected / exposed
    0 / 3 (0.00%)
    0 / 16 (0.00%)
    0 / 19 (0.00%)
    0 / 15 (0.00%)
    1 / 13 (7.69%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Cardiac disorders
    Cardiac arrest
         subjects affected / exposed
    0 / 3 (0.00%)
    0 / 16 (0.00%)
    0 / 19 (0.00%)
    2 / 15 (13.33%)
    0 / 13 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    1 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    Cardiac failure
         subjects affected / exposed
    0 / 3 (0.00%)
    1 / 16 (6.25%)
    0 / 19 (0.00%)
    0 / 15 (0.00%)
    0 / 13 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Respiratory, thoracic and mediastinal disorders
    Acute pulmonary oedema
         subjects affected / exposed
    0 / 3 (0.00%)
    0 / 16 (0.00%)
    0 / 19 (0.00%)
    1 / 15 (6.67%)
    0 / 13 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Dyspnoea
         subjects affected / exposed
    0 / 3 (0.00%)
    1 / 16 (6.25%)
    0 / 19 (0.00%)
    0 / 15 (0.00%)
    0 / 13 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Respiratory arrest
         subjects affected / exposed
    0 / 3 (0.00%)
    0 / 16 (0.00%)
    0 / 19 (0.00%)
    1 / 15 (6.67%)
    0 / 13 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Nervous system disorders
    Akinesia
         subjects affected / exposed
    0 / 3 (0.00%)
    0 / 16 (0.00%)
    0 / 19 (0.00%)
    1 / 15 (6.67%)
    0 / 13 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Balance disorder
         subjects affected / exposed
    0 / 3 (0.00%)
    0 / 16 (0.00%)
    0 / 19 (0.00%)
    0 / 15 (0.00%)
    1 / 13 (7.69%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Cognitive disorder
         subjects affected / exposed
    0 / 3 (0.00%)
    0 / 16 (0.00%)
    0 / 19 (0.00%)
    1 / 15 (6.67%)
    0 / 13 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Freezing phenomenon
         subjects affected / exposed
    0 / 3 (0.00%)
    0 / 16 (0.00%)
    0 / 19 (0.00%)
    0 / 15 (0.00%)
    1 / 13 (7.69%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Hypoxic-ischaemic encephalopathy
         subjects affected / exposed
    0 / 3 (0.00%)
    0 / 16 (0.00%)
    0 / 19 (0.00%)
    1 / 15 (6.67%)
    0 / 13 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    On and off phenomenon
         subjects affected / exposed
    1 / 3 (33.33%)
    0 / 16 (0.00%)
    0 / 19 (0.00%)
    1 / 15 (6.67%)
    0 / 13 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
    0 / 0
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Status epilepticus
         subjects affected / exposed
    0 / 3 (0.00%)
    0 / 16 (0.00%)
    0 / 19 (0.00%)
    1 / 15 (6.67%)
    0 / 13 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Parkinson's disease
         subjects affected / exposed
    0 / 3 (0.00%)
    0 / 16 (0.00%)
    2 / 19 (10.53%)
    2 / 15 (13.33%)
    1 / 13 (7.69%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 2
    0 / 2
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Thoracic outlet syndrome
         subjects affected / exposed
    0 / 3 (0.00%)
    0 / 16 (0.00%)
    0 / 19 (0.00%)
    0 / 15 (0.00%)
    1 / 13 (7.69%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Gastrointestinal disorders
    Gastrooesophageal reflux disease
         subjects affected / exposed
    0 / 3 (0.00%)
    0 / 16 (0.00%)
    1 / 19 (5.26%)
    0 / 15 (0.00%)
    0 / 13 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Renal and urinary disorders
    Calculus bladder
         subjects affected / exposed
    0 / 3 (0.00%)
    0 / 16 (0.00%)
    1 / 19 (5.26%)
    0 / 15 (0.00%)
    0 / 13 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Renal impairment
         subjects affected / exposed
    0 / 3 (0.00%)
    0 / 16 (0.00%)
    0 / 19 (0.00%)
    0 / 15 (0.00%)
    1 / 13 (7.69%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Urinary incontinence
         subjects affected / exposed
    0 / 3 (0.00%)
    0 / 16 (0.00%)
    0 / 19 (0.00%)
    1 / 15 (6.67%)
    0 / 13 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Musculoskeletal and connective tissue disorders
    Arthralgia
         subjects affected / exposed
    0 / 3 (0.00%)
    1 / 16 (6.25%)
    0 / 19 (0.00%)
    0 / 15 (0.00%)
    0 / 13 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Fracture pain
         subjects affected / exposed
    0 / 3 (0.00%)
    0 / 16 (0.00%)
    0 / 19 (0.00%)
    1 / 15 (6.67%)
    0 / 13 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Lumbar spinal stenosis
         subjects affected / exposed
    0 / 3 (0.00%)
    0 / 16 (0.00%)
    0 / 19 (0.00%)
    1 / 15 (6.67%)
    0 / 13 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Musculoskeletal pain
         subjects affected / exposed
    0 / 3 (0.00%)
    0 / 16 (0.00%)
    0 / 19 (0.00%)
    0 / 15 (0.00%)
    1 / 13 (7.69%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Rhabdomyolysis
         subjects affected / exposed
    0 / 3 (0.00%)
    0 / 16 (0.00%)
    0 / 19 (0.00%)
    0 / 15 (0.00%)
    1 / 13 (7.69%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Pain in extremity
         subjects affected / exposed
    0 / 3 (0.00%)
    0 / 16 (0.00%)
    0 / 19 (0.00%)
    1 / 15 (6.67%)
    0 / 13 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Rotator cuff syndrome
         subjects affected / exposed
    0 / 3 (0.00%)
    0 / 16 (0.00%)
    0 / 19 (0.00%)
    0 / 15 (0.00%)
    1 / 13 (7.69%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Infections and infestations
    Meningitis
         subjects affected / exposed
    0 / 3 (0.00%)
    1 / 16 (6.25%)
    0 / 19 (0.00%)
    0 / 15 (0.00%)
    0 / 13 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    Arthritis infective
         subjects affected / exposed
    0 / 3 (0.00%)
    0 / 16 (0.00%)
    0 / 19 (0.00%)
    0 / 15 (0.00%)
    1 / 13 (7.69%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Pneumococcal sepsis
         subjects affected / exposed
    0 / 3 (0.00%)
    1 / 16 (6.25%)
    0 / 19 (0.00%)
    0 / 15 (0.00%)
    0 / 13 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Pyelonephritis
         subjects affected / exposed
    0 / 3 (0.00%)
    0 / 16 (0.00%)
    1 / 19 (5.26%)
    0 / 15 (0.00%)
    0 / 13 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Pneumonia
         subjects affected / exposed
    0 / 3 (0.00%)
    0 / 16 (0.00%)
    0 / 19 (0.00%)
    1 / 15 (6.67%)
    1 / 13 (7.69%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Septic shock
         subjects affected / exposed
    0 / 3 (0.00%)
    0 / 16 (0.00%)
    1 / 19 (5.26%)
    0 / 15 (0.00%)
    0 / 13 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 2
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Urinary tract infection
         subjects affected / exposed
    0 / 3 (0.00%)
    0 / 16 (0.00%)
    1 / 19 (5.26%)
    0 / 15 (0.00%)
    0 / 13 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Frequency threshold for reporting non-serious adverse events: 5%
    Non-serious adverse events
    AFQ056 10mg AFQ056 25mg AFQ056 100mg AFQ056 75mg AFQ056 50mg
    Total subjects affected by non serious adverse events
         subjects affected / exposed
    3 / 3 (100.00%)
    16 / 16 (100.00%)
    17 / 19 (89.47%)
    15 / 15 (100.00%)
    13 / 13 (100.00%)
    Vascular disorders
    Hypertension
         subjects affected / exposed
    0 / 3 (0.00%)
    1 / 16 (6.25%)
    0 / 19 (0.00%)
    2 / 15 (13.33%)
    0 / 13 (0.00%)
         occurrences all number
    0
    1
    0
    2
    0
    Hypotension
         subjects affected / exposed
    0 / 3 (0.00%)
    0 / 16 (0.00%)
    1 / 19 (5.26%)
    1 / 15 (6.67%)
    0 / 13 (0.00%)
         occurrences all number
    0
    0
    1
    1
    0
    Orthostatic hypotension
         subjects affected / exposed
    0 / 3 (0.00%)
    0 / 16 (0.00%)
    1 / 19 (5.26%)
    2 / 15 (13.33%)
    0 / 13 (0.00%)
         occurrences all number
    0
    0
    1
    2
    0
    Neoplasms benign, malignant and unspecified (incl cysts and polyps)
    Basal cell carcinoma
         subjects affected / exposed
    0 / 3 (0.00%)
    0 / 16 (0.00%)
    1 / 19 (5.26%)
    0 / 15 (0.00%)
    0 / 13 (0.00%)
         occurrences all number
    0
    0
    1
    0
    0
    Eyelid tumour
         subjects affected / exposed
    0 / 3 (0.00%)
    1 / 16 (6.25%)
    0 / 19 (0.00%)
    0 / 15 (0.00%)
    0 / 13 (0.00%)
         occurrences all number
    0
    1
    0
    0
    0
    Immune system disorders
    Hypersensitivity
         subjects affected / exposed
    0 / 3 (0.00%)
    0 / 16 (0.00%)
    0 / 19 (0.00%)
    1 / 15 (6.67%)
    0 / 13 (0.00%)
         occurrences all number
    0
    0
    0
    1
    0
    General disorders and administration site conditions
    Asthenia
         subjects affected / exposed
    0 / 3 (0.00%)
    1 / 16 (6.25%)
    1 / 19 (5.26%)
    0 / 15 (0.00%)
    1 / 13 (7.69%)
         occurrences all number
    0
    2
    1
    0
    2
    Fatigue
         subjects affected / exposed
    0 / 3 (0.00%)
    0 / 16 (0.00%)
    3 / 19 (15.79%)
    1 / 15 (6.67%)
    0 / 13 (0.00%)
         occurrences all number
    0
    0
    3
    1
    0
    Feeling abnormal
         subjects affected / exposed
    0 / 3 (0.00%)
    0 / 16 (0.00%)
    0 / 19 (0.00%)
    2 / 15 (13.33%)
    1 / 13 (7.69%)
         occurrences all number
    0
    0
    0
    2
    1
    Feeling hot
         subjects affected / exposed
    0 / 3 (0.00%)
    0 / 16 (0.00%)
    1 / 19 (5.26%)
    0 / 15 (0.00%)
    0 / 13 (0.00%)
         occurrences all number
    0
    0
    1
    0
    0
    Non-cardiac chest pain
         subjects affected / exposed
    0 / 3 (0.00%)
    0 / 16 (0.00%)
    1 / 19 (5.26%)
    0 / 15 (0.00%)
    0 / 13 (0.00%)
         occurrences all number
    0
    0
    1
    0
    0
    Gait disturbance
         subjects affected / exposed
    0 / 3 (0.00%)
    0 / 16 (0.00%)
    1 / 19 (5.26%)
    0 / 15 (0.00%)
    1 / 13 (7.69%)
         occurrences all number
    0
    0
    1
    0
    1
    Oedema peripheral
         subjects affected / exposed
    0 / 3 (0.00%)
    0 / 16 (0.00%)
    2 / 19 (10.53%)
    0 / 15 (0.00%)
    2 / 13 (15.38%)
         occurrences all number
    0
    0
    2
    0
    2
    Psychiatric disorders
    Abnormal behaviour
         subjects affected / exposed
    0 / 3 (0.00%)
    0 / 16 (0.00%)
    1 / 19 (5.26%)
    0 / 15 (0.00%)
    0 / 13 (0.00%)
         occurrences all number
    0
    0
    1
    0
    0
    Acute psychosis
         subjects affected / exposed
    0 / 3 (0.00%)
    0 / 16 (0.00%)
    0 / 19 (0.00%)
    1 / 15 (6.67%)
    0 / 13 (0.00%)
         occurrences all number
    0
    0
    0
    1
    0
    Abnormal dreams
         subjects affected / exposed
    0 / 3 (0.00%)
    3 / 16 (18.75%)
    2 / 19 (10.53%)
    2 / 15 (13.33%)
    0 / 13 (0.00%)
         occurrences all number
    0
    4
    3
    3
    0
    Aggression
         subjects affected / exposed
    0 / 3 (0.00%)
    0 / 16 (0.00%)
    1 / 19 (5.26%)
    0 / 15 (0.00%)
    0 / 13 (0.00%)
         occurrences all number
    0
    0
    1
    0
    0
    Agitation
         subjects affected / exposed
    0 / 3 (0.00%)
    0 / 16 (0.00%)
    1 / 19 (5.26%)
    0 / 15 (0.00%)
    0 / 13 (0.00%)
         occurrences all number
    0
    0
    1
    0
    0
    Anxiety
         subjects affected / exposed
    0 / 3 (0.00%)
    0 / 16 (0.00%)
    0 / 19 (0.00%)
    0 / 15 (0.00%)
    1 / 13 (7.69%)
         occurrences all number
    0
    0
    0
    0
    1
    Confusional state
         subjects affected / exposed
    0 / 3 (0.00%)
    1 / 16 (6.25%)
    0 / 19 (0.00%)
    1 / 15 (6.67%)
    1 / 13 (7.69%)
         occurrences all number
    0
    1
    0
    1
    1
    Compulsive shopping
         subjects affected / exposed
    0 / 3 (0.00%)
    0 / 16 (0.00%)
    0 / 19 (0.00%)
    1 / 15 (6.67%)
    0 / 13 (0.00%)
         occurrences all number
    0
    0
    0
    1
    0
    Depersonalisation
         subjects affected / exposed
    0 / 3 (0.00%)
    1 / 16 (6.25%)
    0 / 19 (0.00%)
    0 / 15 (0.00%)
    0 / 13 (0.00%)
         occurrences all number
    0
    1
    0
    0
    0
    Delusion
         subjects affected / exposed
    0 / 3 (0.00%)
    0 / 16 (0.00%)
    1 / 19 (5.26%)
    0 / 15 (0.00%)
    0 / 13 (0.00%)
         occurrences all number
    0
    0
    1
    0
    0
    Depression
         subjects affected / exposed
    0 / 3 (0.00%)
    2 / 16 (12.50%)
    0 / 19 (0.00%)
    3 / 15 (20.00%)
    1 / 13 (7.69%)
         occurrences all number
    0
    2
    0
    3
    2
    Hallucination, visual
         subjects affected / exposed
    0 / 3 (0.00%)
    3 / 16 (18.75%)
    3 / 19 (15.79%)
    2 / 15 (13.33%)
    1 / 13 (7.69%)
         occurrences all number
    0
    3
    4
    3
    1
    Hallucination, auditory
         subjects affected / exposed
    0 / 3 (0.00%)
    0 / 16 (0.00%)
    1 / 19 (5.26%)
    1 / 15 (6.67%)
    0 / 13 (0.00%)
         occurrences all number
    0
    0
    1
    1
    0
    Hallucinations, mixed
         subjects affected / exposed
    0 / 3 (0.00%)
    0 / 16 (0.00%)
    0 / 19 (0.00%)
    0 / 15 (0.00%)
    1 / 13 (7.69%)
         occurrences all number
    0
    0
    0
    0
    1
    Impulsive behaviour
         subjects affected / exposed
    0 / 3 (0.00%)
    0 / 16 (0.00%)
    0 / 19 (0.00%)
    1 / 15 (6.67%)
    0 / 13 (0.00%)
         occurrences all number
    0
    0
    0
    1
    0
    Illusion
         subjects affected / exposed
    0 / 3 (0.00%)
    2 / 16 (12.50%)
    1 / 19 (5.26%)
    2 / 15 (13.33%)
    1 / 13 (7.69%)
         occurrences all number
    0
    3
    1
    2
    1
    Insomnia
         subjects affected / exposed
    1 / 3 (33.33%)
    0 / 16 (0.00%)
    5 / 19 (26.32%)
    0 / 15 (0.00%)
    1 / 13 (7.69%)
         occurrences all number
    1
    0
    5
    0
    1
    Jealous delusion
         subjects affected / exposed
    0 / 3 (0.00%)
    0 / 16 (0.00%)
    1 / 19 (5.26%)
    1 / 15 (6.67%)
    0 / 13 (0.00%)
         occurrences all number
    0
    0
    1
    2
    0
    Nightmare
         subjects affected / exposed
    0 / 3 (0.00%)
    1 / 16 (6.25%)
    0 / 19 (0.00%)
    0 / 15 (0.00%)
    0 / 13 (0.00%)
         occurrences all number
    0
    1
    0
    0
    0
    Libido increased
         subjects affected / exposed
    0 / 3 (0.00%)
    0 / 16 (0.00%)
    0 / 19 (0.00%)
    1 / 15 (6.67%)
    0 / 13 (0.00%)
         occurrences all number
    0
    0
    0
    2
    0
    Panic attack
         subjects affected / exposed
    0 / 3 (0.00%)
    1 / 16 (6.25%)
    0 / 19 (0.00%)
    0 / 15 (0.00%)
    0 / 13 (0.00%)
         occurrences all number
    0
    1
    0
    0
    0
    Pathological gambling
         subjects affected / exposed
    0 / 3 (0.00%)
    0 / 16 (0.00%)
    0 / 19 (0.00%)
    1 / 15 (6.67%)
    0 / 13 (0.00%)
         occurrences all number
    0
    0
    0
    1
    0
    Sleep disorder
         subjects affected / exposed
    0 / 3 (0.00%)
    1 / 16 (6.25%)
    0 / 19 (0.00%)
    1 / 15 (6.67%)
    0 / 13 (0.00%)
         occurrences all number
    0
    1
    0
    1
    0
    Reproductive system and breast disorders
    Ejaculation disorder
         subjects affected / exposed
    0 / 3 (0.00%)
    0 / 16 (0.00%)
    0 / 19 (0.00%)
    0 / 15 (0.00%)
    1 / 13 (7.69%)
         occurrences all number
    0
    0
    0
    0
    1
    Injury, poisoning and procedural complications
    Contusion
         subjects affected / exposed
    0 / 3 (0.00%)
    0 / 16 (0.00%)
    1 / 19 (5.26%)
    0 / 15 (0.00%)
    0 / 13 (0.00%)
         occurrences all number
    0
    0
    1
    0
    0
    Fall
         subjects affected / exposed
    0 / 3 (0.00%)
    1 / 16 (6.25%)
    2 / 19 (10.53%)
    1 / 15 (6.67%)
    3 / 13 (23.08%)
         occurrences all number
    0
    1
    2
    1
    7
    Fracture
         subjects affected / exposed
    0 / 3 (0.00%)
    0 / 16 (0.00%)
    0 / 19 (0.00%)
    0 / 15 (0.00%)
    1 / 13 (7.69%)
         occurrences all number
    0
    0
    0
    0
    1
    Laceration
         subjects affected / exposed
    0 / 3 (0.00%)
    0 / 16 (0.00%)
    0 / 19 (0.00%)
    1 / 15 (6.67%)
    0 / 13 (0.00%)
         occurrences all number
    0
    0
    0
    1
    0
    Incisional hernia
         subjects affected / exposed
    0 / 3 (0.00%)
    0 / 16 (0.00%)
    1 / 19 (5.26%)
    0 / 15 (0.00%)
    0 / 13 (0.00%)
         occurrences all number
    0
    0
    1
    0
    0
    Tendon rupture
         subjects affected / exposed
    0 / 3 (0.00%)
    0 / 16 (0.00%)
    0 / 19 (0.00%)
    1 / 15 (6.67%)
    0 / 13 (0.00%)
         occurrences all number
    0
    0
    0
    1
    0
    Wound
         subjects affected / exposed
    0 / 3 (0.00%)
    1 / 16 (6.25%)
    0 / 19 (0.00%)
    0 / 15 (0.00%)
    0 / 13 (0.00%)
         occurrences all number
    0
    1
    0
    0
    0
    Investigations
    Amylase increased
         subjects affected / exposed
    0 / 3 (0.00%)
    0 / 16 (0.00%)
    1 / 19 (5.26%)
    0 / 15 (0.00%)
    0 / 13 (0.00%)
         occurrences all number
    0
    0
    1
    0
    0
    Blood creatine phosphokinase increased
         subjects affected / exposed
    0 / 3 (0.00%)
    0 / 16 (0.00%)
    1 / 19 (5.26%)
    2 / 15 (13.33%)
    0 / 13 (0.00%)
         occurrences all number
    0
    0
    2
    2
    0
    Blood creatinine increased
         subjects affected / exposed
    0 / 3 (0.00%)
    0 / 16 (0.00%)
    2 / 19 (10.53%)
    0 / 15 (0.00%)
    0 / 13 (0.00%)
         occurrences all number
    0
    0
    3
    0
    0
    Blood fibrinogen increased
         subjects affected / exposed
    0 / 3 (0.00%)
    0 / 16 (0.00%)
    0 / 19 (0.00%)
    1 / 15 (6.67%)
    0 / 13 (0.00%)
         occurrences all number
    0
    0
    0
    1
    0
    Blood lactate dehydrogenase increased
         subjects affected / exposed
    0 / 3 (0.00%)
    0 / 16 (0.00%)
    1 / 19 (5.26%)
    0 / 15 (0.00%)
    0 / 13 (0.00%)
         occurrences all number
    0
    0
    1
    0
    0
    Blood magnesium decreased
         subjects affected / exposed
    0 / 3 (0.00%)
    0 / 16 (0.00%)
    1 / 19 (5.26%)
    0 / 15 (0.00%)
    0 / 13 (0.00%)
         occurrences all number
    0
    0
    1
    0
    0
    Blood pressure increased
         subjects affected / exposed
    0 / 3 (0.00%)
    0 / 16 (0.00%)
    0 / 19 (0.00%)
    0 / 15 (0.00%)
    1 / 13 (7.69%)
         occurrences all number
    0
    0
    0
    0
    2
    Blood urea increased
         subjects affected / exposed
    0 / 3 (0.00%)
    0 / 16 (0.00%)
    2 / 19 (10.53%)
    0 / 15 (0.00%)
    0 / 13 (0.00%)
         occurrences all number
    0
    0
    2
    0
    0
    Fibrin D dimer increased
         subjects affected / exposed
    0 / 3 (0.00%)
    0 / 16 (0.00%)
    0 / 19 (0.00%)
    1 / 15 (6.67%)
    0 / 13 (0.00%)
         occurrences all number
    0
    0
    0
    1
    0
    Cardiac murmur
         subjects affected / exposed
    0 / 3 (0.00%)
    0 / 16 (0.00%)
    1 / 19 (5.26%)
    0 / 15 (0.00%)
    0 / 13 (0.00%)
         occurrences all number
    0
    0
    1
    0
    0
    Haemoglobin decreased
         subjects affected / exposed
    0 / 3 (0.00%)
    0 / 16 (0.00%)
    3 / 19 (15.79%)
    0 / 15 (0.00%)
    0 / 13 (0.00%)
         occurrences all number
    0
    0
    3
    0
    0
    Lipase increased
         subjects affected / exposed
    0 / 3 (0.00%)
    0 / 16 (0.00%)
    1 / 19 (5.26%)
    0 / 15 (0.00%)
    0 / 13 (0.00%)
         occurrences all number
    0
    0
    1
    0
    0
    Lymphocyte count decreased
         subjects affected / exposed
    0 / 3 (0.00%)
    0 / 16 (0.00%)
    1 / 19 (5.26%)
    1 / 15 (6.67%)
    0 / 13 (0.00%)
         occurrences all number
    0
    0
    1
    1
    0
    Mean cell haemoglobin concentration decreased
         subjects affected / exposed
    0 / 3 (0.00%)
    0 / 16 (0.00%)
    1 / 19 (5.26%)
    0 / 15 (0.00%)
    0 / 13 (0.00%)
         occurrences all number
    0
    0
    1
    0
    0
    Neutrophil count increased
         subjects affected / exposed
    0 / 3 (0.00%)
    0 / 16 (0.00%)
    0 / 19 (0.00%)
    1 / 15 (6.67%)
    0 / 13 (0.00%)
         occurrences all number
    0
    0
    0
    1
    0
    Platelet count decreased
         subjects affected / exposed
    0 / 3 (0.00%)
    0 / 16 (0.00%)
    0 / 19 (0.00%)
    1 / 15 (6.67%)
    0 / 13 (0.00%)
         occurrences all number
    0
    0
    0
    1
    0
    Red blood cell count decreased
         subjects affected / exposed
    0 / 3 (0.00%)
    0 / 16 (0.00%)
    1 / 19 (5.26%)
    0 / 15 (0.00%)
    0 / 13 (0.00%)
         occurrences all number
    0
    0
    1
    0
    0
    Weight decreased
         subjects affected / exposed
    0 / 3 (0.00%)
    0 / 16 (0.00%)
    3 / 19 (15.79%)
    1 / 15 (6.67%)
    2 / 13 (15.38%)
         occurrences all number
    0
    0
    3
    1
    2
    White blood cell count decreased
         subjects affected / exposed
    0 / 3 (0.00%)
    0 / 16 (0.00%)
    1 / 19 (5.26%)
    0 / 15 (0.00%)
    0 / 13 (0.00%)
         occurrences all number
    0
    0
    1
    0
    0
    Weight increased
         subjects affected / exposed
    0 / 3 (0.00%)
    0 / 16 (0.00%)
    0 / 19 (0.00%)
    1 / 15 (6.67%)
    0 / 13 (0.00%)
         occurrences all number
    0
    0
    0
    1
    0
    White blood cells urine positive
         subjects affected / exposed
    0 / 3 (0.00%)
    0 / 16 (0.00%)
    1 / 19 (5.26%)
    0 / 15 (0.00%)
    0 / 13 (0.00%)
         occurrences all number
    0
    0
    1
    0
    0
    Cardiac disorders
    Acute myocardial infarction
         subjects affected / exposed
    0 / 3 (0.00%)
    0 / 16 (0.00%)
    1 / 19 (5.26%)
    0 / 15 (0.00%)
    0 / 13 (0.00%)
         occurrences all number
    0
    0
    1
    0
    0
    Arrhythmia
         subjects affected / exposed
    0 / 3 (0.00%)
    1 / 16 (6.25%)
    0 / 19 (0.00%)
    0 / 15 (0.00%)
    0 / 13 (0.00%)
         occurrences all number
    0
    1
    0
    0
    0
    Atrial fibrillation
         subjects affected / exposed
    0 / 3 (0.00%)
    0 / 16 (0.00%)
    0 / 19 (0.00%)
    1 / 15 (6.67%)
    0 / 13 (0.00%)
         occurrences all number
    0
    0
    0
    1
    0
    Atrioventricular block first degree
         subjects affected / exposed
    0 / 3 (0.00%)
    0 / 16 (0.00%)
    1 / 19 (5.26%)
    0 / 15 (0.00%)
    0 / 13 (0.00%)
         occurrences all number
    0
    0
    1
    0
    0
    Respiratory, thoracic and mediastinal disorders
    Allergic cough
         subjects affected / exposed
    0 / 3 (0.00%)
    0 / 16 (0.00%)
    1 / 19 (5.26%)
    0 / 15 (0.00%)
    0 / 13 (0.00%)
         occurrences all number
    0
    0
    1
    0
    0
    Cough
         subjects affected / exposed
    0 / 3 (0.00%)
    0 / 16 (0.00%)
    0 / 19 (0.00%)
    0 / 15 (0.00%)
    1 / 13 (7.69%)
         occurrences all number
    0
    0
    0
    0
    1
    Dyspnoea
         subjects affected / exposed
    0 / 3 (0.00%)
    1 / 16 (6.25%)
    2 / 19 (10.53%)
    0 / 15 (0.00%)
    0 / 13 (0.00%)
         occurrences all number
    0
    1
    2
    0
    0
    Epistaxis
         subjects affected / exposed
    0 / 3 (0.00%)
    1 / 16 (6.25%)
    1 / 19 (5.26%)
    1 / 15 (6.67%)
    0 / 13 (0.00%)
         occurrences all number
    0
    2
    1
    4
    0
    Hyperventilation
         subjects affected / exposed
    0 / 3 (0.00%)
    0 / 16 (0.00%)
    1 / 19 (5.26%)
    0 / 15 (0.00%)
    0 / 13 (0.00%)
         occurrences all number
    0
    0
    1
    0
    0
    Blood and lymphatic system disorders
    Bicytopenia
         subjects affected / exposed
    0 / 3 (0.00%)
    0 / 16 (0.00%)
    0 / 19 (0.00%)
    1 / 15 (6.67%)
    0 / 13 (0.00%)
         occurrences all number
    0
    0
    0
    1
    0
    Anaemia
         subjects affected / exposed
    0 / 3 (0.00%)
    2 / 16 (12.50%)
    0 / 19 (0.00%)
    0 / 15 (0.00%)
    0 / 13 (0.00%)
         occurrences all number
    0
    2
    0
    0
    0
    Leukopenia
         subjects affected / exposed
    0 / 3 (0.00%)
    1 / 16 (6.25%)
    0 / 19 (0.00%)
    0 / 15 (0.00%)
    0 / 13 (0.00%)
         occurrences all number
    0
    1
    0
    0
    0
    Eosinophilia
         subjects affected / exposed
    0 / 3 (0.00%)
    0 / 16 (0.00%)
    0 / 19 (0.00%)
    0 / 15 (0.00%)
    1 / 13 (7.69%)
         occurrences all number
    0
    0
    0
    0
    1
    Nervous system disorders
    Akinesia
         subjects affected / exposed
    0 / 3 (0.00%)
    4 / 16 (25.00%)
    0 / 19 (0.00%)
    3 / 15 (20.00%)
    1 / 13 (7.69%)
         occurrences all number
    0
    4
    0
    3
    1
    Bradykinesia
         subjects affected / exposed
    0 / 3 (0.00%)
    0 / 16 (0.00%)
    1 / 19 (5.26%)
    0 / 15 (0.00%)
    0 / 13 (0.00%)
         occurrences all number
    0
    0
    1
    0
    0
    Cognitive disorder
         subjects affected / exposed
    0 / 3 (0.00%)
    0 / 16 (0.00%)
    1 / 19 (5.26%)
    0 / 15 (0.00%)
    0 / 13 (0.00%)
         occurrences all number
    0
    0
    1
    0
    0
    Carpal tunnel syndrome
         subjects affected / exposed
    0 / 3 (0.00%)
    1 / 16 (6.25%)
    0 / 19 (0.00%)
    1 / 15 (6.67%)
    0 / 13 (0.00%)
         occurrences all number
    0
    1
    0
    1
    0
    Coordination abnormal
         subjects affected / exposed
    0 / 3 (0.00%)
    0 / 16 (0.00%)
    0 / 19 (0.00%)
    1 / 15 (6.67%)
    0 / 13 (0.00%)
         occurrences all number
    0
    0
    0
    1
    0
    Depressed level of consciousness
         subjects affected / exposed
    0 / 3 (0.00%)
    0 / 16 (0.00%)
    0 / 19 (0.00%)
    0 / 15 (0.00%)
    1 / 13 (7.69%)
         occurrences all number
    0
    0
    0
    0
    1
    Disturbance in attention
         subjects affected / exposed
    1 / 3 (33.33%)
    1 / 16 (6.25%)
    1 / 19 (5.26%)
    2 / 15 (13.33%)
    0 / 13 (0.00%)
         occurrences all number
    1
    1
    1
    2
    0
    Dizziness
         subjects affected / exposed
    0 / 3 (0.00%)
    2 / 16 (12.50%)
    4 / 19 (21.05%)
    6 / 15 (40.00%)
    5 / 13 (38.46%)
         occurrences all number
    0
    4
    4
    8
    5
    Dysarthria
         subjects affected / exposed
    0 / 3 (0.00%)
    0 / 16 (0.00%)
    0 / 19 (0.00%)
    1 / 15 (6.67%)
    0 / 13 (0.00%)
         occurrences all number
    0
    0
    0
    1
    0
    Dysgeusia
         subjects affected / exposed
    0 / 3 (0.00%)
    0 / 16 (0.00%)
    1 / 19 (5.26%)
    0 / 15 (0.00%)
    0 / 13 (0.00%)
         occurrences all number
    0
    0
    1
    0
    0
    Dyskinesia
         subjects affected / exposed
    0 / 3 (0.00%)
    3 / 16 (18.75%)
    3 / 19 (15.79%)
    3 / 15 (20.00%)
    2 / 13 (15.38%)
         occurrences all number
    0
    3
    5
    3
    2
    Dystonia
         subjects affected / exposed
    0 / 3 (0.00%)
    0 / 16 (0.00%)
    0 / 19 (0.00%)
    1 / 15 (6.67%)
    0 / 13 (0.00%)
         occurrences all number
    0
    0
    0
    1
    0
    Headache
         subjects affected / exposed
    0 / 3 (0.00%)
    3 / 16 (18.75%)
    3 / 19 (15.79%)
    3 / 15 (20.00%)
    1 / 13 (7.69%)
         occurrences all number
    0
    5
    3
    3
    1
    Freezing phenomenon
         subjects affected / exposed
    0 / 3 (0.00%)
    2 / 16 (12.50%)
    2 / 19 (10.53%)
    0 / 15 (0.00%)
    1 / 13 (7.69%)
         occurrences all number
    0
    2
    4
    0
    1
    Hyperkinesia
         subjects affected / exposed
    0 / 3 (0.00%)
    0 / 16 (0.00%)
    1 / 19 (5.26%)
    0 / 15 (0.00%)
    0 / 13 (0.00%)
         occurrences all number
    0
    0
    1
    0
    0
    Hypersomnia
         subjects affected / exposed
    0 / 3 (0.00%)
    0 / 16 (0.00%)
    2 / 19 (10.53%)
    0 / 15 (0.00%)
    0 / 13 (0.00%)
         occurrences all number
    0
    0
    2
    0
    0
    Hypoaesthesia
         subjects affected / exposed
    0 / 3 (0.00%)
    2 / 16 (12.50%)
    1 / 19 (5.26%)
    1 / 15 (6.67%)
    0 / 13 (0.00%)
         occurrences all number
    0
    2
    1
    1
    0
    Memory impairment
         subjects affected / exposed
    0 / 3 (0.00%)
    0 / 16 (0.00%)
    0 / 19 (0.00%)
    1 / 15 (6.67%)
    0 / 13 (0.00%)
         occurrences all number
    0
    0
    0
    1
    0
    Motor dysfunction
         subjects affected / exposed
    0 / 3 (0.00%)
    0 / 16 (0.00%)
    1 / 19 (5.26%)
    0 / 15 (0.00%)
    0 / 13 (0.00%)
         occurrences all number
    0
    0
    1
    0
    0
    On and off phenomenon
         subjects affected / exposed
    2 / 3 (66.67%)
    2 / 16 (12.50%)
    6 / 19 (31.58%)
    2 / 15 (13.33%)
    1 / 13 (7.69%)
         occurrences all number
    2
    2
    9
    2
    1
    Paraesthesia
         subjects affected / exposed
    1 / 3 (33.33%)
    1 / 16 (6.25%)
    0 / 19 (0.00%)
    1 / 15 (6.67%)
    0 / 13 (0.00%)
         occurrences all number
    1
    1
    0
    1
    0
    Parkinson's disease
         subjects affected / exposed
    0 / 3 (0.00%)
    0 / 16 (0.00%)
    1 / 19 (5.26%)
    5 / 15 (33.33%)
    2 / 13 (15.38%)
         occurrences all number
    0
    0
    1
    5
    4
    Sciatica
         subjects affected / exposed
    0 / 3 (0.00%)
    0 / 16 (0.00%)
    0 / 19 (0.00%)
    1 / 15 (6.67%)
    1 / 13 (7.69%)
         occurrences all number
    0
    0
    0
    1
    1
    Restless legs syndrome
         subjects affected / exposed
    0 / 3 (0.00%)
    0 / 16 (0.00%)
    1 / 19 (5.26%)
    0 / 15 (0.00%)
    1 / 13 (7.69%)
         occurrences all number
    0
    0
    1
    0
    1
    Presyncope
         subjects affected / exposed
    0 / 3 (0.00%)
    0 / 16 (0.00%)
    0 / 19 (0.00%)
    0 / 15 (0.00%)
    1 / 13 (7.69%)
         occurrences all number
    0
    0
    0
    0
    1
    Sensory disturbance
         subjects affected / exposed
    0 / 3 (0.00%)
    0 / 16 (0.00%)
    0 / 19 (0.00%)
    1 / 15 (6.67%)
    0 / 13 (0.00%)
         occurrences all number
    0
    0
    0
    1
    0
    Somnolence
         subjects affected / exposed
    0 / 3 (0.00%)
    4 / 16 (25.00%)
    2 / 19 (10.53%)
    1 / 15 (6.67%)
    2 / 13 (15.38%)
         occurrences all number
    0
    4
    2
    1
    2
    Speech disorder
         subjects affected / exposed
    0 / 3 (0.00%)
    0 / 16 (0.00%)
    1 / 19 (5.26%)
    0 / 15 (0.00%)
    0 / 13 (0.00%)
         occurrences all number
    0
    0
    1
    0
    0
    Stupor
         subjects affected / exposed
    0 / 3 (0.00%)
    0 / 16 (0.00%)
    0 / 19 (0.00%)
    0 / 15 (0.00%)
    1 / 13 (7.69%)
         occurrences all number
    0
    0
    0
    0
    1
    Syncope
         subjects affected / exposed
    0 / 3 (0.00%)
    0 / 16 (0.00%)
    1 / 19 (5.26%)
    0 / 15 (0.00%)
    0 / 13 (0.00%)
         occurrences all number
    0
    0
    1
    0
    0
    Eye disorders
    Altered visual depth perception
         subjects affected / exposed
    0 / 3 (0.00%)
    0 / 16 (0.00%)
    0 / 19 (0.00%)
    0 / 15 (0.00%)
    1 / 13 (7.69%)
         occurrences all number
    0
    0
    0
    0
    1
    Cataract
         subjects affected / exposed
    0 / 3 (0.00%)
    0 / 16 (0.00%)
    0 / 19 (0.00%)
    0 / 15 (0.00%)
    1 / 13 (7.69%)
         occurrences all number
    0
    0
    0
    0
    2
    Diplopia
         subjects affected / exposed
    0 / 3 (0.00%)
    0 / 16 (0.00%)
    0 / 19 (0.00%)
    0 / 15 (0.00%)
    1 / 13 (7.69%)
         occurrences all number
    0
    0
    0
    0
    1
    Photophobia
         subjects affected / exposed
    0 / 3 (0.00%)
    1 / 16 (6.25%)
    0 / 19 (0.00%)
    0 / 15 (0.00%)
    0 / 13 (0.00%)
         occurrences all number
    0
    1
    0
    0
    0
    Vision blurred
         subjects affected / exposed
    0 / 3 (0.00%)
    2 / 16 (12.50%)
    1 / 19 (5.26%)
    0 / 15 (0.00%)
    0 / 13 (0.00%)
         occurrences all number
    0
    2
    1
    0
    0
    Visual impairment
         subjects affected / exposed
    0 / 3 (0.00%)
    2 / 16 (12.50%)
    2 / 19 (10.53%)
    0 / 15 (0.00%)
    1 / 13 (7.69%)
         occurrences all number
    0
    2
    2
    0
    1
    Ear and labyrinth disorders
    Tinnitus
         subjects affected / exposed
    0 / 3 (0.00%)
    0 / 16 (0.00%)
    0 / 19 (0.00%)
    2 / 15 (13.33%)
    0 / 13 (0.00%)
         occurrences all number
    0
    0
    0
    2
    0
    Vertigo
         subjects affected / exposed
    0 / 3 (0.00%)
    1 / 16 (6.25%)
    0 / 19 (0.00%)
    0 / 15 (0.00%)
    0 / 13 (0.00%)
         occurrences all number
    0
    2
    0
    0
    0
    Gastrointestinal disorders
    Abdominal discomfort
         subjects affected / exposed
    0 / 3 (0.00%)
    1 / 16 (6.25%)
    0 / 19 (0.00%)
    0 / 15 (0.00%)
    0 / 13 (0.00%)
         occurrences all number
    0
    1
    0
    0
    0
    Abdominal pain upper
         subjects affected / exposed
    1 / 3 (33.33%)
    0 / 16 (0.00%)
    0 / 19 (0.00%)
    0 / 15 (0.00%)
    1 / 13 (7.69%)
         occurrences all number
    1
    0
    0
    0
    1
    Constipation
         subjects affected / exposed
    0 / 3 (0.00%)
    0 / 16 (0.00%)
    3 / 19 (15.79%)
    1 / 15 (6.67%)
    0 / 13 (0.00%)
         occurrences all number
    0
    0
    3
    1
    0
    Diarrhoea
         subjects affected / exposed
    0 / 3 (0.00%)
    0 / 16 (0.00%)
    1 / 19 (5.26%)
    1 / 15 (6.67%)
    0 / 13 (0.00%)
         occurrences all number
    0
    0
    1
    1
    0
    Dental caries
         subjects affected / exposed
    0 / 3 (0.00%)
    0 / 16 (0.00%)
    1 / 19 (5.26%)
    0 / 15 (0.00%)
    0 / 13 (0.00%)
         occurrences all number
    0
    0
    1
    0
    0
    Flatulence
         subjects affected / exposed
    0 / 3 (0.00%)
    0 / 16 (0.00%)
    1 / 19 (5.26%)
    0 / 15 (0.00%)
    0 / 13 (0.00%)
         occurrences all number
    0
    0
    1
    0
    0
    Dry mouth
         subjects affected / exposed
    0 / 3 (0.00%)
    0 / 16 (0.00%)
    1 / 19 (5.26%)
    2 / 15 (13.33%)
    0 / 13 (0.00%)
         occurrences all number
    0
    0
    1
    2
    0
    Gastrointestinal hypermotility
         subjects affected / exposed
    0 / 3 (0.00%)
    0 / 16 (0.00%)
    0 / 19 (0.00%)
    1 / 15 (6.67%)
    0 / 13 (0.00%)
         occurrences all number
    0
    0
    0
    1
    0
    Nausea
         subjects affected / exposed
    1 / 3 (33.33%)
    2 / 16 (12.50%)
    1 / 19 (5.26%)
    0 / 15 (0.00%)
    0 / 13 (0.00%)
         occurrences all number
    1
    2
    1
    0
    0
    Hypoaesthesia oral
         subjects affected / exposed
    0 / 3 (0.00%)
    1 / 16 (6.25%)
    0 / 19 (0.00%)
    0 / 15 (0.00%)
    0 / 13 (0.00%)
         occurrences all number
    0
    1
    0
    0
    0
    Paraesthesia oral
         subjects affected / exposed
    0 / 3 (0.00%)
    0 / 16 (0.00%)
    0 / 19 (0.00%)
    1 / 15 (6.67%)
    0 / 13 (0.00%)
         occurrences all number
    0
    0
    0
    1
    0
    Vomiting
         subjects affected / exposed
    1 / 3 (33.33%)
    0 / 16 (0.00%)
    2 / 19 (10.53%)
    0 / 15 (0.00%)
    0 / 13 (0.00%)
         occurrences all number
    1
    0
    2
    0
    0
    Renal and urinary disorders
    Micturition urgency
         subjects affected / exposed
    0 / 3 (0.00%)
    0 / 16 (0.00%)
    0 / 19 (0.00%)
    0 / 15 (0.00%)
    1 / 13 (7.69%)
         occurrences all number
    0
    0
    0
    0
    1
    Pollakiuria
         subjects affected / exposed
    0 / 3 (0.00%)
    0 / 16 (0.00%)
    1 / 19 (5.26%)
    0 / 15 (0.00%)
    0 / 13 (0.00%)
         occurrences all number
    0
    0
    1
    0
    0
    Renal failure
         subjects affected / exposed
    0 / 3 (0.00%)
    0 / 16 (0.00%)
    1 / 19 (5.26%)
    0 / 15 (0.00%)
    0 / 13 (0.00%)
         occurrences all number
    0
    0
    1
    0
    0
    Renal failure chronic
         subjects affected / exposed
    0 / 3 (0.00%)
    0 / 16 (0.00%)
    1 / 19 (5.26%)
    0 / 15 (0.00%)
    0 / 13 (0.00%)
         occurrences all number
    0
    0
    1
    0
    0
    Urge incontinence
         subjects affected / exposed
    0 / 3 (0.00%)
    0 / 16 (0.00%)
    0 / 19 (0.00%)
    1 / 15 (6.67%)
    0 / 13 (0.00%)
         occurrences all number
    0
    0
    0
    1
    0
    Urinary incontinence
         subjects affected / exposed
    0 / 3 (0.00%)
    0 / 16 (0.00%)
    2 / 19 (10.53%)
    0 / 15 (0.00%)
    0 / 13 (0.00%)
         occurrences all number
    0
    0
    2
    0
    0
    Skin and subcutaneous tissue disorders
    Pruritus
         subjects affected / exposed
    0 / 3 (0.00%)
    0 / 16 (0.00%)
    0 / 19 (0.00%)
    0 / 15 (0.00%)
    1 / 13 (7.69%)
         occurrences all number
    0
    0
    0
    0
    2
    Onycholysis
         subjects affected / exposed
    0 / 3 (0.00%)
    0 / 16 (0.00%)
    1 / 19 (5.26%)
    0 / 15 (0.00%)
    0 / 13 (0.00%)
         occurrences all number
    0
    0
    1
    0
    0
    Alopecia
         subjects affected / exposed
    0 / 3 (0.00%)
    0 / 16 (0.00%)
    1 / 19 (5.26%)
    1 / 15 (6.67%)
    0 / 13 (0.00%)
         occurrences all number
    0
    0
    1
    1
    0
    Rash
         subjects affected / exposed
    0 / 3 (0.00%)
    0 / 16 (0.00%)
    0 / 19 (0.00%)
    1 / 15 (6.67%)
    1 / 13 (7.69%)
         occurrences all number
    0
    0
    0
    1
    1
    Skin discolouration
         subjects affected / exposed
    0 / 3 (0.00%)
    0 / 16 (0.00%)
    0 / 19 (0.00%)
    1 / 15 (6.67%)
    0 / 13 (0.00%)
         occurrences all number
    0
    0
    0
    1
    0
    Musculoskeletal and connective tissue disorders
    Arthralgia
         subjects affected / exposed
    0 / 3 (0.00%)
    0 / 16 (0.00%)
    1 / 19 (5.26%)
    0 / 15 (0.00%)
    1 / 13 (7.69%)
         occurrences all number
    0
    0
    1
    0
    1
    Back pain
         subjects affected / exposed
    0 / 3 (0.00%)
    0 / 16 (0.00%)
    2 / 19 (10.53%)
    5 / 15 (33.33%)
    1 / 13 (7.69%)
         occurrences all number
    0
    0
    2
    5
    1
    Bursitis
         subjects affected / exposed
    0 / 3 (0.00%)
    0 / 16 (0.00%)
    2 / 19 (10.53%)
    0 / 15 (0.00%)
    1 / 13 (7.69%)
         occurrences all number
    0
    0
    2
    0
    1
    Fracture pain
         subjects affected / exposed
    0 / 3 (0.00%)
    0 / 16 (0.00%)
    0 / 19 (0.00%)
    1 / 15 (6.67%)
    0 / 13 (0.00%)
         occurrences all number
    0
    0
    0
    1
    0
    Mobility decreased
         subjects affected / exposed
    0 / 3 (0.00%)
    0 / 16 (0.00%)
    1 / 19 (5.26%)
    0 / 15 (0.00%)
    0 / 13 (0.00%)
         occurrences all number
    0
    0
    1
    0
    0
    Muscle spasms
         subjects affected / exposed
    0 / 3 (0.00%)
    0 / 16 (0.00%)
    0 / 19 (0.00%)
    2 / 15 (13.33%)
    1 / 13 (7.69%)
         occurrences all number
    0
    0
    0
    2
    1
    Musculoskeletal pain
         subjects affected / exposed
    0 / 3 (0.00%)
    0 / 16 (0.00%)
    0 / 19 (0.00%)
    0 / 15 (0.00%)
    1 / 13 (7.69%)
         occurrences all number
    0
    0
    0
    0
    1
    Musculoskeletal stiffness
         subjects affected / exposed
    0 / 3 (0.00%)
    0 / 16 (0.00%)
    1 / 19 (5.26%)
    1 / 15 (6.67%)
    0 / 13 (0.00%)
         occurrences all number
    0
    0
    1
    1
    0
    Neck pain
         subjects affected / exposed
    1 / 3 (33.33%)
    0 / 16 (0.00%)
    0 / 19 (0.00%)
    0 / 15 (0.00%)
    0 / 13 (0.00%)
         occurrences all number
    1
    0
    0
    0
    0
    Osteoarthritis
         subjects affected / exposed
    0 / 3 (0.00%)
    0 / 16 (0.00%)
    0 / 19 (0.00%)
    1 / 15 (6.67%)
    0 / 13 (0.00%)
         occurrences all number
    0
    0
    0
    1
    0
    Rotator cuff syndrome
         subjects affected / exposed
    0 / 3 (0.00%)
    0 / 16 (0.00%)
    1 / 19 (5.26%)
    0 / 15 (0.00%)
    0 / 13 (0.00%)
         occurrences all number
    0
    0
    1
    0
    0
    Pain in extremity
         subjects affected / exposed
    0 / 3 (0.00%)
    2 / 16 (12.50%)
    1 / 19 (5.26%)
    1 / 15 (6.67%)
    2 / 13 (15.38%)
         occurrences all number
    0
    2
    1
    1
    2
    Spinal pain
         subjects affected / exposed
    0 / 3 (0.00%)
    1 / 16 (6.25%)
    0 / 19 (0.00%)
    0 / 15 (0.00%)
    0 / 13 (0.00%)
         occurrences all number
    0
    1
    0
    0
    0
    Trigger finger
         subjects affected / exposed
    0 / 3 (0.00%)
    0 / 16 (0.00%)
    0 / 19 (0.00%)
    1 / 15 (6.67%)
    0 / 13 (0.00%)
         occurrences all number
    0
    0
    0
    1
    0
    Endocrine disorders
    Hyperthyroidism
         subjects affected / exposed
    0 / 3 (0.00%)
    0 / 16 (0.00%)
    0 / 19 (0.00%)
    1 / 15 (6.67%)
    0 / 13 (0.00%)
         occurrences all number
    0
    0
    0
    1
    0
    Metabolism and nutrition disorders
    Decreased appetite
         subjects affected / exposed
    1 / 3 (33.33%)
    0 / 16 (0.00%)
    1 / 19 (5.26%)
    1 / 15 (6.67%)
    0 / 13 (0.00%)
         occurrences all number
    1
    0
    1
    1
    0
    Diabetes mellitus inadequate control
         subjects affected / exposed
    0 / 3 (0.00%)
    0 / 16 (0.00%)
    0 / 19 (0.00%)
    0 / 15 (0.00%)
    1 / 13 (7.69%)
         occurrences all number
    0
    0
    0
    0
    1
    Gout
         subjects affected / exposed
    0 / 3 (0.00%)
    0 / 16 (0.00%)
    1 / 19 (5.26%)
    0 / 15 (0.00%)
    0 / 13 (0.00%)
         occurrences all number
    0
    0
    1
    0
    0
    Hypercholesterolaemia
         subjects affected / exposed
    0 / 3 (0.00%)
    0 / 16 (0.00%)
    0 / 19 (0.00%)
    0 / 15 (0.00%)
    1 / 13 (7.69%)
         occurrences all number
    0
    0
    0
    0
    1
    Iron deficiency
         subjects affected / exposed
    0 / 3 (0.00%)
    1 / 16 (6.25%)
    0 / 19 (0.00%)
    0 / 15 (0.00%)
    0 / 13 (0.00%)
         occurrences all number
    0
    1
    0
    0
    0
    Vitamin B12 deficiency
         subjects affected / exposed
    0 / 3 (0.00%)
    0 / 16 (0.00%)
    0 / 19 (0.00%)
    0 / 15 (0.00%)
    1 / 13 (7.69%)
         occurrences all number
    0
    0
    0
    0
    1
    Vitamin D deficiency
         subjects affected / exposed
    0 / 3 (0.00%)
    0 / 16 (0.00%)
    0 / 19 (0.00%)
    1 / 15 (6.67%)
    0 / 13 (0.00%)
         occurrences all number
    0
    0
    0
    1
    0
    Infections and infestations
    Abscess limb
         subjects affected / exposed
    0 / 3 (0.00%)
    1 / 16 (6.25%)
    0 / 19 (0.00%)
    0 / 15 (0.00%)
    0 / 13 (0.00%)
         occurrences all number
    0
    1
    0
    0
    0
    Cellulitis
         subjects affected / exposed
    0 / 3 (0.00%)
    0 / 16 (0.00%)
    1 / 19 (5.26%)
    0 / 15 (0.00%)
    0 / 13 (0.00%)
         occurrences all number
    0
    0
    2
    0
    0
    Bronchitis
         subjects affected / exposed
    0 / 3 (0.00%)
    0 / 16 (0.00%)
    0 / 19 (0.00%)
    1 / 15 (6.67%)
    0 / 13 (0.00%)
         occurrences all number
    0
    0
    0
    1
    0
    Ear infection
         subjects affected / exposed
    0 / 3 (0.00%)
    1 / 16 (6.25%)
    0 / 19 (0.00%)
    0 / 15 (0.00%)
    0 / 13 (0.00%)
         occurrences all number
    0
    1
    0
    0
    0
    Folliculitis
         subjects affected / exposed
    0 / 3 (0.00%)
    0 / 16 (0.00%)
    1 / 19 (5.26%)
    0 / 15 (0.00%)
    0 / 13 (0.00%)
         occurrences all number
    0
    0
    1
    0
    0
    Influenza
         subjects affected / exposed
    0 / 3 (0.00%)
    0 / 16 (0.00%)
    1 / 19 (5.26%)
    0 / 15 (0.00%)
    0 / 13 (0.00%)
         occurrences all number
    0
    0
    1
    0
    0
    Gastroenteritis
         subjects affected / exposed
    0 / 3 (0.00%)
    0 / 16 (0.00%)
    0 / 19 (0.00%)
    1 / 15 (6.67%)
    0 / 13 (0.00%)
         occurrences all number
    0
    0
    0
    1
    0
    Nasopharyngitis
         subjects affected / exposed
    0 / 3 (0.00%)
    2 / 16 (12.50%)
    0 / 19 (0.00%)
    3 / 15 (20.00%)
    0 / 13 (0.00%)
         occurrences all number
    0
    3
    0
    4
    0
    Oral candidiasis
         subjects affected / exposed
    0 / 3 (0.00%)
    0 / 16 (0.00%)
    0 / 19 (0.00%)
    1 / 15 (6.67%)
    0 / 13 (0.00%)
         occurrences all number
    0
    0
    0
    1
    0
    Onychomycosis
         subjects affected / exposed
    0 / 3 (0.00%)
    0 / 16 (0.00%)
    1 / 19 (5.26%)
    0 / 15 (0.00%)
    0 / 13 (0.00%)
         occurrences all number
    0
    0
    1
    0
    0
    Paronychia
         subjects affected / exposed
    0 / 3 (0.00%)
    0 / 16 (0.00%)
    1 / 19 (5.26%)
    0 / 15 (0.00%)
    0 / 13 (0.00%)
         occurrences all number
    0
    0
    1
    0
    0
    Pneumonia
         subjects affected / exposed
    0 / 3 (0.00%)
    0 / 16 (0.00%)
    1 / 19 (5.26%)
    0 / 15 (0.00%)
    0 / 13 (0.00%)
         occurrences all number
    0
    0
    1
    0
    0
    Pulpitis dental
         subjects affected / exposed
    0 / 3 (0.00%)
    1 / 16 (6.25%)
    0 / 19 (0.00%)
    0 / 15 (0.00%)
    0 / 13 (0.00%)
         occurrences all number
    0
    2
    0
    0
    0
    Rhinitis
         subjects affected / exposed
    0 / 3 (0.00%)
    0 / 16 (0.00%)
    0 / 19 (0.00%)
    1 / 15 (6.67%)
    0 / 13 (0.00%)
         occurrences all number
    0
    0
    0
    1
    0
    Sialoadenitis
         subjects affected / exposed
    0 / 3 (0.00%)
    1 / 16 (6.25%)
    0 / 19 (0.00%)
    0 / 15 (0.00%)
    0 / 13 (0.00%)
         occurrences all number
    0
    1
    0
    0
    0
    Tooth infection
         subjects affected / exposed
    0 / 3 (0.00%)
    0 / 16 (0.00%)
    0 / 19 (0.00%)
    2 / 15 (13.33%)
    0 / 13 (0.00%)
         occurrences all number
    0
    0
    0
    2
    0
    Tracheitis
         subjects affected / exposed
    0 / 3 (0.00%)
    0 / 16 (0.00%)
    1 / 19 (5.26%)
    0 / 15 (0.00%)
    0 / 13 (0.00%)
         occurrences all number
    0
    0
    1
    0
    0
    Urinary tract infection
         subjects affected / exposed
    0 / 3 (0.00%)
    1 / 16 (6.25%)
    3 / 19 (15.79%)
    2 / 15 (13.33%)
    0 / 13 (0.00%)
         occurrences all number
    0
    1
    3
    4
    0
    Upper respiratory tract infection
         subjects affected / exposed
    0 / 3 (0.00%)
    0 / 16 (0.00%)
    0 / 19 (0.00%)
    0 / 15 (0.00%)
    1 / 13 (7.69%)
         occurrences all number
    0
    0
    0
    0
    2
    Urosepsis
         subjects affected / exposed
    0 / 3 (0.00%)
    0 / 16 (0.00%)
    1 / 19 (5.26%)
    0 / 15 (0.00%)
    0 / 13 (0.00%)
         occurrences all number
    0
    0
    1
    0
    0

    More information

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    Substantial protocol amendments (globally)

    Were there any global substantial amendments to the protocol? Yes
    Date
    Amendment
    09 Nov 2011
    The protocol is being amended to eliminate the lowest dose (10 mg b.i.d.) based on the results from study CAFQ056A2208. The analyses showed that the dose of 10 mg b.i.d. was nonefficacious and there was a trend for improvement at the dose of 25 mg b.i.d. and a statistically significant improvement at the 100 mg b.i.d. dose. This suggests that patients are unlikely to benefit at the 10 mg b.i.d. dose but may start to see improvement at 25 mg b.i.d. As a result, the 10 mg b.i.d. dose (capsule strength 5 mg) will no longer be provided in this study. The amended protocol also eliminates the previous restrictions on the use of centrally acting anti-cholinergic medication. This exclusion was included in the original protocol as a general precaution to avoid unwarranted side effects due to (centrally mediated) anti-cholinergic effects in this patient population. Elimination of this restriction is in the patients’ best interest as it provides investigators with additional treatment options where appropriate. A potential interaction between the study drug and isoflurane (an inhalational drug used for anesthesia in surgery) was found in a single animal experiment with mice, but was not seen in a bigger mouse study or in several other studies in rats. No experience in humans exists. Therefore, isoflurane is being added to the list of prohibited medications as a precautionary measure. This warning is already included in the Investigator Brochure, Patient Information Card, and the patient Informed Consent Form.

    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.
    The study was terminated based on the results of studies CAFQ056A2222 and CAFQ056A2223 (due to lack of efficacy) and the sponsor’s decision to terminate the program.
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