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    Clinical Trial Results:
    A 5-year study to compare the durability of glycemic control of a combination regimen with vildagliptin & metformin versus standard-of-care monotherapy with metformin, initiated in treatment-naïve patients with type 2 diabetes mellitus

    Summary
    EudraCT number
    		 2011-003712-23
    Trial protocol
    		 LT   FI   LV   IT   HU   DE   EE   SK   BG   PL   NO   CZ   AT   ES  
    Global end of trial date
    04 Apr 2019

    Results information
    Results version number
    		 v1(current)
    This version publication date
    15 Apr 2020
    First version publication date
    15 Apr 2020
    Other versions

    Trial information

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    Trial identification
    Sponsor protocol code
    CLAF237A23156
    Additional study identifiers
    ISRCTN number
    		 -
    US NCT number
    		 NCT01528254
    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, Novartis.email@novartis.com
    Scientific contact
    Clinical Disclosure Office, Novartis Pharma AG, 41 613241111, Novartis.email@novartis.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
    04 Apr 2019
    Is this the analysis of the primary completion data?
    Yes
    Primary completion date
    04 Apr 2019
    Global end of trial reached?
    Yes
    Global end of trial date
    04 Apr 2019
    Was the trial ended prematurely?
    No
    General information about the trial
    Main objective of the trial
    The primary objective was to demonstrate the superiority of combination of vildagliptin 50mg bid and metformin over metformin monotherapy in treatment-naïve patients with T2DM by testing the hypothesis that the risk of confirmed initial treatment failure (defined as HbA1c ≥ 7.0%) is lower with the combination of vildagliptin and metformin compared to that with metformin monotherapy
    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
    30 Mar 2012
    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
    Argentina: 147
    Country: Number of subjects enrolled
    Australia: 10
    Country: Number of subjects enrolled
    Austria: 3
    Country: Number of subjects enrolled
    Brazil: 59
    Country: Number of subjects enrolled
    Bulgaria: 108
    Country: Number of subjects enrolled
    Colombia: 51
    Country: Number of subjects enrolled
    Czech Republic: 26
    Country: Number of subjects enrolled
    Dominican Republic: 15
    Country: Number of subjects enrolled
    Estonia: 17
    Country: Number of subjects enrolled
    Finland: 18
    Country: Number of subjects enrolled
    Germany: 59
    Country: Number of subjects enrolled
    Guatemala: 117
    Country: Number of subjects enrolled
    Hong Kong: 29
    Country: Number of subjects enrolled
    Hungary: 95
    Country: Number of subjects enrolled
    India: 163
    Country: Number of subjects enrolled
    Israel: 20
    Country: Number of subjects enrolled
    Italy: 45
    Country: Number of subjects enrolled
    Korea, Republic of: 39
    Country: Number of subjects enrolled
    Latvia: 62
    Country: Number of subjects enrolled
    Lithuania: 46
    Country: Number of subjects enrolled
    Malaysia: 28
    Country: Number of subjects enrolled
    Mexico: 78
    Country: Number of subjects enrolled
    Norway: 17
    Country: Number of subjects enrolled
    Panama: 11
    Country: Number of subjects enrolled
    Peru: 59
    Country: Number of subjects enrolled
    Philippines: 64
    Country: Number of subjects enrolled
    Poland: 34
    Country: Number of subjects enrolled
    Romania: 79
    Country: Number of subjects enrolled
    Russian Federation: 166
    Country: Number of subjects enrolled
    Slovakia: 206
    Country: Number of subjects enrolled
    South Africa: 62
    Country: Number of subjects enrolled
    Spain: 8
    Country: Number of subjects enrolled
    Taiwan: 21
    Country: Number of subjects enrolled
    Turkey: 39
    Worldwide total number of subjects
    2001
    EEA total number of subjects
    823
    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)
    1710
    From 65 to 84 years
    291
    85 years and over
    0

    Subject disposition

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    Recruitment
    Recruitment details
    		 -

    Pre-assignment
    Screening details
    		 It was planned to screen approximately 4000 patients in order to randomize 2000 patients. Actually, 2001 patients were randomized, 998 patients into the Vilda 50mg bid + metformin group and 1003 into the placebo + metformin group.

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

    Arms
    Are arms mutually exclusive
    Yes

    Arm title
    		 Vilda 50mg bid + metformin
    Arm description
    		 vildagliptin (Vilda 50mg bid) + Metformin
    Arm type
    		 Active comparator

    Investigational medicinal product name
    Vildagliptin
    Investigational medicinal product code
    Other name
    LAF237
    Pharmaceutical forms
    Tablet
    Routes of administration
    Oral use
    Dosage and administration details
    One tablet (50 mg oral) of vildagliptin in the morning and one tablet in the evening with or without food.

    Investigational medicinal product name
    Metformin
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Film-coated tablet
    Routes of administration
    Oral use
    Dosage and administration details
    Twice daily (bid) regimen during or after meals at the same time as vildagliptin.

    Arm title
    		 Placebo + metformin
    Arm description
    		 Placebo of vildagliptin (Vilda 50mg bid) + Metformin
    Arm type
    		 Experimental

    Investigational medicinal product name
    Metformin
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Film-coated tablet
    Routes of administration
    Oral use
    Dosage and administration details
    Twice daily (bid) regimen during or after meals at the same time as vildagliptin matching placebo.

    Investigational medicinal product name
    Placebo of vildagliptin
    Investigational medicinal product code
    Other name
    Placebo
    Pharmaceutical forms
    Tablet
    Routes of administration
    Oral use
    Dosage and administration details
    One tablet (50 mg oral) of vildagliptin matching placebo in the morning and one tablet in the evening with or without food.

    Number of subjects in period 1
    		Vilda 50mg bid + metformin Placebo + metformin
    Started
    998
    1003
    Safety Set
    998
    1001
    Full Analysis Set (FAS)
    983
    989
    Completed Treatment Period 1
    458 [1]
    273 [2]
    Completed Treatment Period 2
    244 [3]
    399 [4]
    Completed Treatment Period 3
    109 [5]
    115 [6]
    Completed
    811
    787
    Not completed
    187
    216
         Adverse event, serious fatal
    13
    9
         Abnormal laboratory value(s)
    3
    7
         Consent withdrawn by subject
    5
    4
         Adverse event, non-fatal
    28
    44
         Protocol deviation
    9
    19
         Unsatisfactory therapeutic effect
    6
    8
         Administrative problems
    96
    94
         No longer requires study drug
    1
    1
         Lost to follow-up
    17
    24
         Abnormal test procedure result(s)
    1
    -
         New therapy for study indication
    8
    6
    Notes
    [1] - The number of subjects at this milestone seems inconsistent with the number of subjects in the arm. It is expected that the number of subjects will be greater than, or equal to the number that completed, minus those who left.
    Justification: This was a multi-center, double-blind, placebo-controlled, 2-arm, parallel group study with a run-in period and up to 5 years treatment period (treatment periods 1, 2 and 3)
    [2] - The number of subjects at this milestone seems inconsistent with the number of subjects in the arm. It is expected that the number of subjects will be greater than, or equal to the number that completed, minus those who left.
    Justification: This was a multi-center, double-blind, placebo-controlled, 2-arm, parallel group study with a run-in period and up to 5 years treatment period (treatment periods 1, 2 and 3)
    [3] - The number of subjects at this milestone seems inconsistent with the number of subjects in the arm. It is expected that the number of subjects will be greater than, or equal to the number that completed, minus those who left.
    Justification: This was a multi-center, double-blind, placebo-controlled, 2-arm, parallel group study with a run-in period and up to 5 years treatment period (treatment periods 1, 2 and 3)
    [4] - The number of subjects at this milestone seems inconsistent with the number of subjects in the arm. It is expected that the number of subjects will be greater than, or equal to the number that completed, minus those who left.
    Justification: This was a multi-center, double-blind, placebo-controlled, 2-arm, parallel group study with a run-in period and up to 5 years treatment period (treatment periods 1, 2 and 3)
    [5] - The number of subjects at this milestone seems inconsistent with the number of subjects in the arm. It is expected that the number of subjects will be greater than, or equal to the number that completed, minus those who left.
    Justification: This was a multi-center, double-blind, placebo-controlled, 2-arm, parallel group study with a run-in period and up to 5 years treatment period (treatment periods 1, 2 and 3)
    [6] - The number of subjects at this milestone seems inconsistent with the number of subjects in the arm. It is expected that the number of subjects will be greater than, or equal to the number that completed, minus those who left.
    Justification: This was a multi-center, double-blind, placebo-controlled, 2-arm, parallel group study with a run-in period and up to 5 years treatment period (treatment periods 1, 2 and 3)

    Baseline characteristics

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    Baseline characteristics reporting groups
    Reporting group title
    Vilda 50mg bid + metformin
    Reporting group description
    		 vildagliptin (Vilda 50mg bid) + Metformin

    Reporting group title
    Placebo + metformin
    Reporting group description
    		 Placebo of vildagliptin (Vilda 50mg bid) + Metformin

    Reporting group values
    		 Vilda 50mg bid + metformin Placebo + metformin Total
    Number of subjects
    		 998 1003 2001
    Age categorical
    Units: Subjects
        In utero
    		 0 0 0
        Preterm newborn infants (gestational age < 37 wks)
    		 0 0 0
        Newborns (0-27 days)
    		 0 0 0
        Infants and toddlers (28 days-23 months)
    		 0 0 0
        Children (2-11 years)
    		 0 0 0
        Adolescents (12-17 years)
    		 0 0 0
        Adults (18-64 years)
    		 854 856 1710
        From 65-84 years
    		 144 147 291
        85 years and over
    		 0 0 0
    Age Continuous
    Units: Years
        arithmetic mean (standard deviation)
    		 54.1 ( 9.54 ) 54.6 ( 9.24 ) -
    Sex: Female, Male
    Units: Participants
        Female
    		 545 515 1060
        Male
    		 453 488 941
    Race/Ethnicity, Customized
    Units: Subjects
        Caucasian
    		 605 612 1217
        Black
    		 26 23 49
        Asian
    		 186 187 373
        Native American
    		 103 107 210
        Other
    		 78 74 152
    Glomerular Filtration Rate (Modification of Diet in Renal Disease)
    GFR (MDRD) = GFR estimated using the MDRD formula. Baseline GFR is calculated using the serum creatinine and body weight value at the Day 1 measurement, or the value obtained at an earlier visit (scheduled or unscheduled) which was closest to Day 1, if the Day 1 measurement is missing. Age is the value at screening.
    Units: Subjects
        Normal (>80)
    		 660 661 1321
        Mild (>=50 - <=80)
    		 333 337 670
        Moderate (>=30 - <50)
    		 3 4 7
        Severe (<30)
    		 0 1 1
        Missing
    		 2 0 2
    Is subject a current smoker?
    Smoking status is collected on the day of the screening measurement (Week -5, Visit 1)
    Units: Subjects
        Is subject a current smoker?=Yes
    		 154 136 290
        Is subject a current smoker?=No
    		 844 867 1711
    glycosylated hemoglobin (HbA1c)
    Baseline HbA1c is the sample obtained on day 1, or the sample obtained at an earlier visit (scheduled or unscheduled) which was closest to Day 1, if the Day 1 measurement is missing.
    Units: Percent
        arithmetic mean (standard deviation)
    		 6.7 ( 0.45 ) 6.7 ( 0.47 ) -
    fasting plasma glucose (FPG)
    Baseline FPG is the sample obtained on day 1, or the sample obtained at an earlier visit (scheduled or unscheduled) which was closest to Day 1, if the Day 1 measurement is missing.
    Units: mmol/l
        arithmetic mean (standard deviation)
    		 7.1 ( 1.40 ) 7.2 ( 1.47 ) -
    Duration of type 2 diabetes
    Duration of type 2 diabetes is collected on the day of the screening measurement (Week -5, Visit 1)
    Units: months
        arithmetic mean (standard deviation)
    		 6.2 ( 7.00 ) 6.6 ( 8.05 ) -

    End points

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    End points reporting groups
    Reporting group title
    Vilda 50mg bid + metformin
    Reporting group description
    		 vildagliptin (Vilda 50mg bid) + Metformin

    Reporting group title
    Placebo + metformin
    Reporting group description
    		 Placebo of vildagliptin (Vilda 50mg bid) + Metformin

    Primary: Time to initial treatment failure

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    End point title
    		 Time to initial treatment failure
    End point description
    Treatment failure was defined as two consecutive scheduled visits with HbA1c >= 7.0% (starting from 13 weeks after randomization) and the time to treatment failure was the number of days from randomization to the second of the consecutive scheduled visits. Participants who discontinued the study for any reason during Period 1 were censored at the date of discontinuation. Participants who remained under the threshold (or whose measurement above the threshold was not confirmed at next scheduled visit) were censored at the date of last study visit.
    End point type
    Primary
    End point timeframe
    Visit 4 (Week 13) up to End of Study (Study Drug Discontinuation or Premature Subject Discontinuation)
    End point values
    		 Vilda 50mg bid + metformin Placebo + metformin
    Number of subjects analysed
    983
    989
    Units: Rate (%)
    number (confidence interval 95%)
        Weeks 13-52
    7.81 (6.28 to 9.70)
    19.97 (17.58 to 22.65)
        Year 2
    17.79 (15.49 to 20.38)
    34.67 (31.72 to 37.82)
        Year 3
    31.24 (28.35 to 34.33)
    48.31 (45.12 to 51.61)
        Year 4
    39.84 (36.74 to 43.11)
    59.29 (56.08 to 62.53)
        Year 5
    46.41 (43.20 to 49.74)
    66.57 (63.43 to 69.69)
        > Year 5
    52.67 (44.29 to 61.58)
    74.39 (68.39 to 80.04)
    Statistical analysis title
    		 Time to initial treatment failure
    Comparison groups
    Vilda 50mg bid + metformin v Placebo + metformin
    Number of subjects included in analysis
    1972
    Analysis specification
    Pre-specified
    Analysis type
    P-value
    		 < 0.001
    Method
    		 Regression, Cox
    Parameter type
    		 Hazard ratio (HR)
    Point estimate
    0.51
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.45
         upper limit
    		 0.58

    Secondary: Rate of loss in glycemic control during Period 1

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    End point title
    		 Rate of loss in glycemic control during Period 1
    End point description
    The rate of loss in glycemic control was estimated using the slope of HbA1c over time (years). HbA1c data collected from Week 26 up to and including the end of Period 1 visit was included in the analysis. Baseline HbA1c was the sample obtained on day 1, or the sample obtained at an earlier visit (scheduled or unscheduled) which was closest to Day 1, if the Day 1 measurement was missing. End of Period 1 was defined as the final post-baseline assessment obtained at any visit within Period 1 (scheduled or unscheduled), up to the last scheduled visit.
    End point type
    Secondary
    End point timeframe
    Visit 5 (Week 26) to End of Period 1
    End point values
    		 Vilda 50mg bid + metformin Placebo + metformin
    Number of subjects analysed
    983
    989
    Units: Rate (%)
        arithmetic mean (standard error)
    0.24 ( 0.01 )
    0.27 ( 0.01 )
    Statistical analysis title
    		 Rate of loss in glycemic control (Period 1)
    Comparison groups
    Vilda 50mg bid + metformin v Placebo + metformin
    Number of subjects included in analysis
    1972
    Analysis specification
    Pre-specified
    Analysis type
    P-value
    		 = 0.042
    Method
    		 Mixed models analysis
    Parameter type
    		 Slope
    Point estimate
    -0.02
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -0.05
         upper limit
    		 0
    Variability estimate
    Standard error of the mean
    Dispersion value
    0.01

    Secondary: Rate of loss in glycemic control in HbA1c over time during Period 2

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    End point title
    		 Rate of loss in glycemic control in HbA1c over time during Period 2
    End point description
    The rate of loss in glycemic control was estimated using the slope of HbA1c over time (years). HbA1c data collected from 26 weeks after the start of Period 2 to the end of Period 2 were included in the analysis, for participants who started insulin therapy in Period 3 or discontinued during Period 2 due to being unable or unwilling to initiate insulin therapy in period 3. Participants who completed the study in Period 1 or Period 2 were not be included in the analysis.
    End point type
    Secondary
    End point timeframe
    From 26 weeks after start of Period 2 to end of Period 2
    End point values
    		 Vilda 50mg bid + metformin Placebo + metformin
    Number of subjects analysed
    410
    588
    Units: Rate (%)
        arithmetic mean (standard error)
    1.11 ( 0.15 )
    1.02 ( 0.12 )
    Statistical analysis title
    		 Rate loss in glycemic control in HbA1c (Period 2)
    Comparison groups
    Vilda 50mg bid + metformin v Placebo + metformin
    Number of subjects included in analysis
    998
    Analysis specification
    Pre-specified
    Analysis type
    P-value
    		 = 0.635
    Method
    		 Mixed models analysis
    Parameter type
    		 Slope
    Point estimate
    0.09
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -0.29
         upper limit
    		 0.47
    Variability estimate
    Standard error of the mean
    Dispersion value
    0.19

    Secondary: Rate of loss in glycemic control in Fasting Plasma Glucose (FPG) during Period 1

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    End point title
    		 Rate of loss in glycemic control in Fasting Plasma Glucose (FPG) during Period 1
    End point description
    Rate of loss in glycemic control was estimated using the slope of FPG over time (years). FPG (fasting plasma glucose) data from Week 26 to the end of Period 1 was included in the analysis. Baseline FPG was the sample obtained on day 1, or the sample obtained at an earlier visit (scheduled or unscheduled) which was closest to Day 1, if the Day 1 measurement is missing. Participants who completed the study in Period 1 or Period 2 were not be included in the analysis.
    End point type
    Secondary
    End point timeframe
    Visit 5 (Week 26) to End of Period 1
    End point values
    		 Vilda 50mg bid + metformin Placebo + metformin
    Number of subjects analysed
    983
    989
    Units: Rate (%)
        arithmetic mean (standard error)
    0.25 ( 0.01 )
    0.26 ( 0.01 )
    Statistical analysis title
    		 Rate of loss in glycemic control in FPG (Period 1)
    Comparison groups
    Vilda 50mg bid + metformin v Placebo + metformin
    Number of subjects included in analysis
    1972
    Analysis specification
    Pre-specified
    Analysis type
    P-value
    		 = 0.53
    Method
    		 Mixed models analysis
    Parameter type
    		 Slope
    Point estimate
    -0.01
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -0.05
         upper limit
    		 0.02
    Variability estimate
    Standard error of the mean
    Dispersion value
    0.02

    Secondary: Rate of loss in glycemic control in Fasting Plasma Glucose (FPG) over time during Period 2

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    End point title
    		 Rate of loss in glycemic control in Fasting Plasma Glucose (FPG) over time during Period 2
    End point description
    Rate of loss in glycemic control was estimated using the slope of FPG over time (years). FPG (fasting plasma glucose) data from 26 weeks after the start of Period 2 to then end of Period 2 was included in the analysis. Only participants who started insulin therapy in Period 3 or discontinued during Period 2 due to being unable or unwilling to initiate insulin therapy in period 3 were included. Participants who completed the study in Period 1 or Period 2 were not be included in the analysis.
    End point type
    Secondary
    End point timeframe
    From 26 weeks after start of Period 2 to end of Period 2
    End point values
    		 Vilda 50mg bid + metformin Placebo + metformin
    Number of subjects analysed
    410
    588
    Units: Rate (%)
        arithmetic mean (standard error)
    1.27 ( 0.25 )
    0.99 ( 0.19 )
    Statistical analysis title
    		 Rate of loss in glycemic control in FPG (Period 2)
    Comparison groups
    Vilda 50mg bid + metformin v Placebo + metformin
    Number of subjects included in analysis
    998
    Analysis specification
    Pre-specified
    Analysis type
    P-value
    		 = 0.381
    Method
    		 Mixed models analysis
    Parameter type
    		 Slope
    Point estimate
    0.28
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -0.35
         upper limit
    		 0.9
    Variability estimate
    Standard error of the mean
    Dispersion value
    0.32

    Secondary: Rate of loss of beta cell function from baseline to end of study

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    End point title
    		 Rate of loss of beta cell function from baseline to end of study
    End point description
    The rate of change of beta cell function was assessed using the slope of AUC of ISR/G over time (years) where AUC of ISR/G is defined as (Area under curve of Insulin secretion rate (derived using c-peptide))/(Area under curve of Glucose), using meal-test data from 0 to 120 minutes. Baseline AUC of ISR/G was derived based on samples obtained on day 1, or samples obtained at an earlier visit (scheduled or unscheduled) which was closest to Day 1, if the Day 1 measurements were missing. Three analyses were included, using data from Week 13 to the end of Period 1, end of Period 2 and end of study, respectively.
    End point type
    Secondary
    End point timeframe
    Visit 4 (Week 13), End of Period 1, End of Period 2, End of Study (Study Drug Discontinuation or Premature Subject Discontinuation)
    End point values
    		 Vilda 50mg bid + metformin Placebo + metformin
    Number of subjects analysed
    228
    227
    Units: Rate (%)
    arithmetic mean (standard error)
        From Week 13 to end of Period 1
    -0.60 ( 0.15 )
    -0.53 ( 0.18 )
        From Week 13 to end of Period 2
    -0.93 ( 0.14 )
    -0.43 ( 0.15 )
        From Week 13 to end of study
    -1.04 ( 0.15 )
    -0.46 ( 0.15 )
    Statistical analysis title
    		 Rate of loss of beta cell function
    Statistical analysis description
    From Week 13 to end of Period 1
    Comparison groups
    Vilda 50mg bid + metformin v Placebo + metformin
    Number of subjects included in analysis
    455
    Analysis specification
    Pre-specified
    Analysis type
    P-value
    		 = 0.744
    Method
    		 Mixed models analysis
    Parameter type
    		 Slope
    Point estimate
    -0.08
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -0.53
         upper limit
    		 0.38
    Variability estimate
    Standard error of the mean
    Dispersion value
    0.23
    Statistical analysis title
    		 Rate of loss of beta cell function
    Statistical analysis description
    From Week 13 to end of Period 2
    Comparison groups
    Vilda 50mg bid + metformin v Placebo + metformin
    Number of subjects included in analysis
    455
    Analysis specification
    Pre-specified
    Analysis type
    P-value
    		 = 0.017
    Method
    		 Mixed models analysis
    Parameter type
    		 Slope
    Point estimate
    -0.5
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -0.91
         upper limit
    		 -0.09
    Variability estimate
    Standard error of the mean
    Dispersion value
    0.21
    Statistical analysis title
    		 Rate of loss of beta cell function
    Statistical analysis description
    From Week 13 to end of study
    Comparison groups
    Vilda 50mg bid + metformin v Placebo + metformin
    Number of subjects included in analysis
    455
    Analysis specification
    Pre-specified
    Analysis type
    P-value
    		 = 0.006
    Method
    		 Mixed models analysis
    Parameter type
    		 Slope
    Point estimate
    -0.58
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -0.99
         upper limit
    		 -0.17
    Variability estimate
    Standard error of the mean
    Dispersion value
    0.21

    Secondary: Rate of change in insulin sensitivity from baseline to end of study

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    End point title
    		 Rate of change in insulin sensitivity from baseline to end of study
    End point description
    The rate of change of insulin sensitivity is assessed using the slope of OGIS over time (years) where Oral glucose insulin sensitivity (OGIS) was calculated as a function of glucose and insulin, using meal-test data from 0 to 120 minutes. Baseline OGIS is derived based on samples obtained on day 1, or samples obtained at an earlier visit (scheduled or unscheduled) which was closest to Day 1, if the Day 1 measurements are missing. Three analyses were included, using data from Week 13 to the end of Period 1, end of Period 2 and end of study, respectively.
    End point type
    Secondary
    End point timeframe
    Visit 4 (Week 13), End of Period 1, End of Period 2, End of Study (Study Drug Discontinuation or Premature Subject Discontinuation)
    End point values
    		 Vilda 50mg bid + metformin Placebo + metformin
    Number of subjects analysed
    228
    227
    Units: Rate (%)
    arithmetic mean (standard error)
        From Week 13 to end of Period 1
    -4.61 ( 1.38 )
    0.41 ( 1.66 )
        From Week 13 to end of Period 2
    -6.07 ( 1.20 )
    -0.99 ( 1.24 )
        From Week 13 to end of study
    -6.39 ( 1.15 )
    -1.01 ( 1.17 )
    Statistical analysis title
    		 Rate of change in insulin sensitivity
    Statistical analysis description
    From Week 13 to end of Period 1
    Comparison groups
    Vilda 50mg bid + metformin v Placebo + metformin
    Number of subjects included in analysis
    455
    Analysis specification
    Pre-specified
    Analysis type
    P-value
    		 = 0.02
    Method
    		 Mixed models analysis
    Parameter type
    		 Slope
    Point estimate
    -5.03
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -9.26
         upper limit
    		 -0.79
    Variability estimate
    Standard error of the mean
    Dispersion value
    2.16
    Statistical analysis title
    		 Rate of change in insulin sensitivity
    Statistical analysis description
    From Week 13 to end of Period 2
    Comparison groups
    Vilda 50mg bid + metformin v Placebo + metformin
    Number of subjects included in analysis
    455
    Analysis specification
    Pre-specified
    Analysis type
    P-value
    		 = 0.003
    Method
    		 Mixed models analysis
    Parameter type
    		 Slope
    Point estimate
    -5.08
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -8.46
         upper limit
    		 -1.69
    Variability estimate
    Standard error of the mean
    Dispersion value
    1.73
    Statistical analysis title
    		 Rate of change in insulin sensitivity
    Statistical analysis description
    From Week 13 to end of study
    Comparison groups
    Vilda 50mg bid + metformin v Placebo + metformin
    Number of subjects included in analysis
    455
    Analysis specification
    Pre-specified
    Analysis type
    P-value
    		 = 0.001
    Method
    		 Mixed models analysis
    Parameter type
    		 Slope
    Point estimate
    -5.38
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -8.61
         upper limit
    		 -2.16
    Variability estimate
    Standard error of the mean
    Dispersion value
    1.64

    Secondary: Percentage of participants with adverse events, serious adverse events and death

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    End point title
    		 Percentage of participants with adverse events, serious adverse events and death
    End point description
    Analysis of absolute and relative frequencies for treatment emergent Adverse Event (AE), Serious Adverse Event (SAE) and Deaths by primary System Organ Class (SOC) in each treatment arm to demonstrate that LAF237 is safe for the treatment of naïve patients with type 2 diabetes mellitus through the monitoring of relevant clinical and laboratory safety parameters.
    End point type
    Secondary
    End point timeframe
    From first dose of study treatment until End of Study (Study Drug Discontinuation or Premature Subject Discontinuation)
    End point values
    		 Vilda 50mg bid + metformin Placebo + metformin
    Number of subjects analysed
    998
    1001
    Units: Percentage of Participants
    number (not applicable)
        On-treatment Adverse Event (AEs)
    83.5
    83.2
        On-treatment Serious Adverse Event (SAEs)
    16.6
    18.3
        On-treatment Deaths
    1.3
    0.9
    No statistical analyses for this end point

    Adverse events

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    Adverse events information
    Timeframe for reporting adverse events
    Adverse events were collected from first dose of study treatment until end of study treatment plus 30 days post treatment, up to a maximum duration of 75.6 months.
    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
    21.1
    Reporting groups
    Reporting group title
    Vilda 50mg bid +@metformin
    Reporting group description
    		 Vilda 50mg bid +@metformin

    Reporting group title
    Placebo +@metformin
    Reporting group description
    		 Placebo +@metformin

    Reporting group title
    Total
    Reporting group description
    		 Total

    Serious adverse events
    		 Vilda 50mg bid +@metformin Placebo +@metformin Total
    Total subjects affected by serious adverse events
         subjects affected / exposed
    166 / 998 (16.63%)
    183 / 1001 (18.28%)
    349 / 1999 (17.46%)
         number of deaths (all causes)
    13
    9
    22
         number of deaths resulting from adverse events
    0
    0
    0
    Neoplasms benign, malignant and unspecified (incl cysts and polyps)
    Adenocarcinoma gastric
         subjects affected / exposed
    1 / 998 (0.10%)
    0 / 1001 (0.00%)
    1 / 1999 (0.05%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    0 / 1
    Adenoma benign
         subjects affected / exposed
    0 / 998 (0.00%)
    1 / 1001 (0.10%)
    1 / 1999 (0.05%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    B-cell lymphoma
         subjects affected / exposed
    0 / 998 (0.00%)
    1 / 1001 (0.10%)
    1 / 1999 (0.05%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Basal cell carcinoma
         subjects affected / exposed
    0 / 998 (0.00%)
    1 / 1001 (0.10%)
    1 / 1999 (0.05%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Bladder cancer
         subjects affected / exposed
    1 / 998 (0.10%)
    1 / 1001 (0.10%)
    2 / 1999 (0.10%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Brain neoplasm
         subjects affected / exposed
    1 / 998 (0.10%)
    0 / 1001 (0.00%)
    1 / 1999 (0.05%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Breast cancer
         subjects affected / exposed
    3 / 998 (0.30%)
    1 / 1001 (0.10%)
    4 / 1999 (0.20%)
         occurrences causally related to treatment / all
    0 / 3
    0 / 1
    0 / 4
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Breast cancer female
         subjects affected / exposed
    0 / 998 (0.00%)
    1 / 1001 (0.10%)
    1 / 1999 (0.05%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Choroid melanoma
         subjects affected / exposed
    1 / 998 (0.10%)
    0 / 1001 (0.00%)
    1 / 1999 (0.05%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Chronic lymphocytic leukaemia
         subjects affected / exposed
    1 / 998 (0.10%)
    0 / 1001 (0.00%)
    1 / 1999 (0.05%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Chronic myeloid leukaemia
         subjects affected / exposed
    0 / 998 (0.00%)
    1 / 1001 (0.10%)
    1 / 1999 (0.05%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Colon cancer
         subjects affected / exposed
    1 / 998 (0.10%)
    0 / 1001 (0.00%)
    1 / 1999 (0.05%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Cystadenocarcinoma ovary
         subjects affected / exposed
    1 / 998 (0.10%)
    0 / 1001 (0.00%)
    1 / 1999 (0.05%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Endometrial cancer
         subjects affected / exposed
    1 / 998 (0.10%)
    0 / 1001 (0.00%)
    1 / 1999 (0.05%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Gallbladder neoplasm
         subjects affected / exposed
    0 / 998 (0.00%)
    1 / 1001 (0.10%)
    1 / 1999 (0.05%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Gastric cancer
         subjects affected / exposed
    0 / 998 (0.00%)
    1 / 1001 (0.10%)
    1 / 1999 (0.05%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Haemangioma
         subjects affected / exposed
    0 / 998 (0.00%)
    1 / 1001 (0.10%)
    1 / 1999 (0.05%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Hepatic neoplasm
         subjects affected / exposed
    0 / 998 (0.00%)
    1 / 1001 (0.10%)
    1 / 1999 (0.05%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Intestinal adenocarcinoma
         subjects affected / exposed
    1 / 998 (0.10%)
    0 / 1001 (0.00%)
    1 / 1999 (0.05%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Invasive ductal breast carcinoma
         subjects affected / exposed
    1 / 998 (0.10%)
    2 / 1001 (0.20%)
    3 / 1999 (0.15%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 2
    0 / 3
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Kaposi's sarcoma
         subjects affected / exposed
    0 / 998 (0.00%)
    1 / 1001 (0.10%)
    1 / 1999 (0.05%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Lung neoplasm malignant
         subjects affected / exposed
    1 / 998 (0.10%)
    0 / 1001 (0.00%)
    1 / 1999 (0.05%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    0 / 1
    Malignant melanoma
         subjects affected / exposed
    2 / 998 (0.20%)
    0 / 1001 (0.00%)
    2 / 1999 (0.10%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Malignant splenic neoplasm
         subjects affected / exposed
    0 / 998 (0.00%)
    1 / 1001 (0.10%)
    1 / 1999 (0.05%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Metastases to bone
         subjects affected / exposed
    0 / 998 (0.00%)
    2 / 1001 (0.20%)
    2 / 1999 (0.10%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 2
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Metastases to central nervous system
         subjects affected / exposed
    0 / 998 (0.00%)
    1 / 1001 (0.10%)
    1 / 1999 (0.05%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Metastases to liver
         subjects affected / exposed
    1 / 998 (0.10%)
    0 / 1001 (0.00%)
    1 / 1999 (0.05%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    0 / 1
    Metastases to lung
         subjects affected / exposed
    0 / 998 (0.00%)
    1 / 1001 (0.10%)
    1 / 1999 (0.05%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 3
    0 / 3
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Metastases to lymph nodes
         subjects affected / exposed
    0 / 998 (0.00%)
    1 / 1001 (0.10%)
    1 / 1999 (0.05%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Neuroendocrine tumour
         subjects affected / exposed
    1 / 998 (0.10%)
    0 / 1001 (0.00%)
    1 / 1999 (0.05%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Oligoastrocytoma
         subjects affected / exposed
    1 / 998 (0.10%)
    0 / 1001 (0.00%)
    1 / 1999 (0.05%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Ovarian adenoma
         subjects affected / exposed
    0 / 998 (0.00%)
    1 / 1001 (0.10%)
    1 / 1999 (0.05%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Ovarian cancer metastatic
         subjects affected / exposed
    1 / 998 (0.10%)
    0 / 1001 (0.00%)
    1 / 1999 (0.05%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    0 / 1
    Ovarian epithelial cancer
         subjects affected / exposed
    0 / 998 (0.00%)
    1 / 1001 (0.10%)
    1 / 1999 (0.05%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Ovarian neoplasm
         subjects affected / exposed
    0 / 998 (0.00%)
    1 / 1001 (0.10%)
    1 / 1999 (0.05%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Pancreatic carcinoma
         subjects affected / exposed
    3 / 998 (0.30%)
    2 / 1001 (0.20%)
    5 / 1999 (0.25%)
         occurrences causally related to treatment / all
    0 / 3
    0 / 2
    0 / 5
         deaths causally related to treatment / all
    0 / 0
    0 / 2
    0 / 2
    Parathyroid tumour benign
         subjects affected / exposed
    0 / 998 (0.00%)
    1 / 1001 (0.10%)
    1 / 1999 (0.05%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Prostate cancer
         subjects affected / exposed
    6 / 998 (0.60%)
    0 / 1001 (0.00%)
    6 / 1999 (0.30%)
         occurrences causally related to treatment / all
    0 / 6
    0 / 0
    0 / 6
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Prostatic adenoma
         subjects affected / exposed
    1 / 998 (0.10%)
    0 / 1001 (0.00%)
    1 / 1999 (0.05%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Rectal cancer
         subjects affected / exposed
    1 / 998 (0.10%)
    1 / 1001 (0.10%)
    2 / 1999 (0.10%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Rectosigmoid cancer
         subjects affected / exposed
    0 / 998 (0.00%)
    1 / 1001 (0.10%)
    1 / 1999 (0.05%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Refractory cytopenia with multilineage dysplasia
         subjects affected / exposed
    0 / 998 (0.00%)
    1 / 1001 (0.10%)
    1 / 1999 (0.05%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Renal cancer
         subjects affected / exposed
    0 / 998 (0.00%)
    1 / 1001 (0.10%)
    1 / 1999 (0.05%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Renal neoplasm
         subjects affected / exposed
    0 / 998 (0.00%)
    1 / 1001 (0.10%)
    1 / 1999 (0.05%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Skin cancer
         subjects affected / exposed
    0 / 998 (0.00%)
    1 / 1001 (0.10%)
    1 / 1999 (0.05%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Skin papilloma
         subjects affected / exposed
    0 / 998 (0.00%)
    1 / 1001 (0.10%)
    1 / 1999 (0.05%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Small cell carcinoma
         subjects affected / exposed
    1 / 998 (0.10%)
    0 / 1001 (0.00%)
    1 / 1999 (0.05%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Superficial spreading melanoma stage unspecified
         subjects affected / exposed
    1 / 998 (0.10%)
    0 / 1001 (0.00%)
    1 / 1999 (0.05%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Thyroid cancer
         subjects affected / exposed
    0 / 998 (0.00%)
    1 / 1001 (0.10%)
    1 / 1999 (0.05%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Tongue neoplasm malignant stage unspecified
         subjects affected / exposed
    0 / 998 (0.00%)
    1 / 1001 (0.10%)
    1 / 1999 (0.05%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Tumour haemorrhage
         subjects affected / exposed
    0 / 998 (0.00%)
    1 / 1001 (0.10%)
    1 / 1999 (0.05%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Undifferentiated sarcoma
         subjects affected / exposed
    1 / 998 (0.10%)
    0 / 1001 (0.00%)
    1 / 1999 (0.05%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Uterine leiomyoma
         subjects affected / exposed
    2 / 998 (0.20%)
    1 / 1001 (0.10%)
    3 / 1999 (0.15%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 1
    0 / 3
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Vascular disorders
    Aortic aneurysm
         subjects affected / exposed
    2 / 998 (0.20%)
    0 / 1001 (0.00%)
    2 / 1999 (0.10%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    0 / 1
    Aortic dissection
         subjects affected / exposed
    1 / 998 (0.10%)
    0 / 1001 (0.00%)
    1 / 1999 (0.05%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Aortic stenosis
         subjects affected / exposed
    2 / 998 (0.20%)
    0 / 1001 (0.00%)
    2 / 1999 (0.10%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Deep vein thrombosis
         subjects affected / exposed
    2 / 998 (0.20%)
    0 / 1001 (0.00%)
    2 / 1999 (0.10%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Haematoma
         subjects affected / exposed
    0 / 998 (0.00%)
    1 / 1001 (0.10%)
    1 / 1999 (0.05%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Hypertension
         subjects affected / exposed
    2 / 998 (0.20%)
    4 / 1001 (0.40%)
    6 / 1999 (0.30%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 4
    0 / 6
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Hypertensive crisis
         subjects affected / exposed
    1 / 998 (0.10%)
    0 / 1001 (0.00%)
    1 / 1999 (0.05%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Pelvic venous thrombosis
         subjects affected / exposed
    0 / 998 (0.00%)
    1 / 1001 (0.10%)
    1 / 1999 (0.05%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Peripheral arterial occlusive disease
         subjects affected / exposed
    0 / 998 (0.00%)
    2 / 1001 (0.20%)
    2 / 1999 (0.10%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 2
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Peripheral artery stenosis
         subjects affected / exposed
    1 / 998 (0.10%)
    0 / 1001 (0.00%)
    1 / 1999 (0.05%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Peripheral venous disease
         subjects affected / exposed
    1 / 998 (0.10%)
    0 / 1001 (0.00%)
    1 / 1999 (0.05%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Varicose vein
         subjects affected / exposed
    2 / 998 (0.20%)
    1 / 1001 (0.10%)
    3 / 1999 (0.15%)
         occurrences causally related to treatment / all
    0 / 2
    1 / 1
    1 / 3
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Pregnancy, puerperium and perinatal conditions
    Abortion missed
         subjects affected / exposed
    1 / 998 (0.10%)
    0 / 1001 (0.00%)
    1 / 1999 (0.05%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Abortion spontaneous
         subjects affected / exposed
    0 / 998 (0.00%)
    2 / 1001 (0.20%)
    2 / 1999 (0.10%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 2
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Abortion threatened
         subjects affected / exposed
    1 / 998 (0.10%)
    0 / 1001 (0.00%)
    1 / 1999 (0.05%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Pregnancy with contraceptive device
         subjects affected / exposed
    1 / 998 (0.10%)
    0 / 1001 (0.00%)
    1 / 1999 (0.05%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    General disorders and administration site conditions
    Chest pain
         subjects affected / exposed
    0 / 998 (0.00%)
    1 / 1001 (0.10%)
    1 / 1999 (0.05%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Death
         subjects affected / exposed
    2 / 998 (0.20%)
    0 / 1001 (0.00%)
    2 / 1999 (0.10%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    0 / 1
    Granuloma
         subjects affected / exposed
    0 / 998 (0.00%)
    1 / 1001 (0.10%)
    1 / 1999 (0.05%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Inflammation
         subjects affected / exposed
    1 / 998 (0.10%)
    0 / 1001 (0.00%)
    1 / 1999 (0.05%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Non-cardiac chest pain
         subjects affected / exposed
    1 / 998 (0.10%)
    0 / 1001 (0.00%)
    1 / 1999 (0.05%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Oedema peripheral
         subjects affected / exposed
    0 / 998 (0.00%)
    1 / 1001 (0.10%)
    1 / 1999 (0.05%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Peripheral swelling
         subjects affected / exposed
    0 / 998 (0.00%)
    1 / 1001 (0.10%)
    1 / 1999 (0.05%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Pyrexia
         subjects affected / exposed
    2 / 998 (0.20%)
    0 / 1001 (0.00%)
    2 / 1999 (0.10%)
         occurrences causally related to treatment / all
    1 / 2
    0 / 0
    1 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Stent-graft endoleak
         subjects affected / exposed
    1 / 998 (0.10%)
    0 / 1001 (0.00%)
    1 / 1999 (0.05%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Sudden death
         subjects affected / exposed
    0 / 998 (0.00%)
    1 / 1001 (0.10%)
    1 / 1999 (0.05%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    0 / 1
    Immune system disorders
    Anaphylactic reaction
         subjects affected / exposed
    2 / 998 (0.20%)
    0 / 1001 (0.00%)
    2 / 1999 (0.10%)
         occurrences causally related to treatment / all
    1 / 2
    0 / 0
    1 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Reproductive system and breast disorders
    Benign prostatic hyperplasia
         subjects affected / exposed
    2 / 998 (0.20%)
    0 / 1001 (0.00%)
    2 / 1999 (0.10%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Cervical cyst
         subjects affected / exposed
    0 / 998 (0.00%)
    1 / 1001 (0.10%)
    1 / 1999 (0.05%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Dysfunctional uterine bleeding
         subjects affected / exposed
    1 / 998 (0.10%)
    0 / 1001 (0.00%)
    1 / 1999 (0.05%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Endometrial hyperplasia
         subjects affected / exposed
    1 / 998 (0.10%)
    0 / 1001 (0.00%)
    1 / 1999 (0.05%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Endometrial thickening
         subjects affected / exposed
    0 / 998 (0.00%)
    1 / 1001 (0.10%)
    1 / 1999 (0.05%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Endometriosis
         subjects affected / exposed
    0 / 998 (0.00%)
    1 / 1001 (0.10%)
    1 / 1999 (0.05%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Genital ulceration
         subjects affected / exposed
    0 / 998 (0.00%)
    1 / 1001 (0.10%)
    1 / 1999 (0.05%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Metrorrhagia
         subjects affected / exposed
    1 / 998 (0.10%)
    0 / 1001 (0.00%)
    1 / 1999 (0.05%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Ovarian cyst
         subjects affected / exposed
    1 / 998 (0.10%)
    4 / 1001 (0.40%)
    5 / 1999 (0.25%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 4
    0 / 5
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Ovarian fibrosis
         subjects affected / exposed
    0 / 998 (0.00%)
    1 / 1001 (0.10%)
    1 / 1999 (0.05%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Prostatomegaly
         subjects affected / exposed
    0 / 998 (0.00%)
    1 / 1001 (0.10%)
    1 / 1999 (0.05%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Uterine polyp
         subjects affected / exposed
    1 / 998 (0.10%)
    2 / 1001 (0.20%)
    3 / 1999 (0.15%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 2
    0 / 3
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Respiratory, thoracic and mediastinal disorders
    Acute respiratory failure
         subjects affected / exposed
    0 / 998 (0.00%)
    2 / 1001 (0.20%)
    2 / 1999 (0.10%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 2
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Asthma
         subjects affected / exposed
    1 / 998 (0.10%)
    0 / 1001 (0.00%)
    1 / 1999 (0.05%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Chronic obstructive pulmonary disease
         subjects affected / exposed
    2 / 998 (0.20%)
    3 / 1001 (0.30%)
    5 / 1999 (0.25%)
         occurrences causally related to treatment / all
    0 / 4
    0 / 3
    0 / 7
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Chronic respiratory failure
         subjects affected / exposed
    0 / 998 (0.00%)
    1 / 1001 (0.10%)
    1 / 1999 (0.05%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Dyspnoea
         subjects affected / exposed
    1 / 998 (0.10%)
    0 / 1001 (0.00%)
    1 / 1999 (0.05%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Laryngeal cyst
         subjects affected / exposed
    1 / 998 (0.10%)
    0 / 1001 (0.00%)
    1 / 1999 (0.05%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Pneumonitis
         subjects affected / exposed
    0 / 998 (0.00%)
    1 / 1001 (0.10%)
    1 / 1999 (0.05%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Pulmonary embolism
         subjects affected / exposed
    1 / 998 (0.10%)
    0 / 1001 (0.00%)
    1 / 1999 (0.05%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Pulmonary mass
         subjects affected / exposed
    1 / 998 (0.10%)
    0 / 1001 (0.00%)
    1 / 1999 (0.05%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Respiratory failure
         subjects affected / exposed
    1 / 998 (0.10%)
    0 / 1001 (0.00%)
    1 / 1999 (0.05%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Psychiatric disorders
    Depression
         subjects affected / exposed
    1 / 998 (0.10%)
    0 / 1001 (0.00%)
    1 / 1999 (0.05%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Eating disorder
         subjects affected / exposed
    0 / 998 (0.00%)
    1 / 1001 (0.10%)
    1 / 1999 (0.05%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Investigations
    Alanine aminotransferase increased
         subjects affected / exposed
    1 / 998 (0.10%)
    0 / 1001 (0.00%)
    1 / 1999 (0.05%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Aspartate aminotransferase increased
         subjects affected / exposed
    1 / 998 (0.10%)
    0 / 1001 (0.00%)
    1 / 1999 (0.05%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Blood lactate dehydrogenase increased
         subjects affected / exposed
    1 / 998 (0.10%)
    0 / 1001 (0.00%)
    1 / 1999 (0.05%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Gamma-glutamyltransferase increased
         subjects affected / exposed
    1 / 998 (0.10%)
    0 / 1001 (0.00%)
    1 / 1999 (0.05%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    HIV test positive
         subjects affected / exposed
    1 / 998 (0.10%)
    0 / 1001 (0.00%)
    1 / 1999 (0.05%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Transaminases increased
         subjects affected / exposed
    0 / 998 (0.00%)
    2 / 1001 (0.20%)
    2 / 1999 (0.10%)
         occurrences causally related to treatment / all
    0 / 0
    2 / 2
    2 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Injury, poisoning and procedural complications
    Ankle fracture
         subjects affected / exposed
    0 / 998 (0.00%)
    2 / 1001 (0.20%)
    2 / 1999 (0.10%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 2
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Burns first degree
         subjects affected / exposed
    0 / 998 (0.00%)
    1 / 1001 (0.10%)
    1 / 1999 (0.05%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Clavicle fracture
         subjects affected / exposed
    0 / 998 (0.00%)
    1 / 1001 (0.10%)
    1 / 1999 (0.05%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Concussion
         subjects affected / exposed
    1 / 998 (0.10%)
    0 / 1001 (0.00%)
    1 / 1999 (0.05%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Contusion
         subjects affected / exposed
    0 / 998 (0.00%)
    1 / 1001 (0.10%)
    1 / 1999 (0.05%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Craniocerebral injury
         subjects affected / exposed
    1 / 998 (0.10%)
    0 / 1001 (0.00%)
    1 / 1999 (0.05%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Face injury
         subjects affected / exposed
    0 / 998 (0.00%)
    1 / 1001 (0.10%)
    1 / 1999 (0.05%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Forearm fracture
         subjects affected / exposed
    1 / 998 (0.10%)
    0 / 1001 (0.00%)
    1 / 1999 (0.05%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Gun shot wound
         subjects affected / exposed
    1 / 998 (0.10%)
    1 / 1001 (0.10%)
    2 / 1999 (0.10%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Heat stroke
         subjects affected / exposed
    0 / 998 (0.00%)
    1 / 1001 (0.10%)
    1 / 1999 (0.05%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Hip fracture
         subjects affected / exposed
    0 / 998 (0.00%)
    1 / 1001 (0.10%)
    1 / 1999 (0.05%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Humerus fracture
         subjects affected / exposed
    0 / 998 (0.00%)
    1 / 1001 (0.10%)
    1 / 1999 (0.05%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Joint dislocation
         subjects affected / exposed
    0 / 998 (0.00%)
    1 / 1001 (0.10%)
    1 / 1999 (0.05%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Joint injury
         subjects affected / exposed
    1 / 998 (0.10%)
    0 / 1001 (0.00%)
    1 / 1999 (0.05%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Ligament rupture
         subjects affected / exposed
    1 / 998 (0.10%)
    0 / 1001 (0.00%)
    1 / 1999 (0.05%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Limb injury
         subjects affected / exposed
    2 / 998 (0.20%)
    1 / 1001 (0.10%)
    3 / 1999 (0.15%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 1
    0 / 3
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Lower limb fracture
         subjects affected / exposed
    0 / 998 (0.00%)
    1 / 1001 (0.10%)
    1 / 1999 (0.05%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Lumbar vertebral fracture
         subjects affected / exposed
    1 / 998 (0.10%)
    0 / 1001 (0.00%)
    1 / 1999 (0.05%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Meniscus injury
         subjects affected / exposed
    1 / 998 (0.10%)
    4 / 1001 (0.40%)
    5 / 1999 (0.25%)
         occurrences causally related to treatment / all
    0 / 1
    1 / 4
    1 / 5
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Multiple injuries
         subjects affected / exposed
    3 / 998 (0.30%)
    0 / 1001 (0.00%)
    3 / 1999 (0.15%)
         occurrences causally related to treatment / all
    0 / 3
    0 / 0
    0 / 3
         deaths causally related to treatment / all
    0 / 2
    0 / 0
    0 / 2
    Muscle rupture
         subjects affected / exposed
    1 / 998 (0.10%)
    2 / 1001 (0.20%)
    3 / 1999 (0.15%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 2
    0 / 3
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Post procedural fistula
         subjects affected / exposed
    0 / 998 (0.00%)
    1 / 1001 (0.10%)
    1 / 1999 (0.05%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Radius fracture
         subjects affected / exposed
    0 / 998 (0.00%)
    3 / 1001 (0.30%)
    3 / 1999 (0.15%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 3
    0 / 3
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Rib fracture
         subjects affected / exposed
    0 / 998 (0.00%)
    1 / 1001 (0.10%)
    1 / 1999 (0.05%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Road traffic accident
         subjects affected / exposed
    0 / 998 (0.00%)
    1 / 1001 (0.10%)
    1 / 1999 (0.05%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    0 / 1
    Skin abrasion
         subjects affected / exposed
    0 / 998 (0.00%)
    1 / 1001 (0.10%)
    1 / 1999 (0.05%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Skull fracture
         subjects affected / exposed
    1 / 998 (0.10%)
    0 / 1001 (0.00%)
    1 / 1999 (0.05%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Tendon rupture
         subjects affected / exposed
    1 / 998 (0.10%)
    0 / 1001 (0.00%)
    1 / 1999 (0.05%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Tooth fracture
         subjects affected / exposed
    0 / 998 (0.00%)
    1 / 1001 (0.10%)
    1 / 1999 (0.05%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Traumatic arthrosis
         subjects affected / exposed
    0 / 998 (0.00%)
    1 / 1001 (0.10%)
    1 / 1999 (0.05%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Ulna fracture
         subjects affected / exposed
    0 / 998 (0.00%)
    1 / 1001 (0.10%)
    1 / 1999 (0.05%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Upper limb fracture
         subjects affected / exposed
    1 / 998 (0.10%)
    0 / 1001 (0.00%)
    1 / 1999 (0.05%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Congenital, familial and genetic disorders
    Congenital intestinal malformation
         subjects affected / exposed
    0 / 998 (0.00%)
    1 / 1001 (0.10%)
    1 / 1999 (0.05%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Heart disease congenital
         subjects affected / exposed
    0 / 998 (0.00%)
    1 / 1001 (0.10%)
    1 / 1999 (0.05%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Cardiac disorders
    Acute coronary syndrome
         subjects affected / exposed
    0 / 998 (0.00%)
    3 / 1001 (0.30%)
    3 / 1999 (0.15%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 3
    0 / 3
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Acute myocardial infarction
         subjects affected / exposed
    3 / 998 (0.30%)
    4 / 1001 (0.40%)
    7 / 1999 (0.35%)
         occurrences causally related to treatment / all
    0 / 3
    0 / 4
    0 / 7
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    0 / 1
    Angina pectoris
         subjects affected / exposed
    2 / 998 (0.20%)
    4 / 1001 (0.40%)
    6 / 1999 (0.30%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 4
    0 / 6
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Angina unstable
         subjects affected / exposed
    2 / 998 (0.20%)
    1 / 1001 (0.10%)
    3 / 1999 (0.15%)
         occurrences causally related to treatment / all
    0 / 3
    0 / 1
    0 / 4
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Aortic valve incompetence
         subjects affected / exposed
    0 / 998 (0.00%)
    1 / 1001 (0.10%)
    1 / 1999 (0.05%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Arrhythmia
         subjects affected / exposed
    0 / 998 (0.00%)
    1 / 1001 (0.10%)
    1 / 1999 (0.05%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Atrial fibrillation
         subjects affected / exposed
    6 / 998 (0.60%)
    5 / 1001 (0.50%)
    11 / 1999 (0.55%)
         occurrences causally related to treatment / all
    0 / 6
    0 / 6
    0 / 12
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Atrial flutter
         subjects affected / exposed
    0 / 998 (0.00%)
    1 / 1001 (0.10%)
    1 / 1999 (0.05%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Atrioventricular block complete
         subjects affected / exposed
    0 / 998 (0.00%)
    1 / 1001 (0.10%)
    1 / 1999 (0.05%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Atrioventricular block second degree
         subjects affected / exposed
    0 / 998 (0.00%)
    1 / 1001 (0.10%)
    1 / 1999 (0.05%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Bundle branch block left
         subjects affected / exposed
    0 / 998 (0.00%)
    1 / 1001 (0.10%)
    1 / 1999 (0.05%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Cardiac arrest
         subjects affected / exposed
    1 / 998 (0.10%)
    1 / 1001 (0.10%)
    2 / 1999 (0.10%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
    0 / 2
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    0 / 1
    Cardiac failure
         subjects affected / exposed
    3 / 998 (0.30%)
    4 / 1001 (0.40%)
    7 / 1999 (0.35%)
         occurrences causally related to treatment / all
    0 / 3
    0 / 4
    0 / 7
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    0 / 1
    Cardiac failure acute
         subjects affected / exposed
    2 / 998 (0.20%)
    1 / 1001 (0.10%)
    3 / 1999 (0.15%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 1
    0 / 3
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    0 / 1
    Cardiac failure chronic
         subjects affected / exposed
    1 / 998 (0.10%)
    0 / 1001 (0.00%)
    1 / 1999 (0.05%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    0 / 1
    Cardiac failure congestive
         subjects affected / exposed
    1 / 998 (0.10%)
    0 / 1001 (0.00%)
    1 / 1999 (0.05%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Cardiogenic shock
         subjects affected / exposed
    0 / 998 (0.00%)
    1 / 1001 (0.10%)
    1 / 1999 (0.05%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    0 / 1
    Conduction disorder
         subjects affected / exposed
    0 / 998 (0.00%)
    2 / 1001 (0.20%)
    2 / 1999 (0.10%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 2
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Coronary artery disease
         subjects affected / exposed
    1 / 998 (0.10%)
    3 / 1001 (0.30%)
    4 / 1999 (0.20%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 3
    0 / 4
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    0 / 1
    Coronary artery insufficiency
         subjects affected / exposed
    0 / 998 (0.00%)
    1 / 1001 (0.10%)
    1 / 1999 (0.05%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Coronary artery stenosis
         subjects affected / exposed
    1 / 998 (0.10%)
    3 / 1001 (0.30%)
    4 / 1999 (0.20%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 3
    0 / 4
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Mitral valve disease
         subjects affected / exposed
    0 / 998 (0.00%)
    1 / 1001 (0.10%)
    1 / 1999 (0.05%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Myocardial infarction
         subjects affected / exposed
    3 / 998 (0.30%)
    7 / 1001 (0.70%)
    10 / 1999 (0.50%)
         occurrences causally related to treatment / all
    0 / 3
    0 / 7
    0 / 10
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Myocardial ischaemia
         subjects affected / exposed
    2 / 998 (0.20%)
    3 / 1001 (0.30%)
    5 / 1999 (0.25%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 3
    0 / 5
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Sinus node dysfunction
         subjects affected / exposed
    0 / 998 (0.00%)
    1 / 1001 (0.10%)
    1 / 1999 (0.05%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Sinus tachycardia
         subjects affected / exposed
    0 / 998 (0.00%)
    1 / 1001 (0.10%)
    1 / 1999 (0.05%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Supraventricular extrasystoles
         subjects affected / exposed
    1 / 998 (0.10%)
    0 / 1001 (0.00%)
    1 / 1999 (0.05%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Supraventricular tachycardia
         subjects affected / exposed
    0 / 998 (0.00%)
    1 / 1001 (0.10%)
    1 / 1999 (0.05%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Ventricular fibrillation
         subjects affected / exposed
    0 / 998 (0.00%)
    2 / 1001 (0.20%)
    2 / 1999 (0.10%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 2
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Ventricular hypokinesia
         subjects affected / exposed
    0 / 998 (0.00%)
    1 / 1001 (0.10%)
    1 / 1999 (0.05%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Ventricular tachycardia
         subjects affected / exposed
    0 / 998 (0.00%)
    1 / 1001 (0.10%)
    1 / 1999 (0.05%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 3
    0 / 3
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Nervous system disorders
    Brain oedema
         subjects affected / exposed
    0 / 998 (0.00%)
    1 / 1001 (0.10%)
    1 / 1999 (0.05%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Carotid artery stenosis
         subjects affected / exposed
    1 / 998 (0.10%)
    0 / 1001 (0.00%)
    1 / 1999 (0.05%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Carpal tunnel syndrome
         subjects affected / exposed
    0 / 998 (0.00%)
    1 / 1001 (0.10%)
    1 / 1999 (0.05%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Cerebral haemorrhage
         subjects affected / exposed
    2 / 998 (0.20%)
    1 / 1001 (0.10%)
    3 / 1999 (0.15%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 1
    0 / 3
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Cerebral infarction
         subjects affected / exposed
    1 / 998 (0.10%)
    2 / 1001 (0.20%)
    3 / 1999 (0.15%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 2
    0 / 3
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Cerebral ischaemia
         subjects affected / exposed
    0 / 998 (0.00%)
    4 / 1001 (0.40%)
    4 / 1999 (0.20%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 5
    0 / 5
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Cerebrovascular accident
         subjects affected / exposed
    2 / 998 (0.20%)
    2 / 1001 (0.20%)
    4 / 1999 (0.20%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 2
    0 / 4
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Cerebrovascular disorder
         subjects affected / exposed
    1 / 998 (0.10%)
    0 / 1001 (0.00%)
    1 / 1999 (0.05%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Coma
         subjects affected / exposed
    0 / 998 (0.00%)
    1 / 1001 (0.10%)
    1 / 1999 (0.05%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Demyelination
         subjects affected / exposed
    1 / 998 (0.10%)
    0 / 1001 (0.00%)
    1 / 1999 (0.05%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Haemorrhage intracranial
         subjects affected / exposed
    1 / 998 (0.10%)
    0 / 1001 (0.00%)
    1 / 1999 (0.05%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Haemorrhagic stroke
         subjects affected / exposed
    0 / 998 (0.00%)
    1 / 1001 (0.10%)
    1 / 1999 (0.05%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Headache
         subjects affected / exposed
    0 / 998 (0.00%)
    1 / 1001 (0.10%)
    1 / 1999 (0.05%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Hemiparesis
         subjects affected / exposed
    1 / 998 (0.10%)
    0 / 1001 (0.00%)
    1 / 1999 (0.05%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Intracranial pressure increased
         subjects affected / exposed
    0 / 998 (0.00%)
    1 / 1001 (0.10%)
    1 / 1999 (0.05%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    0 / 1
    Ischaemic stroke
         subjects affected / exposed
    2 / 998 (0.20%)
    5 / 1001 (0.50%)
    7 / 1999 (0.35%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 5
    0 / 7
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Loss of consciousness
         subjects affected / exposed
    0 / 998 (0.00%)
    1 / 1001 (0.10%)
    1 / 1999 (0.05%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Lumbar radiculopathy
         subjects affected / exposed
    1 / 998 (0.10%)
    0 / 1001 (0.00%)
    1 / 1999 (0.05%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Monoparesis
         subjects affected / exposed
    0 / 998 (0.00%)
    1 / 1001 (0.10%)
    1 / 1999 (0.05%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Paraesthesia
         subjects affected / exposed
    0 / 998 (0.00%)
    2 / 1001 (0.20%)
    2 / 1999 (0.10%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 2
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Radiculopathy
         subjects affected / exposed
    2 / 998 (0.20%)
    0 / 1001 (0.00%)
    2 / 1999 (0.10%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Sciatica
         subjects affected / exposed
    3 / 998 (0.30%)
    1 / 1001 (0.10%)
    4 / 1999 (0.20%)
         occurrences causally related to treatment / all
    0 / 4
    0 / 1
    0 / 5
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Seizure
         subjects affected / exposed
    1 / 998 (0.10%)
    1 / 1001 (0.10%)
    2 / 1999 (0.10%)
         occurrences causally related to treatment / all
    0 / 1
    1 / 2
    1 / 3
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Syncope
         subjects affected / exposed
    0 / 998 (0.00%)
    2 / 1001 (0.20%)
    2 / 1999 (0.10%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 2
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Thrombotic cerebral infarction
         subjects affected / exposed
    0 / 998 (0.00%)
    1 / 1001 (0.10%)
    1 / 1999 (0.05%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Transient ischaemic attack
         subjects affected / exposed
    1 / 998 (0.10%)
    0 / 1001 (0.00%)
    1 / 1999 (0.05%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Vertebrobasilar insufficiency
         subjects affected / exposed
    0 / 998 (0.00%)
    1 / 1001 (0.10%)
    1 / 1999 (0.05%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Blood and lymphatic system disorders
    Anaemia
         subjects affected / exposed
    0 / 998 (0.00%)
    1 / 1001 (0.10%)
    1 / 1999 (0.05%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Cytopenia
         subjects affected / exposed
    0 / 998 (0.00%)
    1 / 1001 (0.10%)
    1 / 1999 (0.05%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Hypochromic anaemia
         subjects affected / exposed
    0 / 998 (0.00%)
    1 / 1001 (0.10%)
    1 / 1999 (0.05%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Iron deficiency anaemia
         subjects affected / exposed
    0 / 998 (0.00%)
    1 / 1001 (0.10%)
    1 / 1999 (0.05%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Lymphadenopathy mediastinal
         subjects affected / exposed
    0 / 998 (0.00%)
    1 / 1001 (0.10%)
    1 / 1999 (0.05%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Ear and labyrinth disorders
    Acute vestibular syndrome
         subjects affected / exposed
    0 / 998 (0.00%)
    1 / 1001 (0.10%)
    1 / 1999 (0.05%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Deafness neurosensory
         subjects affected / exposed
    1 / 998 (0.10%)
    0 / 1001 (0.00%)
    1 / 1999 (0.05%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Tinnitus
         subjects affected / exposed
    1 / 998 (0.10%)
    0 / 1001 (0.00%)
    1 / 1999 (0.05%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Vertigo
         subjects affected / exposed
    0 / 998 (0.00%)
    1 / 1001 (0.10%)
    1 / 1999 (0.05%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Vertigo positional
         subjects affected / exposed
    1 / 998 (0.10%)
    0 / 1001 (0.00%)
    1 / 1999 (0.05%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Eye disorders
    Diplopia
         subjects affected / exposed
    1 / 998 (0.10%)
    0 / 1001 (0.00%)
    1 / 1999 (0.05%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Vitreous haemorrhage
         subjects affected / exposed
    1 / 998 (0.10%)
    0 / 1001 (0.00%)
    1 / 1999 (0.05%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Gastrointestinal disorders
    Abdominal hernia
         subjects affected / exposed
    0 / 998 (0.00%)
    2 / 1001 (0.20%)
    2 / 1999 (0.10%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 2
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Abdominal pain
         subjects affected / exposed
    1 / 998 (0.10%)
    0 / 1001 (0.00%)
    1 / 1999 (0.05%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Abdominal pain lower
         subjects affected / exposed
    1 / 998 (0.10%)
    0 / 1001 (0.00%)
    1 / 1999 (0.05%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Abdominal pain upper
         subjects affected / exposed
    0 / 998 (0.00%)
    1 / 1001 (0.10%)
    1 / 1999 (0.05%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Anal fissure
         subjects affected / exposed
    1 / 998 (0.10%)
    0 / 1001 (0.00%)
    1 / 1999 (0.05%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Anal haemorrhage
         subjects affected / exposed
    0 / 998 (0.00%)
    1 / 1001 (0.10%)
    1 / 1999 (0.05%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 2
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Ascites
         subjects affected / exposed
    0 / 998 (0.00%)
    1 / 1001 (0.10%)
    1 / 1999 (0.05%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Colitis
         subjects affected / exposed
    0 / 998 (0.00%)
    1 / 1001 (0.10%)
    1 / 1999 (0.05%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Diarrhoea
         subjects affected / exposed
    1 / 998 (0.10%)
    0 / 1001 (0.00%)
    1 / 1999 (0.05%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Duodenal ulcer haemorrhage
         subjects affected / exposed
    0 / 998 (0.00%)
    1 / 1001 (0.10%)
    1 / 1999 (0.05%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Food poisoning
         subjects affected / exposed
    1 / 998 (0.10%)
    1 / 1001 (0.10%)
    2 / 1999 (0.10%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Gastric disorder
         subjects affected / exposed
    0 / 998 (0.00%)
    1 / 1001 (0.10%)
    1 / 1999 (0.05%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Gastric mucosal lesion
         subjects affected / exposed
    0 / 998 (0.00%)
    1 / 1001 (0.10%)
    1 / 1999 (0.05%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Gastric ulcer
         subjects affected / exposed
    1 / 998 (0.10%)
    0 / 1001 (0.00%)
    1 / 1999 (0.05%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Gastritis
         subjects affected / exposed
    1 / 998 (0.10%)
    0 / 1001 (0.00%)
    1 / 1999 (0.05%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Gastrointestinal erosion
         subjects affected / exposed
    0 / 998 (0.00%)
    1 / 1001 (0.10%)
    1 / 1999 (0.05%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Gastrointestinal fistula
         subjects affected / exposed
    0 / 998 (0.00%)
    1 / 1001 (0.10%)
    1 / 1999 (0.05%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Gastrointestinal haemorrhage
         subjects affected / exposed
    2 / 998 (0.20%)
    0 / 1001 (0.00%)
    2 / 1999 (0.10%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Gastrooesophageal reflux disease
         subjects affected / exposed
    0 / 998 (0.00%)
    1 / 1001 (0.10%)
    1 / 1999 (0.05%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Ileus
         subjects affected / exposed
    1 / 998 (0.10%)
    0 / 1001 (0.00%)
    1 / 1999 (0.05%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Inguinal hernia
         subjects affected / exposed
    0 / 998 (0.00%)
    7 / 1001 (0.70%)
    7 / 1999 (0.35%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 7
    0 / 7
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Lumbar hernia
         subjects affected / exposed
    0 / 998 (0.00%)
    1 / 1001 (0.10%)
    1 / 1999 (0.05%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Pancreatitis
         subjects affected / exposed
    1 / 998 (0.10%)
    0 / 1001 (0.00%)
    1 / 1999 (0.05%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Pancreatitis acute
         subjects affected / exposed
    0 / 998 (0.00%)
    2 / 1001 (0.20%)
    2 / 1999 (0.10%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 2
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Rectal prolapse
         subjects affected / exposed
    1 / 998 (0.10%)
    0 / 1001 (0.00%)
    1 / 1999 (0.05%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Retroperitoneal fibrosis
         subjects affected / exposed
    0 / 998 (0.00%)
    1 / 1001 (0.10%)
    1 / 1999 (0.05%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Umbilical hernia
         subjects affected / exposed
    1 / 998 (0.10%)
    4 / 1001 (0.40%)
    5 / 1999 (0.25%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 4
    0 / 5
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Upper gastrointestinal haemorrhage
         subjects affected / exposed
    1 / 998 (0.10%)
    2 / 1001 (0.20%)
    3 / 1999 (0.15%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 2
    0 / 3
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Varices oesophageal
         subjects affected / exposed
    0 / 998 (0.00%)
    1 / 1001 (0.10%)
    1 / 1999 (0.05%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Vomiting
         subjects affected / exposed
    1 / 998 (0.10%)
    0 / 1001 (0.00%)
    1 / 1999 (0.05%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Hepatobiliary disorders
    Biliary colic
         subjects affected / exposed
    0 / 998 (0.00%)
    1 / 1001 (0.10%)
    1 / 1999 (0.05%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Cholangitis
         subjects affected / exposed
    0 / 998 (0.00%)
    1 / 1001 (0.10%)
    1 / 1999 (0.05%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Cholecystitis
         subjects affected / exposed
    4 / 998 (0.40%)
    2 / 1001 (0.20%)
    6 / 1999 (0.30%)
         occurrences causally related to treatment / all
    0 / 4
    0 / 2
    0 / 6
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Cholecystitis acute
         subjects affected / exposed
    3 / 998 (0.30%)
    1 / 1001 (0.10%)
    4 / 1999 (0.20%)
         occurrences causally related to treatment / all
    0 / 3
    0 / 1
    0 / 4
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Cholelithiasis
         subjects affected / exposed
    2 / 998 (0.20%)
    5 / 1001 (0.50%)
    7 / 1999 (0.35%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 5
    0 / 7
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Cholestasis
         subjects affected / exposed
    0 / 998 (0.00%)
    1 / 1001 (0.10%)
    1 / 1999 (0.05%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Hepatic cirrhosis
         subjects affected / exposed
    1 / 998 (0.10%)
    0 / 1001 (0.00%)
    1 / 1999 (0.05%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Hepatic cyst
         subjects affected / exposed
    0 / 998 (0.00%)
    1 / 1001 (0.10%)
    1 / 1999 (0.05%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Hepatic failure
         subjects affected / exposed
    0 / 998 (0.00%)
    1 / 1001 (0.10%)
    1 / 1999 (0.05%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Hepatic steatosis
         subjects affected / exposed
    0 / 998 (0.00%)
    1 / 1001 (0.10%)
    1 / 1999 (0.05%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Hepatitis toxic
         subjects affected / exposed
    0 / 998 (0.00%)
    1 / 1001 (0.10%)
    1 / 1999 (0.05%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Hepatorenal syndrome
         subjects affected / exposed
    0 / 998 (0.00%)
    1 / 1001 (0.10%)
    1 / 1999 (0.05%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Hydrocholecystis
         subjects affected / exposed
    1 / 998 (0.10%)
    0 / 1001 (0.00%)
    1 / 1999 (0.05%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Jaundice cholestatic
         subjects affected / exposed
    0 / 998 (0.00%)
    1 / 1001 (0.10%)
    1 / 1999 (0.05%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Liver disorder
         subjects affected / exposed
    0 / 998 (0.00%)
    1 / 1001 (0.10%)
    1 / 1999 (0.05%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Skin and subcutaneous tissue disorders
    Angioedema
         subjects affected / exposed
    1 / 998 (0.10%)
    0 / 1001 (0.00%)
    1 / 1999 (0.05%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Diabetic foot
         subjects affected / exposed
    0 / 998 (0.00%)
    1 / 1001 (0.10%)
    1 / 1999 (0.05%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Eczema
         subjects affected / exposed
    0 / 998 (0.00%)
    1 / 1001 (0.10%)
    1 / 1999 (0.05%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Skin lesion
         subjects affected / exposed
    0 / 998 (0.00%)
    1 / 1001 (0.10%)
    1 / 1999 (0.05%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Skin ulcer haemorrhage
         subjects affected / exposed
    1 / 998 (0.10%)
    0 / 1001 (0.00%)
    1 / 1999 (0.05%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Urticaria
         subjects affected / exposed
    1 / 998 (0.10%)
    0 / 1001 (0.00%)
    1 / 1999 (0.05%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Renal and urinary disorders
    Bladder tamponade
         subjects affected / exposed
    1 / 998 (0.10%)
    0 / 1001 (0.00%)
    1 / 1999 (0.05%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Calculus bladder
         subjects affected / exposed
    1 / 998 (0.10%)
    0 / 1001 (0.00%)
    1 / 1999 (0.05%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Chronic kidney disease
         subjects affected / exposed
    1 / 998 (0.10%)
    1 / 1001 (0.10%)
    2 / 1999 (0.10%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Diabetic nephropathy
         subjects affected / exposed
    1 / 998 (0.10%)
    0 / 1001 (0.00%)
    1 / 1999 (0.05%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Dysuria
         subjects affected / exposed
    0 / 998 (0.00%)
    1 / 1001 (0.10%)
    1 / 1999 (0.05%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Haematuria
         subjects affected / exposed
    1 / 998 (0.10%)
    0 / 1001 (0.00%)
    1 / 1999 (0.05%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Hydronephrosis
         subjects affected / exposed
    1 / 998 (0.10%)
    2 / 1001 (0.20%)
    3 / 1999 (0.15%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 2
    0 / 3
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Nephrolithiasis
         subjects affected / exposed
    3 / 998 (0.30%)
    2 / 1001 (0.20%)
    5 / 1999 (0.25%)
         occurrences causally related to treatment / all
    0 / 3
    0 / 2
    0 / 5
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Renal colic
         subjects affected / exposed
    1 / 998 (0.10%)
    2 / 1001 (0.20%)
    3 / 1999 (0.15%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 2
    0 / 3
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Renal failure
         subjects affected / exposed
    0 / 998 (0.00%)
    3 / 1001 (0.30%)
    3 / 1999 (0.15%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 3
    1 / 3
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Renal impairment
         subjects affected / exposed
    0 / 998 (0.00%)
    1 / 1001 (0.10%)
    1 / 1999 (0.05%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Stag horn calculus
         subjects affected / exposed
    1 / 998 (0.10%)
    0 / 1001 (0.00%)
    1 / 1999 (0.05%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Ureterolithiasis
         subjects affected / exposed
    1 / 998 (0.10%)
    1 / 1001 (0.10%)
    2 / 1999 (0.10%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Urethral stenosis
         subjects affected / exposed
    0 / 998 (0.00%)
    1 / 1001 (0.10%)
    1 / 1999 (0.05%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Urinary incontinence
         subjects affected / exposed
    0 / 998 (0.00%)
    1 / 1001 (0.10%)
    1 / 1999 (0.05%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Urinary retention
         subjects affected / exposed
    1 / 998 (0.10%)
    0 / 1001 (0.00%)
    1 / 1999 (0.05%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Urinary tract obstruction
         subjects affected / exposed
    0 / 998 (0.00%)
    1 / 1001 (0.10%)
    1 / 1999 (0.05%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Endocrine disorders
    Goitre
         subjects affected / exposed
    1 / 998 (0.10%)
    1 / 1001 (0.10%)
    2 / 1999 (0.10%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Hypoparathyroidism
         subjects affected / exposed
    1 / 998 (0.10%)
    0 / 1001 (0.00%)
    1 / 1999 (0.05%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Musculoskeletal and connective tissue disorders
    Exostosis
         subjects affected / exposed
    0 / 998 (0.00%)
    1 / 1001 (0.10%)
    1 / 1999 (0.05%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Gouty tophus
         subjects affected / exposed
    0 / 998 (0.00%)
    1 / 1001 (0.10%)
    1 / 1999 (0.05%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Intervertebral disc protrusion
         subjects affected / exposed
    3 / 998 (0.30%)
    2 / 1001 (0.20%)
    5 / 1999 (0.25%)
         occurrences causally related to treatment / all
    1 / 3
    0 / 2
    1 / 5
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Joint contracture
         subjects affected / exposed
    0 / 998 (0.00%)
    1 / 1001 (0.10%)
    1 / 1999 (0.05%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 2
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Joint range of motion decreased
         subjects affected / exposed
    0 / 998 (0.00%)
    1 / 1001 (0.10%)
    1 / 1999 (0.05%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Lumbar spinal stenosis
         subjects affected / exposed
    1 / 998 (0.10%)
    0 / 1001 (0.00%)
    1 / 1999 (0.05%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Musculoskeletal chest pain
         subjects affected / exposed
    0 / 998 (0.00%)
    1 / 1001 (0.10%)
    1 / 1999 (0.05%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Myalgia
         subjects affected / exposed
    0 / 998 (0.00%)
    1 / 1001 (0.10%)
    1 / 1999 (0.05%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Osteoarthritis
         subjects affected / exposed
    2 / 998 (0.20%)
    5 / 1001 (0.50%)
    7 / 1999 (0.35%)
         occurrences causally related to treatment / all
    0 / 3
    0 / 5
    0 / 8
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Osteochondrosis
         subjects affected / exposed
    1 / 998 (0.10%)
    2 / 1001 (0.20%)
    3 / 1999 (0.15%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 2
    0 / 3
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Pain in extremity
         subjects affected / exposed
    0 / 998 (0.00%)
    1 / 1001 (0.10%)
    1 / 1999 (0.05%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Periarthritis
         subjects affected / exposed
    1 / 998 (0.10%)
    0 / 1001 (0.00%)
    1 / 1999 (0.05%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Pseudarthrosis
         subjects affected / exposed
    0 / 998 (0.00%)
    1 / 1001 (0.10%)
    1 / 1999 (0.05%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Rotator cuff syndrome
         subjects affected / exposed
    0 / 998 (0.00%)
    1 / 1001 (0.10%)
    1 / 1999 (0.05%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Scleroderma
         subjects affected / exposed
    0 / 998 (0.00%)
    1 / 1001 (0.10%)
    1 / 1999 (0.05%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Spinal osteoarthritis
         subjects affected / exposed
    3 / 998 (0.30%)
    1 / 1001 (0.10%)
    4 / 1999 (0.20%)
         occurrences causally related to treatment / all
    0 / 3
    0 / 1
    0 / 4
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Spinal pain
         subjects affected / exposed
    1 / 998 (0.10%)
    1 / 1001 (0.10%)
    2 / 1999 (0.10%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Tendonitis
         subjects affected / exposed
    0 / 998 (0.00%)
    1 / 1001 (0.10%)
    1 / 1999 (0.05%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Infections and infestations
    Abscess limb
         subjects affected / exposed
    0 / 998 (0.00%)
    1 / 1001 (0.10%)
    1 / 1999 (0.05%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Acute sinusitis
         subjects affected / exposed
    0 / 998 (0.00%)
    1 / 1001 (0.10%)
    1 / 1999 (0.05%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Anal abscess
         subjects affected / exposed
    1 / 998 (0.10%)
    1 / 1001 (0.10%)
    2 / 1999 (0.10%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Appendicitis
         subjects affected / exposed
    2 / 998 (0.20%)
    2 / 1001 (0.20%)
    4 / 1999 (0.20%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 2
    0 / 4
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Bartholin's abscess
         subjects affected / exposed
    1 / 998 (0.10%)
    0 / 1001 (0.00%)
    1 / 1999 (0.05%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Bone tuberculosis
         subjects affected / exposed
    1 / 998 (0.10%)
    0 / 1001 (0.00%)
    1 / 1999 (0.05%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Bronchitis
         subjects affected / exposed
    1 / 998 (0.10%)
    0 / 1001 (0.00%)
    1 / 1999 (0.05%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Cervicitis
         subjects affected / exposed
    0 / 998 (0.00%)
    1 / 1001 (0.10%)
    1 / 1999 (0.05%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Dengue fever
         subjects affected / exposed
    2 / 998 (0.20%)
    1 / 1001 (0.10%)
    3 / 1999 (0.15%)
         occurrences causally related to treatment / all
    0 / 2
    1 / 1
    1 / 3
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Diarrhoea infectious
         subjects affected / exposed
    0 / 998 (0.00%)
    1 / 1001 (0.10%)
    1 / 1999 (0.05%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Diverticulitis
         subjects affected / exposed
    1 / 998 (0.10%)
    1 / 1001 (0.10%)
    2 / 1999 (0.10%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Epididymitis
         subjects affected / exposed
    1 / 998 (0.10%)
    0 / 1001 (0.00%)
    1 / 1999 (0.05%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Gastroenteritis
         subjects affected / exposed
    1 / 998 (0.10%)
    0 / 1001 (0.00%)
    1 / 1999 (0.05%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Gastroenteritis viral
         subjects affected / exposed
    0 / 998 (0.00%)
    1 / 1001 (0.10%)
    1 / 1999 (0.05%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Hepatic echinococciasis
         subjects affected / exposed
    0 / 998 (0.00%)
    1 / 1001 (0.10%)
    1 / 1999 (0.05%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Hepatitis viral
         subjects affected / exposed
    1 / 998 (0.10%)
    0 / 1001 (0.00%)
    1 / 1999 (0.05%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Herpes zoster
         subjects affected / exposed
    1 / 998 (0.10%)
    1 / 1001 (0.10%)
    2 / 1999 (0.10%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Infection
         subjects affected / exposed
    1 / 998 (0.10%)
    0 / 1001 (0.00%)
    1 / 1999 (0.05%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Lung infection
         subjects affected / exposed
    1 / 998 (0.10%)
    0 / 1001 (0.00%)
    1 / 1999 (0.05%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Mastoiditis
         subjects affected / exposed
    1 / 998 (0.10%)
    0 / 1001 (0.00%)
    1 / 1999 (0.05%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Meningitis pneumococcal
         subjects affected / exposed
    1 / 998 (0.10%)
    0 / 1001 (0.00%)
    1 / 1999 (0.05%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Otitis media chronic
         subjects affected / exposed
    0 / 998 (0.00%)
    1 / 1001 (0.10%)
    1 / 1999 (0.05%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Pancreas infection
         subjects affected / exposed
    0 / 998 (0.00%)
    1 / 1001 (0.10%)
    1 / 1999 (0.05%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Pneumonia
         subjects affected / exposed
    14 / 998 (1.40%)
    5 / 1001 (0.50%)
    19 / 1999 (0.95%)
         occurrences causally related to treatment / all
    0 / 14
    0 / 5
    0 / 19
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    0 / 1
    Pyelonephritis
         subjects affected / exposed
    1 / 998 (0.10%)
    0 / 1001 (0.00%)
    1 / 1999 (0.05%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Pyelonephritis acute
         subjects affected / exposed
    1 / 998 (0.10%)
    0 / 1001 (0.00%)
    1 / 1999 (0.05%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Pyelonephritis chronic
         subjects affected / exposed
    1 / 998 (0.10%)
    0 / 1001 (0.00%)
    1 / 1999 (0.05%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Rectal abscess
         subjects affected / exposed
    1 / 998 (0.10%)
    1 / 1001 (0.10%)
    2 / 1999 (0.10%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 1
    0 / 3
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Sepsis
         subjects affected / exposed
    1 / 998 (0.10%)
    1 / 1001 (0.10%)
    2 / 1999 (0.10%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    0 / 1
    Subcutaneous abscess
         subjects affected / exposed
    0 / 998 (0.00%)
    1 / 1001 (0.10%)
    1 / 1999 (0.05%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Tooth abscess
         subjects affected / exposed
    0 / 998 (0.00%)
    1 / 1001 (0.10%)
    1 / 1999 (0.05%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Urinary tract infection
         subjects affected / exposed
    2 / 998 (0.20%)
    3 / 1001 (0.30%)
    5 / 1999 (0.25%)
         occurrences causally related to treatment / all
    1 / 3
    0 / 3
    1 / 6
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Urinary tract infection bacterial
         subjects affected / exposed
    0 / 998 (0.00%)
    1 / 1001 (0.10%)
    1 / 1999 (0.05%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Viral infection
         subjects affected / exposed
    1 / 998 (0.10%)
    0 / 1001 (0.00%)
    1 / 1999 (0.05%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Viral myelitis
         subjects affected / exposed
    1 / 998 (0.10%)
    0 / 1001 (0.00%)
    1 / 1999 (0.05%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Metabolism and nutrition disorders
    Diabetes mellitus
         subjects affected / exposed
    2 / 998 (0.20%)
    1 / 1001 (0.10%)
    3 / 1999 (0.15%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 1
    0 / 3
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Diabetes mellitus inadequate control
         subjects affected / exposed
    0 / 998 (0.00%)
    2 / 1001 (0.20%)
    2 / 1999 (0.10%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 3
    0 / 3
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Hyperglycaemia
         subjects affected / exposed
    1 / 998 (0.10%)
    0 / 1001 (0.00%)
    1 / 1999 (0.05%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Hyperkalaemia
         subjects affected / exposed
    0 / 998 (0.00%)
    1 / 1001 (0.10%)
    1 / 1999 (0.05%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Type 2 diabetes mellitus
         subjects affected / exposed
    1 / 998 (0.10%)
    0 / 1001 (0.00%)
    1 / 1999 (0.05%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Frequency threshold for reporting non-serious adverse events: 5%
    Non-serious adverse events
    		 Vilda 50mg bid +@metformin Placebo +@metformin Total
    Total subjects affected by non serious adverse events
         subjects affected / exposed
    582 / 998 (58.32%)
    566 / 1001 (56.54%)
    1148 / 1999 (57.43%)
    Vascular disorders
    Hypertension
         subjects affected / exposed
    103 / 998 (10.32%)
    124 / 1001 (12.39%)
    227 / 1999 (11.36%)
         occurrences all number
    116
    130
    246
    Nervous system disorders
    Dizziness
         subjects affected / exposed
    67 / 998 (6.71%)
    41 / 1001 (4.10%)
    108 / 1999 (5.40%)
         occurrences all number
    99
    61
    160
    Headache
         subjects affected / exposed
    82 / 998 (8.22%)
    72 / 1001 (7.19%)
    154 / 1999 (7.70%)
         occurrences all number
    120
    107
    227
    Gastrointestinal disorders
    Diarrhoea
         subjects affected / exposed
    104 / 998 (10.42%)
    104 / 1001 (10.39%)
    208 / 1999 (10.41%)
         occurrences all number
    127
    132
    259
    Musculoskeletal and connective tissue disorders
    Arthralgia
         subjects affected / exposed
    100 / 998 (10.02%)
    94 / 1001 (9.39%)
    194 / 1999 (9.70%)
         occurrences all number
    115
    124
    239
    Back pain
         subjects affected / exposed
    105 / 998 (10.52%)
    86 / 1001 (8.59%)
    191 / 1999 (9.55%)
         occurrences all number
    127
    108
    235
    Osteoarthritis
         subjects affected / exposed
    54 / 998 (5.41%)
    40 / 1001 (4.00%)
    94 / 1999 (4.70%)
         occurrences all number
    60
    44
    104
    Pain in extremity
         subjects affected / exposed
    67 / 998 (6.71%)
    74 / 1001 (7.39%)
    141 / 1999 (7.05%)
         occurrences all number
    81
    89
    170
    Infections and infestations
    Bronchitis
         subjects affected / exposed
    58 / 998 (5.81%)
    59 / 1001 (5.89%)
    117 / 1999 (5.85%)
         occurrences all number
    87
    79
    166
    Influenza
         subjects affected / exposed
    93 / 998 (9.32%)
    64 / 1001 (6.39%)
    157 / 1999 (7.85%)
         occurrences all number
    118
    89
    207
    Nasopharyngitis
         subjects affected / exposed
    104 / 998 (10.42%)
    108 / 1001 (10.79%)
    212 / 1999 (10.61%)
         occurrences all number
    154
    174
    328
    Upper respiratory tract infection
         subjects affected / exposed
    83 / 998 (8.32%)
    69 / 1001 (6.89%)
    152 / 1999 (7.60%)
         occurrences all number
    136
    111
    247
    Urinary tract infection
         subjects affected / exposed
    72 / 998 (7.21%)
    69 / 1001 (6.89%)
    141 / 1999 (7.05%)
         occurrences all number
    96
    87
    183
    Metabolism and nutrition disorders
    Dyslipidaemia
         subjects affected / exposed
    58 / 998 (5.81%)
    71 / 1001 (7.09%)
    129 / 1999 (6.45%)
         occurrences all number
    62
    72
    134

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    Substantial protocol amendments (globally)
    Were there any global substantial amendments to the protocol? Yes
    Date
    Amendment
    27 Oct 2011
    Amendment no. 1 (released 27-Oct-2011): An additional meal-test was included for patients who were participating in the meal-test sub-study at Visit 4. This change, together with the additional meal-tests, enabled the evaluation of the rate of loss in β-cell function and the rate of change in insulin sensitivity based on the meal-test. Furthermore, clarification related to the timing of administration of the study drug at the visits when the meal-test was performed was inserted.
    08 Feb 2012
    Amendment no. 2 (released 08-Feb-2012): Additional clarification was included related to the occurrence of a contraindication against the treatment with metformin or vildagliptin during the study and to ensure only patients who received appropriate diet and exercise training with respect to lifestyle modifications prior to enrolment could be included.
    04 Oct 2016
    Amendment no. 3 (released 04-Oct-2016): The protocol was amended to accommodate the inclusion of an adjudication committee and a data monitoring committee (DMC), and to specify timelines for safety reporting. Furthermore, due to a metformin 500mg tablet variant introduced in the study with organoleptic properties which were not well perceived by subjects, the protocol now allowed the temporary use of commercial metformin 500mg tablets.
    04 Apr 2019
    Amendment no. 4 (released 22-Oct-2019): The protocol was amended based on a health authority request to incorporate the redefined order of analysis in the protocol to align with the final, published statistical analysis plan (published before LPLV; Matthews et al 2019b). The loss of glycaemic control was analysed as a secondary endpoint instead of a primary endpoint, and an additional detail was provided for the confirmatory visit for the primary analysis of time to initial treatment failure. Following this, only one primary endpoint approach was included in the statistical analysis plan analysis.

    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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