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    Clinical Trial Results:
    A Multicenter, Randomized, Double-Blind, Active-Controlled, Phase 3 Study to Evaluate the Efficacy and Safety of TAK-875 25 mg and 50 mg Compared to Glimepiride When Used in Combination with Metformin in Subjects with Type 2 Diabetes

    Summary
    EudraCT number
    		 2011-001731-24
    Trial protocol
    		 LV   LT   CZ   EE   BG   GB  
    Global end of trial date
    24 Apr 2014

    Results information
    Results version number
    		 v2(current)
    This version publication date
    15 Jul 2016
    First version publication date
    31 Jul 2015
    Other versions
    		 v1
    Version creation reason
    • New data added to full data set
    Correction to full data set

    Trial information

    		 Close Top of page
    Trial identification
    Sponsor protocol code
    TAK-875_304
    Additional study identifiers
    ISRCTN number
    		 -
    US NCT number
    		 NCT01481116
    WHO universal trial number (UTN)
    		 U1111-1124-2296
    Sponsors
    Sponsor organisation name
    Takeda
    Sponsor organisation address
    61 Aldwych, London, United Kingdom, WC2B 4AE
    Public contact
    Program Manager, Takeda Development Centre Europe Ltd., 004 40203116 8000, clinicaloperations@tgrd.com
    Scientific contact
    Program Manager, Takeda Development Centre Europe Ltd., 004 40203116 8000, clinicaloperations@tgrd.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
    17 Dec 2014
    Is this the analysis of the primary completion data?
    No
    Global end of trial reached?
    Yes
    Global end of trial date
    24 Apr 2014
    Was the trial ended prematurely?
    Yes
    General information about the trial
    Main objective of the trial
    To evaluate the efficacy of TAK-875 plus metformin compared to glimepiride plus metformin on glycemic control as assessed by change from baseline in glycosylated hemoglobin (HbA1c) at Weeks 78 and 104.
    Protection of trial subjects
    All study subjects were required to read and sign an Informed Consent Form.
    Background therapy
    		 -
    Evidence for comparator
    		 -
    Actual start date of recruitment
    06 Nov 2011
    Long term follow-up planned
    No
    Independent data monitoring committee (IDMC) involvement?
    No
    Population of trial subjects
    Number of subjects enrolled per country
    Country: Number of subjects enrolled
    Argentina: 113
    Country: Number of subjects enrolled
    Australia: 9
    Country: Number of subjects enrolled
    Bulgaria: 51
    Country: Number of subjects enrolled
    Canada: 121
    Country: Number of subjects enrolled
    Colombia: 3
    Country: Number of subjects enrolled
    Czech Republic: 93
    Country: Number of subjects enrolled
    Estonia: 36
    Country: Number of subjects enrolled
    Hong Kong: 29
    Country: Number of subjects enrolled
    Israel: 150
    Country: Number of subjects enrolled
    Latvia: 43
    Country: Number of subjects enrolled
    Lithuania: 66
    Country: Number of subjects enrolled
    Malaysia: 50
    Country: Number of subjects enrolled
    Mexico: 43
    Country: Number of subjects enrolled
    New Zealand: 44
    Country: Number of subjects enrolled
    Philippines: 114
    Country: Number of subjects enrolled
    Poland: 193
    Country: Number of subjects enrolled
    Romania: 155
    Country: Number of subjects enrolled
    Russian Federation: 78
    Country: Number of subjects enrolled
    South Africa: 247
    Country: Number of subjects enrolled
    Taiwan: 34
    Country: Number of subjects enrolled
    Ukraine: 239
    Country: Number of subjects enrolled
    United Kingdom: 51
    Country: Number of subjects enrolled
    United States: 492
    Worldwide total number of subjects
    2454
    EEA total number of subjects
    688
    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)
    1931
    From 65 to 84 years
    523
    85 years and over
    0

    Subject disposition

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    Recruitment
    Recruitment details
    		 Subjects took part at 291 sites in Argentina, Australia, Bulgaria, Canada, Colombia, Czech Republic, Estonia, Hong Kong, Israel, Latvia, Lithuania, Malaysia, Mexico, New Zealand, Philippines, Poland, Romania, the Russian Federation, South Africa, Taiwan, Ukraine, the United Kingdom and the United States from 06 November 2011 to 24 April 2014.

    Pre-assignment
    Screening details
    		 Subjects with a historical diagnosis of type 2 diabetes mellitus who were inadequately controlled while receiving metformin alone were enrolled in 1 of 3 treatment groups as follows: glimepiride; TAK-875 25 milligram (mg); TAK-875 50 mg.

    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
    		 Glimepiride
    Arm description
    		 TAK-875 placebo-matching tablets, orally, once daily and glimepiride 1 mg, over-encapsulated capsules, orally, once daily for 1 week followed by up-titration in 2 mg increments up to 6 mg, orally, once daily along with metformin greater than or equal to (>=)1500 mg per day or maximum tolerated dose, tablets, orally for up to 104 weeks. Glimepiride dose could be down-titrated from 6 mg in case of recurrent or severe hypoglycemia.
    Arm type
    		 Active comparator

    Investigational medicinal product name
    Glimepiride
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Capsule
    Routes of administration
    Oral use
    Dosage and administration details
    Glimepiride 1 mg, over-encapsulated capsules, orally, once daily for 1 week followed by up-titration in 2 mg increments up to 6 mg, orally, once daily for up to 104 weeks. Glimepiride dose could be down-titrated from 6 mg in case of recurrent or severe hypoglycemia.

    Investigational medicinal product name
    Placebo
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Tablet
    Routes of administration
    Oral use
    Dosage and administration details
    TAK-875 placebo-matching tablets, orally, once daily for up to 104 weeks.

    Investigational medicinal product name
    Metformin
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Tablet
    Routes of administration
    Oral use
    Dosage and administration details
    Metformin >=1500 mg per day or maximum tolerated dose, tablets, orally for up to 104 weeks

    Arm title
    		 TAK-875 25 mg
    Arm description
    		 TAK-875 25 mg, tablets, orally, once daily and glimepiride placebo-matching capsules, orally, once daily along with metformin >=1500 mg per day or maximum tolerated dose, tablets, orally for up to 104 weeks.
    Arm type
    		 Experimental

    Investigational medicinal product name
    TAK-875
    Investigational medicinal product code
    Other name
    Fasiglifam
    Pharmaceutical forms
    Tablet
    Routes of administration
    Oral use
    Dosage and administration details
    TAK-875 25 mg, tablets, orally, once daily for up to 104 weeks.

    Investigational medicinal product name
    Placebo
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Capsule
    Routes of administration
    Oral use
    Dosage and administration details
    Glimepiride placebo ­matching capsules, orally, once daily for up to 104 weeks.

    Investigational medicinal product name
    Metformin
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Tablet
    Routes of administration
    Oral use
    Dosage and administration details
    Metformin >=1500 mg per day or maximum tolerated dose, tablets, orally for up to 104 weeks.

    Arm title
    		 TAK-875 50 mg
    Arm description
    		 TAK-875 50 mg, tablets, orally, once daily and glimepiride placebo-matching capsules, orally, once daily along with metformin >=1500 mg per day or maximum tolerated dose, tablets, orally for up to 104 weeks.
    Arm type
    		 Experimental

    Investigational medicinal product name
    TAK-875
    Investigational medicinal product code
    Other name
    Fasiglifam
    Pharmaceutical forms
    Tablet
    Routes of administration
    Oral use
    Dosage and administration details
    TAK-875 50 mg tablets, orally, once daily for up to 104 weeks.

    Investigational medicinal product name
    Placebo
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Capsule
    Routes of administration
    Oral use
    Dosage and administration details
    Glimepiride placebo-matching capsules, orally, once daily for up to 104 weeks.

    Investigational medicinal product name
    Metformin
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Tablet
    Routes of administration
    Oral use
    Dosage and administration details
    Metformin >=1500 mg per day or maximum tolerated dose, tablets, orally for up to 104 weeks.

    Number of subjects in period 1
    		Glimepiride TAK-875 25 mg TAK-875 50 mg
    Started
    824
    817
    813
    Treated
    822
    816
    813
    Completed
    0
    0
    0
    Not completed
    824
    817
    813
         Major protocol deviation
    3
    7
    1
         Adverse event
    26
    26
    42
         Investigator Decision
    3
    2
    1
         Contraindications
    1
    1
    -
         Non-Compliant With Study Drug
    -
    1
    1
         Hypoglycemic Event
    4
    -
    -
         Consent withdrawn by subject
    37
    33
    37
         Study termination
    730
    729
    713
         Death
    2
    1
    -
         Investigator’s Discretion
    2
    -
    -
         Pregnancy
    -
    -
    1
         Sponsor Decision
    -
    1
    3
         Unspecified
    1
    1
    -
         Subject Moved Out of Area
    2
    -
    1
         Subject Started Taking Glipizide
    1
    -
    -
         Lost to follow-up
    8
    12
    11
         Lack of efficacy
    3
    3
    1
         Subject Moved Out of Country
    1
    -
    1

    Baseline characteristics

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    Baseline characteristics reporting groups
    Reporting group title
    Glimepiride
    Reporting group description
    		 TAK-875 placebo-matching tablets, orally, once daily and glimepiride 1 mg, over-encapsulated capsules, orally, once daily for 1 week followed by up-titration in 2 mg increments up to 6 mg, orally, once daily along with metformin greater than or equal to (>=)1500 mg per day or maximum tolerated dose, tablets, orally for up to 104 weeks. Glimepiride dose could be down-titrated from 6 mg in case of recurrent or severe hypoglycemia.

    Reporting group title
    TAK-875 25 mg
    Reporting group description
    		 TAK-875 25 mg, tablets, orally, once daily and glimepiride placebo-matching capsules, orally, once daily along with metformin >=1500 mg per day or maximum tolerated dose, tablets, orally for up to 104 weeks.

    Reporting group title
    TAK-875 50 mg
    Reporting group description
    		 TAK-875 50 mg, tablets, orally, once daily and glimepiride placebo-matching capsules, orally, once daily along with metformin >=1500 mg per day or maximum tolerated dose, tablets, orally for up to 104 weeks.

    Reporting group values
    		 Glimepiride TAK-875 25 mg TAK-875 50 mg Total
    Number of subjects
    		 824 817 813 2454
    Age categorical
    Units: Subjects
        Less than (<) 65 years
    		 637 646 648 1931
        >=65 years
    		 187 171 165 523
    Age continuous
    Units: years
        arithmetic mean (standard deviation)
    		 57.3 ± 9.56 56.8 ± 9.34 56.6 ± 9.81 -
    Gender categorical
    Units: Subjects
        Female
    		 428 422 362 1212
        Male
    		 396 395 451 1242
    Race/Ethnicity, Customized
    Units: Subjects
        Hispanic or Latino
    		 68 66 70 204
        Non-Hispanic or Latino
    		 105 110 106 321
        Not Available
    		 651 641 637 1929
    Race/Ethnicity, Customized
    Units: Subjects
        American Indian or Alaska Native
    		 8 20 12 40
        Asian
    		 101 99 93 293
        Black or African American
    		 62 70 77 209
        Native Hawaiian or Other Pacific Islander
    		 3 4 7 14
        White
    		 617 598 601 1816
        Multiracial
    		 33 26 23 82
    Region of Enrollment
    Units: Subjects
        Argentina
    		 37 39 37 113
        Australia
    		 4 2 3 9
        Bulgaria
    		 17 18 16 51
        Canada
    		 42 40 39 121
        Colombia
    		 2 0 1 3
        Czech Republic
    		 31 31 31 93
        Estonia
    		 12 12 12 36
        Hong Kong
    		 9 10 10 29
        Israel
    		 50 50 50 150
        Latvia
    		 15 14 14 43
        Lithuania
    		 21 23 22 66
        Malaysia
    		 17 16 17 50
        Mexico
    		 14 14 15 43
        New Zealand
    		 15 14 15 44
        Philippines
    		 39 38 37 114
        Poland
    		 64 66 63 193
        Romania
    		 52 52 51 155
        Russian Federation
    		 26 26 26 78
        South Africa
    		 83 81 83 247
        Taiwan, Province Of China
    		 11 11 12 34
        Ukraine
    		 80 80 79 239
        United Kingdom
    		 18 16 17 51
        United States
    		 165 164 163 492
    Smoking Classification
    Units: Subjects
        Never smoked
    		 552 533 502 1587
        Current smoker
    		 114 143 126 383
        Ex-smoker
    		 158 141 185 484
    Baseline Glycosylated Hemoglobin (HbA1c) Category
    Units: Subjects
        < 8.5 percent (%)
    		 584 584 592 1760
        >=8.5%
    		 238 232 221 691
        Not Available
    		 2 1 0 3
    Height
    For this endpoint, number of subjects evaluable were 823, 817 and 813 for each arm, respectively.
    Units: centimeter
        arithmetic mean (standard deviation)
    		 166.2 ± 10.66 166.2 ± 10.23 167.3 ± 10.19 -
    Weight
    For this endpoint, number of subjects evaluable were 822, 816 and 813 for each arm, respectively.
    Units: kilogram (kg)
        arithmetic mean (standard deviation)
    		 86.95 ± 18.415 87.35 ± 18.283 88.37 ± 18.796 -
    Body Mass Index (BMI)
    For this endpoint, number of subjects evaluable were 821, 816 and 813 for each arm, respectively.
    Units: kilogram per square meter (kg/m^2)
        arithmetic mean (standard deviation)
    		 31.34 ± 5.334 31.5 ± 5.253 31.43 ± 5.403 -
    Duration of Diabetes
    For this endpoint, number of subjects evaluable were 823, 817 and 812 for each arm, respectively.
    Units: years
        arithmetic mean (standard deviation)
    		 6.372 ± 5.293 6.566 ± 5.132 5.995 ± 4.711 -

    End points

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    End points reporting groups
    Reporting group title
    Glimepiride
    Reporting group description
    		 TAK-875 placebo-matching tablets, orally, once daily and glimepiride 1 mg, over-encapsulated capsules, orally, once daily for 1 week followed by up-titration in 2 mg increments up to 6 mg, orally, once daily along with metformin greater than or equal to (>=)1500 mg per day or maximum tolerated dose, tablets, orally for up to 104 weeks. Glimepiride dose could be down-titrated from 6 mg in case of recurrent or severe hypoglycemia.

    Reporting group title
    TAK-875 25 mg
    Reporting group description
    		 TAK-875 25 mg, tablets, orally, once daily and glimepiride placebo-matching capsules, orally, once daily along with metformin >=1500 mg per day or maximum tolerated dose, tablets, orally for up to 104 weeks.

    Reporting group title
    TAK-875 50 mg
    Reporting group description
    		 TAK-875 50 mg, tablets, orally, once daily and glimepiride placebo-matching capsules, orally, once daily along with metformin >=1500 mg per day or maximum tolerated dose, tablets, orally for up to 104 weeks.

    Primary: Change From Baseline in HbA1c at Weeks 78 and 104

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    End point title
    		 Change From Baseline in HbA1c at Weeks 78 and 104 [1]
    End point description
    The change in the value of HbA1c (the concentration of glucose bound to hemoglobin as a percent of the absolute maximum that can be bound) to be collected at Weeks 78 and 104 relative to baseline. Full Analysis Set (FAS) included all randomized subjects who received at least 1 dose of double-blind study medication and who had a baseline and at least 1 post- baseline assessment. Here "99999" in the least square mean and standard error values signifies not estimable (NA), since none of the subjects had data for the arm "Glimepiride" at given time point.
    End point type
    Primary
    End point timeframe
    Baseline and Weeks 78 and 104
    Notes
    [1] - No statistical analyses have been specified for this primary end point. It is expected there is at least one statistical analysis for each primary end point.
    Justification: Only descriptive data was planned to be reported for this endpoint.
    End point values
    		 Glimepiride TAK-875 25 mg TAK-875 50 mg
    Number of subjects analysed
    62
    61
    66
    Units: percentage of glycosylated hemoglobin
    least squares mean (standard error)
        Baseline
    8 ± 0.814
    8.01 ± 0.777
    7.99 ± 0.792
        Change at Week 78
    -0.8 ± 0.957
    -0.82 ± 0.865
    -0.98 ± 0.834
        Change at Week 104
    99999 ± 99999
    -1.03 ± 1.159
    0.03 ± 0.603
    No statistical analyses for this end point

    Secondary: Percentage of Subjects With Hypoglycemia

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    End point title
    		 Percentage of Subjects With Hypoglycemia
    End point description
    Subjects were provided diaries to document any hypoglycemic events that occurred between study visits. Any experience of hypoglycemic signs and symptoms (regardless of the blood glucose value by glucometer) or had a blood glucose value less than or equal to (<=) 70 milligram per deciliter (mg/dL) (3.9 millimole per liter (mmol/L) by glucometer (regardless of symptoms) were to be recorded. Safety analysis set included all subjects who received at least 1 dose of double-blind study medication. Subjects were analyzed according to the study medication they received.
    End point type
    Secondary
    End point timeframe
    Day 1 up to Weeks 78 and 104
    End point values
    		 Glimepiride TAK-875 25 mg TAK-875 50 mg
    Number of subjects analysed
    822
    816
    813
    Units: percentage of subjects
    number (not applicable)
        Day 1 up to Week 78
    30.2
    5.4
    5.3
        Day 1 up to Week 104
    30.2
    5.4
    5.3
    Statistical analysis title
    		 Day 1 up to Week 78: Glimepiride, TAK-875 25 mg
    Statistical analysis description
    Odds Ratios, corresponding confidence interval, and p-values were calculated using logistic regression with factors for treatment, country, schedule and baseline HbA1c value.
    Comparison groups
    Glimepiride v TAK-875 25 mg
    Number of subjects included in analysis
    1638
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 < 0.001 [2]
    Method
    		 Regression, Logistic
    Parameter type
    		 Odds ratio (OR)
    Point estimate
    0.13
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.09
         upper limit
    		 0.18
    Notes
    [2] - The testing procedure at 2-sided significance level of 0.025 was as follows: 1) TAK-875 25 mg vs. glimepiride, 2) TAK-875 50 mg vs. glimepiride. If P-value was not greater than 0.025 at Step 1, then Step 2 was carried out.
    Statistical analysis title
    		 Day 1 up to Week 78: Glimepiride, TAK-875 50 mg
    Statistical analysis description
    Odds Ratios, corresponding confidence interval, and p-values were calculated using logistic regression with factors for treatment, country, schedule and baseline HbA1c value.
    Comparison groups
    Glimepiride v TAK-875 50 mg
    Number of subjects included in analysis
    1635
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 < 0.001 [3]
    Method
    		 Regression, Logistic
    Parameter type
    		 Odds ratio (OR)
    Point estimate
    0.13
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.09
         upper limit
    		 0.18
    Notes
    [3] - The testing procedure at 2-sided significance level of 0.025 was as follows: 1) TAK-875 25 mg vs. glimepiride, 2) TAK-875 50 mg vs. glimepiride. If P-value was not greater than 0.025 at Step 1, then Step 2 was carried out.
    Statistical analysis title
    		 Day 1 up to Week 104: Glimepiride, TAK-875 25 mg
    Statistical analysis description
    Odds Ratios, corresponding confidence interval, and p-values were calculated using logistic regression with factors for treatment, country, schedule and baseline HbA1c value.
    Comparison groups
    Glimepiride v TAK-875 25 mg
    Number of subjects included in analysis
    1638
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 < 0.001 [4]
    Method
    		 Regression, Logistic
    Parameter type
    		 Odds ratio (OR)
    Point estimate
    0.13
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.09
         upper limit
    		 0.18
    Notes
    [4] - The testing procedure at 2-sided significance level of 0.025 was as follows: 1) TAK-875 25 mg vs. glimepiride, 2) TAK-875 50 mg vs. glimepiride. If P-value was not greater than 0.025 at Step 1, then Step 2 was carried out.
    Statistical analysis title
    		 Day 1 up to Week 104: Glimepiride, TAK-875 50 mg
    Statistical analysis description
    Odds Ratios, corresponding confidence interval, and p-values were calculated using logistic regression with factors for treatment, country, schedule and baseline HbA1c value.
    Comparison groups
    Glimepiride v TAK-875 50 mg
    Number of subjects included in analysis
    1635
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 < 0.001 [5]
    Method
    		 Regression, Logistic
    Parameter type
    		 Odds ratio (OR)
    Point estimate
    0.13
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.09
         upper limit
    		 0.18
    Notes
    [5] - The testing procedure at 2-sided significance level of 0.025 was as follows: 1) TAK-875 25 mg vs. glimepiride, 2) TAK-875 50 mg vs. glimepiride. If P-value was not greater than 0.025 at Step 1, then Step 2 was carried out.

    Secondary: Change From Baseline in Body Weight at Weeks 78 and 104

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    End point title
    		 Change From Baseline in Body Weight at Weeks 78 and 104
    End point description
    The change between the body weight to be collected at Weeks 78 and 104 relative to baseline. FAS included all randomized subjects who received at least 1 dose of double-blind study medication and who had a baseline and at least 1 post- baseline value during the double-blind treatment period. Data for body weight was not available at Week 104 due to early termination of the study.
    End point type
    Secondary
    End point timeframe
    Baseline and Weeks 78 and 104
    End point values
    		 Glimepiride TAK-875 25 mg TAK-875 50 mg
    Number of subjects analysed
    51
    44
    55
    Units: kilogram
    least squares mean (standard error)
        Baseline
    84.32 ± 0.981
    84.55 ± 1.003
    85.67 ± 0.995
        Change at Week 78
    1.24 ± 0.492
    -0.07 ± 0.524
    -0.21 ± 0.487
    Statistical analysis title
    		 Change at Week 78: Glimepiride vs TAK-875 25 mg
    Statistical analysis description
    Treatment, schedule and visit-by-treatment interaction as fixed factors and with baseline value and baseline value by visit interaction as covariates.
    Comparison groups
    Glimepiride v TAK-875 25 mg
    Number of subjects included in analysis
    95
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.065 [6]
    Method
    		 Mixed Model Repeated Measures
    Parameter type
    		 Least Squares Mean Difference
    Point estimate
    -1.31
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -2.7
         upper limit
    		 0.08
    Variability estimate
    Standard error of the mean
    Dispersion value
    0.707
    Notes
    [6] - The testing procedure at 2-sided significance level of 0.025 was as follows: 1) TAK-875 25 mg vs. glimepiride, 2) TAK-875 50 mg vs. glimepiride. If P-value was not greater than 0.025 at Step 1, then Step 2 was carried out.
    Statistical analysis title
    		 Change at Week 78: Glimepiride vs TAK-875 50 mg
    Statistical analysis description
    Treatment, schedule and visit-by-treatment interaction as fixed factors and with baseline value and baseline value by visit interaction as covariates.
    Comparison groups
    Glimepiride v TAK-875 50 mg
    Number of subjects included in analysis
    106
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.034 [7]
    Method
    		 Mixed Model Repeated Measures
    Parameter type
    		 Least Squares Mean Difference
    Point estimate
    -1.44
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -2.78
         upper limit
    		 -0.11
    Variability estimate
    Standard error of the mean
    Dispersion value
    0.678
    Notes
    [7] - The testing procedure at 2-sided significance level of 0.025 was as follows: 1) TAK-875 25 mg vs. glimepiride, 2) TAK-875 50 mg vs. glimepiride. If P-value was not greater than 0.025 at Step 1, then Step 2 was carried out.

    Secondary: Change From Baseline in HbA1c at Weeks 26 and 52

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    End point title
    		 Change From Baseline in HbA1c at Weeks 26 and 52
    End point description
    The change in the value of HbA1c collected at Weeks 26 and 52 relative to baseline. FAS included all randomized subjects who received at least 1 dose of double-blind study medication and who had a baseline and at least 1 post- baseline value during the double-blind treatment period.
    End point type
    Secondary
    End point timeframe
    Baseline and Weeks 26 and 52
    End point values
    		 Glimepiride TAK-875 25 mg TAK-875 50 mg
    Number of subjects analysed
    652
    645
    641
    Units: percentage of glycosylated hemoglobin
    least squares mean (standard error)
        Week 26
    -0.91 ± 0.039
    -0.63 ± 0.039
    -0.81 ± 0.039
        Week 52
    -0.78 ± 0.043
    -0.65 ± 0.044
    -0.81 ± 0.043
    No statistical analyses for this end point

    Secondary: Percentage of subjects With HbA1c <7%

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    End point title
    		 Percentage of subjects With HbA1c <7%
    End point description
    FAS included all randomized subjects who received at least 1 dose of double-blind study medication and who had a baseline and at least 1 post- baseline value during the double-blind treatment period. Here "99999" in the data values signifies not estimable (NA), since none of the subjects had data for the arm "Glimepiride" at given time
    End point type
    Secondary
    End point timeframe
    Weeks 26, 52, 78 and 104
    End point values
    		 Glimepiride TAK-875 25 mg TAK-875 50 mg
    Number of subjects analysed
    652
    645
    641
    Units: percentage of subjects
    number (not applicable)
        Week 26
    51.8
    38.3
    48.7
        Week 52
    47.8
    43.3
    54.5
        Week 78
    45.2
    37.7
    54.5
        Week 104
    99999
    33.3
    33.3
    No statistical analyses for this end point

    Secondary: Percentage of Subjects With HbA1c <7% for Subjects Who Did Not Report Hypoglycemia

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    End point title
    		 Percentage of Subjects With HbA1c <7% for Subjects Who Did Not Report Hypoglycemia
    End point description
    Data for this endpoint was not analyzed as prespecified in the protocol.
    End point type
    Secondary
    End point timeframe
    Weeks 26, 52, 78 and 104
    End point values
    		 Glimepiride TAK-875 25 mg TAK-875 50 mg
    Number of subjects analysed
    0 [8]
    0 [9]
    0 [10]
    Units: Percentage of subjects
        number (not applicable)
    Notes
    [8] - Data for this endpoint was not analyzed as prespecified in the protocol.
    [9] - Data for this endpoint was not analyzed as prespecified in the protocol.
    [10] - Data for this endpoint was not analyzed as prespecified in the protocol.
    No statistical analyses for this end point

    Secondary: Change From Baseline in Fasting Plasma Glucose at Weeks 26, 52, 78 and 104

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    End point title
    		 Change From Baseline in Fasting Plasma Glucose at Weeks 26, 52, 78 and 104
    End point description
    The change between the fasting plasma glucose value to be collected at Weeks 26, 52, 78 and 104 relative to baseline. FAS included all randomized subjects who received at least 1 dose of double-blind study medication and who had a baseline and at least 1 post- baseline value during the double-blind treatment period. Here "99999" in the mean and standard deviation values signifies not estimable (NA), since none of the subjects had data for the arm "Glimepiride" at given time.
    End point type
    Secondary
    End point timeframe
    Baseline and Weeks 26, 52, 78 and 104
    End point values
    		 Glimepiride TAK-875 25 mg TAK-875 50 mg
    Number of subjects analysed
    635
    629
    626
    Units: milligram per deciliter (mg/dL)
    least squares mean (standard error)
        Baseline
    164.5 ± 41.25
    165.2 ± 38.45
    163.7 ± 38.65
        Change at Week 26
    -19.5 ± 41.9
    -17.4 ± 34.67
    -23 ± 31.99
        Change at Week 52
    -19.8 ± 40.81
    -19.3 ± 36.85
    -23.7 ± 33.78
        Change at Week 78
    0 ± 41.87
    -17.6 ± 30.03
    -21.4 ± 41.27
        Change at Week 104
    99999 ± 99999
    -24 ± 1.41
    -32 ± 17.58
    No statistical analyses for this end point

    Adverse events

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    Adverse events information
    Timeframe for reporting adverse events
    Treatment-emergent adverse events are adverse events started after first dose of study drug and no more than 30 days for a serious adverse event after the last dose of study drug. Time of individual subject follow-up ranged from 1 to 735 days.
    Adverse event reporting additional description
    At each visit the investigator had to document any occurrence of adverse events and abnormal laboratory findings. Any event spontaneously reported by the subject or observed by the investigator was recorded, irrespective of the relation to study treatment.
    Assessment type
    		 Systematic
    Dictionary used for adverse event reporting
    Dictionary name
    		 MedDRA
    Dictionary version
    16.1
    Reporting groups
    Reporting group title
    Glimepiride
    Reporting group description
    		 TAK-875 placebo-matching tablets, orally, once daily and glimepiride 1 mg, over-encapsulated capsules, orally, once daily for 1 week followed by up-titration in 2 mg increments up to 6 mg, orally, once daily along with metformin >=1500 mg per day or maximum tolerated dose, tablets, orally for up to 104 weeks. Glimepiride dose could be down-titrated from 6 mg in case of recurrent or severe hypoglycemia.

    Reporting group title
    TAK-875 25 mg
    Reporting group description
    		 TAK-875 25 mg, tablets, orally, once daily and glimepiride placebo-matching capsules, orally, once daily along with metformin >=1500 mg per day or maximum tolerated dose, tablets, orally for up to 104 weeks.

    Reporting group title
    TAK-875 50 mg
    Reporting group description
    		 TAK-875 50 mg, tablets, orally, once daily and glimepiride placebo-matching capsules, orally, once daily along with metformin >=1500 mg per day or maximum tolerated dose, tablets, orally for up to 104 weeks.

    Serious adverse events
    		 Glimepiride TAK-875 25 mg TAK-875 50 mg
    Total subjects affected by serious adverse events
         subjects affected / exposed
    63 / 822 (7.66%)
    41 / 816 (5.02%)
    58 / 813 (7.13%)
         number of deaths (all causes)
    5
    3
    3
         number of deaths resulting from adverse events
    0
    0
    0
    Neoplasms benign, malignant and unspecified (incl cysts and polyps)
    Basal cell carcinoma
         subjects affected / exposed
    0 / 822 (0.00%)
    1 / 816 (0.12%)
    0 / 813 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Clear cell renal cell carcinoma
         subjects affected / exposed
    0 / 822 (0.00%)
    1 / 816 (0.12%)
    0 / 813 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Colon cancer
         subjects affected / exposed
    0 / 822 (0.00%)
    1 / 816 (0.12%)
    0 / 813 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Hepatic cancer metastatic
         subjects affected / exposed
    1 / 822 (0.12%)
    0 / 816 (0.00%)
    0 / 813 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Kaposi's sarcoma
         subjects affected / exposed
    1 / 822 (0.12%)
    0 / 816 (0.00%)
    0 / 813 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Linitis plastica
         subjects affected / exposed
    1 / 822 (0.12%)
    0 / 816 (0.00%)
    0 / 813 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    Malignant melanoma
         subjects affected / exposed
    2 / 822 (0.24%)
    0 / 816 (0.00%)
    0 / 813 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Neoplasm
         subjects affected / exposed
    1 / 822 (0.12%)
    0 / 816 (0.00%)
    0 / 813 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Pancreatic carcinoma
         subjects affected / exposed
    0 / 822 (0.00%)
    0 / 816 (0.00%)
    1 / 813 (0.12%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    Small cell lung cancer
         subjects affected / exposed
    0 / 822 (0.00%)
    0 / 816 (0.00%)
    1 / 813 (0.12%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Thyroid cancer
         subjects affected / exposed
    0 / 822 (0.00%)
    1 / 816 (0.12%)
    0 / 813 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Uterine cancer
         subjects affected / exposed
    0 / 822 (0.00%)
    1 / 816 (0.12%)
    0 / 813 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Vascular disorders
    Deep vein thrombosis
         subjects affected / exposed
    0 / 822 (0.00%)
    1 / 816 (0.12%)
    0 / 813 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Hypertension
         subjects affected / exposed
    1 / 822 (0.12%)
    0 / 816 (0.00%)
    2 / 813 (0.25%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Hypertensive crisis
         subjects affected / exposed
    0 / 822 (0.00%)
    0 / 816 (0.00%)
    1 / 813 (0.12%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Intermittent claudication
         subjects affected / exposed
    1 / 822 (0.12%)
    0 / 816 (0.00%)
    0 / 813 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Peripheral ischaemia
         subjects affected / exposed
    0 / 822 (0.00%)
    0 / 816 (0.00%)
    1 / 813 (0.12%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Peripheral vascular disorder
         subjects affected / exposed
    0 / 822 (0.00%)
    1 / 816 (0.12%)
    1 / 813 (0.12%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Surgical and medical procedures
    Coronary artery bypass
         subjects affected / exposed
    0 / 822 (0.00%)
    0 / 816 (0.00%)
    1 / 813 (0.12%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    General disorders and administration site conditions
    Chest discomfort
         subjects affected / exposed
    1 / 822 (0.12%)
    0 / 816 (0.00%)
    0 / 813 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Chest pain
         subjects affected / exposed
    3 / 822 (0.36%)
    2 / 816 (0.25%)
    3 / 813 (0.37%)
         occurrences causally related to treatment / all
    0 / 3
    0 / 2
    0 / 3
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Death
         subjects affected / exposed
    1 / 822 (0.12%)
    0 / 816 (0.00%)
    0 / 813 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    Non-cardiac chest pain
         subjects affected / exposed
    1 / 822 (0.12%)
    0 / 816 (0.00%)
    0 / 813 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Sudden death
         subjects affected / exposed
    0 / 822 (0.00%)
    1 / 816 (0.12%)
    0 / 813 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    Reproductive system and breast disorders
    Cervical polyp
         subjects affected / exposed
    0 / 822 (0.00%)
    0 / 816 (0.00%)
    1 / 813 (0.12%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Menorrhagia
         subjects affected / exposed
    0 / 822 (0.00%)
    0 / 816 (0.00%)
    1 / 813 (0.12%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Uterine polyp
         subjects affected / exposed
    1 / 822 (0.12%)
    0 / 816 (0.00%)
    1 / 813 (0.12%)
         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 prolapse
         subjects affected / exposed
    0 / 822 (0.00%)
    0 / 816 (0.00%)
    1 / 813 (0.12%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Uterovaginal prolapse
         subjects affected / exposed
    0 / 822 (0.00%)
    0 / 816 (0.00%)
    1 / 813 (0.12%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Respiratory, thoracic and mediastinal disorders
    Asthma
         subjects affected / exposed
    1 / 822 (0.12%)
    0 / 816 (0.00%)
    0 / 813 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Chronic obstructive pulmonary disease
         subjects affected / exposed
    0 / 822 (0.00%)
    1 / 816 (0.12%)
    2 / 813 (0.25%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 2
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Pulmonary hypertension
         subjects affected / exposed
    1 / 822 (0.12%)
    0 / 816 (0.00%)
    0 / 813 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Sleep apnoea syndrome
         subjects affected / exposed
    0 / 822 (0.00%)
    0 / 816 (0.00%)
    1 / 813 (0.12%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Psychiatric disorders
    Schizophrenia
         subjects affected / exposed
    0 / 822 (0.00%)
    0 / 816 (0.00%)
    1 / 813 (0.12%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Investigations
    Alanine aminotransferase increased
         subjects affected / exposed
    1 / 822 (0.12%)
    0 / 816 (0.00%)
    0 / 813 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Amylase increased
         subjects affected / exposed
    0 / 822 (0.00%)
    0 / 816 (0.00%)
    1 / 813 (0.12%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Aspartate aminotransferase increased
         subjects affected / exposed
    1 / 822 (0.12%)
    0 / 816 (0.00%)
    0 / 813 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Blood creatinine increased
         subjects affected / exposed
    0 / 822 (0.00%)
    0 / 816 (0.00%)
    1 / 813 (0.12%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Ejection fraction decreased
         subjects affected / exposed
    1 / 822 (0.12%)
    0 / 816 (0.00%)
    0 / 813 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Hepatic enzyme increased
         subjects affected / exposed
    0 / 822 (0.00%)
    0 / 816 (0.00%)
    1 / 813 (0.12%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Lipase increased
         subjects affected / exposed
    0 / 822 (0.00%)
    0 / 816 (0.00%)
    1 / 813 (0.12%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Liver function test abnormal
         subjects affected / exposed
    0 / 822 (0.00%)
    1 / 816 (0.12%)
    0 / 813 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Prostatic specific antigen increased
         subjects affected / exposed
    1 / 822 (0.12%)
    0 / 816 (0.00%)
    0 / 813 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Injury, poisoning and procedural complications
    Contusion
         subjects affected / exposed
    0 / 822 (0.00%)
    1 / 816 (0.12%)
    0 / 813 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Fall
         subjects affected / exposed
    0 / 822 (0.00%)
    0 / 816 (0.00%)
    2 / 813 (0.25%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 3
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Femur fracture
         subjects affected / exposed
    0 / 822 (0.00%)
    0 / 816 (0.00%)
    1 / 813 (0.12%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Hip fracture
         subjects affected / exposed
    0 / 822 (0.00%)
    0 / 816 (0.00%)
    1 / 813 (0.12%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Meniscus injury
         subjects affected / exposed
    1 / 822 (0.12%)
    0 / 816 (0.00%)
    0 / 813 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Post procedural complication
         subjects affected / exposed
    0 / 822 (0.00%)
    0 / 816 (0.00%)
    1 / 813 (0.12%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Radius fracture
         subjects affected / exposed
    0 / 822 (0.00%)
    1 / 816 (0.12%)
    0 / 813 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Subdural haematoma
         subjects affected / exposed
    0 / 822 (0.00%)
    0 / 816 (0.00%)
    1 / 813 (0.12%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Tendon rupture
         subjects affected / exposed
    0 / 822 (0.00%)
    1 / 816 (0.12%)
    0 / 813 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Tibia fracture
         subjects affected / exposed
    0 / 822 (0.00%)
    1 / 816 (0.12%)
    0 / 813 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Congenital, familial and genetic disorders
    Hypertrophic cardiomyopathy
         subjects affected / exposed
    1 / 822 (0.12%)
    0 / 816 (0.00%)
    0 / 813 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Cardiac disorders
    Acute coronary syndrome
         subjects affected / exposed
    0 / 822 (0.00%)
    0 / 816 (0.00%)
    1 / 813 (0.12%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Acute myocardial infarction
         subjects affected / exposed
    2 / 822 (0.24%)
    0 / 816 (0.00%)
    1 / 813 (0.12%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Angina unstable
         subjects affected / exposed
    1 / 822 (0.12%)
    0 / 816 (0.00%)
    4 / 813 (0.49%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 4
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Atrial fibrillation
         subjects affected / exposed
    5 / 822 (0.61%)
    0 / 816 (0.00%)
    1 / 813 (0.12%)
         occurrences causally related to treatment / all
    0 / 5
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Atrial flutter
         subjects affected / exposed
    0 / 822 (0.00%)
    2 / 816 (0.25%)
    0 / 813 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 3
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Atrioventricular block first degree
         subjects affected / exposed
    0 / 822 (0.00%)
    1 / 816 (0.12%)
    0 / 813 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Bundle branch block right
         subjects affected / exposed
    1 / 822 (0.12%)
    0 / 816 (0.00%)
    0 / 813 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Cardiac arrest
         subjects affected / exposed
    0 / 822 (0.00%)
    0 / 816 (0.00%)
    1 / 813 (0.12%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    Cardiac failure
         subjects affected / exposed
    0 / 822 (0.00%)
    0 / 816 (0.00%)
    1 / 813 (0.12%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Cardiac failure acute
         subjects affected / exposed
    0 / 822 (0.00%)
    0 / 816 (0.00%)
    1 / 813 (0.12%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    Cardiac failure congestive
         subjects affected / exposed
    1 / 822 (0.12%)
    0 / 816 (0.00%)
    1 / 813 (0.12%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Cardiomyopathy
         subjects affected / exposed
    1 / 822 (0.12%)
    0 / 816 (0.00%)
    0 / 813 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Coronary artery disease
         subjects affected / exposed
    0 / 822 (0.00%)
    1 / 816 (0.12%)
    2 / 813 (0.25%)
         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 occlusion
         subjects affected / exposed
    1 / 822 (0.12%)
    0 / 816 (0.00%)
    0 / 813 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Ischaemic cardiomyopathy
         subjects affected / exposed
    0 / 822 (0.00%)
    0 / 816 (0.00%)
    1 / 813 (0.12%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Myocardial infarction
         subjects affected / exposed
    2 / 822 (0.24%)
    0 / 816 (0.00%)
    2 / 813 (0.25%)
         occurrences causally related to treatment / all
    1 / 2
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    Palpitations
         subjects affected / exposed
    1 / 822 (0.12%)
    0 / 816 (0.00%)
    0 / 813 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Supraventricular tachycardia
         subjects affected / exposed
    0 / 822 (0.00%)
    1 / 816 (0.12%)
    0 / 813 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Ventricular extrasystoles
         subjects affected / exposed
    0 / 822 (0.00%)
    1 / 816 (0.12%)
    0 / 813 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Nervous system disorders
    Brain stem infarction
         subjects affected / exposed
    0 / 822 (0.00%)
    1 / 816 (0.12%)
    0 / 813 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    Carotid artery stenosis
         subjects affected / exposed
    0 / 822 (0.00%)
    1 / 816 (0.12%)
    0 / 813 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Cerebral haemorrhage
         subjects affected / exposed
    0 / 822 (0.00%)
    1 / 816 (0.12%)
    0 / 813 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Cerebrovascular accident
         subjects affected / exposed
    2 / 822 (0.24%)
    0 / 816 (0.00%)
    1 / 813 (0.12%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    Epilepsy
         subjects affected / exposed
    1 / 822 (0.12%)
    0 / 816 (0.00%)
    0 / 813 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Ischaemic stroke
         subjects affected / exposed
    1 / 822 (0.12%)
    0 / 816 (0.00%)
    1 / 813 (0.12%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Paraesthesia
         subjects affected / exposed
    0 / 822 (0.00%)
    1 / 816 (0.12%)
    0 / 813 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Syncope
         subjects affected / exposed
    1 / 822 (0.12%)
    0 / 816 (0.00%)
    2 / 813 (0.25%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Transient ischaemic attack
         subjects affected / exposed
    1 / 822 (0.12%)
    0 / 816 (0.00%)
    1 / 813 (0.12%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Ear and labyrinth disorders
    Meniere's disease
         subjects affected / exposed
    0 / 822 (0.00%)
    0 / 816 (0.00%)
    1 / 813 (0.12%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Vertigo
         subjects affected / exposed
    0 / 822 (0.00%)
    0 / 816 (0.00%)
    1 / 813 (0.12%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Eye disorders
    Cataract
         subjects affected / exposed
    0 / 822 (0.00%)
    0 / 816 (0.00%)
    1 / 813 (0.12%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Retinal artery thrombosis
         subjects affected / exposed
    0 / 822 (0.00%)
    0 / 816 (0.00%)
    1 / 813 (0.12%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Retinal haemorrhage
         subjects affected / exposed
    1 / 822 (0.12%)
    0 / 816 (0.00%)
    0 / 813 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Gastrointestinal disorders
    Abdominal hernia obstructive
         subjects affected / exposed
    1 / 822 (0.12%)
    0 / 816 (0.00%)
    0 / 813 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Abdominal pain
         subjects affected / exposed
    0 / 822 (0.00%)
    1 / 816 (0.12%)
    0 / 813 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Gastritis
         subjects affected / exposed
    1 / 822 (0.12%)
    0 / 816 (0.00%)
    0 / 813 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Gastrointestinal haemorrhage
         subjects affected / exposed
    0 / 822 (0.00%)
    0 / 816 (0.00%)
    1 / 813 (0.12%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Gastrooesophageal reflux disease
         subjects affected / exposed
    1 / 822 (0.12%)
    1 / 816 (0.12%)
    0 / 813 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Haemorrhoids
         subjects affected / exposed
    0 / 822 (0.00%)
    1 / 816 (0.12%)
    0 / 813 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Intestinal polyp haemorrhage
         subjects affected / exposed
    1 / 822 (0.12%)
    0 / 816 (0.00%)
    0 / 813 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    Lumbar hernia
         subjects affected / exposed
    0 / 822 (0.00%)
    1 / 816 (0.12%)
    0 / 813 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Megacolon
         subjects affected / exposed
    0 / 822 (0.00%)
    1 / 816 (0.12%)
    0 / 813 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Oesophagitis
         subjects affected / exposed
    1 / 822 (0.12%)
    0 / 816 (0.00%)
    0 / 813 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Pancreatitis acute
         subjects affected / exposed
    0 / 822 (0.00%)
    1 / 816 (0.12%)
    0 / 813 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Umbilical hernia, obstructive
         subjects affected / exposed
    0 / 822 (0.00%)
    0 / 816 (0.00%)
    1 / 813 (0.12%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Hepatobiliary disorders
    Cholecystitis acute
         subjects affected / exposed
    1 / 822 (0.12%)
    0 / 816 (0.00%)
    0 / 813 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Cholecystitis chronic
         subjects affected / exposed
    1 / 822 (0.12%)
    0 / 816 (0.00%)
    0 / 813 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Cholelithiasis
         subjects affected / exposed
    2 / 822 (0.24%)
    0 / 816 (0.00%)
    1 / 813 (0.12%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Hepatic failure
         subjects affected / exposed
    1 / 822 (0.12%)
    0 / 816 (0.00%)
    0 / 813 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Hepatitis
         subjects affected / exposed
    1 / 822 (0.12%)
    0 / 816 (0.00%)
    0 / 813 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Hepatitis toxic
         subjects affected / exposed
    0 / 822 (0.00%)
    0 / 816 (0.00%)
    1 / 813 (0.12%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Jaundice
         subjects affected / exposed
    0 / 822 (0.00%)
    0 / 816 (0.00%)
    1 / 813 (0.12%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Renal and urinary disorders
    Calculus ureteric
         subjects affected / exposed
    1 / 822 (0.12%)
    0 / 816 (0.00%)
    0 / 813 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Haematuria
         subjects affected / exposed
    0 / 822 (0.00%)
    0 / 816 (0.00%)
    1 / 813 (0.12%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Nephrolithiasis
         subjects affected / exposed
    0 / 822 (0.00%)
    1 / 816 (0.12%)
    0 / 813 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Renal colic
         subjects affected / exposed
    0 / 822 (0.00%)
    1 / 816 (0.12%)
    0 / 813 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Renal failure
         subjects affected / exposed
    1 / 822 (0.12%)
    1 / 816 (0.12%)
    1 / 813 (0.12%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    Renal failure acute
         subjects affected / exposed
    1 / 822 (0.12%)
    0 / 816 (0.00%)
    0 / 813 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Urethral stenosis
         subjects affected / exposed
    1 / 822 (0.12%)
    0 / 816 (0.00%)
    0 / 813 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Musculoskeletal and connective tissue disorders
    Back pain
         subjects affected / exposed
    0 / 822 (0.00%)
    1 / 816 (0.12%)
    0 / 813 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Intervertebral disc degeneration
         subjects affected / exposed
    0 / 822 (0.00%)
    0 / 816 (0.00%)
    1 / 813 (0.12%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Intervertebral disc protrusion
         subjects affected / exposed
    1 / 822 (0.12%)
    0 / 816 (0.00%)
    0 / 813 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Joint swelling
         subjects affected / exposed
    1 / 822 (0.12%)
    0 / 816 (0.00%)
    0 / 813 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Musculoskeletal chest pain
         subjects affected / exposed
    0 / 822 (0.00%)
    0 / 816 (0.00%)
    1 / 813 (0.12%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Musculoskeletal pain
         subjects affected / exposed
    0 / 822 (0.00%)
    1 / 816 (0.12%)
    0 / 813 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Myopathy
         subjects affected / exposed
    0 / 822 (0.00%)
    0 / 816 (0.00%)
    1 / 813 (0.12%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Neck pain
         subjects affected / exposed
    1 / 822 (0.12%)
    0 / 816 (0.00%)
    0 / 813 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Osteochondrosis
         subjects affected / exposed
    0 / 822 (0.00%)
    0 / 816 (0.00%)
    1 / 813 (0.12%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Spinal osteoarthritis
         subjects affected / exposed
    1 / 822 (0.12%)
    0 / 816 (0.00%)
    0 / 813 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Infections and infestations
    Abscess oral
         subjects affected / exposed
    0 / 822 (0.00%)
    1 / 816 (0.12%)
    0 / 813 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Appendicitis
         subjects affected / exposed
    0 / 822 (0.00%)
    0 / 816 (0.00%)
    2 / 813 (0.25%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Bronchitis
         subjects affected / exposed
    0 / 822 (0.00%)
    1 / 816 (0.12%)
    0 / 813 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Cellulitis
         subjects affected / exposed
    2 / 822 (0.24%)
    0 / 816 (0.00%)
    0 / 813 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Dengue fever
         subjects affected / exposed
    1 / 822 (0.12%)
    0 / 816 (0.00%)
    0 / 813 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Gastroenteritis
         subjects affected / exposed
    0 / 822 (0.00%)
    0 / 816 (0.00%)
    4 / 813 (0.49%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 4
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Groin abscess
         subjects affected / exposed
    1 / 822 (0.12%)
    0 / 816 (0.00%)
    0 / 813 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Keratitis fungal
         subjects affected / exposed
    1 / 822 (0.12%)
    0 / 816 (0.00%)
    0 / 813 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Liver abscess
         subjects affected / exposed
    0 / 822 (0.00%)
    0 / 816 (0.00%)
    1 / 813 (0.12%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Otitis media chronic
         subjects affected / exposed
    1 / 822 (0.12%)
    0 / 816 (0.00%)
    0 / 813 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Peritonitis
         subjects affected / exposed
    0 / 822 (0.00%)
    0 / 816 (0.00%)
    1 / 813 (0.12%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Pneumonia
         subjects affected / exposed
    3 / 822 (0.36%)
    3 / 816 (0.37%)
    0 / 813 (0.00%)
         occurrences causally related to treatment / all
    0 / 3
    0 / 3
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Pyelonephritis acute
         subjects affected / exposed
    1 / 822 (0.12%)
    1 / 816 (0.12%)
    0 / 813 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Sepsis
         subjects affected / exposed
    1 / 822 (0.12%)
    0 / 816 (0.00%)
    0 / 813 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Tonsillitis
         subjects affected / exposed
    0 / 822 (0.00%)
    1 / 816 (0.12%)
    0 / 813 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Urinary tract infection
         subjects affected / exposed
    0 / 822 (0.00%)
    0 / 816 (0.00%)
    2 / 813 (0.25%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Metabolism and nutrition disorders
    Hyperglycaemia
         subjects affected / exposed
    0 / 822 (0.00%)
    0 / 816 (0.00%)
    1 / 813 (0.12%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Hypoglycaemia
         subjects affected / exposed
    1 / 822 (0.12%)
    0 / 816 (0.00%)
    0 / 813 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Hypokalaemia
         subjects affected / exposed
    0 / 822 (0.00%)
    1 / 816 (0.12%)
    0 / 813 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Obesity
         subjects affected / exposed
    1 / 822 (0.12%)
    0 / 816 (0.00%)
    0 / 813 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Frequency threshold for reporting non-serious adverse events: 2%
    Non-serious adverse events
    		 Glimepiride TAK-875 25 mg TAK-875 50 mg
    Total subjects affected by non serious adverse events
         subjects affected / exposed
    334 / 822 (40.63%)
    337 / 816 (41.30%)
    323 / 813 (39.73%)
    Investigations
    Alanine aminotransferase increased
         subjects affected / exposed
    17 / 822 (2.07%)
    22 / 816 (2.70%)
    24 / 813 (2.95%)
         occurrences all number
    21
    24
    25
    Blood creatine phosphokinase increased
         subjects affected / exposed
    26 / 822 (3.16%)
    15 / 816 (1.84%)
    17 / 813 (2.09%)
         occurrences all number
    30
    17
    19
    Vascular disorders
    Hypertension
         subjects affected / exposed
    47 / 822 (5.72%)
    28 / 816 (3.43%)
    26 / 813 (3.20%)
         occurrences all number
    54
    31
    30
    Nervous system disorders
    Dizziness
         subjects affected / exposed
    20 / 822 (2.43%)
    16 / 816 (1.96%)
    9 / 813 (1.11%)
         occurrences all number
    24
    19
    9
    Headache
         subjects affected / exposed
    47 / 822 (5.72%)
    42 / 816 (5.15%)
    34 / 813 (4.18%)
         occurrences all number
    52
    54
    43
    General disorders and administration site conditions
    Fatigue
         subjects affected / exposed
    10 / 822 (1.22%)
    6 / 816 (0.74%)
    17 / 813 (2.09%)
         occurrences all number
    11
    6
    19
    Gastrointestinal disorders
    Diarrhoea
         subjects affected / exposed
    28 / 822 (3.41%)
    35 / 816 (4.29%)
    36 / 813 (4.43%)
         occurrences all number
    35
    44
    41
    Nausea
         subjects affected / exposed
    18 / 822 (2.19%)
    18 / 816 (2.21%)
    16 / 813 (1.97%)
         occurrences all number
    18
    21
    19
    Respiratory, thoracic and mediastinal disorders
    Cough
         subjects affected / exposed
    24 / 822 (2.92%)
    26 / 816 (3.19%)
    16 / 813 (1.97%)
         occurrences all number
    25
    30
    17
    Musculoskeletal and connective tissue disorders
    Arthralgia
         subjects affected / exposed
    29 / 822 (3.53%)
    28 / 816 (3.43%)
    22 / 813 (2.71%)
         occurrences all number
    30
    32
    25
    Back pain
         subjects affected / exposed
    31 / 822 (3.77%)
    33 / 816 (4.04%)
    29 / 813 (3.57%)
         occurrences all number
    31
    40
    29
    Pain in extremity
         subjects affected / exposed
    20 / 822 (2.43%)
    13 / 816 (1.59%)
    14 / 813 (1.72%)
         occurrences all number
    22
    15
    16
    Infections and infestations
    Bronchitis
         subjects affected / exposed
    25 / 822 (3.04%)
    22 / 816 (2.70%)
    25 / 813 (3.08%)
         occurrences all number
    27
    22
    28
    Gastroenteritis
         subjects affected / exposed
    11 / 822 (1.34%)
    12 / 816 (1.47%)
    17 / 813 (2.09%)
         occurrences all number
    11
    14
    20
    Influenza
         subjects affected / exposed
    38 / 822 (4.62%)
    31 / 816 (3.80%)
    31 / 813 (3.81%)
         occurrences all number
    47
    38
    37
    Nasopharyngitis
         subjects affected / exposed
    44 / 822 (5.35%)
    38 / 816 (4.66%)
    45 / 813 (5.54%)
         occurrences all number
    48
    46
    54
    Pharyngitis
         subjects affected / exposed
    16 / 822 (1.95%)
    10 / 816 (1.23%)
    17 / 813 (2.09%)
         occurrences all number
    18
    13
    28
    Upper respiratory tract infection
         subjects affected / exposed
    55 / 822 (6.69%)
    73 / 816 (8.95%)
    59 / 813 (7.26%)
         occurrences all number
    69
    87
    74
    Urinary tract infection
         subjects affected / exposed
    28 / 822 (3.41%)
    22 / 816 (2.70%)
    29 / 813 (3.57%)
         occurrences all number
    35
    31
    42
    Metabolism and nutrition disorders
    Dyslipidaemia
         subjects affected / exposed
    15 / 822 (1.82%)
    10 / 816 (1.23%)
    17 / 813 (2.09%)
         occurrences all number
    15
    10
    19
    Hyperuricaemia
         subjects affected / exposed
    19 / 822 (2.31%)
    12 / 816 (1.47%)
    15 / 813 (1.85%)
         occurrences all number
    23
    15
    19

    More information

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    Substantial protocol amendments (globally)
    Were there any global substantial amendments to the protocol? Yes
    Date
    Amendment
    31 May 2012
    1- Secondary objective was modified by adding measures including incidence of hypoglycemic events, change from baseline in body weight and change from baseline in HbA1c at specific time points. 2- Period of evaluation was changed from 118 weeks to 118-122 weeks in schedule B subjects (on a lower metformin daily dose (<1500 mg) with no documentation of MTD. 3- Provided additional guidance for investigators to be actively engaged in identifying and reporting subjects with potential cardiovascular (CV) events for the study and to clarify reporting procedures for non-serious CV events.

    Interruptions (globally)
    Were there any global interruptions to the trial? Yes
    Date
    Interruption
    Restart date
    26 Dec 2013
    Due to specific liver­ related safety signals that emerged in the phase 3 program, Takeda concluded that based on all available information, the benefits of treating subjects with fasiglifam do not outweigh the potential risks, thus Takeda decided voluntarily to terminate all development activities for fasiglifam based on liver safety concerns.
    -

    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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