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    Clinical Trial Results:
    A Phase III, Multicenter, Randomized, Double-Blind, Active-Comparator-Controlled Clinical Trial to Study the Safety and Efficacy of the Addition of Ertugliflozin (MK-8835/PF-04971729) Compared With the Addition of Glimepiride in Subjects With Type 2 Diabetes Mellitus Who Have Inadequate Glycemic Control on Metformin

    Summary
    EudraCT number
    		 2013-003582-34
    Trial protocol
    		 CZ   LT   HU   SK   RO  
    Global end of trial date
    18 Apr 2017

    Results information
    Results version number
    		 v1(current)
    This version publication date
    26 Apr 2018
    First version publication date
    26 Apr 2018
    Other versions

    Trial information

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    Trial identification
    Sponsor protocol code
    8835-002
    Additional study identifiers
    ISRCTN number
    		 -
    US NCT number
    		 NCT01999218
    WHO universal trial number (UTN)
    		 -
    Other trial identifiers
    		 Merck protocol number: MK-8835-002
    Sponsors
    Sponsor organisation name
    Merck Sharp & Dohme Corp.
    Sponsor organisation address
    2000 Galloping Hill Road, Kenilworth, NJ, United States, 07033
    Public contact
    Clinical Trials Disclosure, Merck Sharp & Dohme Corp., ClinicalTrialsDisclosure@merck.com
    Scientific contact
    Clinical Trials Disclosure, Merck Sharp & Dohme Corp., ClinicalTrialsDisclosure@merck.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
    18 Apr 2017
    Is this the analysis of the primary completion data?
    No
    Global end of trial reached?
    Yes
    Global end of trial date
    18 Apr 2017
    Was the trial ended prematurely?
    No
    General information about the trial
    Main objective of the trial
    This study will evaluate the efficacy and safety of the addition of ertugliflozin (MK-8835/PF04971729) compared with the addition of glimepiride in participants with T2DM who have inadequate glycemic control on metformin. The duration of the trial will be up to approximately 122 weeks. This will include a 1-week screening period, an up to 13-week wash-off/titration/dose stabilization period, a 2-week placebo run-in period, a 104-week double-blind, active comparator-controlled treatment period, and a posttreatment telephone contact 14 days after the last dose of study drug. The primary hypothesis of this study is that after 52 weeks, the change from baseline in hemoglobin A1c (A1C) in participants treated with the addition of ertugliflozin 15 mg once daily is non-inferior compared with that in participants treated with the addition of glimepiride.
    Protection of trial subjects
    This study was conducted in conformance with Good Clinical Practice standards and applicable country and/or local statutes and regulations regarding ethical committee review, informed consent, and the protection of human subjects participating in biomedical research. The following additional measures defined for this individual study were in place for the protection of trial participants: During Year 1, participants who were on the maximum labeled dose (6 or 8 mg q.d.) or maximum tolerated dose (if lower than maximum dose) of glimepiride/matching placebo for at least two weeks and who met progressively more stringent glycemic rescue criteria received open-label sitagliptin glycemic rescue medication. The dose of sitagliptin was initiated according to the local country label.
    Background therapy
    		 Participants remained on their stable dose of metformin (≥1500 mg/day) while they received blinded investigational product during the double-blind treatment period.
    Evidence for comparator
    		 -
    Actual start date of recruitment
    16 Dec 2013
    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: 59
    Country: Number of subjects enrolled
    Canada: 101
    Country: Number of subjects enrolled
    Czech Republic: 76
    Country: Number of subjects enrolled
    Hungary: 68
    Country: Number of subjects enrolled
    Korea, Republic of: 82
    Country: Number of subjects enrolled
    Lithuania: 28
    Country: Number of subjects enrolled
    Mexico: 74
    Country: Number of subjects enrolled
    Philippines: 75
    Country: Number of subjects enrolled
    Poland: 92
    Country: Number of subjects enrolled
    Romania: 109
    Country: Number of subjects enrolled
    Russian Federation: 120
    Country: Number of subjects enrolled
    Slovakia: 84
    Country: Number of subjects enrolled
    South Africa: 38
    Country: Number of subjects enrolled
    Taiwan: 17
    Country: Number of subjects enrolled
    Ukraine: 20
    Country: Number of subjects enrolled
    United States: 283
    Worldwide total number of subjects
    1326
    EEA total number of subjects
    457
    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)
    990
    From 65 to 84 years
    335
    85 years and over
    1

    Subject disposition

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    Recruitment
    Recruitment details
    		 The trial was conducted in Argentina, Canada, Czech Republic, Hungary, South Korea, Lithuania, Mexico, Philippines, Poland, Romania, Russia, Slovakia, South Africa, Taiwan, Ukraine, and the United States. Male and female participants with Type 2 diabetes mellitus of at least 18 years of age were screened for enrollment in this trial.

    Pre-assignment
    Screening details
    		 A total of 1326 participants were randomized. Ten randomized participants from one trial site were excluded from all final analyses (Week 104 and beyond), and one randomized participant did not receive treatment.

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

    Arms
    Are arms mutually exclusive
    Yes

    Arm title
    		 Ertugliflozin 5 mg
    Arm description
    		 Ertugliflozin 5 mg once daily (QD) from Day 1 to Week 104
    Arm type
    		 Experimental

    Investigational medicinal product name
    Ertugliflozin (MK-8835)
    Investigational medicinal product code
    Other name
    MK-8835
    Pharmaceutical forms
    Tablet
    Routes of administration
    Oral use
    Dosage and administration details
    Ertugliflozin 5 mg once daily (QD) from Day 1 to Week 104

    Arm title
    		 Ertugliflozin 15 mg
    Arm description
    		 Ertugliflozin 15 mg QD from Day 1 to Week 104
    Arm type
    		 Experimental

    Investigational medicinal product name
    Ertugliflozin (MK-8835)
    Investigational medicinal product code
    Other name
    MK-8835
    Pharmaceutical forms
    Tablet
    Routes of administration
    Oral use
    Dosage and administration details
    Ertugliflozin 15 mg QD from Day 1 to Week 104

    Arm title
    		 Glimepiride
    Arm description
    		 Glimepiride to a maximum of 8 mg QD from Day 1 to Week 104
    Arm type
    		 Active comparator

    Investigational medicinal product name
    Glimepiride
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Tablet, Capsule
    Routes of administration
    Oral use
    Dosage and administration details
    Glimepiride to a maximum of 8 mg QD from Day 1 to Week 104

    Number of subjects in period 1
    		Ertugliflozin 5 mg Ertugliflozin 15 mg Glimepiride
    Started
    448
    441
    437
    Treated
    448
    440
    437
    Treated (excluding 1 trial site)
    445
    435
    435
    Completed
    339
    340
    327
    Not completed
    109
    101
    110
         Adverse event, serious fatal
    7
    1
    2
         Physician decision
    1
    4
    6
         Screen failure
    -
    1
    -
         Hyperglycemia
    18
    17
    17
         Consent withdrawn by subject
    28
    29
    34
         Treated but excluded at 1 trial site
    3
    5
    2
         Participant moves
    2
    5
    3
         Excluded Medication
    1
    1
    2
         Creatinine/eGFR
    -
    -
    1
         Study Terminated By Sponsor
    7
    5
    12
         Adverse event, non-fatal
    9
    7
    7
         Non-Compliance With Study Drug
    6
    4
    1
         Lost to follow-up
    22
    17
    18
         Lack of efficacy
    1
    -
    1
         Protocol deviation
    4
    5
    4

    Baseline characteristics

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    Baseline characteristics reporting groups
    Reporting group title
    Ertugliflozin 5 mg
    Reporting group description
    		 Ertugliflozin 5 mg once daily (QD) from Day 1 to Week 104

    Reporting group title
    Ertugliflozin 15 mg
    Reporting group description
    		 Ertugliflozin 15 mg QD from Day 1 to Week 104

    Reporting group title
    Glimepiride
    Reporting group description
    		 Glimepiride to a maximum of 8 mg QD from Day 1 to Week 104

    Reporting group values
    		 Ertugliflozin 5 mg Ertugliflozin 15 mg Glimepiride Total
    Number of subjects
    		 448 441 437 1326
    Age categorical
    The analysis population included all randomized participants.
    Units: Subjects
        In utero
    		 0 0 0 0
        Preterm newborn infants (gestational age < 37 wks)
    		 0 0 0 0
        Newborns (0-27 days)
    		 0 0 0 0
        Infants and toddlers (28 days-23 months)
    		 0 0 0 0
        Children (2-11 years)
    		 0 0 0 0
        Adolescents (12-17 years)
    		 0 0 0 0
        Adults (18-64 years)
    		 327 329 334 990
        From 65-84 years
    		 120 112 103 335
        85 years and over
    		 1 0 0 1
    Age Continuous
    The analysis population included all randomized participants.
    Units: years
        arithmetic mean (standard deviation)
    		 58.8 ± 9.7 58.0 ± 9.9 57.8 ± 9.2 -
    Sex: Female, Male
    The analysis population included all randomized participants.
    Units: Subjects
        Female
    		 221 250 213 684
        Male
    		 227 191 224 642
    Race (NIH/OMB)
    The analysis population included all randomized participants.
    Units: Subjects
        American Indian or Alaska Native
    		 5 3 5 13
        Asian
    		 81 86 73 240
        Native Hawaiian or Other Pacific Islander
    		 0 0 0 0
        Black or African American
    		 17 19 25 61
        White
    		 332 316 318 966
        More than one race
    		 13 17 16 46
        Unknown or Not Reported
    		 0 0 0 0
    Prior Antihyperglycemic Medication (Monotherapy or Dual Therapy)
    All randomized participants with information on or baseline data of prior antihyperglycemic medication use
    Units: Subjects
        Prior Antihyperglycemic Medication
    		 448 439 437 1324
        No Prior Use & Not on Antihyperglycemic Medication
    		 0 1 0 1
        Data not available
    		 0 1 0 1
    Body Weight
    The analysis population included all randomized and treated participants (N=448, 440, 437).
    Units: Kilograms
        arithmetic mean (standard deviation)
    		 87.9 ± 18.9 85.6 ± 19.1 86.8 ± 20.7 -
    Hemoglobin A1C
    The analysis population included all randomized participants with a baseline A1C measurement (N=448, 440, 437).
    Units: Percentage
        arithmetic mean (standard deviation)
    		 7.81 ± 0.60 7.80 ± 0.60 7.76 ± 0.60 -
    Sitting Systolic Blood Pressure
    The analysis population included all randomized participants with a baseline sitting systolic blood pressure measurement (N=448, 440, 437).
    Units: Millimeters of mercury
        arithmetic mean (standard deviation)
    		 130.2 ± 12.8 130.8 ± 12.4 129.9 ± 12.0 -
    Estimated Glomerular Filtration Rate (eGFR)
    The analysis population included all randomized and treated participants (N=448, 440, 437).
    Units: milliliters/minute/1.73 meters^2
        arithmetic mean (standard deviation)
    		 88.3 ± 18.7 86.7 ± 18.3 86.6 ± 18.5 -

    End points

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    End points reporting groups
    Reporting group title
    Ertugliflozin 5 mg
    Reporting group description
    		 Ertugliflozin 5 mg once daily (QD) from Day 1 to Week 104

    Reporting group title
    Ertugliflozin 15 mg
    Reporting group description
    		 Ertugliflozin 15 mg QD from Day 1 to Week 104

    Reporting group title
    Glimepiride
    Reporting group description
    		 Glimepiride to a maximum of 8 mg QD from Day 1 to Week 104

    Primary: Change from Baseline in Hemoglobin A1C (A1C) at Week 52: Excluding Rescue Approach

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    End point title
    		 Change from Baseline in Hemoglobin A1C (A1C) at Week 52: Excluding Rescue Approach
    End point description
    A1C is a blood marker used to report average blood glucose levels over prolonged periods of time and is reported as a percentage (%). A1C represents the percentage of glycated hemoglobin. This change from baseline reflects the Week 52 A1C minus the Week 0 A1C. A negative number indicates a reduction in A1C level. Participants who met glycemic rescue criteria received open-label sitagliptin glycemic rescue medication, and all data following the initiation of rescue therapy were excluded from the analysis. The primary study objective was the MK-8835 15 mg vs. glimepiride comparison; the MK-8835 5mg vs glimerpiride comparison was a secondary study objective. The analysis population included all randomized, treated participants with at least one A1C measurement (baseline or a post-baseline).
    End point type
    Primary
    End point timeframe
    Baseline and Week 52
    End point values
    		 Ertugliflozin 5 mg Ertugliflozin 15 mg Glimepiride
    Number of subjects analysed
    448
    440
    437
    Units: Percent
        least squares mean (confidence interval 95%)
    -0.56 (-0.65 to -0.47)
    -0.64 (-0.73 to -0.55)
    -0.74 (-0.83 to -0.65)
    Statistical analysis title
    		 Difference in the Least Squares Means
    Statistical analysis description
    Constrained Longitudinal Data Analysis (cLDA) model with fixed effects for treatment, time, prior antihyperglycemic medication (monotherapy or dual therapy), baseline eGFR (continuous) and the interaction of time by treatment.
    Comparison groups
    Ertugliflozin 15 mg v Glimepiride
    Number of subjects included in analysis
    877
    Analysis specification
    Pre-specified
    Analysis type
    		 non-inferiority [1]
    Method
    Parameter type
    		 Difference in the Least Squares Means
    Point estimate
    0.1
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -0.02
         upper limit
    		 0.22
    Notes
    [1] - Non-inferiority is declared if the upper bound of the two-sided 95% confidence interval (CI) for the mean difference is less than 0.3%.
    Statistical analysis title
    		 Difference in the Least Squares Means
    Statistical analysis description
    Based on cLDA model with fixed effects for treatment, time, prior antihyperglycemic medication (monotherapy or dual therapy), baseline eGFR (continuous) and the interaction of time by treatment.
    Comparison groups
    Ertugliflozin 5 mg v Glimepiride
    Number of subjects included in analysis
    885
    Analysis specification
    Pre-specified
    Analysis type
    		 non-inferiority [2]
    Method
    Parameter type
    		 Difference in the Least Squares means
    Point estimate
    0.18
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.06
         upper limit
    		 0.3
    Notes
    [2] - Non-inferiority is declared if the upper bound of the two-sided 95% confidence interval (CI) for the mean difference is less than 0.3%.

    Primary: Percentage of Participants Experiencing An Adverse Event (AE) Up to Week 106

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    End point title
    		 Percentage of Participants Experiencing An Adverse Event (AE) Up to Week 106
    End point description
    An AE is defined as any unfavorable and unintended sign including an abnormal laboratory finding, symptom or disease associated with the use of a medical treatment or procedure, regardless of whether it is considered related to the medical treatment or procedure, that occurs during the course of the study. The analysis population included all randomized participants who took at least one dose of trial treatment, 10 randomized participants from one trial site were excluded from these analyzes, and one randomized participant did not receive treatment.
    End point type
    Primary
    End point timeframe
    Up to Week 106
    End point values
    		 Ertugliflozin 5 mg Ertugliflozin 15 mg Glimepiride
    Number of subjects analysed
    445
    435
    435
    Units: Percentage of Participants
        number (not applicable)
    70.1
    71.3
    69.7
    Statistical analysis title
    		 Difference in % vs. Glimepiride
    Statistical analysis description
    Based on Miettinen & Nurminen method
    Comparison groups
    Ertugliflozin 15 mg v Glimepiride
    Number of subjects included in analysis
    870
    Analysis specification
    Pre-specified
    Analysis type
    		 other
    Method
    Parameter type
    		 Difference in % vs. Glimepiride
    Point estimate
    1.6
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -4.5
         upper limit
    		 7.7
    Statistical analysis title
    		 Difference in % vs. Glimepiride
    Statistical analysis description
    Based on Miettinen & Nurminen method
    Comparison groups
    Ertugliflozin 5 mg v Glimepiride
    Number of subjects included in analysis
    880
    Analysis specification
    Pre-specified
    Analysis type
    		 other
    Method
    Parameter type
    		 Difference in % vs. Glimepiride
    Point estimate
    0.5
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -5.6
         upper limit
    		 6.5

    Primary: Percentage of Participants Discontinuing Study Treatment Due to an AE Up to Week 104

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    End point title
    		 Percentage of Participants Discontinuing Study Treatment Due to an AE Up to Week 104
    End point description
    An AE is defined as any unfavorable and unintended sign including an abnormal laboratory finding, symptom or disease associated with the use of a medical treatment or procedure, regardless of whether it is considered related to the medical treatment or procedure, that occurs during the course of the study. The analysis population included all randomized participants who took at least one dose of trial treatment, 10 randomized participants from one trial site were excluded from these analyzes, and one randomized participant did not receive treatment.
    End point type
    Primary
    End point timeframe
    Up to Week 104
    End point values
    		 Ertugliflozin 5 mg Ertugliflozin 15 mg Glimepiride
    Number of subjects analysed
    445
    435
    435
    Units: Percentage of Participants
        number (not applicable)
    6.5
    8.0
    5.1
    Statistical analysis title
    		 Difference in % vs. Glimepiride
    Statistical analysis description
    Based on Miettinen & Nurminen method
    Comparison groups
    Ertugliflozin 15 mg v Glimepiride
    Number of subjects included in analysis
    870
    Analysis specification
    Pre-specified
    Analysis type
    		 other
    Method
    Parameter type
    		 Difference in % vs. Glimepiride
    Point estimate
    3
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -0.3
         upper limit
    		 6.4
    Statistical analysis title
    		 Difference in % vs. Glimepiride
    Statistical analysis description
    Based on Miettinen & Nurminen method
    Comparison groups
    Ertugliflozin 5 mg v Glimepiride
    Number of subjects included in analysis
    880
    Analysis specification
    Pre-specified
    Analysis type
    		 other
    Method
    Parameter type
    		 Difference in % vs. Glimepiride
    Point estimate
    1.5
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -1.7
         upper limit
    		 4.7

    Secondary: Percentage of Participants with an Adverse Event of Symptomatic Hypoglycemia Up to Week 52: Excluding Rescue Approach

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    End point title
    		 Percentage of Participants with an Adverse Event of Symptomatic Hypoglycemia Up to Week 52: Excluding Rescue Approach
    End point description
    Symptomatic hypoglycemia was an event with clinical symptoms reported by the investigator as hypoglycemia (biochemical documentation not required). Participants who met glycemic rescue criteria received open-label sitagliptin glycemic rescue medication, and all data following the initiation of rescue therapy were excluded from the analysis. The analysis population included all randomized participants who took at least one dose of trial treatment.
    End point type
    Secondary
    End point timeframe
    Up to Week 52
    End point values
    		 Ertugliflozin 5 mg Ertugliflozin 15 mg Glimepiride
    Number of subjects analysed
    448
    440
    437
    Units: Percentage of Participants
        number (not applicable)
    3.1
    5.2
    19.2
    Statistical analysis title
    		 Difference in % vs. Glimepiride
    Statistical analysis description
    Based on Miettinen & Nurminen method
    Comparison groups
    Ertugliflozin 15 mg v Glimepiride
    Number of subjects included in analysis
    877
    Analysis specification
    Pre-specified
    Analysis type
    		 other
    P-value
    		 < 0.001
    Method
    		 Based on Miettinen & Nurminen method
    Parameter type
    		 Difference in % vs. Glimepiride
    Point estimate
    -14
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -18.4
         upper limit
    		 -9.8
    Statistical analysis title
    		 Difference in % vs. Glimepiride
    Statistical analysis description
    Based on Miettinen & Nurminen method
    Comparison groups
    Ertugliflozin 5 mg v Glimepiride
    Number of subjects included in analysis
    885
    Analysis specification
    Pre-specified
    Analysis type
    		 other
    P-value
    		 < 0.001
    Method
    		 Based on Miettinen & Nurminen method
    Parameter type
    		 Difference in % vs. Glimepiride
    Point estimate
    -16.1
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -20.3
         upper limit
    		 -12.2

    Secondary: Change from Baseline in Body Weight at Week 52 Excluding Rescue Approach

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    End point title
    		 Change from Baseline in Body Weight at Week 52 Excluding Rescue Approach
    End point description
    This change from baseline reflects the Week 52 body weight minus the Week 0 body weight. Participants who met glycemic rescue criteria received open-label sitagliptin glycemic rescue medication, and all data following the initiation of rescue therapy were excluded from the analysis. The analysis population included all randomized, treated participants with at least one body weight measurement (baseline or a post-baseline).
    End point type
    Secondary
    End point timeframe
    Baseline and Week 52
    End point values
    		 Ertugliflozin 5 mg Ertugliflozin 15 mg Glimepiride
    Number of subjects analysed
    448
    440
    437
    Units: Kilograms
        least squares mean (confidence interval 95%)
    -2.96 (-3.31 to -2.61)
    -3.38 (-3.73 to -3.03)
    0.91 (0.56 to 1.25)
    Statistical analysis title
    		 Difference in LSM vs. Glimepiride
    Statistical analysis description
    Fixed effects for treatment, time, interaction of time by treatment, prior antihyperglycemic medication (monotherapy or dual therapy), and baseline eGFR (continuous).
    Comparison groups
    Ertugliflozin 15 mg v Glimepiride
    Number of subjects included in analysis
    877
    Analysis specification
    Pre-specified
    Analysis type
    		 [3]
    P-value
    		 < 0.001
    Method
    		 Constrained Longitudinal Data analysis
    Parameter type
    		 Difference in LSM vs. Glimepiride
    Point estimate
    -4.29
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -4.77
         upper limit
    		 -3.8
    Notes
    [3] - LSM=Least Squares Means
    Statistical analysis title
    		 Difference in LSM vs. Glimepiride
    Statistical analysis description
    Constrained Longitudinal Data analysis with fixed effects for treatment, time, interaction of time by treatment, prior antihyperglycemic medication (monotherapy or dual therapy), and baseline eGFR (continuous).
    Comparison groups
    Ertugliflozin 5 mg v Glimepiride
    Number of subjects included in analysis
    885
    Analysis specification
    Pre-specified
    Analysis type
    		 other
    P-value
    		 < 0.001
    Method
    		 Constrained Longitudinal Data Analysis
    Parameter type
    		 Difference in the LSM vs. Glimepiride
    Point estimate
    -3.87
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -4.36
         upper limit
    		 -3.38

    Secondary: Change from Baseline in Sitting Systolic Blood Pressure (SBP) at Week 52 Excluding Rescue Approach

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    End point title
    		 Change from Baseline in Sitting Systolic Blood Pressure (SBP) at Week 52 Excluding Rescue Approach
    End point description
    This change from baseline reflects the Week 52 SBP minus the Week 0 SBP. Participants who met glycemic rescue criteria received open-label sitagliptin glycemic rescue medication, and all data following the initiation of rescue therapy were excluded from the analysis. The analysis population included all randomized, treated participants with at least one SBP measurement (baseline or a post-baseline).
    End point type
    Secondary
    End point timeframe
    Baseline and Week 52
    End point values
    		 Ertugliflozin 5 mg Ertugliflozin 15 mg Glimepiride
    Number of subjects analysed
    448
    440
    437
    Units: mmHg
        least squares mean (confidence interval 95%)
    -2.25 (-3.36 to -1.13)
    -3.81 (-4.91 to -2.71)
    0.95 (-0.15 to 2.06)
    Statistical analysis title
    		 Difference in the LSM vs. Glimepiride
    Statistical analysis description
    Constrained Logitudinal Data Analysis with fixed effects for treatment, time, interaction of time by treatment, prior anthyperglycemic medication (monotherapy or dual therapy), and baseline eGFR (continuous).
    Comparison groups
    Ertugliflozin 15 mg v Glimepiride
    Number of subjects included in analysis
    877
    Analysis specification
    Pre-specified
    Analysis type
    		 other
    P-value
    		 < 0.001
    Method
    		 Constrained Logitudinal Data Analysis
    Parameter type
    		 Difference in the LSM vs. Glimepiride
    Point estimate
    -4.77
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -6.29
         upper limit
    		 -3.25
    Statistical analysis title
    		 Difference in the LSM vs. Glimepiride
    Statistical analysis description
    Constrained Logitudinal Data Analysis with fixed effects for treatment, time, interaction of time by treatment, prior anthyperglycemic medication (monotherapy or dual therapy), and baseline eGFR (continuous).
    Comparison groups
    Ertugliflozin 5 mg v Glimepiride
    Number of subjects included in analysis
    885
    Analysis specification
    Pre-specified
    Analysis type
    		 other
    P-value
    		 < 0.001
    Method
    		 Constrained Logitudinal Data Analysis
    Parameter type
    		 Difference in the LSM vs. Glimepiride
    Point estimate
    -3.2
    Confidence interval
         level
    		 0%
         sides
    2-sided
         lower limit
    		 -4.73
         upper limit
    		 -1.67

    Adverse events

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    Adverse events information
    Timeframe for reporting adverse events
    Up to Week 106
    Adverse event reporting additional description
    The safety analysis population included all randomized participants who took at least one dose of trial treatment, 10 randomized participants from one trial site were excluded from these analyzes, and one randomized participant did not receive treatment.
    Assessment type
    		 Systematic
    Dictionary used for adverse event reporting
    Dictionary name
    		 MedDRA
    Dictionary version
    20.0
    Reporting groups
    Reporting group title
    Ertugliflozin 5 mg
    Reporting group description
    		 Ertugliflozin 5 mg once daily (QD) from Day 1 to Week 104

    Reporting group title
    Ertugliflozin 15 mg
    Reporting group description
    		 Ertugliflozin 15 mg QD from Day 1 to Week 104

    Reporting group title
    Glimepiride
    Reporting group description
    		 Glimepiride to a maximum of 8 mg QD from Day 1 to Week 104

    Serious adverse events
    		 Ertugliflozin 5 mg Ertugliflozin 15 mg Glimepiride
    Total subjects affected by serious adverse events
         subjects affected / exposed
    41 / 445 (9.21%)
    32 / 435 (7.36%)
    30 / 435 (6.90%)
         number of deaths (all causes)
    7
    2
    1
         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 / 445 (0.00%)
    1 / 435 (0.23%)
    1 / 435 (0.23%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Breast carcinoma
         subjects affected / exposed
    0 / 445 (0.00%)
    2 / 435 (0.46%)
    0 / 435 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Breast ductal carcinoma
         subjects affected / exposed
    0 / 445 (0.00%)
    1 / 435 (0.23%)
    0 / 435 (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
    Cancer of sigmoid colon (excl rectosigmoid)
         subjects affected / exposed
    1 / 445 (0.22%)
    0 / 435 (0.00%)
    0 / 435 (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 lymphocytic leukaemia
         subjects affected / exposed
    1 / 445 (0.22%)
    0 / 435 (0.00%)
    0 / 435 (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
    Colon cancer
         subjects affected / exposed
    0 / 445 (0.00%)
    1 / 435 (0.23%)
    0 / 435 (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
    Intraductal papilloma of breast
         subjects affected / exposed
    0 / 445 (0.00%)
    0 / 435 (0.00%)
    1 / 435 (0.23%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Invasive breast carcinoma
         subjects affected / exposed
    0 / 445 (0.00%)
    0 / 435 (0.00%)
    1 / 435 (0.23%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Lip squamous cell carcinoma
         subjects affected / exposed
    0 / 445 (0.00%)
    1 / 435 (0.23%)
    0 / 435 (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
    Malignant melanoma
         subjects affected / exposed
    0 / 445 (0.00%)
    1 / 435 (0.23%)
    0 / 435 (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
    Metatypical basal cell carcinoma
         subjects affected / exposed
    0 / 445 (0.00%)
    0 / 435 (0.00%)
    1 / 435 (0.23%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Multiple myeloma
         subjects affected / exposed
    1 / 445 (0.22%)
    0 / 435 (0.00%)
    0 / 435 (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
    Ovarian cystadenoma
         subjects affected / exposed
    0 / 445 (0.00%)
    1 / 435 (0.23%)
    0 / 435 (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
    Pelvic neoplasm
         subjects affected / exposed
    0 / 445 (0.00%)
    1 / 435 (0.23%)
    0 / 435 (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
    Prostate cancer
         subjects affected / exposed
    1 / 445 (0.22%)
    0 / 435 (0.00%)
    0 / 435 (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
    Thyroid papillary carcinoma
         subjects affected / exposed
    0 / 445 (0.00%)
    0 / 435 (0.00%)
    1 / 435 (0.23%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Tubular adenocarcinoma gastric
         subjects affected / exposed
    1 / 445 (0.22%)
    0 / 435 (0.00%)
    0 / 435 (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
    Uterine fibroids
         subjects affected / exposed
    0 / 445 (0.00%)
    1 / 435 (0.23%)
    0 / 435 (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 leiomyoma
         subjects affected / exposed
    1 / 445 (0.22%)
    1 / 435 (0.23%)
    0 / 435 (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
    Vascular disorders
    Diabetic peripheral angiopathy
         subjects affected / exposed
    0 / 445 (0.00%)
    0 / 435 (0.00%)
    1 / 435 (0.23%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Leg ischaemia
         subjects affected / exposed
    0 / 445 (0.00%)
    1 / 435 (0.23%)
    0 / 435 (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
    General disorders and administration site conditions
    Incarcerated hernia
         subjects affected / exposed
    0 / 445 (0.00%)
    1 / 435 (0.23%)
    0 / 435 (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
    Multi-organ failure
         subjects affected / exposed
    1 / 445 (0.22%)
    0 / 435 (0.00%)
    0 / 435 (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
    Sudden cardiac death
         subjects affected / exposed
    1 / 445 (0.22%)
    0 / 435 (0.00%)
    0 / 435 (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
    Sudden death
         subjects affected / exposed
    1 / 445 (0.22%)
    0 / 435 (0.00%)
    1 / 435 (0.23%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    0 / 1
    Weakness generalised
         subjects affected / exposed
    0 / 445 (0.00%)
    1 / 435 (0.23%)
    0 / 435 (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
    Reproductive system and breast disorders
    Balanoposthitis
         subjects affected / exposed
    0 / 445 (0.00%)
    1 / 435 (0.23%)
    0 / 435 (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
    Menometrorrhagia
         subjects affected / exposed
    0 / 445 (0.00%)
    0 / 435 (0.00%)
    1 / 435 (0.23%)
         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
    Acute respiratory failure
         subjects affected / exposed
    0 / 445 (0.00%)
    0 / 435 (0.00%)
    1 / 435 (0.23%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Adult respiratory distress syndrome
         subjects affected / exposed
    1 / 445 (0.22%)
    0 / 435 (0.00%)
    0 / 435 (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
    Asthma aggravated
         subjects affected / exposed
    0 / 445 (0.00%)
    0 / 435 (0.00%)
    1 / 435 (0.23%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Choanal polyp
         subjects affected / exposed
    0 / 445 (0.00%)
    0 / 435 (0.00%)
    1 / 435 (0.23%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Chronic obstructive airways disease exacerbated
         subjects affected / exposed
    0 / 445 (0.00%)
    1 / 435 (0.23%)
    0 / 435 (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
    Chronic obstructive pulmonary disease exacerbation
         subjects affected / exposed
    1 / 445 (0.22%)
    0 / 435 (0.00%)
    1 / 435 (0.23%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    Obstructive chronic bronchitis
         subjects affected / exposed
    0 / 445 (0.00%)
    0 / 435 (0.00%)
    1 / 435 (0.23%)
         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 failure
         subjects affected / exposed
    1 / 445 (0.22%)
    0 / 435 (0.00%)
    0 / 435 (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
    Vocal cord nodule
         subjects affected / exposed
    1 / 445 (0.22%)
    0 / 435 (0.00%)
    0 / 435 (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
    Psychiatric disorders
    Depression aggravated
         subjects affected / exposed
    1 / 445 (0.22%)
    0 / 435 (0.00%)
    0 / 435 (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
    Depression worsened
         subjects affected / exposed
    0 / 445 (0.00%)
    0 / 435 (0.00%)
    1 / 435 (0.23%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Recurrent depressive disorder
         subjects affected / exposed
    0 / 445 (0.00%)
    0 / 435 (0.00%)
    1 / 435 (0.23%)
         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
    Blood pressure increased
         subjects affected / exposed
    0 / 445 (0.00%)
    0 / 435 (0.00%)
    1 / 435 (0.23%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Glomerular filtration rate decreased
         subjects affected / exposed
    0 / 445 (0.00%)
    1 / 435 (0.23%)
    0 / 435 (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
    Injury, poisoning and procedural complications
    Chest injury
         subjects affected / exposed
    1 / 445 (0.22%)
    0 / 435 (0.00%)
    0 / 435 (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
    Face injury
         subjects affected / exposed
    1 / 445 (0.22%)
    0 / 435 (0.00%)
    0 / 435 (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
    Knee ligament injury
         subjects affected / exposed
    0 / 445 (0.00%)
    0 / 435 (0.00%)
    1 / 435 (0.23%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Knee sprain
         subjects affected / exposed
    0 / 445 (0.00%)
    1 / 435 (0.23%)
    0 / 435 (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
    Ligament rupture
         subjects affected / exposed
    0 / 445 (0.00%)
    1 / 435 (0.23%)
    0 / 435 (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
    Ligament sprain
         subjects affected / exposed
    0 / 445 (0.00%)
    0 / 435 (0.00%)
    1 / 435 (0.23%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Lumbar sprain
         subjects affected / exposed
    0 / 445 (0.00%)
    1 / 435 (0.23%)
    0 / 435 (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
    Lumbar strain
         subjects affected / exposed
    0 / 445 (0.00%)
    0 / 435 (0.00%)
    1 / 435 (0.23%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Lumbosacral (joint) (ligament) sprain
         subjects affected / exposed
    0 / 445 (0.00%)
    0 / 435 (0.00%)
    1 / 435 (0.23%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Malleolar fracture
         subjects affected / exposed
    0 / 445 (0.00%)
    1 / 435 (0.23%)
    0 / 435 (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
    Neck strain
         subjects affected / exposed
    0 / 445 (0.00%)
    0 / 435 (0.00%)
    1 / 435 (0.23%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Pertrochanteric fracture of femur, closed
         subjects affected / exposed
    0 / 445 (0.00%)
    1 / 435 (0.23%)
    0 / 435 (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
    Polytraumatism
         subjects affected / exposed
    1 / 445 (0.22%)
    0 / 435 (0.00%)
    0 / 435 (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
    Shoulder sprain
         subjects affected / exposed
    0 / 445 (0.00%)
    1 / 435 (0.23%)
    0 / 435 (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
    Spinal column injury
         subjects affected / exposed
    0 / 445 (0.00%)
    0 / 435 (0.00%)
    1 / 435 (0.23%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Traumatic brain injury
         subjects affected / exposed
    1 / 445 (0.22%)
    0 / 435 (0.00%)
    0 / 435 (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
    Upper limb fracture
         subjects affected / exposed
    0 / 445 (0.00%)
    0 / 435 (0.00%)
    1 / 435 (0.23%)
         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 disorders
    Acute coronary syndrome
         subjects affected / exposed
    1 / 445 (0.22%)
    1 / 435 (0.23%)
    0 / 435 (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
    Acute myocardial infarction
         subjects affected / exposed
    1 / 445 (0.22%)
    1 / 435 (0.23%)
    0 / 435 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 1
    0 / 1
    0 / 0
    Angina pectoris aggravated
         subjects affected / exposed
    1 / 445 (0.22%)
    0 / 435 (0.00%)
    0 / 435 (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
    Angina unstable
         subjects affected / exposed
    2 / 445 (0.45%)
    0 / 435 (0.00%)
    2 / 435 (0.46%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Atrial fibrillation aggravated
         subjects affected / exposed
    1 / 445 (0.22%)
    0 / 435 (0.00%)
    0 / 435 (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 failure
         subjects affected / exposed
    1 / 445 (0.22%)
    1 / 435 (0.23%)
    0 / 435 (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
    Coronary artery disease
         subjects affected / exposed
    2 / 445 (0.45%)
    0 / 435 (0.00%)
    0 / 435 (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
    Myocardial infarction
         subjects affected / exposed
    0 / 445 (0.00%)
    1 / 435 (0.23%)
    0 / 435 (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
    Single vessel disease
         subjects affected / exposed
    1 / 445 (0.22%)
    0 / 435 (0.00%)
    0 / 435 (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
    Triple vessel disease
         subjects affected / exposed
    0 / 445 (0.00%)
    1 / 435 (0.23%)
    0 / 435 (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
    Carotid artery stenosis
         subjects affected / exposed
    0 / 445 (0.00%)
    0 / 435 (0.00%)
    1 / 435 (0.23%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Cerebral infarction
         subjects affected / exposed
    1 / 445 (0.22%)
    0 / 435 (0.00%)
    0 / 435 (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
    Cerebrovascular accident
         subjects affected / exposed
    0 / 445 (0.00%)
    0 / 435 (0.00%)
    1 / 435 (0.23%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Epilepsy
         subjects affected / exposed
    0 / 445 (0.00%)
    0 / 435 (0.00%)
    1 / 435 (0.23%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Multiple cerebral infarction
         subjects affected / exposed
    1 / 445 (0.22%)
    0 / 435 (0.00%)
    0 / 435 (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
    Stroke
         subjects affected / exposed
    2 / 445 (0.45%)
    0 / 435 (0.00%)
    0 / 435 (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
    Transient ischaemic attack
         subjects affected / exposed
    1 / 445 (0.22%)
    0 / 435 (0.00%)
    1 / 435 (0.23%)
         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
    Cataract aggravated
         subjects affected / exposed
    0 / 445 (0.00%)
    0 / 435 (0.00%)
    1 / 435 (0.23%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Chorioretinal folds
         subjects affected / exposed
    0 / 445 (0.00%)
    0 / 435 (0.00%)
    1 / 435 (0.23%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Iridocyclitis
         subjects affected / exposed
    0 / 445 (0.00%)
    0 / 435 (0.00%)
    1 / 435 (0.23%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Keratitis
         subjects affected / exposed
    0 / 445 (0.00%)
    0 / 435 (0.00%)
    1 / 435 (0.23%)
         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 detachment
         subjects affected / exposed
    0 / 445 (0.00%)
    0 / 435 (0.00%)
    1 / 435 (0.23%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Senile cataract
         subjects affected / exposed
    0 / 445 (0.00%)
    1 / 435 (0.23%)
    0 / 435 (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
    Gastrointestinal disorders
    Abdominal pain
         subjects affected / exposed
    0 / 445 (0.00%)
    0 / 435 (0.00%)
    1 / 435 (0.23%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Anal fistula
         subjects affected / exposed
    1 / 445 (0.22%)
    0 / 435 (0.00%)
    0 / 435 (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
    Anal ulcer
         subjects affected / exposed
    1 / 445 (0.22%)
    0 / 435 (0.00%)
    0 / 435 (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
    Gastritis
         subjects affected / exposed
    1 / 445 (0.22%)
    0 / 435 (0.00%)
    0 / 435 (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 bleeding
         subjects affected / exposed
    0 / 445 (0.00%)
    0 / 435 (0.00%)
    1 / 435 (0.23%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Pancreatitis acute
         subjects affected / exposed
    1 / 445 (0.22%)
    0 / 435 (0.00%)
    0 / 435 (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
    Umbilical hernia
         subjects affected / exposed
    1 / 445 (0.22%)
    0 / 435 (0.00%)
    0 / 435 (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
    Ventral hernia
         subjects affected / exposed
    0 / 445 (0.00%)
    1 / 435 (0.23%)
    0 / 435 (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
    Hepatobiliary disorders
    Cholecystitis acute
         subjects affected / exposed
    1 / 445 (0.22%)
    0 / 435 (0.00%)
    0 / 435 (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
    0 / 445 (0.00%)
    1 / 435 (0.23%)
    0 / 435 (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
    Chronic calculous cholecystitis
         subjects affected / exposed
    0 / 445 (0.00%)
    2 / 435 (0.46%)
    0 / 435 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Jaundice extrahepatic obstructive
         subjects affected / exposed
    0 / 445 (0.00%)
    1 / 435 (0.23%)
    0 / 435 (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
    Skin and subcutaneous tissue disorders
    Foot ulcer
         subjects affected / exposed
    0 / 445 (0.00%)
    1 / 435 (0.23%)
    0 / 435 (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 and urinary disorders
    Chronic retention of urine
         subjects affected / exposed
    0 / 445 (0.00%)
    1 / 435 (0.23%)
    0 / 435 (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
    Haematuria
         subjects affected / exposed
    1 / 445 (0.22%)
    0 / 435 (0.00%)
    0 / 435 (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
    Hydronephrosis
         subjects affected / exposed
    0 / 445 (0.00%)
    1 / 435 (0.23%)
    0 / 435 (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
    Kidney stone
         subjects affected / exposed
    1 / 445 (0.22%)
    0 / 435 (0.00%)
    0 / 435 (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
    Renal failure acute
         subjects affected / exposed
    0 / 445 (0.00%)
    1 / 435 (0.23%)
    0 / 435 (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
    Urinary retention
         subjects affected / exposed
    1 / 445 (0.22%)
    0 / 435 (0.00%)
    0 / 435 (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
    Calcifying tendinitis of shoulder
         subjects affected / exposed
    0 / 445 (0.00%)
    0 / 435 (0.00%)
    1 / 435 (0.23%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Cervical spinal stenosis
         subjects affected / exposed
    0 / 445 (0.00%)
    1 / 435 (0.23%)
    0 / 435 (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
    Osteoarthritis aggravated
         subjects affected / exposed
    1 / 445 (0.22%)
    0 / 435 (0.00%)
    0 / 435 (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
    Pain in thigh
         subjects affected / exposed
    1 / 445 (0.22%)
    0 / 435 (0.00%)
    0 / 435 (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
    Rotator cuff syndrome
         subjects affected / exposed
    0 / 445 (0.00%)
    0 / 435 (0.00%)
    1 / 435 (0.23%)
         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 stenosis NOS
         subjects affected / exposed
    1 / 445 (0.22%)
    0 / 435 (0.00%)
    0 / 435 (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
    Vertebral pain
         subjects affected / exposed
    0 / 445 (0.00%)
    1 / 435 (0.23%)
    0 / 435 (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
    Infections and infestations
    Cervicitis
         subjects affected / exposed
    0 / 445 (0.00%)
    1 / 435 (0.23%)
    0 / 435 (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
    Diabetic gangrene
         subjects affected / exposed
    0 / 445 (0.00%)
    0 / 435 (0.00%)
    1 / 435 (0.23%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Gangrene toe
         subjects affected / exposed
    1 / 445 (0.22%)
    0 / 435 (0.00%)
    0 / 435 (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
    Influenza A virus infection
         subjects affected / exposed
    1 / 445 (0.22%)
    0 / 435 (0.00%)
    0 / 435 (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
    Klebsiella sepsis
         subjects affected / exposed
    0 / 445 (0.00%)
    1 / 435 (0.23%)
    0 / 435 (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
    Lobar pneumonia
         subjects affected / exposed
    2 / 445 (0.45%)
    0 / 435 (0.00%)
    0 / 435 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    Pelvic inflammatory disease
         subjects affected / exposed
    0 / 445 (0.00%)
    1 / 435 (0.23%)
    0 / 435 (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
    Pneumonia
         subjects affected / exposed
    1 / 445 (0.22%)
    1 / 435 (0.23%)
    1 / 435 (0.23%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Purulent appendicitis
         subjects affected / exposed
    0 / 445 (0.00%)
    1 / 435 (0.23%)
    0 / 435 (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
    Recurrent urinary tract infection
         subjects affected / exposed
    0 / 445 (0.00%)
    0 / 435 (0.00%)
    1 / 435 (0.23%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Sepsis
         subjects affected / exposed
    1 / 445 (0.22%)
    0 / 435 (0.00%)
    0 / 435 (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
    Septic shock
         subjects affected / exposed
    0 / 445 (0.00%)
    1 / 435 (0.23%)
    0 / 435 (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
    Sigmoid diverticulitis
         subjects affected / exposed
    1 / 445 (0.22%)
    0 / 435 (0.00%)
    0 / 435 (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
    Urinary tract infection
         subjects affected / exposed
    1 / 445 (0.22%)
    1 / 435 (0.23%)
    0 / 435 (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
    Metabolism and nutrition disorders
    Hypomagnesaemia
         subjects affected / exposed
    0 / 445 (0.00%)
    0 / 435 (0.00%)
    1 / 435 (0.23%)
         occurrences causally related to treatment / all
    0 / 0
    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
    		 Ertugliflozin 5 mg Ertugliflozin 15 mg Glimepiride
    Total subjects affected by non serious adverse events
         subjects affected / exposed
    110 / 445 (24.72%)
    104 / 435 (23.91%)
    165 / 435 (37.93%)
    Nervous system disorders
    Headache
         subjects affected / exposed
    25 / 445 (5.62%)
    19 / 435 (4.37%)
    19 / 435 (4.37%)
         occurrences all number
    27
    22
    20
    Gastrointestinal disorders
    Diarrhoea
         subjects affected / exposed
    13 / 445 (2.92%)
    12 / 435 (2.76%)
    22 / 435 (5.06%)
         occurrences all number
    17
    12
    24
    Infections and infestations
    Common cold
         subjects affected / exposed
    21 / 445 (4.72%)
    17 / 435 (3.91%)
    23 / 435 (5.29%)
         occurrences all number
    31
    29
    31
    Upper respiratory tract infection
         subjects affected / exposed
    27 / 445 (6.07%)
    14 / 435 (3.22%)
    18 / 435 (4.14%)
         occurrences all number
    39
    19
    27
    Urinary tract infection
         subjects affected / exposed
    27 / 445 (6.07%)
    28 / 435 (6.44%)
    29 / 435 (6.67%)
         occurrences all number
    30
    33
    36
    Metabolism and nutrition disorders
    Asymptomatic hypoglycaemia
         subjects affected / exposed
    7 / 445 (1.57%)
    4 / 435 (0.92%)
    27 / 435 (6.21%)
         occurrences all number
    11
    5
    87
    Hypoglycaemia
         subjects affected / exposed
    14 / 445 (3.15%)
    25 / 435 (5.75%)
    82 / 435 (18.85%)
         occurrences all number
    31
    53
    470

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    Substantial protocol amendments (globally)
    Were there any global substantial amendments to the protocol? Yes
    Date
    Amendment
    06 May 2015
    Amendment 1 - The source for glimepiride/matching placebo changed. The original glimepiride/matching placebo supplies were provided as tablets but were then switched to capsules.

    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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    The status and protocol content of GB trials is no longer updated since 1 January 2021. For the UK, as of 31 January 2021, EU Law applies only to the territory of Northern Ireland (NI) to the extent foreseen in the Protocol on Ireland/NI. Legal notice
    As of 31 January 2023, all EU/EEA initial clinical trial applications must be submitted through CTIS . Updated EudraCT trials information and information on PIP/Art 46 trials conducted exclusively in third countries continues to be submitted through EudraCT and published on this website.

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