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    Clinical Trial Results:
    A Phase III, Multicenter, Randomized, Double-Blind, Placebo-Controlled Clinical Trial to Evaluate the Efficacy and Safety of Ertugliflozin (MK-8835/PF-04971729) in Subjects with Type 2 Diabetes Mellitus with Stage 3 Chronic Kidney Disease Who Have Inadequate Glycemic Control on Background Antihyperglycemic Therapy

    Summary
    EudraCT number
    		 2013-003587-31
    Trial protocol
    		 GB   HU   BG   RO  
    Global end of trial date
    28 Sep 2016

    Results information
    Results version number
    		 v1(current)
    This version publication date
    21 Sep 2017
    First version publication date
    21 Sep 2017
    Other versions

    Trial information

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    Trial identification
    Sponsor protocol code
    MK-8835-001
    Additional study identifiers
    ISRCTN number
    		 -
    US NCT number
    		 NCT01986855
    WHO universal trial number (UTN)
    		 -
    Other trial identifiers
    		 Pfizer Protocol Number: B1521016
    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
    28 Sep 2016
    Is this the analysis of the primary completion data?
    Yes
    Primary completion date
    28 Sep 2016
    Global end of trial reached?
    Yes
    Global end of trial date
    28 Sep 2016
    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 ertugliflozin (MK-8835/PF-04971729) in participants with type 2 diabetes mellitus with Stage 3 Chronic Kidney Disease (CKD) who have inadequate glycemic control on background antihyperglycemic therapy. The duration of this trial will be up to 67 weeks. This will consist of a 1-week Screening Period, a 10-week wash-off period from metformin, if needed, and a 2-week placebo run-in period, a 52-week double-blind treatment period, and a 14-day post-treatment follow-up period. The primary objective of this trial is to assess the Hemoglobin A1C (A1C)-lowering efficacy of the addition of ertugliflozin compared to the addition of placebo with an underlying hypothesis that addition of treatment with ertugliflozin provides greater reduction in A1C compared to the addition of placebo; the primary objective will be tested for both 5-mg and 15-mg doses of ertugliflozin.
    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. Participants who meet progressively more stringent glycemic rescue criteria had their antihyperglycemic agent (AHA) regimen adjusted or initiate treatment with a new AHA medication(s), with intensification of the participant's regimen managed as considered appropriate by the investigator. Participants on insulin should maintain a stable dose unless they meet glycemic rescue criteria.
    Background therapy
    		 -
    Evidence for comparator
    		 -
    Actual start date of recruitment
    02 Dec 2013
    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
    South Africa: 13
    Country: Number of subjects enrolled
    United Kingdom: 17
    Country: Number of subjects enrolled
    United States: 135
    Country: Number of subjects enrolled
    Argentina: 25
    Country: Number of subjects enrolled
    Bulgaria: 11
    Country: Number of subjects enrolled
    Colombia: 14
    Country: Number of subjects enrolled
    Hungary: 59
    Country: Number of subjects enrolled
    Israel: 41
    Country: Number of subjects enrolled
    Mexico: 15
    Country: Number of subjects enrolled
    Philippines: 39
    Country: Number of subjects enrolled
    Poland: 26
    Country: Number of subjects enrolled
    Romania: 45
    Country: Number of subjects enrolled
    Russian Federation: 28
    Worldwide total number of subjects
    468
    EEA total number of subjects
    158
    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)
    163
    From 65 to 84 years
    301
    85 years and over
    4

    Subject disposition

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    Recruitment
    Recruitment details
    		 The trial was conducted in 13 countries, including 171 trial centers; 1709 participants were screened and 468 were randomized.

    Pre-assignment
    Screening details
    		 Eligible participants began a ≥10-week metformin wash-off during which participant’s AHAs could be adjusted. All participants entered a 2-week placebo run-in period.

    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
    		 Investigator, Subject

    Arms
    Are arms mutually exclusive
    Yes

    Arm title
    		 Ertugliflozin 5 mg
    Arm description
    		 Ertugliflozin, oral, 5-mg tablet once daily for 52 weeks. Participants also received a 10-mg matching placebo tablet once daily for 52 weeks.
    Arm type
    		 Experimental

    Investigational medicinal product name
    Ertugliflozin
    Investigational medicinal product code
    Other name
    MK-8835 PF-04971729
    Pharmaceutical forms
    Tablet
    Routes of administration
    Oral use
    Dosage and administration details
    Oral, 5-mg tablet once daily for 52 weeks

    Arm title
    		 Ertugliflozin 15 mg
    Arm description
    		 Ertugliflozin, oral, 5-mg and 10-mg tablet once daily for 52 weeks
    Arm type
    		 Experimental

    Investigational medicinal product name
    Ertugliflozin
    Investigational medicinal product code
    Other name
    MK-8835 PF-04971729
    Pharmaceutical forms
    Tablet
    Routes of administration
    Oral use
    Dosage and administration details
    Oral, 5-mg and a 10-mg tablet once daily for 52 weeks

    Arm title
    		 Placebo
    Arm description
    		 Placebo, oral, tablet, 5-mg or 5-mg and 10-mg tablet once daily for 52 weeks
    Arm type
    		 Placebo

    Investigational medicinal product name
    Placebo to Ertugliflozin
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Tablet
    Routes of administration
    Oral use
    Dosage and administration details
    Oral, 5-mg tablet once daily for 52 weeks or a 5-mg and a 10-mg tablet once daily for 52 weeks

    Number of subjects in period 1
    		Ertugliflozin 5 mg Ertugliflozin 15 mg Placebo
    Started
    158
    156
    154
    Treated
    158
    155
    154
    Completed
    145
    142
    143
    Not completed
    13
    14
    11
         Consent withdrawn by subject
    7
    8
    5
         Screen Failure
    -
    1
    -
         Adverse event, non-fatal
    1
    -
    -
         Death
    3
    4
    4
         Participant Moved
    -
    -
    2
         Lost to follow-up
    2
    1
    -

    Baseline characteristics

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    Baseline characteristics reporting groups
    Reporting group title
    Ertugliflozin 5 mg
    Reporting group description
    		 Ertugliflozin, oral, 5-mg tablet once daily for 52 weeks. Participants also received a 10-mg matching placebo tablet once daily for 52 weeks.

    Reporting group title
    Ertugliflozin 15 mg
    Reporting group description
    		 Ertugliflozin, oral, 5-mg and 10-mg tablet once daily for 52 weeks

    Reporting group title
    Placebo
    Reporting group description
    		 Placebo, oral, tablet, 5-mg or 5-mg and 10-mg tablet once daily for 52 weeks

    Reporting group values
    		 Ertugliflozin 5 mg Ertugliflozin 15 mg Placebo Total
    Number of subjects
    		 158 156 154 468
    Age categorical
    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)
    		 50 58 55 163
        From 65-84 years
    		 107 96 98 301
        85 years and over
    		 1 2 1 4
    Age Continuous
    Units: Years
        arithmetic mean (standard deviation)
    		 66.7 ± 8.3 67.5 ± 8.5 67.5 ± 8.9 -
    Gender, Male/Female
    Units: Subjects
        Female
    		 74 80 82 236
        Male
    		 84 76 72 232
    Estimated glomerular filtration rate (eGFR)
    Stratification Factor: eGFR (mL/min/1.73m^2)
    Units: Subjects
        ≥30 to <45
    		 52 53 54 159
        ≥45 to <60
    		 106 103 100 309
    Insulin at randomization
    Stratification Factor: Insulin at randomization? (Yes/No)
    Units: Subjects
        (No)
    		 69 68 66 203
        (Yes)
    		 89 88 88 265
    Baseline A1C
    n=154, 151, 152, 457
    Units: Percentage
        arithmetic mean (standard deviation)
    		 8.2 ± 1.02 8.17 ± 0.87 8.08 ± 0.89 -
    Baseline Weight
    Units: Kilograms
        arithmetic mean (standard deviation)
    		 89.4 ± 22.5 85.8 ± 17.4 90.4 ± 18.9 -
    Baseline Fasting Plasma Glucose (FPG)
    n=157, 155, 154, 466
    Units: mg/dL
        arithmetic mean (standard deviation)
    		 160.7 ± 56.5 157.5 ± 47.8 156.9 ± 56.4 -

    End points

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    End points reporting groups
    Reporting group title
    Ertugliflozin 5 mg
    Reporting group description
    		 Ertugliflozin, oral, 5-mg tablet once daily for 52 weeks. Participants also received a 10-mg matching placebo tablet once daily for 52 weeks.

    Reporting group title
    Ertugliflozin 15 mg
    Reporting group description
    		 Ertugliflozin, oral, 5-mg and 10-mg tablet once daily for 52 weeks

    Reporting group title
    Placebo
    Reporting group description
    		 Placebo, oral, tablet, 5-mg or 5-mg and 10-mg tablet once daily for 52 weeks

    Primary: Change from Baseline in A1C at Week 26 - Excluding Rescue Approach

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    End point title
    		 Change from Baseline in A1C at Week 26 - Excluding Rescue Approach
    End point description
    A1C is blood marker used to report average blood glucose levels over prolonged periods of time and is reported as a percentage (%). This change from baseline reflects the Week 26 A1C minus the Week 0 A1C. Excluding rescue approach data analysis excluded all data following the initiation of rescue therapy at any time point, in order to avoid the confounding influence of the rescue therapy. The analysis population included all randomized participants who took at least 1 dose of study treatment and had at least 1 assessment at or after baseline for the change from baseline at Week 26 A1C endpoint.
    End point type
    Primary
    End point timeframe
    Baseline and Week 26
    End point values
    		 Ertugliflozin 5 mg Ertugliflozin 15 mg Placebo
    Number of subjects analysed
    158
    155
    154
    Units: Percentage
        least squares mean (confidence interval 95%)
    -0.29 (-0.44 to -0.14)
    -0.41 (-0.56 to -0.27)
    -0.26 (-0.41 to -0.11)
    Statistical analysis title
    		 Difference in the least squares means
    Comparison groups
    Ertugliflozin 5 mg v Placebo
    Number of subjects included in analysis
    312
    Analysis specification
    Pre-specified
    Analysis type
    		 other
    P-value
    		 = 0.807 [1]
    Method
    		 Constrained longitudinal data anal. cLDA
    Parameter type
    		 Difference in the least squares means
    Point estimate
    -0.03
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -0.23
         upper limit
    		 0.18
    Notes
    [1] - The cLDA model included fixed effects for treatment, time, eGFR stratum (<45 or ≥45 mL/min/1.73m^2), baseline treatment with insulin stratum (yes/no) and the interaction of time by treatment. Time was treated as a categorical variable.
    Statistical analysis title
    		 Difference in the least squares means
    Comparison groups
    Ertugliflozin 15 mg v Placebo
    Number of subjects included in analysis
    309
    Analysis specification
    Pre-specified
    Analysis type
    		 other
    P-value
    		 = 0.155 [2]
    Method
    		 Constrained longitudinal data analysis
    Parameter type
    		 Difference in the least squares means
    Point estimate
    -0.15
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -0.35
         upper limit
    		 0.06
    Notes
    [2] - The cLDA model included fixed effects for treatment, time, eGFR stratum (<45 or ≥45 mL/min/1.73m^2), baseline treatment with insulin stratum (yes/no) and the interaction of time by treatment. Time was treated as a categorical variable.

    Primary: Percentage of Participants Who Experienced an Adverse Event (AE)

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    End point title
    		 Percentage of Participants Who Experienced an Adverse Event (AE)
    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 received at least 1 dose of study treatment.
    End point type
    Primary
    End point timeframe
    Up to 54 weeks
    End point values
    		 Ertugliflozin 5 mg Ertugliflozin 15 mg Placebo
    Number of subjects analysed
    158
    155
    154
    Units: Percentage of participants
        number (not applicable)
    84.8
    74.2
    81.2
    Statistical analysis title
    		 Difference in Percentages vs. Placebo
    Comparison groups
    Ertugliflozin 5 mg v Placebo
    Number of subjects included in analysis
    312
    Analysis specification
    Pre-specified
    Analysis type
    		 other
    Method
    Parameter type
    		 Difference in Percentages vs. Placebo
    Point estimate
    3.6
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -4.8
         upper limit
    		 12.1
    Statistical analysis title
    		 Difference in Percentages vs. Placebo
    Comparison groups
    Ertugliflozin 15 mg v Placebo
    Number of subjects included in analysis
    309
    Analysis specification
    Pre-specified
    Analysis type
    		 other
    Method
    Parameter type
    		 Difference in Percentages vs. Placebo
    Point estimate
    -7
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -16.3
         upper limit
    		 2.3

    Primary: Percentage of Participants Who Discontinued Study Treatment due to an AE

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    End point title
    		 Percentage of Participants Who Discontinued Study Treatment due to an AE
    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 received at least 1 dose of study treatment.
    End point type
    Primary
    End point timeframe
    Up to 52 weeks
    End point values
    		 Ertugliflozin 5 mg Ertugliflozin 15 mg Placebo
    Number of subjects analysed
    158
    155
    154
    Units: Percentage of participants
        number (not applicable)
    8.2
    3.9
    5.2
    Statistical analysis title
    		 Difference in Percentages vs. Placebo
    Comparison groups
    Ertugliflozin 5 mg v Placebo
    Number of subjects included in analysis
    312
    Analysis specification
    Pre-specified
    Analysis type
    		 other
    Method
    Parameter type
    		 Difference in Percentages vs. Placebo
    Point estimate
    3
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -2.7
         upper limit
    		 9
    Statistical analysis title
    		 Difference in Percentages vs. Placebo
    Comparison groups
    Ertugliflozin 15 mg v Placebo
    Number of subjects included in analysis
    309
    Analysis specification
    Pre-specified
    Analysis type
    		 other
    Method
    Parameter type
    		 Difference in Percentages vs. Placebo
    Point estimate
    -1.3
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -6.5
         upper limit
    		 3.7

    Secondary: Change from Baseline in A1C at Week 26 - Baseline eGFR ≥45 to <60 mL/min/1.73m^2 Stratum - Excluding Rescue Approach

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    End point title
    		 Change from Baseline in A1C at Week 26 - Baseline eGFR ≥45 to <60 mL/min/1.73m^2 Stratum - Excluding Rescue Approach
    End point description
    A1C is blood marker used to report average blood glucose levels over prolonged periods of time and is reported as a percentage (%). This change from baseline reflects the Week 26 A1C minus the Week 0 A1C. Excluding rescue approach data analysis excluded all data following the initiation of rescue therapy at any time point, in order to avoid the confounding influence of the rescue therapy. The analysis population included all randomized participants with a Baseline eGFR of ≥45 to <60 mL/min/1.73m^2, who took at least 1 dose of study treatment, and had at least 1 assessment at or after baseline for the change from baseline at Week 26 A1C endpoint.
    End point type
    Secondary
    End point timeframe
    Baseline and Week 26
    End point values
    		 Ertugliflozin 5 mg Ertugliflozin 15 mg Placebo
    Number of subjects analysed
    105
    97
    99
    Units: Percentage
        least squares mean (confidence interval 95%)
    -0.31 (-0.49 to -0.13)
    -0.37 (-0.56 to -0.18)
    -0.28 (-0.47 to -0.08)
    Statistical analysis title
    		 Difference in the least squares means
    Comparison groups
    Ertugliflozin 5 mg v Placebo
    Number of subjects included in analysis
    204
    Analysis specification
    Pre-specified
    Analysis type
    		 other
    P-value
    		 = 0.828 [3]
    Method
    		 Constrained longitudinal data analysis
    Parameter type
    		 Difference in the least squares means
    Point estimate
    -0.03
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -0.28
         upper limit
    		 0.23
    Notes
    [3] - The cLDA model included fixed effects for treatment, time, baseline treatment with insulin stratum (yes/no), and the interaction of time by treatment. Time was treated as a categorical variable.
    Statistical analysis title
    		 Difference in the least squares means
    Comparison groups
    Ertugliflozin 15 mg v Placebo
    Number of subjects included in analysis
    196
    Analysis specification
    Pre-specified
    Analysis type
    		 other
    P-value
    		 = 0.496 [4]
    Method
    		 Constrained longitudinal data analysis
    Parameter type
    		 Difference in the least squares means
    Point estimate
    -0.09
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -0.35
         upper limit
    		 0.17
    Notes
    [4] - The cLDA model included fixed effects for treatment, time, baseline treatment with insulin stratum (yes/no), and the interaction of time by treatment. Time was treated as a categorical variable.

    Secondary: Change from Baseline in Body Weight at Week 26 - Baseline eGFR ≥45 to <60 mL/min/1.73m^2 Stratum - Excluding Rescue Approach

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    End point title
    		 Change from Baseline in Body Weight at Week 26 - Baseline eGFR ≥45 to <60 mL/min/1.73m^2 Stratum - Excluding Rescue Approach
    End point description
    This change from baseline reflects the Week 26 body weight minus the Week 0 body weight. Excluding rescue approach data analysis excluded all data following the initiation of rescue therapy at any time point, in order to avoid the confounding influence of the rescue therapy. The analysis population included all randomized participants with a Baseline eGFR of ≥45 to <60 mL/min/1.73m^2, who took at least 1 dose of study treatment, and had at least 1 assessment at or after baseline for the change from baseline at Week 26 body weight endpoint.
    End point type
    Secondary
    End point timeframe
    Baseline and Week 26
    End point values
    		 Ertugliflozin 5 mg Ertugliflozin 15 mg Placebo
    Number of subjects analysed
    105
    97
    99
    Units: Kilograms
        least squares mean (confidence interval 95%)
    -1.31 (-1.86 to -0.76)
    -1.39 (-1.97 to -0.81)
    0.46 (-0.13 to 1.04)
    Statistical analysis title
    		 Difference in the least squares means
    Comparison groups
    Ertugliflozin 5 mg v Placebo
    Number of subjects included in analysis
    204
    Analysis specification
    Pre-specified
    Analysis type
    		 other
    P-value
    		 < 0.001 [5]
    Method
    		 Constrained longitudinal data analysis
    Parameter type
    		 Difference in the least squares means
    Point estimate
    -1.77
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -2.57
         upper limit
    		 -0.96
    Notes
    [5] - The cLDA model included fixed effects for treatment, time, baseline treatment with insulin stratum (yes/no) and the interaction of time by treatment. Time was treated as a categorical variable. P-value is nominal.
    Statistical analysis title
    		 Difference in the least squares means
    Comparison groups
    Ertugliflozin 15 mg v Placebo
    Number of subjects included in analysis
    196
    Analysis specification
    Pre-specified
    Analysis type
    		 other
    P-value
    		 < 0.001 [6]
    Method
    		 Constrained longitudinal data analysis
    Parameter type
    		 Difference in the least squares means
    Point estimate
    -1.84
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -2.66
         upper limit
    		 -1.02
    Notes
    [6] - The cLDA model included fixed effects for treatment, time, baseline treatment with insulin stratum (yes/no) and the interaction of time by treatment. Time was treated as a categorical variable. P-value is nominal.

    Secondary: Change from Baseline in Sitting Systolic Blood Pressure at Week 26 - Baseline eGFR ≥45 to <60 mL/min/1.73m^2 Stratum - Excluding Rescue Approach

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    End point title
    		 Change from Baseline in Sitting Systolic Blood Pressure at Week 26 - Baseline eGFR ≥45 to <60 mL/min/1.73m^2 Stratum - Excluding Rescue Approach
    End point description
    This change from baseline reflects the Week 26 sitting systolic blood pressure minus the Week 0 sitting systolic blood pressure. Excluding rescue approach data analysis excluded all data following the initiation of rescue therapy at any time point, in order to avoid the confounding influence of the rescue therapy. The analysis population included all randomized participants with a Baseline eGFR of ≥45 to <60 mL/min/1.73m^2, who took at least 1 dose of study treatment, and had at least 1 assessment at or after baseline for the change from baseline at Week 26 sitting systolic blood pressure endpoint.
    End point type
    Secondary
    End point timeframe
    Baseline and Week 26
    End point values
    		 Ertugliflozin 5 mg Ertugliflozin 15 mg Placebo
    Number of subjects analysed
    105
    97
    99
    Units: mmHg
        least squares mean (confidence interval 95%)
    -2.33 (-4.98 to 0.33)
    -4.36 (-7.11 to -1.62)
    -0.9 (-3.73 to 1.92)
    Statistical analysis title
    		 Difference in the least squares means
    Comparison groups
    Ertugliflozin 5 mg v Placebo
    Number of subjects included in analysis
    204
    Analysis specification
    Pre-specified
    Analysis type
    		 other
    P-value
    		 = 0.451 [7]
    Method
    		 Constrained longitudinal data analysis
    Parameter type
    		 Difference in the least squares means
    Point estimate
    -1.42
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -5.13
         upper limit
    		 2.29
    Notes
    [7] - The cLDA model included fixed effects for treatment, time, baseline treatment with insulin stratum (yes/no) and the interaction of time by treatment. Time was treated as a categorical variable.
    Statistical analysis title
    		 Difference in the least squares means
    Comparison groups
    Ertugliflozin 15 mg v Placebo
    Number of subjects included in analysis
    196
    Analysis specification
    Pre-specified
    Analysis type
    		 other
    P-value
    		 = 0.072 [8]
    Method
    		 Constrained longitudinal data analysis
    Parameter type
    		 Difference in the least squares means
    Point estimate
    -3.46
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -7.24
         upper limit
    		 0.31
    Notes
    [8] - The cLDA model included fixed effects for treatment, time, baseline treatment with insulin stratum (yes/no) and the interaction of time by treatment. Time was treated as a categorical variable.

    Secondary: Change from Baseline in FPG at Week 26 - Baseline eGFR ≥45 to <60 mL/min/1.73m^2 Stratum - Excluding Rescue Approach

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    End point title
    		 Change from Baseline in FPG at Week 26 - Baseline eGFR ≥45 to <60 mL/min/1.73m^2 Stratum - Excluding Rescue Approach
    End point description
    This change from baseline reflects the Week 26 FPG minus the Week 0 FPG. Excluding rescue approach data analysis excluded all data following the initiation of rescue therapy at any time point, in order to avoid the confounding influence of the rescue therapy. The analysis population included all randomized participants with a Baseline eGFR ≥45 to <60 mL/min/1.73m^2, who took at least 1 dose of study treatment, and had at least 1 assessment at or after baseline for the change from baseline at Week 26 FPG endpoint.
    End point type
    Secondary
    End point timeframe
    Baseline and Week 26
    End point values
    		 Ertugliflozin 5 mg Ertugliflozin 15 mg Placebo
    Number of subjects analysed
    105
    97
    99
    Units: mg/dL
        least squares mean (confidence interval 95%)
    -11.76 (-21.07 to -2.45)
    -20.47 (-30.2 to -10.73)
    -4.95 (-15.03 to 5.13)
    Statistical analysis title
    		 Difference in the least squares means
    Comparison groups
    Ertugliflozin 5 mg v Placebo
    Number of subjects included in analysis
    204
    Analysis specification
    Pre-specified
    Analysis type
    		 other
    P-value
    		 = 0.291 [9]
    Method
    		 Constrained longitudinal data analysis
    Parameter type
    		 Difference in the least squares means
    Point estimate
    -6.81
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -19.47
         upper limit
    		 5.85
    Notes
    [9] - The cLDA model included fixed effects for treatment, time, baseline treatment with insulin stratum (yes/no) and the interaction of time by treatment. Time was treated as a categorical variable.
    Statistical analysis title
    		 Difference in the least squares means
    Comparison groups
    Ertugliflozin 15 mg v Placebo
    Number of subjects included in analysis
    196
    Analysis specification
    Pre-specified
    Analysis type
    		 other
    P-value
    		 = 0.019 [10]
    Method
    		 Constrained longitudinal data analysis
    Parameter type
    		 Difference in the least squares means
    Point estimate
    -15.51
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -28.5
         upper limit
    		 -2.53
    Notes
    [10] - The cLDA model included fixed effects for treatment, time, baseline treatment with insulin stratum (yes/no) and the interaction of time by treatment. Time was treated as a categorical variable. P-value is nominal.

    Secondary: Percentage of Participants With A1C <7.0% (<53 mmol/mol) at Week 26 - Baseline eGFR ≥45 to <60 mL/min/1.73m^2 Stratum - Excluding Rescue Approach

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    End point title
    		 Percentage of Participants With A1C <7.0% (<53 mmol/mol) at Week 26 - Baseline eGFR ≥45 to <60 mL/min/1.73m^2 Stratum - Excluding Rescue Approach
    End point description
    A1C is blood marker used to report average blood glucose levels over prolonged periods of time and is reported as a percentage (%). Excluding rescue approach data analysis excluded all data following the initiation of rescue therapy at any time point, in order to avoid the confounding influence of the rescue therapy. The analysis population included all randomized participants with a Baseline eGFR ≥45 to <60 mL/min/1.73m^2, who took at least 1 dose of study medication, and had at least 1 assessment at Week 26 for the percentage of participants with an A1C <7% at Week 26 endpoint.
    End point type
    Secondary
    End point timeframe
    Week 26
    End point values
    		 Ertugliflozin 5 mg Ertugliflozin 15 mg Placebo
    Number of subjects analysed
    105
    97
    99
    Units: Percentage of participants
        number (not applicable)
    16.2
    11.3
    12.1
    Statistical analysis title
    		 Adjusted Odds Ratio relative to Placebo
    Comparison groups
    Ertugliflozin 5 mg v Placebo
    Number of subjects included in analysis
    204
    Analysis specification
    Pre-specified
    Analysis type
    		 other
    P-value
    		 = 0.713 [11]
    Method
    		 Logistic regression model
    Parameter type
    		 Adjusted Odds Ratio
    Point estimate
    1.16
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.53
         upper limit
    		 2.56
    Notes
    [11] - Logistic regression model fitted with terms for treatment, baseline A1C and baseline treatment with insulin stratum (yes/no).
    Statistical analysis title
    		 Adjusted Odds Ratio relative to Placebo
    Comparison groups
    Ertugliflozin 15 mg v Placebo
    Number of subjects included in analysis
    196
    Analysis specification
    Pre-specified
    Analysis type
    		 other
    P-value
    		 = 0.89 [12]
    Method
    		 Logistic regression model
    Parameter type
    		 Adjusted Odds Ratio
    Point estimate
    1.06
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.44
         upper limit
    		 2.55
    Notes
    [12] - Logistic regression model fitted with terms for treatment, baseline A1C and baseline treatment with insulin stratum (yes/no).

    Adverse events

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    Adverse events information
    Timeframe for reporting adverse events
    Up to 54 weeks
    Adverse event reporting additional 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.
    Assessment type
    		 Systematic
    Dictionary used for adverse event reporting
    Dictionary name
    		 MedDRA
    Dictionary version
    19.0
    Reporting groups
    Reporting group title
    Placebo
    Reporting group description
    		 Placebo, oral, tablet, 5-mg or 5-mg and 10-mg tablet once daily for 52 weeks

    Reporting group title
    Ertugliflozin 15 mg
    Reporting group description
    		 Ertugliflozin, oral, tablet, 5-mg and 10-mg tablet once daily for 52 weeks

    Reporting group title
    Ertugliflozin 5 mg
    Reporting group description
    		 Ertugliflozin, oral, 5-mg tablet once daily for 52 weeks. Participants also received a 10-mg matching placebo tablet once daily for 52 weeks.

    Serious adverse events
    		 Placebo Ertugliflozin 15 mg Ertugliflozin 5 mg
    Total subjects affected by serious adverse events
         subjects affected / exposed
    24 / 154 (15.58%)
    30 / 155 (19.35%)
    26 / 158 (16.46%)
         number of deaths (all causes)
    4
    4
    3
         number of deaths resulting from adverse events
    0
    0
    0
    Neoplasms benign, malignant and unspecified (incl cysts and polyps)
    Carcinoma in situ of skin
         subjects affected / exposed
    0 / 154 (0.00%)
    1 / 155 (0.65%)
    0 / 158 (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 / 154 (0.00%)
    0 / 155 (0.00%)
    1 / 158 (0.63%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Myelodysplastic syndrome
         subjects affected / exposed
    0 / 154 (0.00%)
    0 / 155 (0.00%)
    1 / 158 (0.63%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Non-Hodgkin's lymphoma
         subjects affected / exposed
    0 / 154 (0.00%)
    1 / 155 (0.65%)
    0 / 158 (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 adenoma
         subjects affected / exposed
    1 / 154 (0.65%)
    0 / 155 (0.00%)
    0 / 158 (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
    Squamous cell carcinoma
         subjects affected / exposed
    0 / 154 (0.00%)
    1 / 155 (0.65%)
    0 / 158 (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
    Squamous cell carcinoma of skin
         subjects affected / exposed
    1 / 154 (0.65%)
    0 / 155 (0.00%)
    0 / 158 (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
    Vascular disorders
    Peripheral arterial occlusive disease
         subjects affected / exposed
    0 / 154 (0.00%)
    1 / 155 (0.65%)
    0 / 158 (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
    Peripheral artery occlusion
         subjects affected / exposed
    0 / 154 (0.00%)
    1 / 155 (0.65%)
    0 / 158 (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
    Peripheral artery stenosis
         subjects affected / exposed
    1 / 154 (0.65%)
    0 / 155 (0.00%)
    0 / 158 (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
    General disorders and administration site conditions
    Cardiac death
         subjects affected / exposed
    0 / 154 (0.00%)
    0 / 155 (0.00%)
    1 / 158 (0.63%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    Non-cardiac chest pain
         subjects affected / exposed
    1 / 154 (0.65%)
    0 / 155 (0.00%)
    0 / 158 (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
    1 / 154 (0.65%)
    1 / 155 (0.65%)
    2 / 158 (1.27%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
    0 / 2
         deaths causally related to treatment / all
    0 / 1
    0 / 1
    0 / 2
    Respiratory, thoracic and mediastinal disorders
    Asthma
         subjects affected / exposed
    1 / 154 (0.65%)
    1 / 155 (0.65%)
    0 / 158 (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
    Dyspnoea
         subjects affected / exposed
    0 / 154 (0.00%)
    1 / 155 (0.65%)
    0 / 158 (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
    Epistaxis
         subjects affected / exposed
    1 / 154 (0.65%)
    0 / 155 (0.00%)
    0 / 158 (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
    Confusional state
         subjects affected / exposed
    1 / 154 (0.65%)
    0 / 155 (0.00%)
    0 / 158 (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
    Investigations
    Alanine aminotransferase increased
         subjects affected / exposed
    0 / 154 (0.00%)
    0 / 155 (0.00%)
    1 / 158 (0.63%)
         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
    0 / 154 (0.00%)
    0 / 155 (0.00%)
    1 / 158 (0.63%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Intraocular pressure increased
         subjects affected / exposed
    0 / 154 (0.00%)
    0 / 155 (0.00%)
    1 / 158 (0.63%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Injury, poisoning and procedural complications
    Femur fracture
         subjects affected / exposed
    1 / 154 (0.65%)
    0 / 155 (0.00%)
    0 / 158 (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
    Humerus fracture
         subjects affected / exposed
    0 / 154 (0.00%)
    0 / 155 (0.00%)
    1 / 158 (0.63%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Injury
         subjects affected / exposed
    1 / 154 (0.65%)
    0 / 155 (0.00%)
    0 / 158 (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 vertebral fracture
         subjects affected / exposed
    0 / 154 (0.00%)
    0 / 155 (0.00%)
    1 / 158 (0.63%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Tibia fracture
         subjects affected / exposed
    0 / 154 (0.00%)
    0 / 155 (0.00%)
    1 / 158 (0.63%)
         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 myocardial infarction
         subjects affected / exposed
    0 / 154 (0.00%)
    3 / 155 (1.94%)
    2 / 158 (1.27%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 3
    0 / 2
         deaths causally related to treatment / all
    0 / 1
    0 / 2
    0 / 0
    Angina pectoris
         subjects affected / exposed
    0 / 154 (0.00%)
    4 / 155 (2.58%)
    0 / 158 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 4
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Angina unstable
         subjects affected / exposed
    1 / 154 (0.65%)
    0 / 155 (0.00%)
    1 / 158 (0.63%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Atrial fibrillation
         subjects affected / exposed
    0 / 154 (0.00%)
    1 / 155 (0.65%)
    0 / 158 (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
    Bradycardia
         subjects affected / exposed
    1 / 154 (0.65%)
    0 / 155 (0.00%)
    0 / 158 (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
    Bundle branch block left
         subjects affected / exposed
    1 / 154 (0.65%)
    0 / 155 (0.00%)
    0 / 158 (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
    0 / 154 (0.00%)
    1 / 155 (0.65%)
    0 / 158 (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
    Cardiac failure congestive
         subjects affected / exposed
    1 / 154 (0.65%)
    0 / 155 (0.00%)
    0 / 158 (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
    Cardiogenic shock
         subjects affected / exposed
    1 / 154 (0.65%)
    0 / 155 (0.00%)
    0 / 158 (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
    Coronary artery disease
         subjects affected / exposed
    2 / 154 (1.30%)
    1 / 155 (0.65%)
    1 / 158 (0.63%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Coronary artery stenosis
         subjects affected / exposed
    0 / 154 (0.00%)
    0 / 155 (0.00%)
    2 / 158 (1.27%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Myocardial ischaemia
         subjects affected / exposed
    0 / 154 (0.00%)
    2 / 155 (1.29%)
    1 / 158 (0.63%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 2
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Sinus node dysfunction
         subjects affected / exposed
    0 / 154 (0.00%)
    1 / 155 (0.65%)
    0 / 158 (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 arteriosclerosis
         subjects affected / exposed
    0 / 154 (0.00%)
    0 / 155 (0.00%)
    1 / 158 (0.63%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Carotid artery stenosis
         subjects affected / exposed
    0 / 154 (0.00%)
    0 / 155 (0.00%)
    1 / 158 (0.63%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Encephalopathy
         subjects affected / exposed
    0 / 154 (0.00%)
    1 / 155 (0.65%)
    0 / 158 (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
    Haemorrhagic stroke
         subjects affected / exposed
    0 / 154 (0.00%)
    1 / 155 (0.65%)
    0 / 158 (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
    Ischaemic stroke
         subjects affected / exposed
    2 / 154 (1.30%)
    0 / 155 (0.00%)
    0 / 158 (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
    Sciatic nerve palsy
         subjects affected / exposed
    0 / 154 (0.00%)
    0 / 155 (0.00%)
    1 / 158 (0.63%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Sciatica
         subjects affected / exposed
    0 / 154 (0.00%)
    0 / 155 (0.00%)
    1 / 158 (0.63%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Syncope
         subjects affected / exposed
    0 / 154 (0.00%)
    0 / 155 (0.00%)
    1 / 158 (0.63%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Transient ischaemic attack
         subjects affected / exposed
    0 / 154 (0.00%)
    1 / 155 (0.65%)
    0 / 158 (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
    Blood and lymphatic system disorders
    Lymph node haemorrhage
         subjects affected / exposed
    0 / 154 (0.00%)
    1 / 155 (0.65%)
    0 / 158 (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
    Eye disorders
    Retinal detachment
         subjects affected / exposed
    0 / 154 (0.00%)
    1 / 155 (0.65%)
    0 / 158 (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 / 154 (0.00%)
    2 / 155 (1.29%)
    0 / 158 (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
    Cyclic vomiting syndrome
         subjects affected / exposed
    0 / 154 (0.00%)
    1 / 155 (0.65%)
    0 / 158 (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
    Inguinal hernia
         subjects affected / exposed
    0 / 154 (0.00%)
    1 / 155 (0.65%)
    0 / 158 (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
    Peritoneal haemorrhage
         subjects affected / exposed
    0 / 154 (0.00%)
    0 / 155 (0.00%)
    1 / 158 (0.63%)
         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
    0 / 154 (0.00%)
    1 / 155 (0.65%)
    0 / 158 (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
    Diabetic foot
         subjects affected / exposed
    0 / 154 (0.00%)
    0 / 155 (0.00%)
    1 / 158 (0.63%)
         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
    Acute kidney injury
         subjects affected / exposed
    0 / 154 (0.00%)
    0 / 155 (0.00%)
    2 / 158 (1.27%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    1 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Chronic kidney disease
         subjects affected / exposed
    1 / 154 (0.65%)
    0 / 155 (0.00%)
    0 / 158 (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
    Nephrolithiasis
         subjects affected / exposed
    1 / 154 (0.65%)
    0 / 155 (0.00%)
    0 / 158 (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
    Ureterolithiasis
         subjects affected / exposed
    1 / 154 (0.65%)
    0 / 155 (0.00%)
    0 / 158 (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 retention
         subjects affected / exposed
    1 / 154 (0.65%)
    0 / 155 (0.00%)
    0 / 158 (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
    Intervertebral disc protrusion
         subjects affected / exposed
    1 / 154 (0.65%)
    0 / 155 (0.00%)
    1 / 158 (0.63%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Lumbar spinal stenosis
         subjects affected / exposed
    1 / 154 (0.65%)
    0 / 155 (0.00%)
    1 / 158 (0.63%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Osteoarthritis
         subjects affected / exposed
    0 / 154 (0.00%)
    0 / 155 (0.00%)
    1 / 158 (0.63%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Infections and infestations
    Appendicitis
         subjects affected / exposed
    0 / 154 (0.00%)
    0 / 155 (0.00%)
    1 / 158 (0.63%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Cellulitis
         subjects affected / exposed
    0 / 154 (0.00%)
    3 / 155 (1.94%)
    0 / 158 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 7
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Cystitis
         subjects affected / exposed
    0 / 154 (0.00%)
    1 / 155 (0.65%)
    0 / 158 (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
    Diarrhoea infectious
         subjects affected / exposed
    1 / 154 (0.65%)
    0 / 155 (0.00%)
    0 / 158 (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
    Escherichia urinary tract infection
         subjects affected / exposed
    1 / 154 (0.65%)
    0 / 155 (0.00%)
    0 / 158 (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
    Extradural abscess
         subjects affected / exposed
    1 / 154 (0.65%)
    0 / 155 (0.00%)
    0 / 158 (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 / 154 (0.00%)
    0 / 155 (0.00%)
    1 / 158 (0.63%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Lower respiratory tract infection
         subjects affected / exposed
    1 / 154 (0.65%)
    0 / 155 (0.00%)
    0 / 158 (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
    Pneumonia
         subjects affected / exposed
    1 / 154 (0.65%)
    1 / 155 (0.65%)
    2 / 158 (1.27%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Pneumonia influenzal
         subjects affected / exposed
    0 / 154 (0.00%)
    0 / 155 (0.00%)
    1 / 158 (0.63%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Postoperative wound infection
         subjects affected / exposed
    1 / 154 (0.65%)
    0 / 155 (0.00%)
    0 / 158 (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
    Pyelonephritis
         subjects affected / exposed
    0 / 154 (0.00%)
    0 / 155 (0.00%)
    1 / 158 (0.63%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Pyelonephritis acute
         subjects affected / exposed
    1 / 154 (0.65%)
    0 / 155 (0.00%)
    0 / 158 (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
    Sepsis
         subjects affected / exposed
    1 / 154 (0.65%)
    0 / 155 (0.00%)
    0 / 158 (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
    0 / 154 (0.00%)
    2 / 155 (1.29%)
    0 / 158 (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
    Viral infection
         subjects affected / exposed
    0 / 154 (0.00%)
    0 / 155 (0.00%)
    1 / 158 (0.63%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Metabolism and nutrition disorders
    Dehydration
         subjects affected / exposed
    0 / 154 (0.00%)
    0 / 155 (0.00%)
    1 / 158 (0.63%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Hyperglycaemia
         subjects affected / exposed
    1 / 154 (0.65%)
    0 / 155 (0.00%)
    0 / 158 (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
    Hyperkalaemia
         subjects affected / exposed
    1 / 154 (0.65%)
    0 / 155 (0.00%)
    0 / 158 (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
    Hypoglycaemia
         subjects affected / exposed
    1 / 154 (0.65%)
    0 / 155 (0.00%)
    0 / 158 (0.00%)
         occurrences causally related to treatment / all
    0 / 3
    0 / 0
    0 / 0
         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
    		 Placebo Ertugliflozin 15 mg Ertugliflozin 5 mg
    Total subjects affected by non serious adverse events
         subjects affected / exposed
    68 / 154 (44.16%)
    62 / 155 (40.00%)
    82 / 158 (51.90%)
    Nervous system disorders
    Dizziness
         subjects affected / exposed
    1 / 154 (0.65%)
    2 / 155 (1.29%)
    9 / 158 (5.70%)
         occurrences all number
    1
    2
    10
    Gastrointestinal disorders
    Diarrhoea
         subjects affected / exposed
    9 / 154 (5.84%)
    4 / 155 (2.58%)
    10 / 158 (6.33%)
         occurrences all number
    9
    4
    10
    Respiratory, thoracic and mediastinal disorders
    Cough
         subjects affected / exposed
    2 / 154 (1.30%)
    3 / 155 (1.94%)
    9 / 158 (5.70%)
         occurrences all number
    2
    3
    9
    Infections and infestations
    Bronchitis
         subjects affected / exposed
    6 / 154 (3.90%)
    2 / 155 (1.29%)
    8 / 158 (5.06%)
         occurrences all number
    7
    2
    8
    Nasopharyngitis
         subjects affected / exposed
    7 / 154 (4.55%)
    6 / 155 (3.87%)
    9 / 158 (5.70%)
         occurrences all number
    8
    6
    10
    Upper respiratory tract infection
         subjects affected / exposed
    7 / 154 (4.55%)
    11 / 155 (7.10%)
    9 / 158 (5.70%)
         occurrences all number
    8
    12
    9
    Urinary tract infection
         subjects affected / exposed
    15 / 154 (9.74%)
    12 / 155 (7.74%)
    9 / 158 (5.70%)
         occurrences all number
    20
    13
    11
    Metabolism and nutrition disorders
    Hypoglycaemia
         subjects affected / exposed
    45 / 154 (29.22%)
    32 / 155 (20.65%)
    49 / 158 (31.01%)
         occurrences all number
    216
    281
    423

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    Substantial protocol amendments (globally)
    Were there any global substantial amendments to the protocol? No

    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.
    After unblinding, analysis of retained plasma samples revealed unreported metformin use by ~17% of participants. Neither dose nor frequency of the protocol-prohibited metformin use is known. This potentially confounds glycemic analyses.
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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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