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    Clinical Trial Results:
    A Phase 3, Randomized, Double-blind, Placebo-controlled, 26-week Multicenter Study with a 26-Week Extension to Evaluate the Efficacy and Safety of Ertugliflozin Monotherapy in the Treatment of Subjects with Type 2 Diabetes Mellitus and Inadequate Glycemic Control Despite Diet and Exercise

    Summary
    EudraCT number
    		 2013-002519-90
    Trial protocol
    		 GB   IT  
    Global end of trial date
    28 Jul 2016

    Results information
    Results version number
    		 v1(current)
    This version publication date
    06 Aug 2017
    First version publication date
    06 Aug 2017
    Other versions

    Trial information

    		 Close Top of page
    Trial identification
    Sponsor protocol code
    MK-8835-003
    Additional study identifiers
    ISRCTN number
    		 -
    US NCT number
    		 NCT01958671
    WHO universal trial number (UTN)
    		 -
    Other trial identifiers
    		 Pfizer protocol number: B1521022
    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 Jul 2016
    Is this the analysis of the primary completion data?
    No
    Global end of trial reached?
    Yes
    Global end of trial date
    28 Jul 2016
    Was the trial ended prematurely?
    No
    General information about the trial
    Main objective of the trial
    This trial will evaluate the efficacy and safety of ertugliflozin monotherapy in the treatment of participants with type 2 diabetes mellitus (T2DM) and inadequate glycemic control on diet and exercise. This trial consists of a run-in period of 3 to 11 weeks, a 26-week placebo-controlled treatment period (Phase A), and a 26-week active-controlled treatment period (Phase B). The primary hypotheses of the trial are that at Week 26, the mean reduction from baseline in hemoglobin A1c (A1C) for 15 mg ertugliflozin is greater than that for placebo and the mean reduction from baseline in A1C for 5 mg ertugliflozin is greater than that for placebo.
    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 subjects: participants were prescribed glycemic rescue therapy in the form of open-label metformin in Phase A or glimepiride in Phase B if they met, progressively more stringent, specific glycemic criteria.
    Background therapy
    		 -
    Evidence for comparator
    		 -
    Actual start date of recruitment
    09 Oct 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
    Canada: 128
    Country: Number of subjects enrolled
    Israel: 6
    Country: Number of subjects enrolled
    Italy: 32
    Country: Number of subjects enrolled
    Mexico: 9
    Country: Number of subjects enrolled
    South Africa: 20
    Country: Number of subjects enrolled
    United Kingdom: 86
    Country: Number of subjects enrolled
    United States: 180
    Worldwide total number of subjects
    461
    EEA total number of subjects
    118
    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)
    341
    From 65 to 84 years
    118
    85 years and over
    2

    Subject disposition

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    Recruitment
    Recruitment details
    		 -

    Pre-assignment
    Screening details
    		 Eligibility criteria included participants with T2DM and with no prior allowable oral anti-hyperglycemic agents (AHA) for at least 8 weeks prior to study participation or if on a single allowable AHA pre-study, willing to discontinue this medication at the screening visit and remain off this medication for the duration of the trial.

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

    Arms
    Are arms mutually exclusive
    Yes

    Arm title
    		 Ertugliflozin 5 mg/Ertugliflozin 5 mg
    Arm description
    		 Phase A: Ertugliflozin 5 mg administered once daily for 26 weeks. Participants requiring rescue therapy will receive open-label metformin. Phase B: Ertugliflozin 5 mg administered once daily for 26 weeks. Participants not rescued with metformin in Phase A, will receive placebo to metformin. Participants rescued with metformin in Phase A will continue to receive metformin. Participants requiring rescue therapy during Phase B will receive open-label glimepiride.
    Arm type
    		 Experimental

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

    Investigational medicinal product name
    Placebo to ertugliflozin 10 mg
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Tablet
    Routes of administration
    Oral use
    Dosage and administration details
    One placebo tablet matching the ertugliflozin 10 mg tablet daily in the morning

    Investigational medicinal product name
    Metformin 500 mg
    Investigational medicinal product code
    Other name
    Glucophage XR, Carbophage SR, Riomet, Fortamet, Glumetza, Obimet, Gluformin, Dianben, Diabex, Diaformin, Siofor and Metfogamma.
    Pharmaceutical forms
    Tablet
    Routes of administration
    Oral use
    Dosage and administration details
    1 tablet in the morning and 1 tablet in the evening for 2 weeks, 2 tablets in the morning and 1 tablet in the evening for 2 weeks and 2 tablets in the morning and 2 tablets in the evening, thereafter.

    Investigational medicinal product name
    Placebo to metformin 500 mg
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Tablet
    Routes of administration
    Oral use
    Dosage and administration details
    1 tablet in the morning and 1 tablet in the evening for 2 weeks, 2 tablets in the morning and 1 tablet in the evening for 2 weeks and 2 tablets in the morning and 2 tablets in the evening, thereafter.

    Investigational medicinal product name
    Glimepiride
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Tablet
    Routes of administration
    Oral use
    Dosage and administration details
    Dosing and titration of glimepiride as rescue therapy was determined by the investigator.

    Arm title
    		 Ertugliflozin 15 mg/Ertugliflozin 15 mg
    Arm description
    		 Phase A: Ertugliflozin 15 mg administered once daily for 26 weeks. Participants requiring rescue therapy will receive open-label metformin. Phase B: Ertugliflozin 15 mg administered once daily for 26 weeks. Participants not rescued with metformin in Phase A, will receive placebo to metformin. Participants rescued with metformin in Phase A will continue to receive metformin. Participants requiring rescue therapy during Phase B will receive open-label glimepiride.
    Arm type
    		 Experimental

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

    Investigational medicinal product name
    Ertugliflozin 10 mg
    Investigational medicinal product code
    Other name
    MK-8835, PF-04971729
    Pharmaceutical forms
    Tablet
    Routes of administration
    Oral use
    Dosage and administration details
    10 mg once daily in the morning

    Investigational medicinal product name
    Metformin 500 mg
    Investigational medicinal product code
    Other name
    Glucophage XR, Carbophage SR, Riomet, Fortamet, Glumetza, Obimet, Gluformin, Dianben, Diabex, Diaformin, Siofor and Metfogamma.
    Pharmaceutical forms
    Tablet
    Routes of administration
    Oral use
    Dosage and administration details
    1 tablet in the morning and 1 tablet in the evening for 2 weeks, 2 tablets in the morning and 1 tablet in the evening for 2 weeks and 2 tablets in the morning and 2 tablets in the evening, thereafter.

    Investigational medicinal product name
    Placebo to metformin 500 mg
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Tablet
    Routes of administration
    Oral use
    Dosage and administration details
    1 tablet in the morning and 1 tablet in the evening for 2 weeks, 2 tablets in the morning and 1 tablet in the evening for 2 weeks and 2 tablets in the morning and 2 tablets in the evening, thereafter.

    Investigational medicinal product name
    Glimepiride
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Tablet
    Routes of administration
    Oral use
    Dosage and administration details
    Dosing and titration of glimepiride as rescue therapy was determined by the investigator.

    Arm title
    		 Placebo/Metformin
    Arm description
    		 Phase A: Placebo to ertugliflozin administered once daily for 26 weeks. Participants requiring rescue therapy will receive open-label metformin. Phase B: Participants not rescued with open-label metformin in Phase A will also receive blinded metformin up to twice daily for 26 weeks in addition to placebo. Participants rescued with metformin in Phase A will continue to receive open-label metformin. Participants requiring rescue therapy during Phase B will receive open-label glimepiride.
    Arm type
    		 Placebo/Active comparator

    Investigational medicinal product name
    Placebo to ertugliflozin 5mg
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Tablet
    Routes of administration
    Oral use
    Dosage and administration details
    One placebo tablet matching the ertugliflozin 5mg tablet daily in the morning

    Investigational medicinal product name
    Placebo to ertugliflozin 10 mg
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Tablet
    Routes of administration
    Oral use
    Dosage and administration details
    One placebo tablet matching the ertugliflozin 10 mg tablet daily in the morning

    Investigational medicinal product name
    Metformin 500 mg
    Investigational medicinal product code
    Other name
    Glucophage XR, Carbophage SR, Riomet, Fortamet, Glumetza, Obimet, Gluformin, Dianben, Diabex, Diaformin, Siofor and Metfogamma.
    Pharmaceutical forms
    Tablet
    Routes of administration
    Oral use
    Dosage and administration details
    1 tablet in the morning and 1 tablet in the evening for 2 weeks, 2 tablets in the morning and 1 tablet in the evening for 2 weeks and 2 tablets in the morning and 2 tablets in the evening, thereafter.

    Investigational medicinal product name
    Glimepiride
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Tablet
    Routes of administration
    Oral use
    Dosage and administration details
    Dosing and titration of glimepiride as rescue therapy was determined by the investigator.

    Number of subjects in period 1
    		Ertugliflozin 5 mg/Ertugliflozin 5 mg Ertugliflozin 15 mg/Ertugliflozin 15 mg Placebo/Metformin
    Started
    156
    152
    153
    Completed
    137
    128
    121
    Not completed
    19
    24
    32
         Adverse event, serious fatal
    1
    -
    -
         Participant moved
    -
    -
    1
         Consent withdrawn by subject
    8
    10
    13
         Adverse event, non-fatal
    1
    1
    5
         Excluded medication
    -
    -
    1
         Pregnancy
    -
    -
    1
         Non-compliance with study drug
    1
    1
    1
         Study site terminated by sponsor
    1
    -
    1
         Lost to follow-up
    7
    11
    7
         Hyperglycemia
    -
    -
    2
         Protocol deviation
    -
    1
    -

    Baseline characteristics

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    Baseline characteristics reporting groups
    Reporting group title
    Ertugliflozin 5 mg/Ertugliflozin 5 mg
    Reporting group description
    		 Phase A: Ertugliflozin 5 mg administered once daily for 26 weeks. Participants requiring rescue therapy will receive open-label metformin. Phase B: Ertugliflozin 5 mg administered once daily for 26 weeks. Participants not rescued with metformin in Phase A, will receive placebo to metformin. Participants rescued with metformin in Phase A will continue to receive metformin. Participants requiring rescue therapy during Phase B will receive open-label glimepiride.

    Reporting group title
    Ertugliflozin 15 mg/Ertugliflozin 15 mg
    Reporting group description
    		 Phase A: Ertugliflozin 15 mg administered once daily for 26 weeks. Participants requiring rescue therapy will receive open-label metformin. Phase B: Ertugliflozin 15 mg administered once daily for 26 weeks. Participants not rescued with metformin in Phase A, will receive placebo to metformin. Participants rescued with metformin in Phase A will continue to receive metformin. Participants requiring rescue therapy during Phase B will receive open-label glimepiride.

    Reporting group title
    Placebo/Metformin
    Reporting group description
    		 Phase A: Placebo to ertugliflozin administered once daily for 26 weeks. Participants requiring rescue therapy will receive open-label metformin. Phase B: Participants not rescued with open-label metformin in Phase A will also receive blinded metformin up to twice daily for 26 weeks in addition to placebo. Participants rescued with metformin in Phase A will continue to receive open-label metformin. Participants requiring rescue therapy during Phase B will receive open-label glimepiride.

    Reporting group values
    		 Ertugliflozin 5 mg/Ertugliflozin 5 mg Ertugliflozin 15 mg/Ertugliflozin 15 mg Placebo/Metformin Total
    Number of subjects
    		 156 152 153 461
    Age categorical
    Units: Subjects
    Age Continuous
    Units: Years
        arithmetic mean (standard deviation)
    		 56.8 ± 11.4 56.2 ± 10.8 56.1 ± 10.9 -
    Gender, Male/Female
    Units: Subjects
        Female
    		 67 62 71 200
        Male
    		 89 90 82 261
    Study Specific Characteristic | Hemoglobin A1c (A1C)
    Ertugliflozin 5 mg/Ertugliflozin 5 mg, n=155 ; Ertugliflozin 15 mg/Ertugliflozin 15 mg, n= 151; Placebo/Metformin, n=153
    Units: Percent
        arithmetic mean (standard deviation)
    		 8.16 ± 0.88 8.35 ± 1.12 8.11 ± 0.92 -
    Study Specific Characteristic | Fasting plasma glucose (FPG)
    Ertugliflozin 5 mg/Ertugliflozin 5 mg, n=151 ; Ertugliflozin 15 mg/Ertugliflozin 15 mg, n= 149; Placebo/Metformin, n=150
    Units: mg/dL
        arithmetic mean (standard deviation)
    		 180.9 ± 48.5 179.1 ± 48.2 180.2 ± 45.8 -
    Study Specific Characteristic | Estimated glomerular filtration rate (eGFR)
    Units: mL/min/1.73m^2
        arithmetic mean (standard deviation)
    		 88.5 ± 18.4 88.3 ± 18 86.2 ± 19.4 -
    Study Specific Characteristic | Body weight (BW)
    Units: Kilograms
        arithmetic mean (standard deviation)
    		 94 ± 25.4 90.6 ± 18.3 94.2 ± 25.2 -
    2-hour post-prandial glucose (2-hr PPG) level
    Ertugliflozin 5 mg/Ertugliflozin 5 mg, n=145 ; Ertugliflozin 15 mg/Ertugliflozin 15 mg, n= 141; Placebo/Metformin, n=150
    Units: mg/dL
        arithmetic mean (standard deviation)
    		 260.32 ± 76.11 262.91 ± 78.189 256.21 ± 76.917 -
    Sitting systolic blood pressure (SBP)
    Ertugliflozin 5 mg/Ertugliflozin 5 mg, n=155 ; Ertugliflozin 15 mg/Ertugliflozin 15 mg, n= 152; Placebo/Metformin, n=150
    Units: mmHg
        arithmetic mean (standard deviation)
    		 130.49 ± 13.511 129.67 ± 14.208 129.8 ± 14.464 -
    Sitting diastolic blood pressure (DBP)
    Ertugliflozin 5 mg/Ertugliflozin 5 mg, n=155 ; Ertugliflozin 15 mg/Ertugliflozin 15 mg, n= 152; Placebo/Metformin, n=150
    Units: mmHg
        arithmetic mean (standard deviation)
    		 78.46 ± 8.117 78.53 ± 7.714 78.13 ± 7.458 -

    End points

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    End points reporting groups
    Reporting group title
    Ertugliflozin 5 mg/Ertugliflozin 5 mg
    Reporting group description
    		 Phase A: Ertugliflozin 5 mg administered once daily for 26 weeks. Participants requiring rescue therapy will receive open-label metformin. Phase B: Ertugliflozin 5 mg administered once daily for 26 weeks. Participants not rescued with metformin in Phase A, will receive placebo to metformin. Participants rescued with metformin in Phase A will continue to receive metformin. Participants requiring rescue therapy during Phase B will receive open-label glimepiride.

    Reporting group title
    Ertugliflozin 15 mg/Ertugliflozin 15 mg
    Reporting group description
    		 Phase A: Ertugliflozin 15 mg administered once daily for 26 weeks. Participants requiring rescue therapy will receive open-label metformin. Phase B: Ertugliflozin 15 mg administered once daily for 26 weeks. Participants not rescued with metformin in Phase A, will receive placebo to metformin. Participants rescued with metformin in Phase A will continue to receive metformin. Participants requiring rescue therapy during Phase B will receive open-label glimepiride.

    Reporting group title
    Placebo/Metformin
    Reporting group description
    		 Phase A: Placebo to ertugliflozin administered once daily for 26 weeks. Participants requiring rescue therapy will receive open-label metformin. Phase B: Participants not rescued with open-label metformin in Phase A will also receive blinded metformin up to twice daily for 26 weeks in addition to placebo. Participants rescued with metformin in Phase A will continue to receive open-label metformin. Participants requiring rescue therapy during Phase B will receive open-label glimepiride.

    Subject analysis set title
    Ertugliflozin 5 mg
    Subject analysis set type
    		 Full analysis
    Subject analysis set description
    Participants randomized to ertugliflozin 5 mg who received at least one dose of study medication and had at least one measurement of each of the following endpoints in Phase A: A1C, BW, SBP, DBP.

    Subject analysis set title
    Ertugliflozin 15 mg
    Subject analysis set type
    		 Full analysis
    Subject analysis set description
    Participants randomized to ertugliflozin 15 mg who received at least one dose of study medication and had at least one measurement of the following endpoint in Phase A: A1C.

    Subject analysis set title
    Placebo
    Subject analysis set type
    		 Full analysis
    Subject analysis set description
    Participants randomized to placebo who received at least one dose of study medication and had at least one measurement of each of the following endpoints in Phase A: A1C, FPG, BW.

    Subject analysis set title
    Ertugliflozin 5 mg
    Subject analysis set type
    		 Full analysis
    Subject analysis set description
    Participants randomized to ertugliflozin 5 mg who received at least one dose of study medication and had at least one measurement of the following endpoint in Phase A: FPG.

    Subject analysis set title
    Ertugliflozin 15 mg
    Subject analysis set type
    		 Full analysis
    Subject analysis set description
    Participants randomized to ertugliflozin 15 mg who received at least one dose of study medication and had at least one measurement of each of the following endpoints in Phase A: FPG, BW, SBP, DBP.

    Subject analysis set title
    Ertugliflozin 5 mg
    Subject analysis set type
    		 Full analysis
    Subject analysis set description
    Participants randomized to ertugliflozin 5 mg who received at least one dose of study medication and had at least one measurement of the following endpoint in Phase A: 2-hr PPG.

    Subject analysis set title
    Ertugliflozin 15 mg
    Subject analysis set type
    		 Full analysis
    Subject analysis set description
    Participants randomized to ertugliflozin 15 mg who received at least one dose of study medication and had at least one measurement of the following endpoint in Phase A: 2-hr PPG

    Subject analysis set title
    Placebo
    Subject analysis set type
    		 Full analysis
    Subject analysis set description
    Participants randomized to placebo who received at least one dose of study medication and had at least one measurement of the following endpoint in Phase A: 2-hr PPG.

    Subject analysis set title
    Placebo
    Subject analysis set type
    		 Full analysis
    Subject analysis set description
    Participants randomized to placebo who received at least one dose of study medication and had at least one measurement of each of the following endpoints in Phase A: SBP, DBP.

    Primary: Change from Baseline In A1C at Week 26

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    End point title
    		 Change from Baseline In A1C at Week 26
    End point description
    A1C is measured as percent. The change from baseline is the Week 26 A1C percent minus the Week 0 A1C percent. Data presented exclude data following the initiation of rescue therapy. Analysis population consisted of all randomized participants who received at least 1 dose of study treatment and had a baseline A1C measurement or at least 1 post-randomization A1C measurement subsequent to at least 1 dose of study treatment.
    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
    156
    151
    153
    Units: Percent
        least squares mean (confidence interval 95%)
    -0.79 (-0.95 to -0.63)
    -0.96 (-1.12 to -0.8)
    0.2 (0.02 to 0.37)
    Statistical analysis title
    		 Between group comparison
    Comparison groups
    Ertugliflozin 5 mg v Placebo
    Number of subjects included in analysis
    309
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 < 0.001 [1]
    Method
    		 Constrained longitudinal data analysis
    Parameter type
    		 Difference in least squares means
    Point estimate
    -0.99
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -1.22
         upper limit
    		 -0.76
    Notes
    [1] - Fixed effects for treatment, time, prior antihyperglycemic medication, baseline eGFR and the interaction of time by treatment.
    Statistical analysis title
    		 Between group comparison
    Comparison groups
    Ertugliflozin 15 mg v Placebo
    Number of subjects included in analysis
    304
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 < 0.001 [2]
    Method
    		 Constrained longitudinal data analysis
    Parameter type
    		 Difference in least squares means
    Point estimate
    -1.16
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -1.39
         upper limit
    		 -0.93
    Notes
    [2] - Fixed effects for treatment, time, prior antihyperglycemic medication, baseline eGFR and the interaction of time by treatment.

    Primary: Percentage of Participants Experiencing An Adverse Event (AE)

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    End point title
    		 Percentage of Participants Experiencing An Adverse Event (AE)
    End point description
    An AE is defined as any untoward medical occurrence in a patient or clinical investigation participant administered a pharmaceutical product and which does not necessarily have to have a causal relationship with this treatment. Data presented include data following the initiation of rescue therapy. Analysis population consisted of all randomized participants who received at least 1 dose of study treatment. Participants were classified according to randomized treatment.
    End point type
    Primary
    End point timeframe
    Up to 54 weeks (including 2 weeks following last dose)
    End point values
    		 Ertugliflozin 5 mg/Ertugliflozin 5 mg Ertugliflozin 15 mg/Ertugliflozin 15 mg Placebo/Metformin
    Number of subjects analysed
    156
    152
    153
    Units: Percentage of participants
        number (not applicable)
    64.1
    62.5
    66.7
    Statistical analysis title
    		 Between group comparison
    Statistical analysis description
    Difference in percentage based on Miettinen & Nurminen method
    Comparison groups
    Ertugliflozin 5 mg/Ertugliflozin 5 mg v Placebo/Metformin
    Number of subjects included in analysis
    309
    Analysis specification
    Pre-specified
    Analysis type
    		 other
    Method
    Parameter type
    		 Difference in percentage
    Point estimate
    -2.6
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -13.1
         upper limit
    		 8.1
    Statistical analysis title
    		 Between group comparison
    Statistical analysis description
    Difference in percentage based on Miettinen & Nurminen method
    Comparison groups
    Ertugliflozin 15 mg/Ertugliflozin 15 mg v Placebo/Metformin
    Number of subjects included in analysis
    305
    Analysis specification
    Pre-specified
    Analysis type
    		 other
    Method
    Parameter type
    		 Difference in percentage
    Point estimate
    -4.2
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -14.8
         upper limit
    		 6.6

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

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    End point title
    		 Percentage of Participants Discontinuing Study Treatment Due to an AE
    End point description
    An AE is defined as any untoward medical occurrence in a patient or clinical investigation participant administered a pharmaceutical product and which does not necessarily have to have a causal relationship with this treatment. Data presented include data following the initiation of rescue therapy. Analysis population consisted of all randomized participants who received at least 1 dose of study treatment. Participants were classified according to randomized treatment.
    End point type
    Primary
    End point timeframe
    Up to 52 weeks
    End point values
    		 Ertugliflozin 5 mg/Ertugliflozin 5 mg Ertugliflozin 15 mg/Ertugliflozin 15 mg Placebo/Metformin
    Number of subjects analysed
    156
    152
    153
    Units: Percentage of participants
        number (not applicable)
    4.5
    3.9
    6.5
    Statistical analysis title
    		 Between group comparison
    Statistical analysis description
    Difference in percentage based on Miettinen & Nurminen method
    Comparison groups
    Ertugliflozin 5 mg/Ertugliflozin 5 mg v Placebo/Metformin
    Number of subjects included in analysis
    309
    Analysis specification
    Pre-specified
    Analysis type
    		 other
    Method
    Parameter type
    		 Difference in percentage
    Point estimate
    -2
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -7.7
         upper limit
    		 3.3
    Statistical analysis title
    		 Between group comparison
    Statistical analysis description
    Difference in percentage based on Miettinen & Nurminen method
    Comparison groups
    Ertugliflozin 15 mg/Ertugliflozin 15 mg v Placebo/Metformin
    Number of subjects included in analysis
    305
    Analysis specification
    Pre-specified
    Analysis type
    		 other
    Method
    Parameter type
    		 Difference in percentage
    Point estimate
    -2.6
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -8.2
         upper limit
    		 2.7

    Secondary: Change from Baseline in FPG at Week 26

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    End point title
    		 Change from Baseline in FPG at Week 26
    End point description
    The change from baseline is the Week 26 FPG minus the Week 0 FPG. Laboratory measurements were performed after an overnight fast ≥10 hours in duration. Data presented exclude data following the initiation of glycemic rescue therapy. Analysis population consisted of all randomized participants who received at least 1 dose of study treatment and had a baseline FPG measurement or at least 1 post-randomization FPG measurement subsequent to at least 1 dose of study treatment.
    End point type
    Secondary
    End point timeframe
    Baseline and Week 26
    End point values
    		 Placebo Ertugliflozin 5 mg Ertugliflozin 15 mg
    Number of subjects analysed
    153
    155
    152
    Units: mg/dL
        least squares mean (confidence interval 95%)
    0.57 (-6.02 to 7.16)
    -33.96 (-39.85 to -28.06)
    -43.44 (-49.39 to -37.49)
    Statistical analysis title
    		 Between group comparison
    Comparison groups
    Ertugliflozin 5 mg v Placebo
    Number of subjects included in analysis
    308
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 < 0.001 [3]
    Method
    		 Constrained longitudinal data analysis
    Parameter type
    		 Difference in least squares means
    Point estimate
    -34.53
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -42.76
         upper limit
    		 -26.29
    Notes
    [3] - Fixed effects for treatment, time, prior antihyperglycemic medication, baseline eGFR and the interaction of time by treatment.
    Statistical analysis title
    		 Between group comparison
    Comparison groups
    Ertugliflozin 15 mg v Placebo
    Number of subjects included in analysis
    305
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 < 0.001 [4]
    Method
    		 Constrained longitudinal data analysis
    Parameter type
    		 Difference in least squares means
    Point estimate
    -44.01
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -52.28
         upper limit
    		 -35.74
    Notes
    [4] - Fixed effects for treatment, time, prior antihyperglycemic medication, baseline eGFR and the interaction of time by treatment.

    Secondary: Change from Baseline in Body Weight at Week 26

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    End point title
    		 Change from Baseline in Body Weight at Week 26
    End point description
    The change from baseline is the Week 26 body weight minus the Week 0 body weight. Data presented exclude data following the initiation of rescue therapy. Analysis population consisted of all randomized participants who received at least 1 dose of study treatment and had a baseline body weight measurement or at least 1 post-randomization body weight measurement subsequent to at least 1 dose of study treatment.
    End point type
    Secondary
    End point timeframe
    Baseline and Week 26
    End point values
    		 Ertugliflozin 5 mg Placebo Ertugliflozin 15 mg
    Number of subjects analysed
    156
    153
    152
    Units: Kilograms
        least squares mean (confidence interval 95%)
    -3.18 (-3.72 to -2.63)
    -1.42 (-2.02 to -0.81)
    -3.58 (-4.13 to -3.02)
    Statistical analysis title
    		 Between group comparison
    Comparison groups
    Ertugliflozin 5 mg v Placebo
    Number of subjects included in analysis
    309
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 < 0.001 [5]
    Method
    		 Constrained longitudinal data analysis
    Parameter type
    		 Difference in least squares means
    Point estimate
    -1.76
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -2.57
         upper limit
    		 -0.95
    Notes
    [5] - Fixed effects for treatment, time, prior antihyperglycemic medication, baseline eGFR and the interaction of time by treatment.
    Statistical analysis title
    		 Between group comparison
    Comparison groups
    Ertugliflozin 15 mg v Placebo
    Number of subjects included in analysis
    305
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 < 0.001 [6]
    Method
    		 Constrained longitudinal data analysis
    Parameter type
    		 Difference in least squares means
    Point estimate
    -2.16
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -2.98
         upper limit
    		 -1.34
    Notes
    [6] - Fixed effects for treatment, time, prior antihyperglycemic medication, baseline eGFR and the interaction of time by treatment.

    Secondary: Percentage of Participants with A1C <7% (<53 mmol/mol) at Week 26

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    End point title
    		 Percentage of Participants with A1C <7% (<53 mmol/mol) at Week 26
    End point description
    A1C is measured as percent. Data presented exclude data following the initiation of rescue therapy. Analysis population consisted of all randomized participants who received at least 1 dose of study treatment and had a baseline A1C measurement or at least 1 post-randomization A1C measurement subsequent to at least 1 dose of study treatment.
    End point type
    Secondary
    End point timeframe
    Week 26
    End point values
    		 Ertugliflozin 5 mg Ertugliflozin 15 mg Placebo
    Number of subjects analysed
    156
    151
    153
    Units: Percentage of participants
        number (not applicable)
    28.2
    35.8
    13.1
    Statistical analysis title
    		 Between group comparison
    Comparison groups
    Ertugliflozin 5 mg v Placebo
    Number of subjects included in analysis
    309
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 < 0.001 [7]
    Method
    		 Regression, Logistic
    Parameter type
    		 Odds ratio (OR)
    Point estimate
    3.59
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 1.85
         upper limit
    		 6.95
    Notes
    [7] - Fixed effects for treatment, prior antihyperglycemic medication, covariates for baseline A1C and baseline eGFR.
    Statistical analysis title
    		 Between group comparison
    Comparison groups
    Ertugliflozin 15 mg v Placebo
    Number of subjects included in analysis
    304
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 < 0.001 [8]
    Method
    		 Regression, Logistic
    Parameter type
    		 Odds ratio (OR)
    Point estimate
    6.77
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 3.46
         upper limit
    		 13.24
    Notes
    [8] - Fixed effects for treatment, prior antihyperglycemic medication, covariates for baseline A1C and baseline eGFR.

    Secondary: Change from Baseline in 2-hr PPG at Week 26

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    End point title
    		 Change from Baseline in 2-hr PPG at Week 26
    End point description
    The change from baseline is the Week 26 2-hr PPG minus the Week 0 2-hr PPG. Laboratory measurements were performed 120 minutes following the start of the administration of the meal for the Mixed Meal Tolerance Test (MMTT). Data presented exclude data following the initiation of rescue therapy. Analysis population consisted of all randomized participants who received at least 1 dose of study treatment and had a baseline 2-hr PPG measurement or at least 1 post-randomization 2-hr PPG measurement subsequent to at least 1 dose of study treatment.
    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
    153
    148
    151
    Units: mg/dL
        least squares mean (confidence interval 95%)
    -64.15 (-74.34 to -53.96)
    -62.45 (-72.91 to -51.98)
    4.88 (-6.15 to 15.92)
    Statistical analysis title
    		 Between group comparison
    Comparison groups
    Ertugliflozin 5 mg v Placebo
    Number of subjects included in analysis
    304
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 < 0.001 [9]
    Method
    		 Constrained longitudinal data analysis
    Parameter type
    		 Difference in least squares means
    Point estimate
    -69.03
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -83.24
         upper limit
    		 -54.83
    Notes
    [9] - Fixed effects for treatment, time, prior antihyperglycemic medication, baseline eGFR and the interaction of time by treatment.
    Statistical analysis title
    		 Between group comparison
    Comparison groups
    Ertugliflozin 15 mg v Placebo
    Number of subjects included in analysis
    299
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 < 0.001 [10]
    Method
    		 Constrained longitudinal data analysis
    Parameter type
    		 Difference in least squares means
    Point estimate
    -67.33
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -81.73
         upper limit
    		 -52.93
    Notes
    [10] - Fixed effects for treatment, time, prior antihyperglycemic medication, baseline eGFR and the interaction of time by treatment.

    Secondary: Change from Baseline in SBP at Week 26

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    End point title
    		 Change from Baseline in SBP at Week 26
    End point description
    The change from baseline is the Week 26 SBP minus the Week 0 SBP. Sitting blood pressure was measured in triplicate and the average of the measurements taken at a single assessment time was analyzed. Data presented exclude data following the initiation of rescue therapy. Analysis population consisted of all randomized participants who received at least 1 dose of study treatment and had a baseline SBP measurement or at least 1 post-randomization SBP measurement subsequent to at least 1 dose of study treatment.
    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
    156
    152
    152
    Units: mmHg
        least squares mean (confidence interval 95%)
    -5.54 (-7.32 to -3.76)
    -3.93 (-5.74 to -2.12)
    -2.22 (-4.3 to -0.14)
    Statistical analysis title
    		 Between group comparison
    Comparison groups
    Ertugliflozin 5 mg v Placebo
    Number of subjects included in analysis
    308
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.015 [11]
    Method
    		 Constrained longitudinal data analysis
    Parameter type
    		 Difference in least squares means
    Point estimate
    -3.31
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -5.98
         upper limit
    		 -0.65
    Notes
    [11] - Nominal p- value. Fixed effects for treatment, time, prior antihyperglycemic medication, baseline eGFR and the interaction of time by treatment.
    Statistical analysis title
    		 Between group comparison
    Comparison groups
    Ertugliflozin 15 mg v Placebo
    Number of subjects included in analysis
    304
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.213 [12]
    Method
    		 Constrained longitudinal data analysis
    Parameter type
    		 Difference in least squares means
    Point estimate
    -1.71
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -4.4
         upper limit
    		 0.98
    Notes
    [12] - Fixed effects for treatment, time, prior antihyperglycemic medication, baseline eGFR and the interaction of time by treatment.

    Secondary: Change from Baseline in DBP at Week 26

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    End point title
    		 Change from Baseline in DBP at Week 26
    End point description
    The change from baseline is the Week 26 DBP minus the Week 0 DBP. Sitting blood pressure was measured in triplicate and the average of the measurements taken at a single assessment time was analyzed. Data presented exclude data following the initiation of rescue therapy. Analysis population consisted of all randomized participants who received at least 1 dose of study treatment and had a baseline DBP measurement or at least 1 post-randomization DBP measurement subsequent to at least 1 dose of study treatment.
    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
    156
    152
    152
    Units: mmHg
        least squares mean (confidence interval 95%)
    -2.52 (-3.65 to -1.4)
    -1.1 (-2.24 to 0.05)
    -0.72 (-2.05 to 0.6)
    Statistical analysis title
    		 Between group comparison
    Comparison groups
    Ertugliflozin 5 mg v Placebo
    Number of subjects included in analysis
    308
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.039 [13]
    Method
    		 Constrained longitudinal data analysis
    Parameter type
    		 Difference in least squares means
    Point estimate
    -1.8
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -3.51
         upper limit
    		 -0.09
    Notes
    [13] - Nominal p- value. Fixed effects for treatment, time, prior antihyperglycemic medication, baseline eGFR and the interaction of time by treatment.
    Statistical analysis title
    		 Between group comparison
    Comparison groups
    Ertugliflozin 15 mg v Placebo
    Number of subjects included in analysis
    304
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.669 [14]
    Method
    		 Constrained longitudinal data analysis
    Parameter type
    		 Difference in least squares means
    Point estimate
    -0.37
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -2.09
         upper limit
    		 1.35
    Notes
    [14] - Nominal p- value. Fixed effects for treatment, time, prior antihyperglycemic medication, baseline eGFR and the interaction of time by treatment.

    Adverse events

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    Adverse events information
    Timeframe for reporting adverse events
    Up to 54 weeks (+/- 3 days)
    Adverse event reporting additional description
    Data presented below include data following the initiation of rescue therapy for the entire study (ie, all data after randomization, with no upper limit on the follow-up window for participants who discontinued study drug).
    Assessment type
    		 Systematic
    Dictionary used for adverse event reporting
    Dictionary name
    		 MedDRA
    Dictionary version
    19.0
    Reporting groups
    Reporting group title
    Ertugliflozin 5 mg/Ertugliflozin 5 mg
    Reporting group description
    		 Phase A: Ertugliflozin 5 mg administered once daily for 26 weeks. Participants requiring rescue therapy will receive open-label metformin. Phase B: Ertugliflozin 5 mg administered once daily for 26 weeks. Participants not rescued with metformin in Phase A, will receive placebo to metformin. Participants rescued with metformin in Phase A will continue to receive open-label metformin. Participants requiring rescue therapy during Phase B will receive open-label glimepiride.

    Reporting group title
    Placebo/Metformin
    Reporting group description
    		 Phase A: Placebo to ertugliflozin administered once daily for 26 weeks. Participants requiring rescue therapy will receive open-label metformin. Phase B: Participants not rescued with open-label metformin in Phase A will also receive blinded metformin up to twice daily for 26 weeks in addition to placebo. Participants rescued with metformin in Phase A will continue to receive open-label metformin. Participants requiring rescue therapy during Phase B will receive open-label glimepiride.

    Reporting group title
    Ertugliflozin 15 mg/Ertugliflozin 15 mg
    Reporting group description
    		 Phase A: Ertugliflozin 15 mg administered once daily for 26 weeks. Participants requiring rescue therapy will receive open-label metformin. Phase B: Ertugliflozin 15 mg administered once daily for 26 weeks. Participants not rescued with metformin in Phase A, will receive placebo to metformin. Participants rescued with metformin in Phase A will continue to receive open-label metformin. Participants requiring rescue therapy during Phase B will receive open-label glimepiride.

    Serious adverse events
    		 Ertugliflozin 5 mg/Ertugliflozin 5 mg Placebo/Metformin Ertugliflozin 15 mg/Ertugliflozin 15 mg
    Total subjects affected by serious adverse events
         subjects affected / exposed
    11 / 156 (7.05%)
    8 / 153 (5.23%)
    6 / 152 (3.95%)
         number of deaths (all causes)
    1
    0
    0
         number of deaths resulting from adverse events
    0
    0
    0
    Neoplasms benign, malignant and unspecified (incl cysts and polyps)
    Breast cancer
         subjects affected / exposed
    1 / 156 (0.64%)
    1 / 153 (0.65%)
    0 / 152 (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
    Hepatic cancer metastatic
         subjects affected / exposed
    0 / 156 (0.00%)
    0 / 153 (0.00%)
    1 / 152 (0.66%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Squamous cell carcinoma of lung
         subjects affected / exposed
    0 / 156 (0.00%)
    0 / 153 (0.00%)
    1 / 152 (0.66%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Squamous cell carcinoma of the cervix
         subjects affected / exposed
    0 / 156 (0.00%)
    0 / 153 (0.00%)
    1 / 152 (0.66%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Vascular disorders
    Deep vein thrombosis
         subjects affected / exposed
    0 / 156 (0.00%)
    1 / 153 (0.65%)
    0 / 152 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Hypertension
         subjects affected / exposed
    1 / 156 (0.64%)
    0 / 153 (0.00%)
    0 / 152 (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
    Pregnancy, puerperium and perinatal conditions
    Abortion spontaneous
         subjects affected / exposed
    0 / 156 (0.00%)
    1 / 153 (0.65%)
    0 / 152 (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
    Respiratory, thoracic and mediastinal disorders
    Acute respiratory failure
         subjects affected / exposed
    1 / 156 (0.64%)
    0 / 153 (0.00%)
    0 / 152 (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
    Epistaxis
         subjects affected / exposed
    0 / 156 (0.00%)
    0 / 153 (0.00%)
    1 / 152 (0.66%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Haemoptysis
         subjects affected / exposed
    0 / 156 (0.00%)
    0 / 153 (0.00%)
    1 / 152 (0.66%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Pneumothorax
         subjects affected / exposed
    0 / 156 (0.00%)
    0 / 153 (0.00%)
    1 / 152 (0.66%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Pulmonary embolism
         subjects affected / exposed
    0 / 156 (0.00%)
    1 / 153 (0.65%)
    0 / 152 (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
    Psychiatric disorders
    Bipolar disorder
         subjects affected / exposed
    1 / 156 (0.64%)
    0 / 153 (0.00%)
    0 / 152 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Injury, poisoning and procedural complications
    Joint injury
         subjects affected / exposed
    0 / 156 (0.00%)
    1 / 153 (0.65%)
    0 / 152 (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
    Cerebrovascular accident
         subjects affected / exposed
    1 / 156 (0.64%)
    0 / 153 (0.00%)
    0 / 152 (0.00%)
         occurrences causally related to treatment / all
    1 / 2
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Ruptured cerebral aneurysm
         subjects affected / exposed
    1 / 156 (0.64%)
    0 / 153 (0.00%)
    0 / 152 (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
    Eye disorders
    Papilloedema
         subjects affected / exposed
    0 / 156 (0.00%)
    1 / 153 (0.65%)
    0 / 152 (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
    Retinal artery occlusion
         subjects affected / exposed
    1 / 156 (0.64%)
    0 / 153 (0.00%)
    0 / 152 (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
    Ulcerative keratitis
         subjects affected / exposed
    0 / 156 (0.00%)
    1 / 153 (0.65%)
    0 / 152 (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
    Blindness transient
         subjects affected / exposed
    1 / 156 (0.64%)
    0 / 153 (0.00%)
    0 / 152 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Gastrointestinal disorders
    Pancreatitis
         subjects affected / exposed
    0 / 156 (0.00%)
    1 / 153 (0.65%)
    0 / 152 (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
    Hepatobiliary disorders
    Cholecystitis acute
         subjects affected / exposed
    1 / 156 (0.64%)
    0 / 153 (0.00%)
    0 / 152 (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
    0 / 156 (0.00%)
    0 / 153 (0.00%)
    1 / 152 (0.66%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Osteoarthritis
         subjects affected / exposed
    1 / 156 (0.64%)
    0 / 153 (0.00%)
    0 / 152 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Infections and infestations
    Bacterial infection
         subjects affected / exposed
    0 / 156 (0.00%)
    1 / 153 (0.65%)
    0 / 152 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Cellulitis of male external genital organ
         subjects affected / exposed
    1 / 156 (0.64%)
    0 / 153 (0.00%)
    0 / 152 (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
    Labyrinthitis
         subjects affected / exposed
    0 / 156 (0.00%)
    0 / 153 (0.00%)
    1 / 152 (0.66%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Periorbital abscess
         subjects affected / exposed
    0 / 156 (0.00%)
    0 / 153 (0.00%)
    1 / 152 (0.66%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Periorbital cellulitis
         subjects affected / exposed
    0 / 156 (0.00%)
    0 / 153 (0.00%)
    1 / 152 (0.66%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Pneumonia
         subjects affected / exposed
    1 / 156 (0.64%)
    0 / 153 (0.00%)
    0 / 152 (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 / 156 (0.64%)
    0 / 153 (0.00%)
    0 / 152 (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
    Metabolism and nutrition disorders
    Diabetes mellitus inadequate control
         subjects affected / exposed
    1 / 156 (0.64%)
    0 / 153 (0.00%)
    0 / 152 (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
    Hyperglycaemia
         subjects affected / exposed
    0 / 156 (0.00%)
    1 / 153 (0.65%)
    0 / 152 (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
    Frequency threshold for reporting non-serious adverse events: 5%
    Non-serious adverse events
    		 Ertugliflozin 5 mg/Ertugliflozin 5 mg Placebo/Metformin Ertugliflozin 15 mg/Ertugliflozin 15 mg
    Total subjects affected by non serious adverse events
         subjects affected / exposed
    50 / 156 (32.05%)
    68 / 153 (44.44%)
    48 / 152 (31.58%)
    Nervous system disorders
    Headache
         subjects affected / exposed
    6 / 156 (3.85%)
    9 / 153 (5.88%)
    7 / 152 (4.61%)
         occurrences all number
    10
    9
    9
    Gastrointestinal disorders
    Constipation
         subjects affected / exposed
    11 / 156 (7.05%)
    4 / 153 (2.61%)
    2 / 152 (1.32%)
         occurrences all number
    11
    4
    2
    Diarrhoea
         subjects affected / exposed
    8 / 156 (5.13%)
    23 / 153 (15.03%)
    5 / 152 (3.29%)
         occurrences all number
    10
    26
    5
    Nausea
         subjects affected / exposed
    4 / 156 (2.56%)
    12 / 153 (7.84%)
    3 / 152 (1.97%)
         occurrences all number
    4
    14
    4
    Infections and infestations
    Bronchitis
         subjects affected / exposed
    5 / 156 (3.21%)
    8 / 153 (5.23%)
    1 / 152 (0.66%)
         occurrences all number
    5
    9
    1
    Nasopharyngitis
         subjects affected / exposed
    8 / 156 (5.13%)
    6 / 153 (3.92%)
    11 / 152 (7.24%)
         occurrences all number
    8
    7
    12
    Upper respiratory tract infection
         subjects affected / exposed
    9 / 156 (5.77%)
    9 / 153 (5.88%)
    10 / 152 (6.58%)
         occurrences all number
    10
    15
    11
    Urinary tract infection
         subjects affected / exposed
    13 / 156 (8.33%)
    19 / 153 (12.42%)
    10 / 152 (6.58%)
         occurrences all number
    15
    30
    14
    Vulvovaginal mycotic infection
         subjects affected / exposed
    12 / 156 (7.69%)
    2 / 153 (1.31%)
    8 / 152 (5.26%)
         occurrences all number
    17
    2
    11
    Metabolism and nutrition disorders
    Hypoglycaemia
         subjects affected / exposed
    2 / 156 (1.28%)
    10 / 153 (6.54%)
    6 / 152 (3.95%)
         occurrences all number
    4
    23
    14

    More information

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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.
    None reported

    Online references
    http://www.ncbi.nlm.nih.gov/pubmed/28116776
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