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    Clinical Trial Results:
    A Phase III, Randomized, Double-Blind, Placebo-Controlled, Parallel-Group, Multicenter Clinical Trial to Evaluate the Efficacy and Safety of the Initial Combination of Ertugliflozin (MK-8835/PF-04971729) with Sitagliptin in the Treatment of Subjects with T2DM with Inadequate Glycemic Control on Diet and Exercise

    Summary
    EudraCT number
    		 2014-001049-25
    Trial protocol
    		 HU   GB   CZ   EE   BG   HR  
    Global end of trial date
    23 Feb 2016

    Results information
    Results version number
    		 v1(current)
    This version publication date
    07 Jan 2017
    First version publication date
    07 Jan 2017
    Other versions

    Trial information

    		 Close Top of page
    Trial identification
    Sponsor protocol code
    MK-8835-017
    Additional study identifiers
    ISRCTN number
    		 -
    US NCT number
    		 NCT02226003
    WHO universal trial number (UTN)
    		 -
    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
    23 Feb 2016
    Is this the analysis of the primary completion data?
    Yes
    Primary completion date
    23 Feb 2016
    Global end of trial reached?
    Yes
    Global end of trial date
    23 Feb 2016
    Was the trial ended prematurely?
    No
    General information about the trial
    Main objective of the trial
    This is a study to evaluate the efficacy and safety of the ertugliflozin (MK8835/PF04971729) in combination with sitagliptin in the treatment of participants with Type 2 diabetes mellitus (T2DM) with inadequate glycemic control on diet and exercise. The primary hypothesis of the study is that ertugliflozin plus sitagliptin is more effective in lowering of hemoglobin A1C (HbA1C) than 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: Open-label glimepiride rescue therapy was initiated at 1 or 2 mg/day and may be titrated to the maximum labeled dose or maximum tolerated dose (if lower than labeled dose), as considered appropriate by the investigator, based on blood glucose measurements and in accordance with the local, approved label.
    Background therapy
    		 -
    Evidence for comparator
    		 -
    Actual start date of recruitment
    23 Sep 2014
    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
    Bulgaria: 8
    Country: Number of subjects enrolled
    Croatia: 20
    Country: Number of subjects enrolled
    Czech Republic: 29
    Country: Number of subjects enrolled
    Estonia: 14
    Country: Number of subjects enrolled
    Hungary: 9
    Country: Number of subjects enrolled
    Serbia: 16
    Country: Number of subjects enrolled
    United Kingdom: 15
    Country: Number of subjects enrolled
    United States: 143
    Country: Number of subjects enrolled
    Ukraine: 37
    Worldwide total number of subjects
    291
    EEA total number of subjects
    95
    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)
    233
    From 65 to 84 years
    58
    85 years and over
    0

    Subject disposition

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    Recruitment
    Recruitment details
    		 Participants were randomized at 66 clinical trial sites in 9 countries. This trial included an 8-week (or greater) antihyperglycemic agent (AHA) wash-off period and a 2-week single-blind placebo run-in period.

    Pre-assignment
    Screening details
    		 Male and female participants with Type 2 diabetes mellitus of at least 18 years of age were enrolled in this 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 + Sitagliptin 100 mg
    Arm description
    		 Ertugliflozin, 5 mg, administered orally, once daily for 26 weeks. Sitagliptin, 100 mg, administered orally, once daily for 26 weeks. Placebo to ertugliflozin, 10 mg, administered orally, once daily for 26 weeks.
    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
    Ertugliflozin, 5 mg, administered orally, once daily for 26 weeks.

    Investigational medicinal product name
    Sitagliptin
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Tablet
    Routes of administration
    Oral use
    Dosage and administration details
    Sitagliptin, 100 mg, administered orally, once daily for 26 weeks.

    Investigational medicinal product name
    Glimepiride
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Tablet
    Routes of administration
    Oral use
    Dosage and administration details
    Open-label glimepiride as a rescue medication, daily, dose determined per the investigator's discretion and according to the local approved label.

    Investigational medicinal product name
    Placebo to 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
    Placebo to ertugliflozin, 10 mg, administered orally, once daily for 26 weeks.

    Arm title
    		 Ertugliflozin 15 mg + Sitagliptin 100 mg
    Arm description
    		 Ertugliflozin, 15 mg, administered orally, once daily for 26 weeks. Sitagliptin, 100 mg, administered orally, once daily for 26 weeks.
    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
    Ertugliflozin, 5 mg, administered orally, once daily for 26 weeks.

    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
    Ertugliflozin, 10 mg, administered orally, once daily for 26 weeks.

    Investigational medicinal product name
    Sitagliptin
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Tablet
    Routes of administration
    Oral use
    Dosage and administration details
    Sitagliptin, 100 mg, administered orally, once daily for 26 weeks.

    Investigational medicinal product name
    Glimepiride
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Tablet
    Routes of administration
    Oral use
    Dosage and administration details
    Open-label glimepiride as a rescue medication, daily, dose determined per the investigator's discretion and according to the local approved label.

    Arm title
    		 Placebo
    Arm description
    		 Placebo to ertugliflozin, 5 mg and 10 mg, administered orally, once daily for 26 weeks. Placebo to sitagliptin, 100 mg, administered orally, once daily for 26 weeks.
    Arm type
    		 Placebo

    Investigational medicinal product name
    Placebo to ertugliflozin 5 mg
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Tablet
    Routes of administration
    Oral use
    Dosage and administration details
    Placebo to ertugliflozin, 5 mg, once daily for 26 weeks

    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
    Placebo to ertugliflozin, 10 mg, once daily for 26 weeks

    Investigational medicinal product name
    Placebo to sitagliptin 100 mg
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Tablet
    Routes of administration
    Oral use
    Dosage and administration details
    Placebo to sitagliptin, 100 mg, once daily for 26 weeks

    Investigational medicinal product name
    Glimepiride
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Tablet
    Routes of administration
    Oral use
    Dosage and administration details
    Open-label glimepiride as a rescue medication, daily, dose determined per the investigator's discretion and according to the local approved label.

    Number of subjects in period 1
    		Ertugliflozin 5 mg + Sitagliptin 100 mg Ertugliflozin 15 mg + Sitagliptin 100 mg Placebo
    Started
    98
    96
    97
    Completed
    96
    95
    91
    Not completed
    2
    1
    6
         Consent withdrawn by subject
    -
    -
    3
         Lost to follow-up
    2
    1
    3

    Baseline characteristics

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    Baseline characteristics reporting groups
    Reporting group title
    Ertugliflozin 5 mg + Sitagliptin 100 mg
    Reporting group description
    		 Ertugliflozin, 5 mg, administered orally, once daily for 26 weeks. Sitagliptin, 100 mg, administered orally, once daily for 26 weeks. Placebo to ertugliflozin, 10 mg, administered orally, once daily for 26 weeks.

    Reporting group title
    Ertugliflozin 15 mg + Sitagliptin 100 mg
    Reporting group description
    		 Ertugliflozin, 15 mg, administered orally, once daily for 26 weeks. Sitagliptin, 100 mg, administered orally, once daily for 26 weeks.

    Reporting group title
    Placebo
    Reporting group description
    		 Placebo to ertugliflozin, 5 mg and 10 mg, administered orally, once daily for 26 weeks. Placebo to sitagliptin, 100 mg, administered orally, once daily for 26 weeks.

    Reporting group values
    		 Ertugliflozin 5 mg + Sitagliptin 100 mg Ertugliflozin 15 mg + Sitagliptin 100 mg Placebo Total
    Number of subjects
    		 98 96 97 291
    Age Categorical
    Units: Subjects
        Adults (18-64 years)
    		 75 75 83 233
        From 65-84 years
    		 23 21 14 58
    Age Continuous
    Units: years
        arithmetic mean (standard deviation)
    		 56.4 ± 9.3 56.1 ± 10.1 54.3 ± 10.3 -
    Gender Categorical
    Units: Subjects
        Female
    		 41 43 40 124
        Male
    		 57 53 57 167

    End points

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    End points reporting groups
    Reporting group title
    Ertugliflozin 5 mg + Sitagliptin 100 mg
    Reporting group description
    		 Ertugliflozin, 5 mg, administered orally, once daily for 26 weeks. Sitagliptin, 100 mg, administered orally, once daily for 26 weeks. Placebo to ertugliflozin, 10 mg, administered orally, once daily for 26 weeks.

    Reporting group title
    Ertugliflozin 15 mg + Sitagliptin 100 mg
    Reporting group description
    		 Ertugliflozin, 15 mg, administered orally, once daily for 26 weeks. Sitagliptin, 100 mg, administered orally, once daily for 26 weeks.

    Reporting group title
    Placebo
    Reporting group description
    		 Placebo to ertugliflozin, 5 mg and 10 mg, administered orally, once daily for 26 weeks. Placebo to sitagliptin, 100 mg, administered orally, once daily for 26 weeks.

    Primary: Change from Baseline in HbA1C at Week 26 - Full Analysis Set Excluding Rescue Approach

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    End point title
    		 Change from Baseline in HbA1C at Week 26 - Full Analysis Set Excluding Rescue Approach
    End point description
    HbA1C is blood marker used to report average blood glucose levels over prolonged periods of time and is reported as a percentage (%). HbA1c represents the percentage of glycated hemoglobin. A negative number indicates a reduction in HbA1c level. FAS population includes randomized participants who took at least 1 dose of study medication and had at least one assessment at or after baseline.
    End point type
    Primary
    End point timeframe
    Baseline and Week 26
    End point values
    		 Ertugliflozin 5 mg + Sitagliptin 100 mg Ertugliflozin 15 mg + Sitagliptin 100 mg Placebo
    Number of subjects analysed
    98
    96
    96
    Units: Percentage
        least squares mean (confidence interval 95%)
    -1.6 (-1.82 to -1.39)
    -1.68 (-1.9 to -1.46)
    -0.44 (-0.69 to -0.19)
    Statistical analysis title
    		 Difference in the Least Squares Means
    Statistical analysis description
    Based on constrained longitudinal data analysis (cLDA) model with fixed effects for treatment, time, antihyperglycemic medication wash-off status (yes, no), baseline estimated glomerular filtration rate (eGFR, continuous) and the interaction of time by treatment. Time was treated as a categorical variable.
    Comparison groups
    Ertugliflozin 5 mg + Sitagliptin 100 mg v Placebo
    Number of subjects included in analysis
    194
    Analysis specification
    Pre-specified
    Analysis type
    		 other
    P-value
    		 < 0.001
    Method
    		 cLDA
    Parameter type
    		 Difference in the Least Squares Means
    Point estimate
    -1.16
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -1.49
         upper limit
    		 -0.84
    Statistical analysis title
    		 Difference in the Least Squares Means
    Statistical analysis description
    Based on cLDA model with fixed effects for treatment, time, antihyperglycemic medication wash-off status (yes, no), baseline eGFR (continuous) and the interaction of time by treatment. Time was treated as a categorical variable.
    Comparison groups
    Ertugliflozin 15 mg + Sitagliptin 100 mg v Placebo
    Number of subjects included in analysis
    192
    Analysis specification
    Pre-specified
    Analysis type
    		 other
    P-value
    		 < 0.001
    Method
    		 cLDA
    Parameter type
    		 Difference in the Least Squares Means
    Point estimate
    -1.24
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -1.57
         upper limit
    		 -0.91

    Primary: Percentage of Participants Who Experienced an Adverse Event (AE) - All Participants as Treated Excluding Rescue Approach

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    End point title
    		 Percentage of Participants Who Experienced an Adverse Event (AE) - All Participants as Treated Excluding Rescue Approach
    End point description
    An adverse event (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. All Subjects as Treated (ASaT) population consisted of all randomized participants who received at least one dose of a study drug.
    End point type
    Primary
    End point timeframe
    Up to Week 28
    End point values
    		 Ertugliflozin 5 mg + Sitagliptin 100 mg Ertugliflozin 15 mg + Sitagliptin 100 mg Placebo
    Number of subjects analysed
    98
    96
    97
    Units: Percentage of Participants
        number (not applicable)
    44.9
    44.8
    42.3
    Statistical analysis title
    		 Difference in Percentage vs Placebo
    Comparison groups
    Ertugliflozin 5 mg + Sitagliptin 100 mg v Placebo
    Number of subjects included in analysis
    195
    Analysis specification
    Pre-specified
    Analysis type
    		 other
    Method
    Parameter type
    		 Difference in Percentage vs Placebo
    Point estimate
    2.6
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -11.2
         upper limit
    		 16.4
    Statistical analysis title
    		 Difference in Percentage vs Placebo
    Comparison groups
    Ertugliflozin 15 mg + Sitagliptin 100 mg v Placebo
    Number of subjects included in analysis
    193
    Analysis specification
    Pre-specified
    Analysis type
    		 other
    Method
    Parameter type
    		 Difference in Percentage vs Placebo
    Point estimate
    2.5
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -11.4
         upper limit
    		 16.4

    Primary: Percentage of Participants Who Discontinued Study Medication Due to an AE - All Participants as Treated Excluding Rescue Approach

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    End point title
    		 Percentage of Participants Who Discontinued Study Medication Due to an AE - All Participants as Treated Excluding Rescue Approach [1]
    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. ASaT population consisted of all randomized participants who received at least one dose of a study drug.
    End point type
    Primary
    End point timeframe
    Up to Week 26
    Notes
    [1] - No statistical analyses have been specified for this primary end point. It is expected there is at least one statistical analysis for each primary end point.
    Justification: Statistical analysis was not planned or performed for this endpoint.
    End point values
    		 Ertugliflozin 5 mg + Sitagliptin 100 mg Ertugliflozin 15 mg + Sitagliptin 100 mg Placebo
    Number of subjects analysed
    98
    96
    97
    Units: Percentage of Participants
        number (not applicable)
    2
    2.1
    2.1
    No statistical analyses for this end point

    Secondary: Change from Baseline in Fasting Plasma Glucose (FPG) at Week 26 - Full Analysis Set Excluding Rescue Approach

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    End point title
    		 Change from Baseline in Fasting Plasma Glucose (FPG) at Week 26 - Full Analysis Set Excluding Rescue Approach
    End point description
    Blood glucose was measured after a ≥10 hour fast. Blood was drawn at predose on Day 1 and after 26 weeks of treatment to determine change in plasma glucose levels (i.e., FPG at Week 26 minus FPG at baseline). FAS population includes randomized participants who took at least 1 dose of study medication and had at least one assessment at or after baseline.
    End point type
    Secondary
    End point timeframe
    Baseline and Week 26
    End point values
    		 Ertugliflozin 5 mg + Sitagliptin 100 mg Ertugliflozin 15 mg + Sitagliptin 100 mg Placebo
    Number of subjects analysed
    98
    96
    96
    Units: milligrams/deciliter
        least squares mean (confidence interval 95%)
    -48.25 (-56.12 to -40.38)
    -55.36 (-63.29 to -47.42)
    -9.3 (-18.58 to -0.02)
    Statistical analysis title
    		 Difference in the Least Squares Means
    Statistical analysis description
    Based on cLDA model with fixed effects for treatment, time, antihyperglycemic medication wash-off status (yes, no), baseline eGFR (continuous) and the interaction of time by treatment. Time was treated as a categorical variable.
    Comparison groups
    Ertugliflozin 5 mg + Sitagliptin 100 mg v Placebo
    Number of subjects included in analysis
    194
    Analysis specification
    Pre-specified
    Analysis type
    		 other
    P-value
    		 < 0.001
    Method
    		 cLDA
    Parameter type
    		 Difference in the Least Squares Means
    Point estimate
    -38.94
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -49.93
         upper limit
    		 -27.96
    Statistical analysis title
    		 Difference in the Least Squares Means
    Statistical analysis description
    Based on cLDA model with fixed effects for treatment, time, antihyperglycemic medication wash-off status (yes, no), baseline eGFR (continuous) and the interaction of time by treatment. Time was treated as a categorical variable.
    Comparison groups
    Ertugliflozin 15 mg + Sitagliptin 100 mg v Placebo
    Number of subjects included in analysis
    192
    Analysis specification
    Pre-specified
    Analysis type
    		 other
    P-value
    		 < 0.001
    Method
    		 cLDA
    Parameter type
    		 Difference in the Least Squares Means
    Point estimate
    -46.05
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -57.09
         upper limit
    		 -35.02

    Secondary: Change from Baseline in 2-hour Post-Meal Glucose (PMG) at Week 26 - Full Analysis Set Excluding Rescue Approach

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    End point title
    		 Change from Baseline in 2-hour Post-Meal Glucose (PMG) at Week 26 - Full Analysis Set Excluding Rescue Approach
    End point description
    Change from baseline at Week 26 is defined as 2-hour PMG at Week 26 minus 2-hour PMG at Week 0. Two-hour post-meal glucose was measured following a standard meal. FAS population is all randomized participants who took at least 1 dose of study medication and had at least one assessment at or after baseline.
    End point type
    Secondary
    End point timeframe
    Baseline and Week 26
    End point values
    		 Ertugliflozin 5 mg + Sitagliptin 100 mg Ertugliflozin 15 mg + Sitagliptin 100 mg Placebo
    Number of subjects analysed
    97
    95
    91
    Units: milligrams/deciliter
        least squares mean (confidence interval 95%)
    -82.8 (-95.96 to -69.64)
    -90.03 (-103.34 to -76.71)
    -20.38 (-35.62 to -5.14)
    Statistical analysis title
    		 Difference in the Least Squares Means
    Statistical analysis description
    Based on cLDA model with fixed effects for treatment, time, antihyperglycemic medication wash-off status (yes, no), baseline eGFR (continuous) and the interaction of time by treatment. Time was treated as a categorical variable.
    Comparison groups
    Ertugliflozin 5 mg + Sitagliptin 100 mg v Placebo
    Number of subjects included in analysis
    188
    Analysis specification
    Pre-specified
    Analysis type
    		 other
    P-value
    		 < 0.001
    Method
    		 cLDA
    Parameter type
    		 Difference in the Least Squares Means
    Point estimate
    -62.42
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -80.47
         upper limit
    		 -44.37
    Statistical analysis title
    		 Difference in the Least Squares Means
    Statistical analysis description
    Based on cLDA model with fixed effects for treatment, time, antihyperglycemic medication wash-off status (yes, no), baseline eGFR (continuous) and the interaction of time by treatment. Time was treated as a categorical variable.
    Comparison groups
    Ertugliflozin 15 mg + Sitagliptin 100 mg v Placebo
    Number of subjects included in analysis
    186
    Analysis specification
    Pre-specified
    Analysis type
    		 other
    P-value
    		 < 0.001
    Method
    		 cLDA
    Parameter type
    		 Difference in the Least Squares Means
    Point estimate
    -69.65
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -87.83
         upper limit
    		 -51.46

    Secondary: Percentage of Participants with HbA1C <7% (<53 mmol/mol) at Week 26

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    End point title
    		 Percentage of Participants with HbA1C <7% (<53 mmol/mol) at Week 26
    End point description
    HbA1C is blood marker used to report average blood glucose levels over prolonged periods of time and is reported as a percentage (%). HbA1c represents the percentage of glycated hemoglobin. FAS population includes randomized participants who took at least 1 dose of study medication and had at least one assessment at or after baseline.
    End point type
    Secondary
    End point timeframe
    Week 26
    End point values
    		 Ertugliflozin 5 mg + Sitagliptin 100 mg Ertugliflozin 15 mg + Sitagliptin 100 mg Placebo
    Number of subjects analysed
    98
    96
    96
    Units: Percentage of participants
        number (not applicable)
    35.7
    31.3
    8.3
    Statistical analysis title
    		 Adjusted Odds Ratio Relative to Placebo
    Statistical analysis description
    Adjusted Odds Ratio based on a logistic regression model fitted with fixed effects for treatment, antihyperglycemic medication wash-off status (yes, no). Missing data imputed using the cLDA model fitted with fixed effects as in the primary analysis.
    Comparison groups
    Ertugliflozin 5 mg + Sitagliptin 100 mg v Placebo
    Number of subjects included in analysis
    194
    Analysis specification
    Pre-specified
    Analysis type
    		 other
    P-value
    		 < 0.001
    Method
    		 cLDA
    Parameter type
    		 Odds ratio (OR)
    Point estimate
    6.88
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 2.81
         upper limit
    		 16.83
    Statistical analysis title
    		 Adjusted Odds Ratio Relative to Placebo
    Statistical analysis description
    Adjusted Odds Ratio based on a logistic regression model fitted with fixed effects for treatment, antihyperglycemic medication wash-off status (yes, no). Missing data imputed using the cLDA model fitted with fixed effects as in the primary analysis.
    Comparison groups
    Ertugliflozin 15 mg + Sitagliptin 100 mg v Placebo
    Number of subjects included in analysis
    192
    Analysis specification
    Pre-specified
    Analysis type
    		 other
    P-value
    		 < 0.001
    Method
    		 cLDA
    Parameter type
    		 Odds ratio (OR)
    Point estimate
    7.39
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 2.98
         upper limit
    		 18.31

    Secondary: Change from Baseline in Body Weight at Week 26 - Full Analysis Set Excluding Rescue Approach

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    End point title
    		 Change from Baseline in Body Weight at Week 26 - Full Analysis Set Excluding Rescue Approach
    End point description
    Body weight was measured using a standardized, digital scale at each of the pre-defined nominal time points. Weight was taken in duplicate throughout the trial at approximately the same time of day, after voiding (i.e., forced void) and while wearing only a gown and underwear. FAS population is all randomized participants who took at least 1 dose of study medication and had at least one assessment at or after baseline.
    End point type
    Secondary
    End point timeframe
    Baseline and Week 26
    End point values
    		 Ertugliflozin 5 mg + Sitagliptin 100 mg Ertugliflozin 15 mg + Sitagliptin 100 mg Placebo
    Number of subjects analysed
    98
    96
    97
    Units: Kilograms
        least squares mean (confidence interval 95%)
    -2.94 (-3.6 to -2.28)
    -3.04 (-3.71 to -2.38)
    -0.94 (-1.7 to -0.18)
    Statistical analysis title
    		 Difference in the Least Squares Means
    Statistical analysis description
    Based on cLDA model with fixed effects for treatment, time, antihyperglycemic medication wash-off status (yes, no), baseline eGFR (continuous) and the interaction of time by treatment. Time was treated as a categorical variable.
    Comparison groups
    Ertugliflozin 5 mg + Sitagliptin 100 mg v Placebo
    Number of subjects included in analysis
    195
    Analysis specification
    Pre-specified
    Analysis type
    		 other
    P-value
    		 < 0.001
    Method
    		 cLDA
    Parameter type
    		 Difference in the Least Squares Means
    Point estimate
    -2
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -2.99
         upper limit
    		 -1.01
    Statistical analysis title
    		 Difference in the Least Squares Means
    Statistical analysis description
    Based on cLDA model with fixed effects for treatment, time, antihyperglycemic medication wash-off status (yes, no), baseline eGFR (continuous) and the interaction of time by treatment. Time was treated as a categorical variable.
    Comparison groups
    Ertugliflozin 15 mg + Sitagliptin 100 mg v Placebo
    Number of subjects included in analysis
    193
    Analysis specification
    Pre-specified
    Analysis type
    		 other
    P-value
    		 < 0.001
    Method
    		 cLDA
    Parameter type
    		 Difference in the Least Squares Means
    Point estimate
    -2.1
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -3.1
         upper limit
    		 -1.11

    Secondary: Change from Baseline in Sitting Systolic Blood Pressure at Week 26 - Full Analysis Set Excluding Rescue Approach

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    End point title
    		 Change from Baseline in Sitting Systolic Blood Pressure at Week 26 - Full Analysis Set Excluding Rescue Approach
    End point description
    Blood pressure measurements were taken after at least 5 minutes of rest. Three measurements were taken approximately 2 minutes apart with the triplicate set recorded. FAS population included all randomized participants who took at least 1 dose of study medication and had at least one assessment at or after baseline.
    End point type
    Secondary
    End point timeframe
    Baseline and Week 26
    End point values
    		 Ertugliflozin 5 mg + Sitagliptin 100 mg Ertugliflozin 15 mg + Sitagliptin 100 mg Placebo
    Number of subjects analysed
    98
    96
    97
    Units: millimeters of mercury
        least squares mean (confidence interval 95%)
    -2.04 (-4.23 to 0.16)
    -3.98 (-6.19 to -1.78)
    2.41 (-0.34 to 5.15)
    Statistical analysis title
    		 Difference in the Least Squares Means
    Statistical analysis description
    Based on cLDA model with fixed effects for treatment, time, antihyperglycemic medication wash-off status (yes, no), baseline eGFR (continuous) and the interaction of time by treatment. Time was treated as a categorical variable.
    Comparison groups
    Ertugliflozin 5 mg + Sitagliptin 100 mg v Placebo
    Number of subjects included in analysis
    195
    Analysis specification
    Pre-specified
    Analysis type
    		 other
    P-value
    		 = 0.011
    Method
    		 Difference in the Least Squares Means
    Parameter type
    		 cLDA
    Point estimate
    -4.44
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -7.87
         upper limit
    		 -1.01
    Statistical analysis title
    		 Difference in the Least Squares Means
    Statistical analysis description
    Based on cLDA model with fixed effects for treatment, time, antihyperglycemic medication wash-off status (yes, no), baseline eGFR (continuous) and the interaction of time by treatment. Time was treated as a categorical variable.
    Comparison groups
    Ertugliflozin 15 mg + Sitagliptin 100 mg v Placebo
    Number of subjects included in analysis
    193
    Analysis specification
    Pre-specified
    Analysis type
    		 other
    P-value
    		 < 0.001
    Method
    		 cLDA
    Parameter type
    		 Difference in the Least Squares Means
    Point estimate
    -6.39
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -9.83
         upper limit
    		 -2.95

    Secondary: Change from Baseline in Sitting Diastolic Blood Pressure at Week 26 - Full Analysis Set Excluding Rescue Approach

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    End point title
    		 Change from Baseline in Sitting Diastolic Blood Pressure at Week 26 - Full Analysis Set Excluding Rescue Approach
    End point description
    Blood pressure measurements were taken after at least 5 minutes of rest. Three measurements were taken approximately 2 minutes apart with the triplicate set recorded. The FAS population included all randomized participants who took at least 1 dose of study medication and had at least one assessment at or after baseline.
    End point type
    Secondary
    End point timeframe
    Baseline and Week 26
    End point values
    		 Ertugliflozin 5 mg + Sitagliptin 100 mg Ertugliflozin 15 mg + Sitagliptin 100 mg Placebo
    Number of subjects analysed
    98
    96
    97
    Units: millimeters of mercury
        least squares mean (confidence interval 95%)
    -0.44 (-1.99 to 1.11)
    -0.97 (-2.52 to 0.59)
    1.21 (-0.73 to 3.15)
    Statistical analysis title
    		 Difference in the Least Squares Means
    Statistical analysis description
    Based on cLDA model with fixed effects for treatment, time, antihyperglycemic medication wash-off status (yes, no), baseline eGFR (continuous) and the interaction of time by treatment. Time was treated as a categorical variable.
    Comparison groups
    Ertugliflozin 5 mg + Sitagliptin 100 mg v Placebo
    Number of subjects included in analysis
    195
    Analysis specification
    Pre-specified
    Analysis type
    		 other
    P-value
    		 = 0.184
    Method
    		 cLDA
    Parameter type
    		 Difference in the Least Squares Means
    Point estimate
    -1.65
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -4.09
         upper limit
    		 0.79
    Statistical analysis title
    		 Difference in the Least Squares Means
    Statistical analysis description
    Based on cLDA model with fixed effects for treatment, time, antihyperglycemic medication wash-off status (yes, no), baseline eGFR (continuous) and the interaction of time by treatment. Time was treated as a categorical variable.
    Comparison groups
    Ertugliflozin 15 mg + Sitagliptin 100 mg v Placebo
    Number of subjects included in analysis
    193
    Analysis specification
    Pre-specified
    Analysis type
    		 other
    P-value
    		 = 0.08
    Method
    		 cLDA
    Parameter type
    		 Difference in the Least Squares Means
    Point estimate
    -2.18
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -4.62
         upper limit
    		 0.26

    Adverse events

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    Adverse events information
    Timeframe for reporting adverse events
    Up to Week 28
    Adverse event reporting additional description
    The serious adverse event table includes events after the initiation of glycemic rescue. The non-serious adverse event table excludes events after the initiation of glycemic rescue.
    Assessment type
    		 Systematic
    Dictionary used for adverse event reporting
    Dictionary name
    		 MedDRA
    Dictionary version
    18.1
    Reporting groups
    Reporting group title
    Ertugliflozin 5 mg + Sitagliptin 100 mg
    Reporting group description
    		 Ertugliflozin, 5 mg, administered orally, once daily for 26 weeks. Sitagliptin, 100 mg, administered orally, once daily for 26 weeks. Placebo to ertugliflozin administered orally, once daily for 26 weeks.

    Reporting group title
    Ertugliflozin 15 mg + Sitagliptin 100 mg
    Reporting group description
    		 Ertugliflozin, 15 mg, administered orally, once daily for 26 weeks. Sitagliptin, 100 mg, administered orally, once daily for 26 weeks.

    Reporting group title
    Placebo
    Reporting group description
    		 Placebo to ertugliflozin administered orally, once daily for 26 weeks.

    Serious adverse events
    		 Ertugliflozin 5 mg + Sitagliptin 100 mg Ertugliflozin 15 mg + Sitagliptin 100 mg Placebo
    Total subjects affected by serious adverse events
         subjects affected / exposed
    2 / 98 (2.04%)
    3 / 96 (3.13%)
    5 / 97 (5.15%)
         number of deaths (all causes)
    0
    0
    0
         number of deaths resulting from adverse events
    0
    0
    0
    Neoplasms benign, malignant and unspecified (incl cysts and polyps)
    Endometrial adenocarcinoma
         subjects affected / exposed
    0 / 98 (0.00%)
    1 / 96 (1.04%)
    0 / 97 (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
    Injury, poisoning and procedural complications
    Multiple fractures
         subjects affected / exposed
    0 / 98 (0.00%)
    0 / 96 (0.00%)
    1 / 97 (1.03%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Toxicity to various agents
         subjects affected / exposed
    1 / 98 (1.02%)
    0 / 96 (0.00%)
    0 / 97 (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
    Nervous system disorders
    Ischaemic stroke
         subjects affected / exposed
    0 / 98 (0.00%)
    0 / 96 (0.00%)
    1 / 97 (1.03%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Immune system disorders
    Allergy to arthropod sting
         subjects affected / exposed
    0 / 98 (0.00%)
    1 / 96 (1.04%)
    0 / 97 (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
    Angioedema
         subjects affected / exposed
    0 / 98 (0.00%)
    0 / 96 (0.00%)
    1 / 97 (1.03%)
         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
    Nephrolithiasis
         subjects affected / exposed
    0 / 98 (0.00%)
    0 / 96 (0.00%)
    1 / 97 (1.03%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Musculoskeletal and connective tissue disorders
    Spinal column stenosis
         subjects affected / exposed
    1 / 98 (1.02%)
    0 / 96 (0.00%)
    0 / 97 (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
    Appendicitis
         subjects affected / exposed
    0 / 98 (0.00%)
    0 / 96 (0.00%)
    1 / 97 (1.03%)
         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 staphylococcal
         subjects affected / exposed
    0 / 98 (0.00%)
    0 / 96 (0.00%)
    1 / 97 (1.03%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Peritonitis
         subjects affected / exposed
    0 / 98 (0.00%)
    0 / 96 (0.00%)
    1 / 97 (1.03%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Urinary tract infection
         subjects affected / exposed
    0 / 98 (0.00%)
    1 / 96 (1.04%)
    0 / 97 (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 + Sitagliptin 100 mg Ertugliflozin 15 mg + Sitagliptin 100 mg Placebo
    Total subjects affected by non serious adverse events
         subjects affected / exposed
    8 / 98 (8.16%)
    3 / 96 (3.13%)
    12 / 97 (12.37%)
    Investigations
    Blood glucose increased
         subjects affected / exposed
    3 / 98 (3.06%)
    0 / 96 (0.00%)
    7 / 97 (7.22%)
         occurrences all number
    4
    0
    14
    Infections and infestations
    Urinary tract infection
         subjects affected / exposed
    5 / 98 (5.10%)
    2 / 96 (2.08%)
    1 / 97 (1.03%)
         occurrences all number
    6
    2
    1
    Metabolism and nutrition disorders
    Hyperglycaemia
         subjects affected / exposed
    0 / 98 (0.00%)
    1 / 96 (1.04%)
    6 / 97 (6.19%)
         occurrences all number
    0
    1
    6

    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
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