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    Clinical Trial Results:
    A Phase 3, Randomized, Double-Blind, Placebo-Controlled, 26-Week Multicenter Study With A 78-Week Extension To Evaluate The Efficacy And Safety Of Ertugliflozin In Subjects With Type 2 Diabetes Mellitus And Inadequate Glycemic Control On Metformin Monotherapy

    Summary
    EudraCT number
    		 2013-003290-95
    Trial protocol
    		 HU   SK   CZ   PL   RO  
    Global end of trial date
    03 Aug 2017

    Results information
    Results version number
    		 v2(current)
    This version publication date
    30 Dec 2018
    First version publication date
    03 Aug 2018
    Other versions
    		 v1
    Version creation reason

    Trial information

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    Trial identification
    Sponsor protocol code
    8835-007
    Additional study identifiers
    ISRCTN number
    		 -
    US NCT number
    		 NCT02033889
    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
    03 Aug 2017
    Is this the analysis of the primary completion data?
    No
    Global end of trial reached?
    Yes
    Global end of trial date
    03 Aug 2017
    Was the trial ended prematurely?
    No
    General information about the trial
    Main objective of the trial
    This is an efficacy and safety study of ertugliflozin in participants with type 2 diabetes mellitus and inadequate glycemic control on metformin monotherapy. The primary study hypothesis is that at Week 26, the mean reduction from baseline in hemoglobin A1c (HbA1c) for ertugliflozin is equal or above that for placebo. The trial included a 1-week screening period, a variable interval for metformin titration (if needed), and at least an 8-week metformin stable dose period when participants discontinued and remained off any previous allowable background diabetes therapy (except for metformin), a 2-week single-blind placebo run-in period prior to randomization, and a 26-week, double-blind, placebo-controlled treatment period followed by a 78-week double-blind, extension period.
    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: Glycemic rescue therapy with glimepiride and basal insulin was initiated in participants with glucose values exceeding protocol-specified values. Dosing and titration of open-label glimepiride rescue therapy were at the discretion of the Investigator. After the 26-week treatment period, participants randomized to the placebo arm received glimepiride, if their fingerstick fasting glucose was ≥110 mg/dL.
    Background therapy
    		 The trial included a variable interval for metformin titration (if needed), and at least an 8-week metformin stable dose period when participants discontinued and remained off any previous allowable background diabetes therapy (except for metformin). Participants received metformin ≥1500 mg/day, orally, once a day, through-out the remainder of trial.
    Evidence for comparator
    		 -
    Actual start date of recruitment
    13 Dec 2013
    Long term follow-up planned
    No
    Independent data monitoring committee (IDMC) involvement?
    Yes
    Population of trial subjects
    Number of subjects enrolled per country
    Country: Number of subjects enrolled
    Australia: 11
    Country: Number of subjects enrolled
    Czech Republic: 15
    Country: Number of subjects enrolled
    Hong Kong: 36
    Country: Number of subjects enrolled
    Hungary: 60
    Country: Number of subjects enrolled
    Israel: 16
    Country: Number of subjects enrolled
    Mexico: 21
    Country: Number of subjects enrolled
    Poland: 16
    Country: Number of subjects enrolled
    Romania: 59
    Country: Number of subjects enrolled
    Russian Federation: 22
    Country: Number of subjects enrolled
    Slovakia: 50
    Country: Number of subjects enrolled
    South Africa: 111
    Country: Number of subjects enrolled
    Taiwan: 33
    Country: Number of subjects enrolled
    United Kingdom: 2
    Country: Number of subjects enrolled
    United States: 169
    Worldwide total number of subjects
    621
    EEA total number of subjects
    202
    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)
    523
    From 65 to 84 years
    98
    85 years and over
    0

    Subject disposition

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    Recruitment
    Recruitment details
    		 1535 participants were screened and 621 participants were randomized at clinical trial sites in 14 countries.

    Pre-assignment
    Screening details
    		 Male and female participants 18 years of age at the time of the initial Screening Visit with a diagnosis of Type 2 diabetes mellitus (T2DM) in accordance with American Diabetes Association (ADA) guidelines were eligible to participate 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
    		 Placebo/Glimepiride
    Arm description
    		 Placebo to ertugliflozin, orally once daily from Day 1 to Week 104. Participants meeting glycemic rescue criteria up to Week 26 were rescued with open-label glimepiride (up to a maximum of 6 or 8 mg per day, based on the local label of glimepiride) and if they met glycemic rescue criteria again, and they were on maximal tolerated doses of open-label glimepiride, they received open-label basal insulin. After Week 26, participants in the placebo ertugliflozin arm, who had not received glycemic rescue prior to Week 26 and whose fasting finger-stick glucose was 110 mg/dL or more, received blinded glimepiride. Participants in the placebo ertugliflozin arm who met glycemic rescue criteria from Week 26 onwards, and who were on maximal tolerated doses of glimepiride, open label or blinded, received open-label basal insulin.
    Arm type
    		 Placebo

    Investigational medicinal product name
    Placebo to ertugliflozin
    Investigational medicinal product code
    Other name
    Placebo
    Pharmaceutical forms
    Tablet
    Routes of administration
    Oral use
    Dosage and administration details
    Placebo to ertugliflozin, (1 placebo ertugliflozin 5 mg tablet and 1 placebo ertugliflozin 10 mg tablet), orally once daily from Day 1 to Week 104.

    Investigational medicinal product name
    Glimepiride
    Investigational medicinal product code
    Other name
    Amaryl; GLIMPID; GLIMY
    Pharmaceutical forms
    Tablet
    Routes of administration
    Oral use
    Dosage and administration details
    Participants meeting glycemic rescue criteria up to Week 26 were rescued with open-label glimepiride (up to a maximum of 6 or 8 mg per day, based on the local label of glimepiride). After Week 26, participants in the placebo ertugliflozin arm, who had not received glycemic rescue prior to Week 26 and whose fasting finger-stick glucose was 110 mg/dL or more, received blinded glimepiride. Dosing and titration of glimepiride was at the discretion of the investigator.

    Investigational medicinal product name
    Basal insulin
    Investigational medicinal product code
    Other name
    Insulin glargine; Insulin Detemir; NPH Insulin; Insulin Degludec
    Pharmaceutical forms
    Solution for injection
    Routes of administration
    Subcutaneous use
    Dosage and administration details
    Up to 26 weeks, participants meeting glycemic rescue criteria were rescued with glimepiride, and if they met glycemic rescue criteria again, and they were on maximal tolerated doses of glimepiride, they received basal insulin. If a participant met glycemic rescue criteria from Week 26 onward, and they were on maximal tolerated dose of glimepiride, then rescue with basal insulin was initiated.

    Investigational medicinal product name
    Metformin
    Investigational medicinal product code
    Other name
    Glucophage XR; Carbophage SR Riomet; Fortamet Glumetza Obimet; Gluformin Dianben; Diabex Diaformin Siofor; Metfogamma
    Pharmaceutical forms
    Tablet
    Routes of administration
    Oral use
    Dosage and administration details
    Metformin ≥1500 mg/day, orally, once a day

    Arm title
    		 Ertugliflozin 5 mg
    Arm description
    		 Ertugliflozin 5 mg orally, once daily from Day 1 to Week 104. Participants meeting glycemic rescue criteria up to Week 26 were rescued with open-label glimepiride (up to a maximum of 6 or 8 mg per day, based on the local label of glimepiride) and if they met glycemic rescue criteria again, and they were on maximal tolerated doses of open-label glimepiride, they received open-label basal insulin. After Week 26, participants in the ertugliflozin 5 mg arm, who had not received glycemic rescue prior to Week 26 and whose fasting finger-stick glucose was 110 mg/dL or more, received blinded placebo glimepiride. Participants in the ertugliflozin 5 mg arm who met glycemic rescue criteria from Week 26 onwards, and who were on maximal tolerated doses of glimepiride, open-label or blinded placebo glimepiride, received open-label basal insulin.
    Arm type
    		 Experimental

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

    Investigational medicinal product name
    Placebo to ertugliflozin
    Investigational medicinal product code
    Other name
    Placebo
    Pharmaceutical forms
    Tablet
    Routes of administration
    Oral use
    Dosage and administration details
    Placebo to ertugliflozin, (1 placebo ertugliflozin 10 mg tablet), orally once daily from Day 1 to Week 104.

    Investigational medicinal product name
    Glimepiride
    Investigational medicinal product code
    Other name
    Amaryl; GLIMPID; GLIMY
    Pharmaceutical forms
    Tablet
    Routes of administration
    Oral use
    Dosage and administration details
    Participants meeting glycemic rescue criteria up to Week 26 were rescued with open-label glimepiride (up to a maximum of 6 or 8 mg per day, based on the local label of glimepiride). Dosing and titration of glimepiride was at the discretion of the investigator.

    Investigational medicinal product name
    Basal insulin
    Investigational medicinal product code
    Other name
    Insulin glargine; Insulin Detemir; NPH insulin; Degludec
    Pharmaceutical forms
    Solution for injection
    Routes of administration
    Subcutaneous use
    Dosage and administration details
    Up to 26 weeks, participants meeting glycemic rescue criteria were rescued with glimepiride, and if they met glycemic rescue criteria again, and they were on maximal tolerated doses of glimepiride, they received basal insulin. If a participant met glycemic rescue criteria Week 26 onward, and they were on maximal tolerated dose of glimepiride, then rescue with basal insulin was initiated.

    Investigational medicinal product name
    Placebo to glimepiride
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Tablet
    Routes of administration
    Oral use
    Dosage and administration details
    Placebo to glimepiride was used in the 78-week extension period in participants who were not rescued with glimepiride during the 26-week initial period and who had a fingerstick fasting plasma glucose ≥110 mg/dL.

    Investigational medicinal product name
    Metformin
    Investigational medicinal product code
    Other name
    Glucophage XR; Carbophage SR Riomet; Fortamet Glumetza Obimet; Gluformin Dianben Diabex; Diaformin Siofor; Metfogamma
    Pharmaceutical forms
    Tablet
    Routes of administration
    Oral use
    Dosage and administration details
    Metformin ≥1500 mg/day, orally, once a day

    Arm title
    		 Ertugliflozin 15 mg
    Arm description
    		 Ertugliflozin 15 mg orally, once daily from Day 1 to Week 104. Participants meeting glycemic rescue criteria up to Week 26 were rescued with open-label glimepiride (up to a maximum of 6 or 8 mg per day, based on the local label of glimepiride) and if they met glycemic rescue criteria again, and they were on maximal tolerated doses of open-label glimepiride, they received open-label basal insulin. After Week 26, participants in the ertugliflozin 15 mg arm, who had not received glycemic rescue prior to Week 26 and whose fasting finger-stick glucose was 110 mg/dL or more, received blinded placebo glimepiride. Participants in the ertugliflozin 15 mg arm who met glycemic rescue criteria from Week 26 onwards, and who were on maximal tolerated doses of glimepiride, open-label or blinded placebo glimepiride, received open-label basal insulin.
    Arm type
    		 Experimental

    Investigational medicinal product name
    Ertugliflozin
    Investigational medicinal product code
    Other name
    MK-8835
    Pharmaceutical forms
    Tablet
    Routes of administration
    Oral use
    Dosage and administration details
    Ertugliflozin 15 mg orally (1 ertugliflozin 5 mg tablet and 1 ertugliflozin 10 mg tablet), once daily from Day 1 to Week 104.

    Investigational medicinal product name
    Glimepiride
    Investigational medicinal product code
    Other name
    Amaryl; GLIMPID; GLIMY
    Pharmaceutical forms
    Tablet
    Routes of administration
    Oral use
    Dosage and administration details
    Glimepiride was used for glycemic rescue therapy (up to a maximum of 6 or 8 mg per day, based on the local label of glimepiride) up to 26 weeks. Glimepiride (up to a maximum of 6 or 8 mg per day, based on the local label of glimepiride was used in the 78-week extension period in participants who were not rescued with glimepiride up to 26 weeks and who had a fingerstick fasting plasma glucose ≥110 mg/dL. Dosing and titration of glimepiride was at the discretion of the investigator.

    Investigational medicinal product name
    Basal insulin
    Investigational medicinal product code
    Other name
    Insulin glargine; Insulin Detemir; NPH insulin; Degludec
    Pharmaceutical forms
    Solution for injection
    Routes of administration
    Subcutaneous use
    Dosage and administration details
    Up to 26 weeks, participants meeting glycemic rescue criteria were rescued with glimepiride, and if they met glycemic rescue criteria again, and they were on maximal tolerated doses of glimepiride, they received basal insulin. If a participant met glycemic rescue criteria after Week 26 onward, and they were on maximal tolerated dose of glimepiride, then rescue with basal insulin was initiated.

    Investigational medicinal product name
    Placebo to glimepiride
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Tablet
    Routes of administration
    Oral use
    Dosage and administration details
    Placebo to glimepiride was used in the 78-week extension period in participants who were not rescued with glimepiride during the 26-week initial period and who had a fingerstick fasting plasma glucose ≥110 mg/dL. Dosing and titration of placebo to glimepiride was at the discretion of the investigator.

    Investigational medicinal product name
    Metformin
    Investigational medicinal product code
    Other name
    Glucophage XR; Carbophage SR Riomet; Fortamet Glumetza Obimet; Gluformin Dianben Diabex; Diaformin Siofor; Metfogamma
    Pharmaceutical forms
    Tablet
    Routes of administration
    Oral use
    Dosage and administration details
    Metformin ≥1500 mg/day, orally, once a day

    Number of subjects in period 1
    		Placebo/Glimepiride Ertugliflozin 5 mg Ertugliflozin 15 mg
    Started
    209
    207
    205
    Completed
    175
    187
    180
    Not completed
    34
    20
    25
         Participant moved
    -
    1
    -
         Consent withdrawn by subject
    18
    10
    13
         Physician decision
    -
    1
    1
         Excluded Medication
    1
    1
    -
         Adverse event, non-fatal
    3
    1
    3
         Death
    3
    1
    2
         Non-Compliance With Study Drug
    1
    -
    -
         Lost to follow-up
    8
    5
    6

    Baseline characteristics

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    Baseline characteristics reporting groups
    Reporting group title
    Placebo/Glimepiride
    Reporting group description
    		 Placebo to ertugliflozin, orally once daily from Day 1 to Week 104. Participants meeting glycemic rescue criteria up to Week 26 were rescued with open-label glimepiride (up to a maximum of 6 or 8 mg per day, based on the local label of glimepiride) and if they met glycemic rescue criteria again, and they were on maximal tolerated doses of open-label glimepiride, they received open-label basal insulin. After Week 26, participants in the placebo ertugliflozin arm, who had not received glycemic rescue prior to Week 26 and whose fasting finger-stick glucose was 110 mg/dL or more, received blinded glimepiride. Participants in the placebo ertugliflozin arm who met glycemic rescue criteria from Week 26 onwards, and who were on maximal tolerated doses of glimepiride, open label or blinded, received open-label basal insulin.

    Reporting group title
    Ertugliflozin 5 mg
    Reporting group description
    		 Ertugliflozin 5 mg orally, once daily from Day 1 to Week 104. Participants meeting glycemic rescue criteria up to Week 26 were rescued with open-label glimepiride (up to a maximum of 6 or 8 mg per day, based on the local label of glimepiride) and if they met glycemic rescue criteria again, and they were on maximal tolerated doses of open-label glimepiride, they received open-label basal insulin. After Week 26, participants in the ertugliflozin 5 mg arm, who had not received glycemic rescue prior to Week 26 and whose fasting finger-stick glucose was 110 mg/dL or more, received blinded placebo glimepiride. Participants in the ertugliflozin 5 mg arm who met glycemic rescue criteria from Week 26 onwards, and who were on maximal tolerated doses of glimepiride, open-label or blinded placebo glimepiride, received open-label basal insulin.

    Reporting group title
    Ertugliflozin 15 mg
    Reporting group description
    		 Ertugliflozin 15 mg orally, once daily from Day 1 to Week 104. Participants meeting glycemic rescue criteria up to Week 26 were rescued with open-label glimepiride (up to a maximum of 6 or 8 mg per day, based on the local label of glimepiride) and if they met glycemic rescue criteria again, and they were on maximal tolerated doses of open-label glimepiride, they received open-label basal insulin. After Week 26, participants in the ertugliflozin 15 mg arm, who had not received glycemic rescue prior to Week 26 and whose fasting finger-stick glucose was 110 mg/dL or more, received blinded placebo glimepiride. Participants in the ertugliflozin 15 mg arm who met glycemic rescue criteria from Week 26 onwards, and who were on maximal tolerated doses of glimepiride, open-label or blinded placebo glimepiride, received open-label basal insulin.

    Reporting group values
    		 Placebo/Glimepiride Ertugliflozin 5 mg Ertugliflozin 15 mg Total
    Number of subjects
    		 209 207 205 621
    Age categorical
    Units: Subjects
        In utero
    		 0 0 0 0
        Preterm newborn infants (gestational age < 37 wks)
    		 0 0 0 0
        Newborns (0-27 days)
    		 0 0 0 0
        Infants and toddlers (28 days-23 months)
    		 0 0 0 0
        Children (2-11 years)
    		 0 0 0 0
        Adolescents (12-17 years)
    		 0 0 0 0
        Adults (18-64 years)
    		 174 180 169 523
        From 65-84 years
    		 35 27 36 98
        85 years and over
    		 0 0 0 0
    Age Continuous
    Units: Years
        arithmetic mean (standard deviation)
    		 56.5 ( 8.7 ) 56.6 ( 8.2 ) 56.9 ( 9.4 ) -
    Sex: Female, Male
    Units: Subjects
        Female
    		 111 110 112 333
        Male
    		 98 97 93 288
    Menopausal Status
    Menopausal status includes men, premenopausal women, women who are perimenopausal or <3 years postmenopausal, women who are ≥3 years postmenopausal.
    Units: Subjects
        Male
    		 98 97 93 288
        Premenopausal Women
    		 16 17 16 49
        Perimenopausal or <3 yrs. postmenopausal
    		 9 10 11 30
        Women ≥3 years postmenopausal
    		 86 83 85 254
    Race (NIH/OMB)
    Units: Subjects
        American Indian or Alaska Native
    		 0 0 0 0
        Asian
    		 31 34 35 100
        Native Hawaiian or Other Pacific Islander
    		 0 0 0 0
        Black or African American
    		 19 22 23 64
        White
    		 144 134 133 411
        More than one race
    		 15 17 14 46
        Unknown or Not Reported
    		 0 0 0 0
    Baseline Hemoglobin A1C (A1C)
    Percentage A1C is the ratio of glycated hemoglobin to total hemoglobin x 100. N=209, 207, 205
    Units: Percentage A1C
        arithmetic mean (standard deviation)
    		 8.17 ( 0.90 ) 8.06 ( 0.89 ) 8.13 ( 0.93 ) -
    Fasting Plasma Glucose (FPG)
    N=202, 199, 203
    Units: mg/dL
        arithmetic mean (standard deviation)
    		 169.1 ( 41.7 ) 168.1 ( 45.5 ) 167.5 ( 44.4 ) -
    Body Weight
    N=209, 207, 205
    Units: Kilograms
        arithmetic mean (standard deviation)
    		 84.5 ( 17.1 ) 84.8 ( 17.2 ) 85.3 ( 16.5 ) -
    Sitting Systolic Blood Pressure (SBP)
    N=201, 201, 198
    Units: mmHg
        arithmetic mean (standard deviation)
    		 129.30 ( 15.43 ) 130.48 ( 13.77 ) 130.37 ( 12.00 ) -
    Sitting Diastolic Blood Pressure (DBP)
    N=201, 201, 198
    Units: mmHg
        arithmetic mean (standard deviation)
    		 77.45 ( 7.55 ) 78.45 ( 8.32 ) 78.08 ( 7.45 ) -
    Bone Mineral Density (BMD) as Measured by Dual Energy X-Ray Absorptiometry (DXA) of the Femoral Neck
    BMD at the femoral neck was assessed by DXA at baseline. N=209, 207, 205
    Units: g/cm^2
        arithmetic mean (standard deviation)
    		 0.92 ( 0.17 ) 0.92 ( 0.16 ) 0.89 ( 0.15 ) -
    BMD as Measured by DXA of the Lumbar Spine (L1-L4)
    BMD at the lumbar spine (L1-L4) was assessed by DXA at baseline. N=209, 207, 204
    Units: g/cm^2
        arithmetic mean (standard deviation)
    		 1.15 ( 0.18 ) 1.13 ( 0.18 ) 1.10 ( 0.17 ) -
    BMD as Measured by DXA of the Total Hip
    BMD at the total hip was assessed by DXA at baseline. N=209, 207, 205
    Units: g/cm^2
        arithmetic mean (standard deviation)
    		 1.06 ( 0.15 ) 1.07 ( 0.15 ) 1.04 ( 0.14 ) -
    BMD as Measured by DXA at the Distal Forearm
    BMD at the distal forearm was assessed by DXA at baseline. N=209, 205, 205
    Units: g/cm^2
        arithmetic mean (standard deviation)
    		 0.81 ( 0.14 ) 0.81 ( 0.14 ) 0.79 ( 0.13 ) -
    Bone Biomarker Carboxy-Terminal Cross-Linking Telopeptides of Type I Collagen (CTX)
    CTX is a biochemical marker of bone resorption. N=200, 196, 195
    Units: ng/L
        arithmetic mean (standard deviation)
    		 268.3 ( 132.9 ) 266.9 ( 129.9 ) 273.0 ( 135.2 ) -
    Bone Biomarker Procollagen Type I N-terminal Propeptide (P1NP)
    P1NP is a biochemical marker of bone resorption. N=200, 198, 198
    Units: microgm/L
        arithmetic mean (standard deviation)
    		 32.0 ( 15.0 ) 32.8 ( 14.5 ) 31.6 ( 16.5 ) -
    Bone Biomarker Parathyroid Hormone (PTH)
    PTH is a biochemical marker of bone resorption. N=202, 194, 200
    Units: ng/L
        arithmetic mean (standard deviation)
    		 19.29 ( 8.17 ) 19.52 ( 6.91 ) 19.97 ( 7.73 ) -
    Estimated Glomerular Filtration Rate (eGFR)
    N=209, 207, 205
    Units: mL/min/1.73 m^2
        arithmetic mean (standard deviation)
    		 91.6 ( 19.8 ) 88.9 ( 17.5 ) 91.1 ( 20.6 ) -

    End points

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    End points reporting groups
    Reporting group title
    Placebo/Glimepiride
    Reporting group description
    		 Placebo to ertugliflozin, orally once daily from Day 1 to Week 104. Participants meeting glycemic rescue criteria up to Week 26 were rescued with open-label glimepiride (up to a maximum of 6 or 8 mg per day, based on the local label of glimepiride) and if they met glycemic rescue criteria again, and they were on maximal tolerated doses of open-label glimepiride, they received open-label basal insulin. After Week 26, participants in the placebo ertugliflozin arm, who had not received glycemic rescue prior to Week 26 and whose fasting finger-stick glucose was 110 mg/dL or more, received blinded glimepiride. Participants in the placebo ertugliflozin arm who met glycemic rescue criteria from Week 26 onwards, and who were on maximal tolerated doses of glimepiride, open label or blinded, received open-label basal insulin.

    Reporting group title
    Ertugliflozin 5 mg
    Reporting group description
    		 Ertugliflozin 5 mg orally, once daily from Day 1 to Week 104. Participants meeting glycemic rescue criteria up to Week 26 were rescued with open-label glimepiride (up to a maximum of 6 or 8 mg per day, based on the local label of glimepiride) and if they met glycemic rescue criteria again, and they were on maximal tolerated doses of open-label glimepiride, they received open-label basal insulin. After Week 26, participants in the ertugliflozin 5 mg arm, who had not received glycemic rescue prior to Week 26 and whose fasting finger-stick glucose was 110 mg/dL or more, received blinded placebo glimepiride. Participants in the ertugliflozin 5 mg arm who met glycemic rescue criteria from Week 26 onwards, and who were on maximal tolerated doses of glimepiride, open-label or blinded placebo glimepiride, received open-label basal insulin.

    Reporting group title
    Ertugliflozin 15 mg
    Reporting group description
    		 Ertugliflozin 15 mg orally, once daily from Day 1 to Week 104. Participants meeting glycemic rescue criteria up to Week 26 were rescued with open-label glimepiride (up to a maximum of 6 or 8 mg per day, based on the local label of glimepiride) and if they met glycemic rescue criteria again, and they were on maximal tolerated doses of open-label glimepiride, they received open-label basal insulin. After Week 26, participants in the ertugliflozin 15 mg arm, who had not received glycemic rescue prior to Week 26 and whose fasting finger-stick glucose was 110 mg/dL or more, received blinded placebo glimepiride. Participants in the ertugliflozin 15 mg arm who met glycemic rescue criteria from Week 26 onwards, and who were on maximal tolerated doses of glimepiride, open-label or blinded placebo glimepiride, received open-label basal insulin.

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

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    End point title
    		 Change from Baseline in A1C at Week 26 (Excluding Rescue Approach)
    End point description
    Percentage A1C is the ratio of glycated hemoglobin to total hemoglobin x 100 and reflects the average blood glucose levels over prolonged periods of time. This change from baseline reflects the Week 26 A1C minus the Week 0 A1C (which is estimated on average for each treatment group using a constrained longitudinal data analysis model, which allows for participants with missing data to be included in the analysis). Participants who met pre-specified glycemic criteria were rescued with oral tablets of glimepiride up to Week 26 or basal insulin injected subcutaneously, and dosed according to Investigator judgment. Per protocol, this data set excludes data for any participant after the initiation of glycemic rescue therapy. The analysis population included all randomized participants who received at least one dose of investigational product and had at least one measurement of the respective endpoint at baseline or post-baseline up to Week 26.
    End point type
    Primary
    End point timeframe
    Baseline and Week 26
    End point values
    		 Placebo/Glimepiride Ertugliflozin 5 mg Ertugliflozin 15 mg
    Number of subjects analysed
    209
    207
    205
    Units: Percent A1C
        least squares mean (confidence interval 95%)
    -0.03 (-0.15 to 0.10)
    -0.73 (-0.85 to -0.61)
    -0.91 (-1.03 to -0.78)
    Statistical analysis title
    		 Difference in Least Squares Means
    Statistical analysis description
    Based on Constrained Longitudinal Data Analysis (cLDA) model with fixed effects for treatment, time, prior anti hyperglycemic medication (metformin monotherapy or metformin + another anti-hyperglycemic agent, AHA), baseline eGFR (continuous), menopausal status, and the interaction of time by treatment. Time was treated as a categorical variable.
    Comparison groups
    Placebo/Glimepiride v Ertugliflozin 15 mg
    Number of subjects included in analysis
    414
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 < 0.001
    Method
    		 Constrained Longitudinal Data Analysis
    Parameter type
    		 Difference in Least Squares Means
    Point estimate
    -0.88
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -1.05
         upper limit
    		 -0.71
    Statistical analysis title
    		 Difference in Least Squares Means
    Statistical analysis description
    Based on Constrained Longitudinal Data Analysis (cLDA) model with fixed effects for treatment, time, prior anti hyperglycemic medication (metformin monotherapy or metformin + another anti-hyperglycemic agent, AHA), baseline eGFR (continuous), menopausal status, and the interaction of time by treatment. Time was treated as a categorical variable.
    Comparison groups
    Placebo/Glimepiride v Ertugliflozin 5 mg
    Number of subjects included in analysis
    416
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 < 0.001
    Method
    		 Constrained Longitudinal Data Analysis
    Parameter type
    		 Difference in Least Squares Means
    Point estimate
    -0.7
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -0.87
         upper limit
    		 -0.53

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

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    End point title
    		 Percentage of Participants Experiencing An Adverse Event (AE) (Including Rescue Approach)
    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. Per protocol, participants who met pre-specified glycemic criteria were rescued with glimepiride up to Week 26 or basal insulin according to Investigator judgment. Per protocol, this data set includes data regardless of glycemic rescue therapy initiation (including rescue approach). The analysis population included all participants who received at least one dose of investigational product.
    End point type
    Primary
    End point timeframe
    Up to Week 106
    End point values
    		 Placebo/Glimepiride Ertugliflozin 5 mg Ertugliflozin 15 mg
    Number of subjects analysed
    209
    207
    205
    Units: Percentage of Participants
        number (not applicable)
    76.1
    70.5
    75.6
    Statistical analysis title
    		 Difference in % vs Placebo/Glimepiride
    Statistical analysis description
    Miettinen & Nurminen method was used to construct the 95% CI
    Comparison groups
    Placebo/Glimepiride v Ertugliflozin 15 mg
    Number of subjects included in analysis
    414
    Analysis specification
    Pre-specified
    Analysis type
    		 other
    Method
    Parameter type
    		 Difference in % vs Placebo/Glimepiride
    Point estimate
    -0.5
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -8.7
         upper limit
    		 7.8
    Statistical analysis title
    		 Difference in % vs Placebo/Glimepiride
    Statistical analysis description
    Miettinen & Nurminen method was used to construct the 95% CI
    Comparison groups
    Placebo/Glimepiride v Ertugliflozin 5 mg
    Number of subjects included in analysis
    416
    Analysis specification
    Pre-specified
    Analysis type
    		 other
    Method
    Parameter type
    		 Difference in % vs Placebo/Glimepiride
    Point estimate
    -5.5
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -14
         upper limit
    		 3

    Primary: Percentage of Participants Discontinuing Study Treatment Due to an AE (Including Rescue Approach)

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    End point title
    		 Percentage of Participants Discontinuing Study Treatment Due to an AE (Including Rescue Approach)
    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. Per protocol, participants who met pre-specified glycemic criteria were rescued with glimepiride up to Week 26 or basal insulin according to Investigator judgment. Per protocol, this data set includes data regardless of glycemic rescue therapy initiation (including rescue approach). The analysis population included all participants who received at least one dose of investigational product.
    End point type
    Primary
    End point timeframe
    Up to Week 104
    End point values
    		 Placebo/Glimepiride Ertugliflozin 5 mg Ertugliflozin 15 mg
    Number of subjects analysed
    209
    207
    205
    Units: Percentage of Participants
        number (not applicable)
    2.4
    3.4
    3.9
    Statistical analysis title
    		 Difference in % vs Placebo/Glimepiride
    Statistical analysis description
    Miettinen & Nurminen method was used to construct the 95% CI
    Comparison groups
    Placebo/Glimepiride v Ertugliflozin 15 mg
    Number of subjects included in analysis
    414
    Analysis specification
    Pre-specified
    Analysis type
    		 other
    Method
    Parameter type
    		 Difference in % vs Placebo/Glimepiride
    Point estimate
    1.5
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -2.1
         upper limit
    		 5.4
    Statistical analysis title
    		 Difference in % vs Placebo/Glimepiride
    Statistical analysis description
    Miettinen & Nurminen method was used to construct the 95% CI
    Comparison groups
    Placebo/Glimepiride v Ertugliflozin 5 mg
    Number of subjects included in analysis
    416
    Analysis specification
    Pre-specified
    Analysis type
    		 other
    Method
    Parameter type
    		 Difference in % vs Placebo/Glimepiride
    Point estimate
    1
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -2.5
         upper limit
    		 4.7

    Secondary: Change from Baseline in Fasting Plasma Glucose at Week 26 (Excluding Rescue Approach)

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    End point title
    		 Change from Baseline in Fasting Plasma Glucose at Week 26 (Excluding Rescue Approach)
    End point description
    Blood glucose was measured on a fasting basis. 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 Week 0) (which is estimated on average for each treatment group using a constrained longitudinal data analysis model, which allows for participants with missing data to be included in the analysis). Participants who met pre-specified glycemic criteria were rescued with oral tablets of glimepiride up to Week 26 or basal insulin injected subcutaneously, and dosed according to Investigator judgment. Per protocol, this data set excludes data for any participant after the initiation of glycemic rescue therapy. The analysis population included all randomized participants who received at least one dose of investigational product and had measurements of the respective endpoint at baseline or post-baseline up to Week 26.
    End point type
    Secondary
    End point timeframe
    Baseline and Week 26
    End point values
    		 Placebo/Glimepiride Ertugliflozin 5 mg Ertugliflozin 15 mg
    Number of subjects analysed
    209
    207
    205
    Units: mg/dL
        least squares mean (confidence interval 95%)
    -0.85 (-5.93 to 4.23)
    -27.54 (-32.36 to -22.73)
    -39.10 (-43.96 to -34.23)
    Statistical analysis title
    		 Difference in Least Squares Means
    Statistical analysis description
    Based on the cLDA model with fixed effects for treatment, time, prior antihyperglycemic medication (metformin monotherapy or metformin + another AHA), baseline eGFR (continuous), menopausal status, and the interaction of time by treatment. Time was treated as a categorical variable.
    Comparison groups
    Placebo/Glimepiride v Ertugliflozin 15 mg
    Number of subjects included in analysis
    414
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 < 0.001
    Method
    		 Constrained Longitudinal Data Analysis
    Parameter type
    		 Difference in Least Squares Means
    Point estimate
    -38.25
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -44.5
         upper limit
    		 -31.99
    Statistical analysis title
    		 Difference in Least Squares Means
    Statistical analysis description
    Based on the cLDA model with fixed effects for treatment, time, prior antihyperglycemic medication (metformin monotherapy or metformin + another AHA), baseline eGFR (continuous), menopausal status, and the interaction of time by treatment. Time was treated as a categorical variable.
    Comparison groups
    Placebo/Glimepiride v Ertugliflozin 5 mg
    Number of subjects included in analysis
    416
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 < 0.001
    Method
    		 Constrained Longitudinal Data Analysis
    Parameter type
    		 Difference in the Least Squares Means
    Point estimate
    -26.69
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -32.9
         upper limit
    		 -20.48

    Secondary: Change from Baseline in Body Weight at Week 26 (Excluding Rescue Approach)

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    End point title
    		 Change from Baseline in Body Weight at Week 26 (Excluding Rescue Approach)
    End point description
    The change in body weight from baseline reflects the Week 26 body weight minus the Week 0 body weight (which is estimated on average for each treatment group using a constrained longitudinal data analysis model, which allows for participants with missing data to be included in the analysis). Participants who met pre-specified glycemic criteria were rescued with oral tablets of glimepiride up to Week 26 or basal insulin injected subcutaneously, and dosed according to Investigator judgment. Per protocol, this data set excludes data for any participant after the initiation of glycemic rescue therapy. The analysis population included all randomized participants who took at least one dose of study medication and had at least one assessment of the respective endpoint at baseline or post-baseline up to Week 26.
    End point type
    Secondary
    End point timeframe
    Baseline and Week 26
    End point values
    		 Placebo/Glimepiride Ertugliflozin 5 mg Ertugliflozin 15 mg
    Number of subjects analysed
    209
    207
    205
    Units: Kilograms
        least squares mean (confidence interval 95%)
    -1.33 (-1.74 to -0.92)
    -3.01 (-3.40 to -2.62)
    -2.93 (-3.33 to -2.53)
    Statistical analysis title
    		 Difference in Least Squares Means
    Statistical analysis description
    Based on the cLDA model with fixed effects for treatment, time, prior antihyperglycemic medication (metformin monotherapy or metformin + another AHA), baseline eGFR (continuous), menopausal status, and the interaction of time by treatment. Time was treated as a categorical variable.
    Comparison groups
    Placebo/Glimepiride v Ertugliflozin 15 mg
    Number of subjects included in analysis
    414
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 < 0.001
    Method
    		 Constrained Longitudinal Data Analysis
    Parameter type
    		 Difference in Least Squares Means
    Point estimate
    -1.6
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -2.16
         upper limit
    		 -1.03
    Statistical analysis title
    		 Difference in Least Squares Means
    Statistical analysis description
    Based on the cLDA model with fixed effects for treatment, time, prior antihyperglycemic medication (metformin monotherapy or metformin + another AHA), baseline eGFR (continuous), menopausal status, and the interaction of time by treatment. Time was treated as a categorical variable.
    Comparison groups
    Placebo/Glimepiride v Ertugliflozin 5 mg
    Number of subjects included in analysis
    416
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 < 0.001
    Method
    		 Constrained Longitudinal Data Analysis
    Parameter type
    		 Difference in Least Squares Means
    Point estimate
    -1.67
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -2.24
         upper limit
    		 -1.11

    Secondary: Percentage of Participants with an A1C of <7% (53 mmol/mol) at Week 26 (Logistic Regression using Multiple Imputation: Excluding Rescue Approach)

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    End point title
    		 Percentage of Participants with an A1C of <7% (53 mmol/mol) at Week 26 (Logistic Regression using Multiple Imputation: Excluding Rescue Approach)
    End point description
    A1C is blood marker used to report average blood glucose levels over prolonged periods of time and is reported as a percentage (%). Percentage A1C is the ratio of glycated hemoglobin to total hemoglobin x 100. Participants who met pre-specified glycemic criteria were rescued with oral tablets of glimepiride up to Week 26 or basal insulin injected subcutaneously, and dosed according to Investigator judgment. Per protocol, this data set excludes data for any participant after the initiation of glycemic rescue therapy. The analysis population included all randomized participants who received at least one dose of investigational product and had at least one assessment of the respective endpoint at baseline or post-baseline up to Week 26.
    End point type
    Secondary
    End point timeframe
    Week 26
    End point values
    		 Placebo/Glimepiride Ertugliflozin 5 mg Ertugliflozin 15 mg
    Number of subjects analysed
    209
    207
    205
    Units: Percentage of Participants
        number (not applicable)
    15.8
    35.3
    40.0
    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, prior antihyperglycemic medication (metformin monotherapy or metformin + another AHA), menopausal status, covariates for baseline A1C and baseline eGFR (continuous). Missing data imputed using a multiple imputation procedure based on cLDA prediction modeling with fixed effects as in the primary analysis, which allows for participants with missing data to be included in the analysis.
    Comparison groups
    Placebo/Glimepiride v Ertugliflozin 15 mg
    Number of subjects included in analysis
    414
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 < 0.001
    Method
    		 Regression, Logistic
    Parameter type
    		 Adjusted Odds Ratio Relative to Placebo
    Point estimate
    4.48
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 2.64
         upper limit
    		 7.62
    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, prior antihyperglycemic medication (metformin monotherapy or metformin + another AHA), menopausal status, covariates for baseline A1C and baseline eGFR (continuous). Missing data imputed using a multiple imputation procedure based on cLDA prediction modeling with fixed effects as in the primary analysis, which allows for participants with missing data to be included in the analysis.
    Comparison groups
    Placebo/Glimepiride v Ertugliflozin 5 mg
    Number of subjects included in analysis
    416
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 < 0.001
    Method
    		 Regression, Logistic
    Parameter type
    		 Adjusted Odds Ratio Relative to Placebo
    Point estimate
    3.03
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 1.81
         upper limit
    		 5.06

    Secondary: Change from Baseline in Sitting Systolic Blood Pressure at Week 26 (Excluding Rescue Approach)

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    End point title
    		 Change from Baseline in Sitting Systolic Blood Pressure at Week 26 (Excluding Rescue Approach)
    End point description
    This change from baseline reflects the Week 26 sitting systolic blood pressure (SBP) minus the Week 0 sitting SBP (which is estimated on average for each treatment group using a constrained longitudinal data analysis model, which allows for participants with missing data to be included in the analysis). Participants who met pre-specified glycemic criteria were rescued with oral tablets of glimepiride up to Week 26 or basal insulin injected subcutaneously, and dosed according to Investigator judgment. Per protocol, this data set excludes data for any participant after the initiation of glycemic rescue therapy. The analysis population included all randomized participants who took at least one dose of study medication and had at least one assessment of the respective endpoint at baseline or post-baseline up to Week 26.
    End point type
    Secondary
    End point timeframe
    Baseline and Week 26
    End point values
    		 Placebo/Glimepiride Ertugliflozin 5 mg Ertugliflozin 15 mg
    Number of subjects analysed
    209
    207
    204
    Units: mmHg
        least squares mean (confidence interval 95%)
    -0.70 (-2.46 to 1.06)
    -4.38 (-6.01 to -2.75)
    -5.20 (-6.87 to -3.54)
    Statistical analysis title
    		 Difference in Least Squares Means
    Statistical analysis description
    Based on the cLDA model with fixed effects for treatment, time, prior antihyperglycemic medication (metformin monotherapy or metformin + another AHA), baseline eGFR (continuous), menopausal status, and the interaction of time by treatment. Time was treated as a categorical variable.
    Comparison groups
    Placebo/Glimepiride v Ertugliflozin 15 mg
    Number of subjects included in analysis
    413
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 < 0.001
    Method
    		 Constrained Longitudinal Data Analysis
    Parameter type
    		 Difference in Least Squares Means
    Point estimate
    -4.5
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -6.81
         upper limit
    		 -2.19
    Statistical analysis title
    		 Difference in Least Squares Means
    Statistical analysis description
    Based on the cLDA model with fixed effects for treatment, time, prior antihyperglycemic medication (metformin monotherapy or metformin + another AHA), baseline eGFR (continuous), menopausal status, and the interaction of time by treatment. Time was treated as a categorical variable.
    Comparison groups
    Placebo/Glimepiride v Ertugliflozin 5 mg
    Number of subjects included in analysis
    416
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.002
    Method
    		 Constrained Longitudinal Data Analysis
    Parameter type
    		 Difference in Least Squares Means
    Point estimate
    -3.68
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -5.96
         upper limit
    		 -1.39

    Secondary: Change from Baseline in Sitting Diastolic Blood Pressure at Week 26 (Excluding Rescue Approach)

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    End point title
    		 Change from Baseline in Sitting Diastolic Blood Pressure at Week 26 (Excluding Rescue Approach)
    End point description
    This change from baseline reflects the Week 26 sitting diastolic blood pressure (DBP) minus the Week 0 sitting DBP (which is estimated on average for each treatment group using a constrained longitudinal data analysis model, which allows for participants with missing data to be included in the analysis). Participants who met pre-specified glycemic criteria were rescued with oral tablets of glimepiride up to Week 26 or basal insulin injected subcutaneously, and dosed according to Investigator judgment. Per protocol, this data set excludes data for any participant after the initiation of glycemic rescue therapy. The analysis population included all randomized participants who took at least one dose of study medication and had at least one assessment of the respective endpoint at baseline or post-baseline up to Week 26.
    End point type
    Secondary
    End point timeframe
    Baseline and Week 26
    End point values
    		 Placebo/Glimepiride Ertugliflozin 5 mg Ertugliflozin 15 mg
    Number of subjects analysed
    209
    207
    204
    Units: mmHg
        least squares mean (confidence interval 95%)
    0.23 (-0.85 to 1.31)
    -1.59 (-2.59 to -0.59)
    -2.19 (-3.21 to -1.17)
    Statistical analysis title
    		 Difference in Least Squares Means
    Statistical analysis description
    Based on the cLDA model with fixed effects for treatment, time, prior antihyperglycemic medication (metformin monotherapy or metformin + another AHA), baseline eGFR (continuous), menopausal status, and the interaction of time by treatment. Time was treated as a categorical variable.
    Comparison groups
    Placebo/Glimepiride v Ertugliflozin 15 mg
    Number of subjects included in analysis
    413
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.001
    Method
    		 Constrained Longitudinal Data Analysis
    Parameter type
    		 Difference in Least Squares Means
    Point estimate
    -2.42
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -3.86
         upper limit
    		 -0.98
    Statistical analysis title
    		 Difference in Least Squares Means
    Statistical analysis description
    Based on the cLDA model with fixed effects for treatment, time, prior antihyperglycemic medication (metformin monotherapy or metformin + another AHA), baseline eGFR (continuous), menopausal status, and the interaction of time by treatment. Time was treated as a categorical variable.
    Comparison groups
    Placebo/Glimepiride v Ertugliflozin 5 mg
    Number of subjects included in analysis
    416
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.013
    Method
    		 Constrained Longitudinal Data Analysis
    Parameter type
    		 Difference in Least Squares Means
    Point estimate
    -1.82
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -3.24
         upper limit
    		 -0.39

    Secondary: Percentage of Participants with an A1C of <6.5% (48 mmol/mol) at Week 26 (Logistic Regression using Multiple Imputation: Excluding Rescue Approach)

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    End point title
    		 Percentage of Participants with an A1C of <6.5% (48 mmol/mol) at Week 26 (Logistic Regression using Multiple Imputation: Excluding Rescue Approach)
    End point description
    A1C is blood marker used to report average blood glucose levels over prolonged periods of time and is reported as a percentage (%). Percentage A1C is the ratio of glycated hemoglobin to total hemoglobin x 100. Participants who met pre-specified glycemic criteria were rescued with oral tablets of glimepiride up to Week 26 or basal insulin injected subcutaneously, and dosed according to Investigator judgment. Per protocol, this data set excludes data for any participant after the initiation of glycemic rescue therapy. The analysis population included all randomized participants who received at least one dose of investigational product and had at least one assessment of the respective endpoint at baseline or post-baseline up to Week 26
    End point type
    Secondary
    End point timeframe
    Week 26
    End point values
    		 Placebo/Glimepiride Ertugliflozin 5 mg Ertugliflozin 15 mg
    Number of subjects analysed
    209
    207
    205
    Units: Percentage of Participants
        number (not applicable)
    2.9
    8.7
    12.2
    Statistical analysis title
    		 Adjusted Odds Ratio
    Statistical analysis description
    Adjusted odds ratio based on a logistic regression model fitted with fixed effects for treatment, prior antihyperglycemic medication (metformin monotherapy or metformin + another AHA), menopausal status, covariates for baseline A1C and baseline eGFR (continuous). Missing data imputed using the cLDA model fitted with fixed effects as in the primary analysis.
    Comparison groups
    Placebo/Glimepiride v Ertugliflozin 15 mg
    Number of subjects included in analysis
    414
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 < 0.001
    Method
    		 Regression, Logistic
    Parameter type
    		 Adjusted Odds Ratio
    Point estimate
    5.41
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 2.1
         upper limit
    		 13.9
    Statistical analysis title
    		 Adjusted Odds Ratio
    Statistical analysis description
    Adjusted odds ratio based on a logistic regression model fitted with fixed effects for treatment, prior antihyperglycemic medication (metformin monotherapy or metformin + another AHA), menopausal status, covariates for baseline A1C and baseline eGFR (continuous). Missing data imputed using the cLDA model fitted with fixed effects as in the primary analysis.
    Comparison groups
    Placebo/Glimepiride v Ertugliflozin 5 mg
    Number of subjects included in analysis
    416
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.023
    Method
    		 Regression, Logistic
    Parameter type
    		 Adjusted Odds Ratio
    Point estimate
    3.1
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 1.17
         upper limit
    		 8.22

    Secondary: Percentage of Participants Receiving Glycemic Rescue Therapy up to Week 26

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    End point title
    		 Percentage of Participants Receiving Glycemic Rescue Therapy up to Week 26
    End point description
    Per protocol, participants who met pre-specified glycemic criteria were rescued with oral tablets of glimepiride up to Week 26 or basal insulin injected subcutaneously, and dosed according to Investigator judgment. The analysis population included all participants who received at least one dose of investigational product.
    End point type
    Secondary
    End point timeframe
    Up to Week 26
    End point values
    		 Placebo/Glimepiride Ertugliflozin 5 mg Ertugliflozin 15 mg
    Number of subjects analysed
    209
    207
    205
    Units: Percentage of Participants
        number (not applicable)
    17.7
    2.9
    1.5
    Statistical analysis title
    		 Difference in % vs Placebo
    Statistical analysis description
    Miettinen & Nurminen method was used to construct both the 95% CI and derive p-value for the difference between the proportions (i.e. percentages).
    Comparison groups
    Placebo/Glimepiride v Ertugliflozin 15 mg
    Number of subjects included in analysis
    414
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 < 0.001
    Method
    		 Miettinen & Nurminen method
    Parameter type
    		 Difference in % vs Placebo
    Point estimate
    -16.2
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -22.2
         upper limit
    		 -11.2
    Statistical analysis title
    		 Difference in % vs Placebo
    Statistical analysis description
    Miettinen & Nurminen method was used to construct both the 95% CI and derive p-value for the difference between the proportions (i.e. percentages).
    Comparison groups
    Placebo/Glimepiride v Ertugliflozin 5 mg
    Number of subjects included in analysis
    416
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 < 0.001
    Method
    		 Miettinen & Nurminen method.
    Parameter type
    		 Difference in % vs Placebo
    Point estimate
    -14.8
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -20.9
         upper limit
    		 -9.4

    Secondary: Time to Glycemic Rescue Therapy at Week 26

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    End point title
    		 Time to Glycemic Rescue Therapy at Week 26
    End point description
    Per protocol, participants who met pre-specified glycemic criteria were rescued with oral tablets of glimepiride up to Week 26 or basal insulin injected subcutaneously, and dosed according to Investigator judgment. The analysis population included all participants who received at least one dose of investigational product and received glycemic rescue through Week 26.
    End point type
    Secondary
    End point timeframe
    Week 26
    End point values
    		 Placebo/Glimepiride Ertugliflozin 5 mg Ertugliflozin 15 mg
    Number of subjects analysed
    36
    6
    3
    Units: Days
        median (full range (min-max))
    105 (15 to 183)
    112 (23 to 151)
    139 (127 to 145)
    No statistical analyses for this end point

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

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    End point title
    		 Change from Baseline in A1C at Week 52 (Excluding Rescue Approach)
    End point description
    A1C is blood marker used to report average blood glucose levels over prolonged periods of time. Percentage A1C is the ratio of glycated hemoglobin to total hemoglobin x 100. Thus, this change from baseline reflects the Week 52 A1C minus the Week 0 A1C. Participants who met pre-specified glycemic criteria were rescued with oral tablets of glimepiride up to Week 26 or basal insulin injected subcutaneously, and dosed according to Investigator judgment. Per protocol, this data set excludes data for any participant after the initiation of glycemic rescue therapy. The analysis population included all randomized participants who received at least one dose of investigational product and had measurements of the respective endpoint at both baseline and Week 52.
    End point type
    Secondary
    End point timeframe
    Baseline and Week 52
    End point values
    		 Placebo/Glimepiride Ertugliflozin 5 mg Ertugliflozin 15 mg
    Number of subjects analysed
    140
    179
    173
    Units: Percent A1C
        arithmetic mean (standard deviation)
    -0.68 ( 0.99 )
    -0.72 ( 0.95 )
    -0.96 ( 0.88 )
    No statistical analyses for this end point

    Secondary: Change from Baseline in Fasting Plasma Glucose at Week 52 (Excluding Rescue Therapy)

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    End point title
    		 Change from Baseline in Fasting Plasma Glucose at Week 52 (Excluding Rescue Therapy)
    End point description
    Blood glucose was measured on a fasting basis. Blood was drawn at predose on Day 1 and after 52 weeks of treatment to determine change in plasma glucose levels (i.e., FPG at Week 52 minus FPG at Week 0). Participants who met pre-specified glycemic criteria were rescued with oral tablets of glimepiride up to Week 26 or basal insulin injected subcutaneously, and dosed according to Investigator judgment. Per protocol, this data set excludes data for any participant after the initiation of glycemic rescue therapy. The analysis population included all randomized participants who received at least one dose of investigational product and had measurements of the respective endpoint at both baseline and Week 52.
    End point type
    Secondary
    End point timeframe
    Baseline and Week 52
    End point values
    		 Placebo/Glimepiride Ertugliflozin 5 mg Ertugliflozin 15 mg
    Number of subjects analysed
    136
    173
    173
    Units: mg/dL
        arithmetic mean (standard deviation)
    -12.0 ( 40.0 )
    -22.4 ( 39.3 )
    -35.2 ( 40.7 )
    No statistical analyses for this end point

    Secondary: Percentage of Participants with an A1C of <7% (53 mmol/mol) at Week 52 (Excluding Rescue Approach)

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    End point title
    		 Percentage of Participants with an A1C of <7% (53 mmol/mol) at Week 52 (Excluding Rescue Approach)
    End point description
    A1C is blood marker used to report average blood glucose levels over prolonged periods of time and is reported as a percentage (%). Percentage A1C is the ratio of glycated hemoglobin to total hemoglobin x 100. Participants who met pre-specified glycemic criteria were rescued with oral tablets of glimepiride up to Week 26 or basal insulin injected subcutaneously, and dosed according to Investigator judgment. Per protocol, this data set excludes data for any participant after the initiation of glycemic rescue therapy. The analysis population included all randomized participants who received at least one dose of investigational product. Any participant without post-baseline data at Week 52 is assumed to be "not at goal" (where "at goal" is A1C <7%) for the calculation of the percentages.
    End point type
    Secondary
    End point timeframe
    Week 52
    End point values
    		 Placebo/Glimepiride Ertugliflozin 5 mg Ertugliflozin 15 mg
    Number of subjects analysed
    209
    207
    205
    Units: Percentage of Participants
        number (not applicable)
    30.6
    34.8
    36.6
    No statistical analyses for this end point

    Secondary: Percentage of Participants with an A1C of <6.5% (48 mmol/mol) at Week 52 (Excluding Rescue Approach)

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    End point title
    		 Percentage of Participants with an A1C of <6.5% (48 mmol/mol) at Week 52 (Excluding Rescue Approach)
    End point description
    A1C is blood marker used to report average blood glucose levels over prolonged periods of time. Percentage A1C is the ratio of glycated hemoglobin to total hemoglobin x 100. Participants who met pre-specified glycemic criteria were rescued with oral tablets of glimepiride up to Week 26 or basal insulin injected subcutaneously, and dosed according to Investigator judgment. Per protocol, this data set excludes data for any participant after the initiation of glycemic rescue therapy. The analysis population included all randomized participants who received at least one dose of investigational product. Any participant without post-baseline data at Week 52 is assumed to be "not at goal" (where "at goal" is A1C <6.5%) for the calculation of the percentages.
    End point type
    Secondary
    End point timeframe
    Week 52
    End point values
    		 Placebo/Glimepiride Ertugliflozin 5 mg Ertugliflozin 15 mg
    Number of subjects analysed
    209
    207
    205
    Units: Percentage of Participants
        number (not applicable)
    11.0
    10.6
    14.6
    No statistical analyses for this end point

    Secondary: Percentage of Participants Receiving Glycemic Rescue Therapy up to Week 52

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    End point title
    		 Percentage of Participants Receiving Glycemic Rescue Therapy up to Week 52
    End point description
    Per protocol, participants who met pre-specified glycemic criteria were rescued with oral tablets of glimepiride up to Week 26 or basal insulin injected subcutaneously, and dosed according to Investigator judgment. The analysis population included all participants who received at least one dose of investigational product.
    End point type
    Secondary
    End point timeframe
    Up to Week 52
    End point values
    		 Placebo/Glimepiride Ertugliflozin 5 mg Ertugliflozin 15 mg
    Number of subjects analysed
    209
    207
    205
    Units: Percentage of Participants
        number (confidence interval 95%)
    17.2 (12.37 to 23.04)
    4.3 (2.01 to 8.09)
    1.5 (0.3 to 4.22)
    No statistical analyses for this end point

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

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    End point title
    		 Change from Baseline in Body Weight at Week 52 (Excluding Rescue Approach)
    End point description
    The change in body weight from baseline reflects the Week 52 body weight minus the Week 0 body weight. Participants who met pre-specified glycemic criteria were rescued with oral tablets of glimepiride up to Week 26 or basal insulin injected subcutaneously, and dosed according to Investigator judgment. Per protocol, this data set excludes data for any participant after the initiation of glycemic rescue therapy. The analysis population included all randomized participants who received at least one dose of investigational product and had measurements of the respective endpoint at both baseline and Week 52.
    End point type
    Secondary
    End point timeframe
    Baseline and Week 52
    End point values
    		 Placebo/Glimepiride Ertugliflozin 5 mg Ertugliflozin 15 mg
    Number of subjects analysed
    142
    181
    178
    Units: Kilograms
        arithmetic mean (standard deviation)
    0.07 ( 2.85 )
    -3.23 ( 3.68 )
    -3.35 ( 3.27 )
    No statistical analyses for this end point

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

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    End point title
    		 Change from Baseline in Sitting Systolic Blood Pressure at Week 52 (Excluding Rescue Approach)
    End point description
    This change from baseline reflects the Week 52 sitting SBP minus the Week 0 sitting SBP. Participants who met pre-specified glycemic criteria were rescued with oral tablets of glimepiride up to Week 26 or basal insulin injected subcutaneously, and dosed according to Investigator judgment. Per protocol, this data set excludes data for any participant after the initiation of glycemic rescue therapy. The analysis population included all randomized participants who received at least one dose of investigational product and had measurements of the respective endpoint at both baseline and Week 52.
    End point type
    Secondary
    End point timeframe
    Baseline and Week 52
    End point values
    		 Placebo/Glimepiride Ertugliflozin 5 mg Ertugliflozin 15 mg
    Number of subjects analysed
    134
    177
    173
    Units: mmHg
        arithmetic mean (standard deviation)
    0.65 ( 13.38 )
    -2.63 ( 14.40 )
    -4.28 ( 13.28 )
    No statistical analyses for this end point

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

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    End point title
    		 Change from Baseline in Sitting Diastolic Blood Pressure at Week 52 (Excluding Rescue Approach)
    End point description
    This change from baseline reflects the Week 52 sitting DBP minus the Week 0 sitting DBP. Participants who met pre-specified glycemic criteria were rescued with oral tablets of glimepiride up to Week 26 or basal insulin injected subcutaneously, and dosed according to Investigator judgment. Per protocol, this data set excludes data for any participant after the initiation of glycemic rescue therapy. The analysis population included all randomized participants who received at least one dose of investigational product and had measurements of the respective endpoint at both baseline and Week 52.
    End point type
    Secondary
    End point timeframe
    Baseline and Week 52
    End point values
    		 Placebo/Glimepiride Ertugliflozin 5 mg Ertugliflozin 15 mg
    Number of subjects analysed
    134
    177
    173
    Units: mmHg
        arithmetic mean (standard deviation)
    0.38 ( 8.16 )
    -1.40 ( 9.60 )
    -1.19 ( 7.74 )
    No statistical analyses for this end point

    Secondary: Change from Baseline in A1C at Week 104 (Excluding Rescue Approach)

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    End point title
    		 Change from Baseline in A1C at Week 104 (Excluding Rescue Approach)
    End point description
    A1C is blood marker used to report average blood glucose levels over prolonged periods of time. Percentage A1C is the ratio of glycated hemoglobin to total hemoglobin x 100. Thus, this change from baseline reflects the Week 104 A1C minus the Week 0 A1C. Participants who met pre-specified glycemic criteria were rescued with oral tablets of glimepiride up to Week 26 or basal insulin injected subcutaneously, and dosed according to Investigator judgment. Per protocol, this data set excludes data for any participant after the initiation of glycemic rescue therapy. The analysis population included all randomized participants who had received at least one dose of investigational product and had measurements of the respective endpoint at both baseline and Week 104.
    End point type
    Secondary
    End point timeframe
    Baseline and Week 104
    End point values
    		 Placebo/Glimepiride Ertugliflozin 5 mg Ertugliflozin 15 mg
    Number of subjects analysed
    109
    147
    142
    Units: Percent A1C
        arithmetic mean (standard deviation)
    -0.58 ( 0.93 )
    -0.60 ( 0.97 )
    -0.89 ( 0.90 )
    No statistical analyses for this end point

    Secondary: Change from Baseline in Fasting Plasma Glucose at Week 104 (Excluding Rescue Approach)

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    End point title
    		 Change from Baseline in Fasting Plasma Glucose at Week 104 (Excluding Rescue Approach)
    End point description
    Blood glucose was measured on a fasting basis. Blood was drawn at predose on Day 1 and after 104 weeks of treatment to determine change in plasma glucose levels (i.e., FPG at Week 104 minus FPG at Week 0). Participants who met pre-specified glycemic criteria were rescued with oral tablets of glimepiride up to Week 26 or basal insulin injected subcutaneously, and dosed according to Investigator judgment. Per protocol, this data set excludes data for any participant after the initiation of glycemic rescue therapy. The analysis population included all randomized participants who received at least one dose of investigational product and had measurements of the respective endpoint at both baseline and Week 104.
    End point type
    Secondary
    End point timeframe
    Baseline and Week 104
    End point values
    		 Placebo/Glimepiride Ertugliflozin 5 mg Ertugliflozin 15 mg
    Number of subjects analysed
    104
    143
    144
    Units: mg/dL
        arithmetic mean (standard deviation)
    -10.9 ( 44.3 )
    -18.2 ( 43.5 )
    -28.2 ( 44.9 )
    No statistical analyses for this end point

    Secondary: Percentage of Participants with an A1C of <7% (53 mmol/mol) at Week 104 (Excluding Rescue approach)

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    End point title
    		 Percentage of Participants with an A1C of <7% (53 mmol/mol) at Week 104 (Excluding Rescue approach)
    End point description
    A1C is blood marker used to report average blood glucose levels over prolonged periods of time. Percentage A1C is the ratio of glycated hemoglobin to total hemoglobin x 100. Participants who met pre-specified glycemic criteria were rescued with oral tablets of glimepiride up to Week 26 or basal insulin injected subcutaneously, and dosed according to Investigator judgment. Per protocol, this data set excludes data for any participant after the initiation of glycemic rescue therapy. The analysis population included all randomized participants who received at least one dose of investigational product. Any participant without post-baseline data at Week 104 is assumed to be "not at goal" (where "at goal" is A1C <7%) for the calculation of the percentages.
    End point type
    Secondary
    End point timeframe
    Week 104
    End point values
    		 Placebo/Glimepiride Ertugliflozin 5 mg Ertugliflozin 15 mg
    Number of subjects analysed
    209
    207
    205
    Units: Percentage of Participants
        number (not applicable)
    19.1
    24.6
    33.7
    No statistical analyses for this end point

    Secondary: Percentage of Participants with an A1C of <6.5% (48 mmol/mol) at Week 104 (Excluding Rescue Approach)

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    End point title
    		 Percentage of Participants with an A1C of <6.5% (48 mmol/mol) at Week 104 (Excluding Rescue Approach)
    End point description
    A1C is blood marker used to report average blood glucose levels over prolonged periods of time. Percentage A1C is the ratio of glycated hemoglobin to total hemoglobin x 100. Participants who met pre-specified glycemic criteria were rescued with oral tablets of glimepiride up to Week 26 or basal insulin injected subcutaneously, and dosed according to Investigator judgment. Per protocol, this data set excludes data for any participant after the initiation of glycemic rescue therapy. The analysis population included all randomized participants who received at least one dose of investigational product. Any participant without post-baseline data at Week 104 is assumed to be "not at goal" (where "at goal" is A1C <6.5%) for the calculation of the percentages..
    End point type
    Secondary
    End point timeframe
    Week 104
    End point values
    		 Placebo/Glimepiride Ertugliflozin 5 mg Ertugliflozin 15 mg
    Number of subjects analysed
    209
    207
    205
    Units: Percentage of Participants
        number (not applicable)
    7.2
    10.6
    12.2
    No statistical analyses for this end point

    Secondary: Percentage of Participants Receiving Glycemic Rescue Therapy up to Week 104

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    End point title
    		 Percentage of Participants Receiving Glycemic Rescue Therapy up to Week 104
    End point description
    Per protocol participants who met pre-specified glycemic criteria were rescued with oral tablets of glimepiride up to Week 26 or basal insulin injected subcutaneously, and dosed according to Investigator judgment. The analysis population included all randomized participants who received at least one dose of investigational product.
    End point type
    Secondary
    End point timeframe
    Up to Week 104
    End point values
    		 Placebo/Glimepiride Ertugliflozin 5 mg Ertugliflozin 15 mg
    Number of subjects analysed
    209
    207
    205
    Units: Percentage of participants
        number (confidence interval 95%)
    24.4 (18.74 to 30.8)
    11.1 (7.18 to 16.2)
    10.7 (6.85 to 15.8)
    No statistical analyses for this end point

    Secondary: Change from Baseline in Body Weight at Week 104 (Excluding Rescue Approach)

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    End point title
    		 Change from Baseline in Body Weight at Week 104 (Excluding Rescue Approach)
    End point description
    The change in body weight from baseline reflects the Week 104 body weight minus the Week 0 body weight. Participants who met pre-specified glycemic criteria were rescued with oral tablets of glimepiride up to Week 26 or basal insulin injected subcutaneously, and dosed according to Investigator judgment. Per protocol, this data set excludes data for any participant after the initiation of glycemic rescue therapy. The analysis population included all randomized participants who received at least one dose of investigational product and had measurements of the respective endpoint at both baseline and Week 104.
    End point type
    Secondary
    End point timeframe
    Baseline and Week 104
    End point values
    		 Placebo/Glimepiride Ertugliflozin 5 mg Ertugliflozin 15 mg
    Number of subjects analysed
    112
    148
    145
    Units: Kilograms
        arithmetic mean (standard deviation)
    -0.18 ( 3.38 )
    -3.77 ( 4.29 )
    -3.63 ( 3.86 )
    No statistical analyses for this end point

    Secondary: Change from Baseline in Sitting Systolic Blood Pressure at Week 104 (Excluding Rescue Approach)

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    End point title
    		 Change from Baseline in Sitting Systolic Blood Pressure at Week 104 (Excluding Rescue Approach)
    End point description
    This change from baseline reflects the Week 104 sitting SBP minus the Week 0 sitting SBP. Participants who met pre-specified glycemic criteria were rescued with oral tablets of glimepiride up to Week 26 or basal insulin injected subcutaneously, and dosed according to Investigator judgment. Per protocol, this data set excludes data for any participant after the initiation of glycemic rescue therapy. The analysis population included all randomized participants who received at least one dose of investigational product and had measurements of the respective endpoint at both baseline and Week 104.
    End point type
    Secondary
    End point timeframe
    Baseline and Week 104
    End point values
    		 Placebo/Glimepiride Ertugliflozin 5 mg Ertugliflozin 15 mg
    Number of subjects analysed
    104
    145
    142
    Units: mmHg
        arithmetic mean (standard deviation)
    0.05 ( 13.76 )
    -3.61 ( 12.78 )
    -3.13 ( 14.11 )
    No statistical analyses for this end point

    Secondary: Change from Baseline in Sitting Diastolic Blood Pressure at Week 104 (Excluding Rescue Approach)

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    End point title
    		 Change from Baseline in Sitting Diastolic Blood Pressure at Week 104 (Excluding Rescue Approach)
    End point description
    This change from baseline reflects the Week 104 sitting DBP minus the Week 0 sitting DBP. Participants who met pre-specified glycemic criteria were rescued with oral tablets of glimepiride up to Week 26 or basal insulin injected subcutaneously, and dosed according to Investigator judgment. Per protocol, this data set excludes data for any participant after the initiation of glycemic rescue therapy. The analysis population included all randomized participants who received at least one dose of investigational product and had measurements of the respective endpoint at both baseline and Week 104.
    End point type
    Secondary
    End point timeframe
    Baseline and Week 104
    End point values
    		 Placebo/Glimepiride Ertugliflozin 5 mg Ertugliflozin 15 mg
    Number of subjects analysed
    104
    145
    142
    Units: mmHg
        arithmetic mean (standard deviation)
    -0.46 ( 8.77 )
    -2.36 ( 9.23 )
    -1.52 ( 8.61 )
    No statistical analyses for this end point

    Secondary: Ertugliflozin Plasma Concentrations (ng/mL): Summary Statistics Over Time (Excluding Rescue Approach)

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    End point title
    		 Ertugliflozin Plasma Concentrations (ng/mL): Summary Statistics Over Time (Excluding Rescue Approach)
    End point description
    Pharmacokinetic samples were collected at approximately 24 hours following the prior day’s dose and before administration of the current day’s dose. The lower limit of quantitation (LLOQ) was 0.500 ng/mL. Participants who met pre-specified glycemic criteria were rescued with oral tablets of glimepiride up to Week 26 or basal insulin injected subcutaneously, and dosed according to Investigator judgment. Per protocol, this data set excludes data for any participant after the initiation of glycemic rescue therapy. A value of 9999 indicates that data for this field was not available as it was below the lower limit of quantification for these assays. The analysis population included all participants as treated (including those with all concentrations below the lower limit of quantification) and was included in the calculation of the summary statistics. Numbers of participants with non-missing concentrations at the respective time points are displayed.
    End point type
    Secondary
    End point timeframe
    Pre-dose and/or 60 minutes post-dose on Weeks 6, 12, 18, and 30
    End point values
    		 Placebo/Glimepiride Ertugliflozin 5 mg Ertugliflozin 15 mg
    Number of subjects analysed
    209
    207
    205
    Units: ng/mL
    arithmetic mean (standard deviation)
        Week 6:Pre-dose|
    9999 ( 9999 )
    14.89 ( 28.11 )
    38.38 ( 74.83 )
        Week 12:Pre-dose|
    9999 ( 9999 )
    12.34 ( 26.07 )
    29.23 ( 55.63 )
        Week 12:60 mins post-dose|
    9999 ( 9999 )
    74.84 ( 51.58 )
    228.13 ( 139.14 )
        Week 18:Pre-dose|
    0.01 ( 0.10 )
    9.91 ( 21.18 )
    24.46 ( 39.97 )
        Week 18:60 mins post-dose|
    0.01 ( 0.09 )
    74.39 ( 49.77 )
    214.96 ( 147.36 )
        Week 30:Pre-dose|
    0.15 ( 1.07 )
    12.66 ( 25.50 )
    30.55 ( 60.33 )
    No statistical analyses for this end point

    Secondary: Percent Change from Baseline in BMD at Week 26 as Measured by DXA at the Lumbar Spine (L1-L4) Using Raw Data (Excluding Bone Rescue Approach)

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    End point title
    		 Percent Change from Baseline in BMD at Week 26 as Measured by DXA at the Lumbar Spine (L1-L4) Using Raw Data (Excluding Bone Rescue Approach)
    End point description
    BMD at the femoral neck was assessed by DXA at Week 0 and Week 26. Participants who exhibited a significant reduction in BMD according to the protocol defined criteria completed an unscheduled DXA scan and, if required, received bone-active therapy. This table excludes measurements obtained after initiation of bone rescue medications. The analysis population included all randomized participants who received at least one dose of investigational product and had a measurement at baseline and at least one post-baseline measurement.
    End point type
    Secondary
    End point timeframe
    Baseline and Week 26
    End point values
    		 Placebo/Glimepiride Ertugliflozin 5 mg Ertugliflozin 15 mg
    Number of subjects analysed
    191
    200
    189
    Units: Percentage change
        least squares mean (confidence interval 95%)
    0.22 (-0.20 to 0.65)
    -0.01 (-0.42 to 0.41)
    0.12 (-0.31 to 0.55)
    Statistical analysis title
    		 Difference in the Least Squares Means
    Statistical analysis description
    Based on cLDA model with fixed effects for treatment, time, prior antihyperglycemic medication (Metformin monotherapy or Metformin + another AHA), baseline eGFR (continuous), menopausal status, and the interaction of time by treatment. Time was treated as a categorical variable.
    Comparison groups
    Placebo/Glimepiride v Ertugliflozin 15 mg
    Number of subjects included in analysis
    380
    Analysis specification
    Pre-specified
    Analysis type
    		 other
    Method
    Parameter type
    		 Difference in the Least Squares Means
    Point estimate
    -0.1
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -0.71
         upper limit
    		 0.5
    Statistical analysis title
    		 Difference in the Least Squares Means
    Statistical analysis description
    Based on cLDA model with fixed effects for treatment, time, prior antihyperglycemic medication (Metformin monotherapy or Metformin + another AHA), baseline eGFR (continuous), menopausal status, and the interaction of time by treatment. Time was treated as a categorical variable.
    Comparison groups
    Placebo/Glimepiride v Ertugliflozin 5 mg
    Number of subjects included in analysis
    391
    Analysis specification
    Pre-specified
    Analysis type
    		 other
    Method
    Parameter type
    		 Difference in the Least Squares Means
    Point estimate
    -0.23
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -0.83
         upper limit
    		 0.37

    Secondary: Percent Change from Baseline in BMD at Week 26 as Measured by DXA at the Femoral Neck Using Raw Data (Excluding Bone Rescue Approach)

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    End point title
    		 Percent Change from Baseline in BMD at Week 26 as Measured by DXA at the Femoral Neck Using Raw Data (Excluding Bone Rescue Approach)
    End point description
    BMD at the femoral neck was assessed by DXA at Week 0 and Week 26. Participants who exhibited a significant reduction in BMD according to the protocol defined criteria completed an unscheduled DXA scan and, if required, received bone-active therapy. This table excludes measurements obtained after initiation of bone rescue medications. The analysis population included all randomized participants who received at least one dose of investigational product and had a measurement at baseline and at least one post-baseline measurement. The analysis population included all randomized participants who received at least one dose of investigational product and had a measurement at baseline and at least one post-baseline measurement.
    End point type
    Secondary
    End point timeframe
    Baseline and Week 26
    End point values
    		 Placebo/Glimepiride Ertugliflozin 5 mg Ertugliflozin 15 mg
    Number of subjects analysed
    191
    200
    190
    Units: Percent change
        least squares mean (confidence interval 95%)
    -0.40 (-0.89 to 0.09)
    -0.10 (-0.57 to 0.38)
    0.30 (-0.19 to 0.79)
    Statistical analysis title
    		 Difference in the Least Squares Means
    Statistical analysis description
    Based on cLDA model with fixed effects for treatment, time, prior antihyperglycemic medication (Metformin monotherapy or Metformin + another AHA), baseline eGFR (continuous), menopausal status, and the interaction of time by treatment. Time was treated as a categorical variable.
    Comparison groups
    Placebo/Glimepiride v Ertugliflozin 15 mg
    Number of subjects included in analysis
    381
    Analysis specification
    Pre-specified
    Analysis type
    		 other
    Method
    Parameter type
    		 Difference in the Least Squares Means
    Point estimate
    0.7
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0
         upper limit
    		 1.39
    Statistical analysis title
    		 Difference in the Least Squares Means
    Statistical analysis description
    Based on cLDA model with fixed effects for treatment, time, prior antihyperglycemic medication (Metformin monotherapy or Metformin + another AHA), baseline eGFR (continuous), menopausal status, and the interaction of time by treatment. Time was treated as a categorical variable.
    Comparison groups
    Placebo/Glimepiride v Ertugliflozin 5 mg
    Number of subjects included in analysis
    391
    Analysis specification
    Pre-specified
    Analysis type
    		 other
    Method
    Parameter type
    		 Difference in the Least Squares Means
    Point estimate
    0.3
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -0.38
         upper limit
    		 0.99

    Secondary: Percent Change from Baseline in BMD at Week 26 as Measured by DXA at the Total Hip Using Raw Data (Excluding Bone Rescue Approach)

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    End point title
    		 Percent Change from Baseline in BMD at Week 26 as Measured by DXA at the Total Hip Using Raw Data (Excluding Bone Rescue Approach)
    End point description
    BMD at the total hip was assessed by DXA at Week 0 and Week 26. Participants who exhibited a significant reduction in BMD according to the protocol defined criteria completed an unscheduled DXA scan and, if required, received bone-active therapy. This table excludes measurements obtained after initiation of bone rescue medications. The analysis population included all randomized participants who received at least one dose of investigational product and had a measurement at baseline and at least one post-baseline measurement.
    End point type
    Secondary
    End point timeframe
    Baseline and Week 26
    End point values
    		 Placebo/Glimepiride Ertugliflozin 5 mg Ertugliflozin 15 mg
    Number of subjects analysed
    191
    200
    190
    Units: Percent change
        least squares mean (confidence interval 95%)
    -0.63 (-0.92 to -0.34)
    -0.55 (-0.83 to -0.27)
    -0.36 (-0.65 to -0.07)
    Statistical analysis title
    		 Difference in the Least Squares Means
    Statistical analysis description
    Based on cLDA model with fixed effects for treatment, time, prior antihyperglycemic medication (Metformin monotherapy or Metformin + another AHA), baseline eGFR (continuous), menopausal status, and the interaction of time by treatment. Time was treated as a categorical variable.
    Comparison groups
    Placebo/Glimepiride v Ertugliflozin 15 mg
    Number of subjects included in analysis
    381
    Analysis specification
    Pre-specified
    Analysis type
    		 other
    Method
    Parameter type
    		 Difference in the Least Squares Means
    Point estimate
    0.27
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -0.15
         upper limit
    		 0.68
    Statistical analysis title
    		 Difference in the Least Squares Means
    Statistical analysis description
    Based on cLDA model with fixed effects for treatment, time, prior antihyperglycemic medication (Metformin monotherapy or Metformin + another AHA), baseline eGFR (continuous), menopausal status, and the interaction of time by treatment. Time was treated as a categorical variable.
    Comparison groups
    Placebo/Glimepiride v Ertugliflozin 5 mg
    Number of subjects included in analysis
    391
    Analysis specification
    Pre-specified
    Analysis type
    		 other
    Method
    Parameter type
    		 Difference in the Least Squares Means
    Point estimate
    0.08
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -0.33
         upper limit
    		 0.48

    Secondary: Percent Change from Baseline in BMD at Week 26 as Measured by DXA at the Distal Forearm Using Raw Data (Excluding Bone Rescue Approach)

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    End point title
    		 Percent Change from Baseline in BMD at Week 26 as Measured by DXA at the Distal Forearm Using Raw Data (Excluding Bone Rescue Approach)
    End point description
    BMD at the distal forearm was assessed by DXA at Week 0 and Week 26. Participants who exhibited a significant reduction in BMD according to the protocol defined criteria completed an unscheduled DXA scan and, if required, received bone-active therapy. This table excludes measurements obtained after initiation of bone rescue medications. The analysis population included all randomized participants who received at least one dose of investigational product and had a measurement at baseline and at least one post-baseline measurement.
    End point type
    Secondary
    End point timeframe
    Baseline and Week 26
    End point values
    		 Placebo/Glimepiride Ertugliflozin 5 mg Ertugliflozin 15 mg
    Number of subjects analysed
    190
    200
    189
    Units: Percent change
        least squares mean (confidence interval 95%)
    0.06 (-0.35 to 0.47)
    -0.15 (-0.55 to 0.24)
    -0.13 (-0.53 to 0.28)
    Statistical analysis title
    		 Difference in the Least Squares Means
    Statistical analysis description
    Based on cLDA model with fixed effects for treatment, time, prior antihyperglycemic medication (Metformin monotherapy or Metformin + another AHA), baseline eGFR (continuous), menopausal status, and the interaction of time by treatment. Time was treated as a categorical variable.
    Comparison groups
    Placebo/Glimepiride v Ertugliflozin 15 mg
    Number of subjects included in analysis
    379
    Analysis specification
    Pre-specified
    Analysis type
    		 other
    Method
    Parameter type
    		 Difference in the Least Squares Means
    Point estimate
    -0.19
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -0.76
         upper limit
    		 0.39
    Statistical analysis title
    		 Difference in the Least Squares Means
    Statistical analysis description
    Based on cLDA model with fixed effects for treatment, time, prior antihyperglycemic medication (Metformin monotherapy or Metformin + another AHA), baseline eGFR (continuous), menopausal status, and the interaction of time by treatment. Time was treated as a categorical variable.
    Comparison groups
    Placebo/Glimepiride v Ertugliflozin 5 mg
    Number of subjects included in analysis
    390
    Analysis specification
    Pre-specified
    Analysis type
    		 other
    Method
    Parameter type
    		 Difference in the Least Squares Means
    Point estimate
    -0.21
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -0.78
         upper limit
    		 0.35

    Secondary: Change from Baseline in Bone Biomarker Carboxy-Terminal Cross-Linking Telopeptides of Type I Collagen (CTX) at Week 26 (Excluding Bone Rescue Approach)

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    End point title
    		 Change from Baseline in Bone Biomarker Carboxy-Terminal Cross-Linking Telopeptides of Type I Collagen (CTX) at Week 26 (Excluding Bone Rescue Approach)
    End point description
    CTX is a biochemical marker of bone resorption. Participants who exhibited a significant reduction in BMD according to the protocol defined criteria completed an unscheduled DXA scan and, if required, received bone-active therapy. This table excludes measurements obtained after initiation of bone rescue medications. The analysis population included all randomized participants who received at least one dose of investigational product and had measurements of the respective endpoint at both baseline and Week 26.
    End point type
    Secondary
    End point timeframe
    Baseline and Week 26
    End point values
    		 Placebo/Glimepiride Ertugliflozin 5 mg Ertugliflozin 15 mg
    Number of subjects analysed
    185
    179
    180
    Units: ng/L
        arithmetic mean (standard deviation)
    10.8 ( 106.6 )
    51.9 ( 121.9 )
    80.2 ( 149.7 )
    No statistical analyses for this end point

    Secondary: Change from Baseline in Bone Biomarker Procollagen Type I N-terminal Propeptide (P1NP) at Week 26 (Excluding Bone Rescue Approach)

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    End point title
    		 Change from Baseline in Bone Biomarker Procollagen Type I N-terminal Propeptide (P1NP) at Week 26 (Excluding Bone Rescue Approach)
    End point description
    P1NP is a biochemical marker of bone resorption. Participants who exhibited a significant reduction in BMD according to the protocol defined criteria completed an unscheduled DXA scan and, if required, received bone-active therapy. This table excludes measurements obtained after initiation of bone rescue medications. The analysis population included all randomized participants who received at least one dose of investigational product and had measurements of the respective endpoint at both baseline and Week 26.
    End point type
    Secondary
    End point timeframe
    Baseline and Week 26
    End point values
    		 Placebo/Glimepiride Ertugliflozin 5 mg Ertugliflozin 15 mg
    Number of subjects analysed
    186
    183
    183
    Units: ug/L
        arithmetic mean (standard deviation)
    0.5 ( 11.7 )
    0.8 ( 12.1 )
    0.5 ( 15.0 )
    No statistical analyses for this end point

    Secondary: Change from Baseline in Bone Biomarker Parathyroid Hormone (PTH) at Week 26 (Excluding Bone Rescue Approach)

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    End point title
    		 Change from Baseline in Bone Biomarker Parathyroid Hormone (PTH) at Week 26 (Excluding Bone Rescue Approach)
    End point description
    PTH is a biochemical marker of bone resorption. Participants who exhibited a significant reduction in BMD according to the protocol defined criteria completed an unscheduled DXA scan and, if required, received bone-active therapy. This table excludes measurements obtained after initiation of bone rescue medications. The analysis population included all randomized participants who received at least one dose of investigational product and had measurements of the respective endpoint at both baseline and Week 26.
    End point type
    Secondary
    End point timeframe
    Baseline and Week 26
    End point values
    		 Placebo/Glimepiride Ertugliflozin 5 mg Ertugliflozin 15 mg
    Number of subjects analysed
    186
    182
    184
    Units: ng/L
        arithmetic mean (standard deviation)
    -0.98 ( 6.71 )
    0.28 ( 7.52 )
    0.14 ( 7.53 )
    No statistical analyses for this end point

    Secondary: Percent Change from Baseline in BMD at Week 52 as Measured by DXA at the Lumbar Spine (L1-L4) Using Raw Data (Excluding Bone Rescue Approach)

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    End point title
    		 Percent Change from Baseline in BMD at Week 52 as Measured by DXA at the Lumbar Spine (L1-L4) Using Raw Data (Excluding Bone Rescue Approach)
    End point description
    BMD at the femoral neck was assessed by DXA at Week 0 and Week 52. Participants who exhibited a significant reduction in BMD according to the protocol defined criteria completed an unscheduled DXA scan and, if required, received bone-active therapy. This table excludes measurements obtained after initiation of bone rescue medications. The analysis population included all randomized participants who received at least one dose of investigational product and had a measurement at baseline and at least one post-baseline measurement.
    End point type
    Secondary
    End point timeframe
    Baseline and Week 52
    End point values
    		 Placebo/Glimepiride Ertugliflozin 5 mg Ertugliflozin 15 mg
    Number of subjects analysed
    191
    202
    189
    Units: Percent change
        least squares mean (confidence interval 95%)
    -0.10 (-0.60 to 0.40)
    -0.28 (-0.77 to 0.20)
    0.07 (-0.43 to 0.57)
    Statistical analysis title
    		 Difference in the Least Squares Means
    Statistical analysis description
    Based on cLDA model with fixed effects for treatment, time, prior antihyperglycemic medication (Metformin monotherapy or Metformin + another AHA), baseline eGFR (continuous), menopausal status, and the interaction of time by treatment. Time was treated as a categorical variable.
    Comparison groups
    Placebo/Glimepiride v Ertugliflozin 15 mg
    Number of subjects included in analysis
    380
    Analysis specification
    Pre-specified
    Analysis type
    		 other
    Method
    Parameter type
    		 Difference in the Least Squares Means
    Point estimate
    0.17
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -0.53
         upper limit
    		 0.88
    Statistical analysis title
    		 Difference in the Least Squares Means
    Statistical analysis description
    Based on cLDA model with fixed effects for treatment, time, prior antihyperglycemic medication (Metformin monotherapy or Metformin + another AHA), baseline eGFR (continuous), menopausal status, and the interaction of time by treatment. Time was treated as a categorical variable.
    Comparison groups
    Placebo/Glimepiride v Ertugliflozin 5 mg
    Number of subjects included in analysis
    393
    Analysis specification
    Pre-specified
    Analysis type
    		 other
    Method
    Parameter type
    		 Difference in the Least Squares Means
    Point estimate
    -0.18
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -0.88
         upper limit
    		 0.51

    Secondary: Percent Change from Baseline in BMD at Week 52 as Measured by DXA at the Femoral Neck Using Raw Data (Excluding Bone Rescue Approach)

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    End point title
    		 Percent Change from Baseline in BMD at Week 52 as Measured by DXA at the Femoral Neck Using Raw Data (Excluding Bone Rescue Approach)
    End point description
    BMD at the femoral neck was assessed by DXA at Week 0 and Week 52. Participants who exhibited a significant reduction in BMD according to the protocol defined criteria completed an unscheduled DXA scan and, if required, received bone-active therapy. This table excludes measurements obtained after initiation of bone rescue medications. The analysis population included all randomized participants who received at least one dose of investigational product and had a measurement at baseline and at least one post-baseline measurement.
    End point type
    Secondary
    End point timeframe
    Baseline and Week 52
    End point values
    		 Placebo/Glimepiride Ertugliflozin 5 mg Ertugliflozin 15 mg
    Number of subjects analysed
    191
    202
    190
    Units: Percent change
        least squares mean (confidence interval 95%)
    -0.69 (-1.25 to -0.14)
    -0.49 (-1.04 to 0.06)
    -0.44 (-1.06 to 0.17)
    Statistical analysis title
    		 Difference in the Least Squares Means
    Statistical analysis description
    Based on cLDA model with fixed effects for treatment, time, prior antihyperglycemic medication (Metformin monotherapy or Metformin + another AHA), baseline eGFR (continuous), menopausal status, and the interaction of time by treatment. Time was treated as a categorical variable.
    Comparison groups
    Placebo/Glimepiride v Ertugliflozin 15 mg
    Number of subjects included in analysis
    381
    Analysis specification
    Pre-specified
    Analysis type
    		 other
    Method
    Parameter type
    		 Difference in the Least Squares Means
    Point estimate
    0.25
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -0.48
         upper limit
    		 0.98
    Statistical analysis title
    		 Difference in the Least Squares Means
    Statistical analysis description
    Based on cLDA model with fixed effects for treatment, time, prior antihyperglycemic medication (Metformin monotherapy or Metformin + another AHA), baseline eGFR (continuous), menopausal status, and the interaction of time by treatment. Time was treated as a categorical variable.
    Comparison groups
    Placebo/Glimepiride v Ertugliflozin 5 mg
    Number of subjects included in analysis
    393
    Analysis specification
    Pre-specified
    Analysis type
    		 other
    Method
    Parameter type
    		 Difference in the Least Squares Means
    Point estimate
    0.2
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -0.51
         upper limit
    		 0.91

    Secondary: Percent Change from Baseline in BMD at Week 52 as Measured by DXA at the Total Hip Using Raw Data (Excluding Bone Rescue Approach)

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    End point title
    		 Percent Change from Baseline in BMD at Week 52 as Measured by DXA at the Total Hip Using Raw Data (Excluding Bone Rescue Approach)
    End point description
    BMD at the total hip was assessed by DXA at Week 0 and Week 52. Participants who exhibited a significant reduction in BMD according to the protocol defined criteria completed an unscheduled DXA scan and, if required, received bone-active therapy. This table excludes measurements obtained after initiation of bone rescue medications. The analysis population included all randomized participants who received at least one dose of investigational product and had a measurement at baseline and at least one post-baseline measurement.
    End point type
    Secondary
    End point timeframe
    Baseline and Week 52
    End point values
    		 Placebo/Glimepiride Ertugliflozin 5 mg Ertugliflozin 15 mg
    Number of subjects analysed
    191
    202
    190
    Units: Percent change
        least squares mean (confidence interval 95%)
    -0.82 (-1.19 to -0.46)
    -1.04 (-1.41 to -0.67)
    -1.32 (-1.69 to -0.94)
    Statistical analysis title
    		 Difference in the Least Squares Means
    Statistical analysis description
    Based on cLDA model with fixed effects for treatment, time, prior antihyperglycemic medication (Metformin monotherapy or Metformin + another AHA), baseline eGFR (continuous), menopausal status, and the interaction of time by treatment. Time was treated as a categorical variable.
    Comparison groups
    Placebo/Glimepiride v Ertugliflozin 15 mg
    Number of subjects included in analysis
    381
    Analysis specification
    Pre-specified
    Analysis type
    		 other
    Method
    Parameter type
    		 Difference in the Least Squares Means
    Point estimate
    -0.5
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -0.95
         upper limit
    		 -0.04
    Statistical analysis title
    		 Difference in the Least Squares Means
    Statistical analysis description
    Based on cLDA model with fixed effects for treatment, time, prior antihyperglycemic medication (Metformin monotherapy or Metformin + another AHA), baseline eGFR (continuous), menopausal status, and the interaction of time by treatment. Time was treated as a categorical variable.
    Comparison groups
    Placebo/Glimepiride v Ertugliflozin 5 mg
    Number of subjects included in analysis
    393
    Analysis specification
    Pre-specified
    Analysis type
    		 other
    Method
    Parameter type
    		 Difference in the Least Squares Means
    Point estimate
    -0.22
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -0.66
         upper limit
    		 0.23

    Secondary: Percent Change from Baseline in BMD at Week 52 as Measured by DXA at the Distal Forearm Using Raw Data (Excluding Bone Rescue Approach)

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    End point title
    		 Percent Change from Baseline in BMD at Week 52 as Measured by DXA at the Distal Forearm Using Raw Data (Excluding Bone Rescue Approach)
    End point description
    BMD at the distal forearm was assessed by DXA at Week 0 and Week 52. Participants who exhibited a significant reduction in BMD according to the protocol defined criteria completed an unscheduled DXA scan and, if required, received bone-active therapy. This table excludes measurements obtained after initiation of bone rescue medications. The analysis population included all randomized participants who received at least one dose of investigational product and had a measurement at baseline and at least one post-baseline measurement.
    End point type
    Secondary
    End point timeframe
    Baseline and Week 52
    End point values
    		 Placebo/Glimepiride Ertugliflozin 5 mg Ertugliflozin 15 mg
    Number of subjects analysed
    190
    200
    189
    Units: Percent change
        least squares mean (confidence interval 95%)
    -0.44 (-0.95 to 0.06)
    -0.59 (-1.04 to 0.14)
    -0.39 (-0.90 to 0.12)
    Statistical analysis title
    		 Difference in the Least Squares Means
    Statistical analysis description
    Based on cLDA model with fixed effects for treatment, time, prior antihyperglycemic medication (Metformin monotherapy or Metformin + another AHA), baseline eGFR (continuous), menopausal status, and the interaction of time by treatment. Time was treated as a categorical variable.
    Comparison groups
    Placebo/Glimepiride v Ertugliflozin 15 mg
    Number of subjects included in analysis
    379
    Analysis specification
    Pre-specified
    Analysis type
    		 other
    Method
    Parameter type
    		 Difference in the Least Squares Means
    Point estimate
    0.06
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -0.61
         upper limit
    		 0.72
    Statistical analysis title
    		 Difference in the Least Squares Means
    Statistical analysis description
    Based on cLDA model with fixed effects for treatment, time, prior antihyperglycemic medication (Metformin monotherapy or Metformin + another AHA), baseline eGFR (continuous), menopausal status, and the interaction of time by treatment. Time was treated as a categorical variable.
    Comparison groups
    Placebo/Glimepiride v Ertugliflozin 5 mg
    Number of subjects included in analysis
    390
    Analysis specification
    Pre-specified
    Analysis type
    		 other
    Method
    Parameter type
    		 Difference in the Least Squares Means
    Point estimate
    -0.15
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -0.78
         upper limit
    		 0.49

    Secondary: Percent Change from Baseline in Bone Biomarker CTX at Week 52 (Excluding Bone Rescue Approach)

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    End point title
    		 Percent Change from Baseline in Bone Biomarker CTX at Week 52 (Excluding Bone Rescue Approach)
    End point description
    CTX is a biochemical marker of bone resorption. Participants who exhibited a significant reduction in BMD according to the protocol defined criteria completed an unscheduled DXA scan and, if required, received bone-active therapy. This table excludes measurements obtained after initiation of bone rescue medications. The analysis population included all participants who received at least one dose of investigational product and had measurements of the respective endpoint at both baseline and Week 52.
    End point type
    Secondary
    End point timeframe
    Baseline and Week 52
    End point values
    		 Placebo/Glimepiride Ertugliflozin 5 mg Ertugliflozin 15 mg
    Number of subjects analysed
    171
    178
    171
    Units: Percent change
        arithmetic mean (standard deviation)
    15.54 ( 43.34 )
    34.36 ( 52.74 )
    41.57 ( 50.69 )
    No statistical analyses for this end point

    Secondary: Percent Change from Baseline in Bone Biomarker P1NP at Week 52 (Excluding Bone Rescue Approach)

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    End point title
    		 Percent Change from Baseline in Bone Biomarker P1NP at Week 52 (Excluding Bone Rescue Approach)
    End point description
    P1NP is a biochemical marker of bone resorption. Participants who exhibited a significant reduction in BMD according to the protocol defined criteria completed an unscheduled DXA scan and, if required, received bone-active therapy. This table excludes measurements obtained after initiation of bone rescue medications. The analysis population included all participants who received at least one dose of investigational product and had measurements of the respective endpoint at both baseline and Week 52.
    End point type
    Secondary
    End point timeframe
    Baseline and Week 52
    End point values
    		 Placebo/Glimepiride Ertugliflozin 5 mg Ertugliflozin 15 mg
    Number of subjects analysed
    171
    179
    173
    Units: Percent Change
        arithmetic mean (standard deviation)
    24.50 ( 120.29 )
    8.41 ( 30.95 )
    19.79 ( 79.57 )
    No statistical analyses for this end point

    Secondary: Percent Change from Baseline in Bone Biomarker PTH at Week 52 (Excluding Bone Rescue Approach)

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    End point title
    		 Percent Change from Baseline in Bone Biomarker PTH at Week 52 (Excluding Bone Rescue Approach)
    End point description
    PTH is a biochemical marker of bone resorption. Participants who exhibited a significant reduction in BMD according to the protocol defined criteria completed an unscheduled DXA scan and, if required, received bone-active therapy. This table excludes measurements obtained after initiation of bone rescue medications. The analysis population included all participants who received at least one dose of investigational product and had measurements of the respective endpoint at both baseline and Week 52.
    End point type
    Secondary
    End point timeframe
    Baseline and Week 52
    End point values
    		 Placebo/Glimepiride Ertugliflozin 5 mg Ertugliflozin 15 mg
    Number of subjects analysed
    171
    177
    175
    Units: Percent Change
        arithmetic mean (standard deviation)
    8.11 ( 52.05 )
    11.09 ( 41.80 )
    2.48 ( 36.57 )
    No statistical analyses for this end point

    Secondary: Percent Change from Baseline in BMD at Week 104 as Measured by DXA at the Lumbar Spine (L1-L4) Using Raw Data (Excluding Bone Rescue Approach)

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    End point title
    		 Percent Change from Baseline in BMD at Week 104 as Measured by DXA at the Lumbar Spine (L1-L4) Using Raw Data (Excluding Bone Rescue Approach)
    End point description
    BMD at the lumbar spine was assessed by DXA at Week 0 and Week 104. Participants who exhibited a significant reduction in BMD according to the protocol defined criteria completed an unscheduled DXA scan and, if required, received bone-active therapy. This table excludes measurements obtained after initiation of bone rescue medications. The analysis population included all randomized participants who received at least one dose of investigational product and had a measurement at baseline and at least one post-baseline measurement.
    End point type
    Secondary
    End point timeframe
    Baseline and Week 104
    End point values
    		 Placebo/Glimepiride Ertugliflozin 5 mg Ertugliflozin 15 mg
    Number of subjects analysed
    191
    202
    189
    Units: Percent change
        least squares mean (confidence interval 95%)
    0.09 (-0.47 to 0.66)
    -0.19 (-0.72 to 0.35)
    -0.13 (-0.68 to 0.42)
    Statistical analysis title
    		 Difference in the Least Squares Means
    Statistical analysis description
    Based on cLDA model with fixed effects for treatment, time, prior antihyperglycemic medication (Metformin monotherapy or Metformin + another AHA), baseline eGFR (continuous), menopausal status, and the interaction of time by treatment. Time was treated as a categorical variable.
    Comparison groups
    Placebo/Glimepiride v Ertugliflozin 15 mg
    Number of subjects included in analysis
    380
    Analysis specification
    Pre-specified
    Analysis type
    		 other
    Method
    Parameter type
    		 Difference in the Least Squares Means
    Point estimate
    -0.23
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -1.01
         upper limit
    		 0.56
    Statistical analysis title
    		 Difference in the Least Squares Means
    Statistical analysis description
    Based on cLDA model with fixed effects for treatment, time, prior antihyperglycemic medication (Metformin monotherapy or Metformin + another AHA), baseline eGFR (continuous), menopausal status, and the interaction of time by treatment. Time was treated as a categorical variable.
    Comparison groups
    Placebo/Glimepiride v Ertugliflozin 5 mg
    Number of subjects included in analysis
    393
    Analysis specification
    Pre-specified
    Analysis type
    		 other
    Method
    Parameter type
    		 Difference in the Least Squares Means
    Point estimate
    -0.28
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -1.06
         upper limit
    		 0.5

    Secondary: Percent Change from Baseline in BMD at Week 104 as Measured by DXA at the Femoral Neck Using Raw Data (Excluding Bone Rescue Approach)

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    End point title
    		 Percent Change from Baseline in BMD at Week 104 as Measured by DXA at the Femoral Neck Using Raw Data (Excluding Bone Rescue Approach)
    End point description
    BMD at the femoral neck was assessed by DXA at Week 0 and Week 104. Participants who exhibited a significant reduction in BMD according to the protocol defined criteria completed an unscheduled DXA scan and, if required, received bone-active therapy. This table excludes measurements obtained after initiation of bone rescue medications. The analysis population included all randomized participants who received at least one dose of investigational product and had a measurement at baseline and at least one post-baseline measurement.
    End point type
    Secondary
    End point timeframe
    Baseline and Week 104
    End point values
    		 Placebo/Glimepiride Ertugliflozin 5 mg Ertugliflozin 15 mg
    Number of subjects analysed
    191
    202
    190
    Units: Percent change
        least squares mean (confidence interval 95%)
    -1.23 (-1.86 to -0.61)
    -1.11 (-1.74 to -0.49)
    -0.96 (-1.67 to -0.26)
    Statistical analysis title
    		 Difference in the Least Squares Means
    Statistical analysis description
    Based on cLDA model with fixed effects for treatment, time, prior antihyperglycemic medication (Metformin monotherapy or Metformin + another AHA), baseline eGFR (continuous), menopausal status, and the interaction of time by treatment. Time was treated as a categorical variable.
    Comparison groups
    Placebo/Glimepiride v Ertugliflozin 15 mg
    Number of subjects included in analysis
    381
    Analysis specification
    Pre-specified
    Analysis type
    		 other
    Method
    Parameter type
    		 Difference in the Least Squares Means
    Point estimate
    0.27
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -0.58
         upper limit
    		 1.13
    Statistical analysis title
    		 Difference in the Least Squares Means
    Statistical analysis description
    Based on cLDA model with fixed effects for treatment, time, prior antihyperglycemic medication (Metformin monotherapy or Metformin + another AHA), baseline eGFR (continuous), menopausal status, and the interaction of time by treatment. Time was treated as a categorical variable.
    Comparison groups
    Placebo/Glimepiride v Ertugliflozin 5 mg
    Number of subjects included in analysis
    393
    Analysis specification
    Pre-specified
    Analysis type
    		 other
    Method
    Parameter type
    		 Difference in the Least Squares Means
    Point estimate
    0.12
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -0.7
         upper limit
    		 0.93

    Secondary: Percent Change from Baseline in BMD at Week 104 as Measured by DXA at the Total Hip Using Raw Data (Excluding Bone Rescue Approach)

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    End point title
    		 Percent Change from Baseline in BMD at Week 104 as Measured by DXA at the Total Hip Using Raw Data (Excluding Bone Rescue Approach)
    End point description
    BMD at the total hip was assessed by DXA at Week 0 and Week 104. Participants who exhibited a significant reduction in BMD according to the protocol defined criteria completed an unscheduled DXA scan and, if required, received bone-active therapy. This table excludes measurements obtained after initiation of bone rescue medications. The analysis population included all randomized participants who received at least one dose of investigational product and had a measurement at baseline and at least one post-baseline measurement.
    End point type
    Secondary
    End point timeframe
    Baseline and Week 104
    End point values
    		 Placebo/Glimepiride Ertugliflozin 5 mg Ertugliflozin 15 mg
    Number of subjects analysed
    191
    202
    190
    Units: Percent change
        least squares mean (confidence interval 95%)
    -1.18 (-1.63 to -0.73)
    -1.72 (-2.19 to -1.25)
    -2.02 (-2.51 to -1.53)
    Statistical analysis title
    		 Difference in the Least Squares Means
    Statistical analysis description
    Based on cLDA model with fixed effects for treatment, time, prior antihyperglycemic medication (Metformin monotherapy or Metformin + another AHA), baseline eGFR (continuous), menopausal status, and the interaction of time by treatment. Time was treated as a categorical variable.
    Comparison groups
    Placebo/Glimepiride v Ertugliflozin 15 mg
    Number of subjects included in analysis
    381
    Analysis specification
    Pre-specified
    Analysis type
    		 other
    Method
    Parameter type
    		 Difference in the Least Squares Means
    Point estimate
    -0.84
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -1.44
         upper limit
    		 -0.24
    Statistical analysis title
    		 Difference in the Least Squares Means
    Statistical analysis description
    Based on cLDA model with fixed effects for treatment, time, prior antihyperglycemic medication (Metformin monotherapy or Metformin + another AHA), baseline eGFR (continuous), menopausal status, and the interaction of time by treatment. Time was treated as a categorical variable.
    Comparison groups
    Placebo/Glimepiride v Ertugliflozin 5 mg
    Number of subjects included in analysis
    393
    Analysis specification
    Pre-specified
    Analysis type
    		 other
    Method
    Parameter type
    		 Difference in the least Squares Means
    Point estimate
    -0.54
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -1.12
         upper limit
    		 0.05

    Secondary: Percent Change from BMD at Week 104 as Measured by DXA at the Distal Forearm Using Raw Data (Excluding Bone Rescue Approach)

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    End point title
    		 Percent Change from BMD at Week 104 as Measured by DXA at the Distal Forearm Using Raw Data (Excluding Bone Rescue Approach)
    End point description
    BMD at the distal forearm was assessed by DXA at Week 0 and Week 104. Participants who exhibited a significant reduction in BMD according to the protocol defined criteria completed an unscheduled DXA scan and, if required, received bone-active therapy. This table excludes measurements obtained after initiation of bone rescue medications. The analysis population included all randomized participants who received at least one dose of investigational product and had a measurement at baseline and at least one post-baseline measurement.
    End point type
    Secondary
    End point timeframe
    Baseline and Week 104
    End point values
    		 Placebo/Glimepiride Ertugliflozin 5 mg Ertugliflozin 15 mg
    Number of subjects analysed
    190
    200
    189
    Units: Percent change
        least squares mean (confidence interval 95%)
    -0.58 (-1.13 to -0.03)
    -0.40 (-0.87 to 0.06)
    -0.64 (-1.19 to -0.09)
    Statistical analysis title
    		 Difference in the Least Squares Means
    Statistical analysis description
    Based on cLDA model with fixed effects for treatment, time, prior antihyperglycemic medication (Metformin monotherapy or Metformin + another AHA), baseline eGFR (continuous), menopausal status, and the interaction of time by treatment. Time was treated as a categorical variable.
    Comparison groups
    Placebo/Glimepiride v Ertugliflozin 15 mg
    Number of subjects included in analysis
    379
    Analysis specification
    Pre-specified
    Analysis type
    		 other
    Method
    Parameter type
    		 Difference in the Least Squares Means
    Point estimate
    -0.06
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -0.77
         upper limit
    		 0.65
    Statistical analysis title
    		 Difference in the Least Squares Means
    Statistical analysis description
    Based on cLDA model with fixed effects for treatment, time, prior antihyperglycemic medication (Metformin monotherapy or Metformin + another AHA), baseline eGFR (continuous), menopausal status, and the interaction of time by treatment. Time was treated as a categorical variable.
    Comparison groups
    Placebo/Glimepiride v Ertugliflozin 5 mg
    Number of subjects included in analysis
    390
    Analysis specification
    Pre-specified
    Analysis type
    		 other
    Method
    Parameter type
    		 Difference in the Least Squares Means
    Point estimate
    0.18
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -0.5
         upper limit
    		 0.85

    Secondary: Percent Change from Baseline in Bone Biomarker CTX at Week 104 (Excluding Bone Rescue Approach)

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    End point title
    		 Percent Change from Baseline in Bone Biomarker CTX at Week 104 (Excluding Bone Rescue Approach)
    End point description
    CTX is a biochemical marker of bone resorption. Participants who exhibited a significant reduction in BMD according to the protocol defined criteria completed an unscheduled DXA scan and, if required, received bone-active therapy. This table excludes measurements obtained after initiation of bone rescue medications. The analysis population included all randomized participants who received at least one dose of investigational product and had measurements of the respective endpoint at both baseline and Week 104.
    End point type
    Secondary
    End point timeframe
    Baseline and Week 104
    End point values
    		 Placebo/Glimepiride Ertugliflozin 5 mg Ertugliflozin 15 mg
    Number of subjects analysed
    149
    160
    159
    Units: Percent change
        arithmetic mean (standard deviation)
    19.29 ( 71.73 )
    26.94 ( 58.44 )
    32.53 ( 59.29 )
    No statistical analyses for this end point

    Secondary: Percent Change from Baseline in Bone Biomarker P1NP at Week 104 (Excluding Bone Rescue Approach)

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    End point title
    		 Percent Change from Baseline in Bone Biomarker P1NP at Week 104 (Excluding Bone Rescue Approach)
    End point description
    P1NP is a biochemical marker of bone resorption. Participants who exhibited a significant reduction in BMD according to the protocol defined criteria completed an unscheduled DXA scan and, if required, received bone-active therapy. This table excludes measurements obtained after initiation of bone rescue medications. The analysis population included all randomized participants who received at least one dose of investigational product and had measurements of the respective endpoint at both baseline and Week 104.
    End point type
    Secondary
    End point timeframe
    Baseline and Week 104
    End point values
    		 Placebo/Glimepiride Ertugliflozin 5 mg Ertugliflozin 15 mg
    Number of subjects analysed
    149
    162
    162
    Units: Percent change
        arithmetic mean (standard deviation)
    19.38 ( 93.02 )
    10.11 ( 39.14 )
    24.21 ( 83.23 )
    No statistical analyses for this end point

    Secondary: Percent Change from Baseline in Bone Biomarker PTH at Week 104 (Excluding Bone Rescue Approach)

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    End point title
    		 Percent Change from Baseline in Bone Biomarker PTH at Week 104 (Excluding Bone Rescue Approach)
    End point description
    PTH is a biochemical marker of bone resorption. Participants who exhibited a significant reduction in BMD according to the protocol defined criteria completed an unscheduled DXA scan and, if required, received bone-active therapy. This table excludes measurements obtained after initiation of bone rescue medications. The analysis population included all randomized participants who received at least one dose of investigational product and had measurements of the respective endpoint at both baseline and Week 104.
    End point type
    Secondary
    End point timeframe
    Baseline and Week 104
    End point values
    		 Placebo/Glimepiride Ertugliflozin 5 mg Ertugliflozin 15 mg
    Number of subjects analysed
    148
    158
    161
    Units: Percent change
        arithmetic mean (standard deviation)
    10.12 ( 60.13 )
    8.16 ( 40.97 )
    5.46 ( 38.53 )
    No statistical analyses for this end point

    Adverse events

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    Adverse events information
    Timeframe for reporting adverse events
    Up to Week 106
    Adverse event reporting additional description
    Participants who met pre-specified glycemic criteria were rescued with glimepiride up to Week 26 or basal insulin. This data set includes data regardless of glycemic rescue therapy initiation (including rescue approach). The analysis population was all participants who received at least one dose of investigational product.
    Assessment type
    		 Systematic
    Dictionary used for adverse event reporting
    Dictionary name
    		 MedDRA
    Dictionary version
    20.0
    Reporting groups
    Reporting group title
    Placebo/Glimepiride
    Reporting group description
    		 Placebo to ertugliflozin, orally once daily from Day 1 to Week 104. Participants meeting glycemic rescue criteria up to Week 26 were rescued with open-label glimepiride (up to a maximum of 6 or 8 mg per day, based on the local label of glimepiride) and if they met glycemic rescue criteria again, and they were on maximal tolerated doses of open-label glimepiride, they received open-label basal insulin. After Week 26, participants in the placebo ertugliflozin arm, who had not received glycemic rescue prior to Week 26 and whose fasting finger-stick glucose was 110 mg/dL or more, received blinded glimepiride. Participants in the placebo ertugliflozin arm who met glycemic rescue criteria from Week 26 onwards, and who were on maximal tolerated doses of glimepiride, open label or blinded, received open-label basal insulin.

    Reporting group title
    Ertugliflozin 5 mg
    Reporting group description
    		 Ertugliflozin 5 mg orally, once daily from Day 1 to Week 104. Participants meeting glycemic rescue criteria up to Week 26 were rescued with open-label glimepiride (up to a maximum of 6 or 8 mg per day, based on the local label of glimepiride) and if they met glycemic rescue criteria again, and they were on maximal tolerated doses of open-label glimepiride, they received open-label basal insulin. After Week 26, participants in the ertugliflozin 5 mg arm, who had not received glycemic rescue prior to Week 26 and whose fasting finger-stick glucose was 110 mg/dL or more, received blinded placebo glimepiride. Participants in the ertugliflozin 5 mg arm who met glycemic rescue criteria from Week 26 onwards, and who were on maximal tolerated doses of glimepiride, open-label or blinded placebo glimepiride, received open-label basal insulin.

    Reporting group title
    Ertugliflozin 15 mg
    Reporting group description
    		 Ertugliflozin 15 mg orally, once daily from Day 1 to Week 104. Participants meeting glycemic rescue criteria up to Week 26 were rescued with open-label glimepiride (up to a maximum of 6 or 8 mg per day, based on the local label of glimepiride) and if they met glycemic rescue criteria again, and they were on maximal tolerated doses of open-label glimepiride, they received open-label basal insulin. After Week 26, participants in the ertugliflozin 15 mg arm, who had not received glycemic rescue prior to Week 26 and whose fasting finger-stick glucose was 110 mg/dL or more, received blinded placebo glimepiride. Participants in the ertugliflozin 15 mg arm who met glycemic rescue criteria from Week 26 onwards, and who were on maximal tolerated doses of glimepiride, open-label or blinded placebo glimepiride, received open-label basal insulin.

    Serious adverse events
    		 Placebo/Glimepiride Ertugliflozin 5 mg Ertugliflozin 15 mg
    Total subjects affected by serious adverse events
         subjects affected / exposed
    22 / 209 (10.53%)
    20 / 207 (9.66%)
    20 / 205 (9.76%)
         number of deaths (all causes)
    3
    1
    2
         number of deaths resulting from adverse events
    0
    0
    0
    Neoplasms benign, malignant and unspecified (incl cysts and polyps)
    Basal cell carcinoma
         subjects affected / exposed
    0 / 209 (0.00%)
    1 / 207 (0.48%)
    0 / 205 (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
    Bowen's disease
         subjects affected / exposed
    0 / 209 (0.00%)
    1 / 207 (0.48%)
    0 / 205 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Hepatic cancer
         subjects affected / exposed
    1 / 209 (0.48%)
    0 / 207 (0.00%)
    0 / 205 (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
    Plasma cell myeloma
         subjects affected / exposed
    0 / 209 (0.00%)
    0 / 207 (0.00%)
    1 / 205 (0.49%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    Prostate cancer
         subjects affected / exposed
    0 / 209 (0.00%)
    0 / 207 (0.00%)
    1 / 205 (0.49%)
         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 cancer metastatic
         subjects affected / exposed
    0 / 209 (0.00%)
    1 / 207 (0.48%)
    0 / 205 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Vascular disorders
    Aortic dissection
         subjects affected / exposed
    0 / 209 (0.00%)
    1 / 207 (0.48%)
    0 / 205 (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 / 209 (0.48%)
    0 / 207 (0.00%)
    0 / 205 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Peripheral ischaemia
         subjects affected / exposed
    0 / 209 (0.00%)
    0 / 207 (0.00%)
    2 / 205 (0.98%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Thrombophlebitis
         subjects affected / exposed
    0 / 209 (0.00%)
    1 / 207 (0.48%)
    0 / 205 (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
    Venous thrombosis limb
         subjects affected / exposed
    0 / 209 (0.00%)
    1 / 207 (0.48%)
    0 / 205 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    General disorders and administration site conditions
    Cardiac death
         subjects affected / exposed
    1 / 209 (0.48%)
    0 / 207 (0.00%)
    0 / 205 (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
    Chest pain
         subjects affected / exposed
    0 / 209 (0.00%)
    1 / 207 (0.48%)
    0 / 205 (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
    Death
         subjects affected / exposed
    0 / 209 (0.00%)
    0 / 207 (0.00%)
    1 / 205 (0.49%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    Reproductive system and breast disorders
    Benign prostatic hyperplasia
         subjects affected / exposed
    0 / 209 (0.00%)
    1 / 207 (0.48%)
    0 / 205 (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
    Asthma
         subjects affected / exposed
    0 / 209 (0.00%)
    1 / 207 (0.48%)
    0 / 205 (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
    Pulmonary embolism
         subjects affected / exposed
    0 / 209 (0.00%)
    0 / 207 (0.00%)
    1 / 205 (0.49%)
         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 fibrosis
         subjects affected / exposed
    0 / 209 (0.00%)
    1 / 207 (0.48%)
    0 / 205 (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
    Sleep apnoea syndrome
         subjects affected / exposed
    1 / 209 (0.48%)
    0 / 207 (0.00%)
    0 / 205 (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
    Ankle fracture
         subjects affected / exposed
    1 / 209 (0.48%)
    0 / 207 (0.00%)
    0 / 205 (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
    Laceration
         subjects affected / exposed
    0 / 209 (0.00%)
    0 / 207 (0.00%)
    1 / 205 (0.49%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Limb crushing injury
         subjects affected / exposed
    1 / 209 (0.48%)
    0 / 207 (0.00%)
    0 / 205 (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
    Traumatic intracranial haemorrhage
         subjects affected / exposed
    0 / 209 (0.00%)
    1 / 207 (0.48%)
    0 / 205 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Congenital, familial and genetic disorders
    Myocardial bridging
         subjects affected / exposed
    0 / 209 (0.00%)
    0 / 207 (0.00%)
    1 / 205 (0.49%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Phimosis
         subjects affected / exposed
    0 / 209 (0.00%)
    0 / 207 (0.00%)
    1 / 205 (0.49%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Cardiac disorders
    Acute myocardial infarction
         subjects affected / exposed
    1 / 209 (0.48%)
    1 / 207 (0.48%)
    0 / 205 (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
    Angina pectoris
         subjects affected / exposed
    1 / 209 (0.48%)
    0 / 207 (0.00%)
    0 / 205 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Angina unstable
         subjects affected / exposed
    0 / 209 (0.00%)
    2 / 207 (0.97%)
    1 / 205 (0.49%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 2
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Atrial fibrillation
         subjects affected / exposed
    0 / 209 (0.00%)
    2 / 207 (0.97%)
    1 / 205 (0.49%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 2
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Cardiac failure
         subjects affected / exposed
    0 / 209 (0.00%)
    0 / 207 (0.00%)
    1 / 205 (0.49%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Cardiac failure acute
         subjects affected / exposed
    0 / 209 (0.00%)
    1 / 207 (0.48%)
    0 / 205 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    Cardiac failure congestive
         subjects affected / exposed
    0 / 209 (0.00%)
    1 / 207 (0.48%)
    0 / 205 (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
    Cardiomyopathy
         subjects affected / exposed
    0 / 209 (0.00%)
    1 / 207 (0.48%)
    0 / 205 (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
    Coronary artery disease
         subjects affected / exposed
    1 / 209 (0.48%)
    0 / 207 (0.00%)
    0 / 205 (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
    Myocardial infarction
         subjects affected / exposed
    1 / 209 (0.48%)
    2 / 207 (0.97%)
    1 / 205 (0.49%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 2
    0 / 1
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    Myocardial ischaemia
         subjects affected / exposed
    0 / 209 (0.00%)
    0 / 207 (0.00%)
    1 / 205 (0.49%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Sinus node dysfunction
         subjects affected / exposed
    0 / 209 (0.00%)
    0 / 207 (0.00%)
    1 / 205 (0.49%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Nervous system disorders
    Ischaemic stroke
         subjects affected / exposed
    1 / 209 (0.48%)
    1 / 207 (0.48%)
    0 / 205 (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
    Loss of consciousness
         subjects affected / exposed
    1 / 209 (0.48%)
    0 / 207 (0.00%)
    0 / 205 (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
    Ear and labyrinth disorders
    Hypoacusis
         subjects affected / exposed
    0 / 209 (0.00%)
    0 / 207 (0.00%)
    1 / 205 (0.49%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Eye disorders
    Cataract
         subjects affected / exposed
    0 / 209 (0.00%)
    0 / 207 (0.00%)
    1 / 205 (0.49%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Gastrointestinal disorders
    Duodenal ulcer haemorrhage
         subjects affected / exposed
    1 / 209 (0.48%)
    0 / 207 (0.00%)
    0 / 205 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Gastritis haemorrhagic
         subjects affected / exposed
    1 / 209 (0.48%)
    0 / 207 (0.00%)
    0 / 205 (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
    Haemorrhoidal haemorrhage
         subjects affected / exposed
    0 / 209 (0.00%)
    0 / 207 (0.00%)
    1 / 205 (0.49%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Pancreatitis
         subjects affected / exposed
    2 / 209 (0.96%)
    0 / 207 (0.00%)
    0 / 205 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Hepatobiliary disorders
    Cholecystitis
         subjects affected / exposed
    1 / 209 (0.48%)
    0 / 207 (0.00%)
    0 / 205 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Cholelithiasis
         subjects affected / exposed
    0 / 209 (0.00%)
    0 / 207 (0.00%)
    1 / 205 (0.49%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Skin and subcutaneous tissue disorders
    Actinic keratosis
         subjects affected / exposed
    0 / 209 (0.00%)
    0 / 207 (0.00%)
    1 / 205 (0.49%)
         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
    Stress urinary incontinence
         subjects affected / exposed
    1 / 209 (0.48%)
    0 / 207 (0.00%)
    0 / 205 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Ureterolithiasis
         subjects affected / exposed
    1 / 209 (0.48%)
    0 / 207 (0.00%)
    0 / 205 (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 disorder
         subjects affected / exposed
    0 / 209 (0.00%)
    0 / 207 (0.00%)
    1 / 205 (0.49%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Intervertebral disc protrusion
         subjects affected / exposed
    1 / 209 (0.48%)
    0 / 207 (0.00%)
    1 / 205 (0.49%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Musculoskeletal pain
         subjects affected / exposed
    0 / 209 (0.00%)
    1 / 207 (0.48%)
    0 / 205 (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
    Necrotising myositis
         subjects affected / exposed
    0 / 209 (0.00%)
    1 / 207 (0.48%)
    0 / 205 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Osteoarthritis
         subjects affected / exposed
    1 / 209 (0.48%)
    1 / 207 (0.48%)
    0 / 205 (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
    Pain in extremity
         subjects affected / exposed
    0 / 209 (0.00%)
    0 / 207 (0.00%)
    1 / 205 (0.49%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Spinal osteoarthritis
         subjects affected / exposed
    1 / 209 (0.48%)
    0 / 207 (0.00%)
    0 / 205 (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
    Cellulitis
         subjects affected / exposed
    0 / 209 (0.00%)
    0 / 207 (0.00%)
    1 / 205 (0.49%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Gastroenteritis
         subjects affected / exposed
    1 / 209 (0.48%)
    0 / 207 (0.00%)
    0 / 205 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Influenza
         subjects affected / exposed
    1 / 209 (0.48%)
    0 / 207 (0.00%)
    1 / 205 (0.49%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Osteomyelitis acute
         subjects affected / exposed
    0 / 209 (0.00%)
    1 / 207 (0.48%)
    0 / 205 (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
    Otitis media chronic
         subjects affected / exposed
    1 / 209 (0.48%)
    0 / 207 (0.00%)
    0 / 205 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Pneumonia
         subjects affected / exposed
    1 / 209 (0.48%)
    1 / 207 (0.48%)
    0 / 205 (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
    Urinary tract infection
         subjects affected / exposed
    0 / 209 (0.00%)
    0 / 207 (0.00%)
    1 / 205 (0.49%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Wound infection staphylococcal
         subjects affected / exposed
    0 / 209 (0.00%)
    1 / 207 (0.48%)
    0 / 205 (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
    Metabolism and nutrition disorders
    Diabetes mellitus
         subjects affected / exposed
    1 / 209 (0.48%)
    0 / 207 (0.00%)
    0 / 205 (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
    Diabetes mellitus inadequate control
         subjects affected / exposed
    1 / 209 (0.48%)
    0 / 207 (0.00%)
    0 / 205 (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
    Diabetic ketoacidosis
         subjects affected / exposed
    0 / 209 (0.00%)
    0 / 207 (0.00%)
    1 / 205 (0.49%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Frequency threshold for reporting non-serious adverse events: 5%
    Non-serious adverse events
    		 Placebo/Glimepiride Ertugliflozin 5 mg Ertugliflozin 15 mg
    Total subjects affected by non serious adverse events
         subjects affected / exposed
    103 / 209 (49.28%)
    79 / 207 (38.16%)
    100 / 205 (48.78%)
    Investigations
    Weight decreased
         subjects affected / exposed
    3 / 209 (1.44%)
    9 / 207 (4.35%)
    15 / 205 (7.32%)
         occurrences all number
    3
    9
    15
    Nervous system disorders
    Headache
         subjects affected / exposed
    10 / 209 (4.78%)
    14 / 207 (6.76%)
    11 / 205 (5.37%)
         occurrences all number
    15
    18
    15
    Respiratory, thoracic and mediastinal disorders
    Cough
         subjects affected / exposed
    11 / 209 (5.26%)
    8 / 207 (3.86%)
    8 / 205 (3.90%)
         occurrences all number
    13
    8
    8
    Musculoskeletal and connective tissue disorders
    Arthralgia
         subjects affected / exposed
    7 / 209 (3.35%)
    7 / 207 (3.38%)
    11 / 205 (5.37%)
         occurrences all number
    7
    9
    12
    Back pain
         subjects affected / exposed
    10 / 209 (4.78%)
    9 / 207 (4.35%)
    20 / 205 (9.76%)
         occurrences all number
    10
    10
    20
    Infections and infestations
    Influenza
         subjects affected / exposed
    12 / 209 (5.74%)
    11 / 207 (5.31%)
    10 / 205 (4.88%)
         occurrences all number
    13
    13
    13
    Upper respiratory tract infection
         subjects affected / exposed
    33 / 209 (15.79%)
    23 / 207 (11.11%)
    21 / 205 (10.24%)
         occurrences all number
    44
    30
    22
    Urinary tract infection
         subjects affected / exposed
    13 / 209 (6.22%)
    6 / 207 (2.90%)
    17 / 205 (8.29%)
         occurrences all number
    18
    9
    22
    Viral upper respiratory tract infection
         subjects affected / exposed
    21 / 209 (10.05%)
    12 / 207 (5.80%)
    9 / 205 (4.39%)
         occurrences all number
    27
    16
    11
    Metabolism and nutrition disorders
    Hypoglycaemia
         subjects affected / exposed
    43 / 209 (20.57%)
    14 / 207 (6.76%)
    18 / 205 (8.78%)
         occurrences all number
    213
    119
    66

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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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    As of 31 January 2023, all EU/EEA initial clinical trial applications must be submitted through CTIS . Updated EudraCT trials information and information on PIP/Art 46 trials conducted exclusively in third countries continues to be submitted through EudraCT and published on this website.

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