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    Clinical Trial Results:
    A Randomized, Parallel-Arm, Double-Blind Study of Efficacy and Safety of Dulaglutide When Added to SGLT2 Inhibitors in Patients with Type 2 Diabetes Mellitus

    Summary
    EudraCT number
    		 2015-002095-24
    Trial protocol
    		 DE   HU   CZ   AT   ES  
    Global end of trial date
    02 Feb 2017

    Results information
    Results version number
    		 v1(current)
    This version publication date
    18 Feb 2018
    First version publication date
    18 Feb 2018
    Other versions

    Trial information

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    Trial identification
    Sponsor protocol code
    H9X-MC-GBGE
    Additional study identifiers
    ISRCTN number
    		 -
    US NCT number
    		 NCT02597049
    WHO universal trial number (UTN)
    		 -
    Other trial identifiers
    		 Trial Number: 15361
    Sponsors
    Sponsor organisation name
    Eli Lilly and Company
    Sponsor organisation address
    Lilly Corporate Center, Indianapolis, United States, 46285
    Public contact
    Available Mon ‐ Fri 9 AM ‐ 5 PM EST, Eli Lilly and Company, 1 877‐CTLilly, ClinicalTrials.gov@lilly.com
    Scientific contact
    Available Mon ‐ Fri 9 AM ‐ 5 PM EST, Eli Lilly and Company, 1 877‐285‐4559, ClinicalTrials.gov@lilly.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
    02 Feb 2017
    Is this the analysis of the primary completion data?
    No
    Global end of trial reached?
    Yes
    Global end of trial date
    02 Feb 2017
    Was the trial ended prematurely?
    No
    General information about the trial
    Main objective of the trial
    The main purpose of this study was to evaluate the efficacy and safety of the study drug known as dulaglutide when added to sodium-glucose co-transporter 2 (SGLT2) inhibitors in participants with type 2 diabetes mellitus.
    Protection of trial subjects
    This study was conducted in accordance with International Conference on Harmonization (ICH) Good Clinical Practice, and the principles of the Declaration of Helsinki, in addition to following the laws and regulations of the country or countries in which a study is conducted.
    Background therapy
    		 -
    Evidence for comparator
    		 -
    Actual start date of recruitment
    24 Nov 2015
    Long term follow-up planned
    No
    Independent data monitoring committee (IDMC) involvement?
    No
    Population of trial subjects
    Number of subjects enrolled per country
    Country: Number of subjects enrolled
    Austria: 29
    Country: Number of subjects enrolled
    Hungary: 57
    Country: Number of subjects enrolled
    United States: 89
    Country: Number of subjects enrolled
    Czech Republic: 73
    Country: Number of subjects enrolled
    Mexico: 83
    Country: Number of subjects enrolled
    Israel: 18
    Country: Number of subjects enrolled
    Germany: 33
    Country: Number of subjects enrolled
    Spain: 42
    Worldwide total number of subjects
    424
    EEA total number of subjects
    234
    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)
    326
    From 65 to 84 years
    98
    85 years and over
    0

    Subject disposition

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    Recruitment
    Recruitment details
    		 -

    Pre-assignment
    Screening details
    		 No Text Entered

    Period 1
    Period 1 title
    Period 1
    Is this the baseline period?
    		 No
    Allocation method
    Randomised - controlled
    Blinding used
    		 Double blind
    Roles blinded
    		 Subject, Investigator

    Arms
    Are arms mutually exclusive
    Yes

    Arm title
    		 1.5 mg Dulaglutide
    Arm description
    		 Dulaglutide 1.5 milligrams (mg) given subcutaneously (SC) once a week (QW) for 24 weeks.
    Arm type
    		 Experimental

    Investigational medicinal product name
    1.5 mg Dulaglutide
    Investigational medicinal product code
    Other name
    LY2189265
    Pharmaceutical forms
    Injection
    Routes of administration
    Subcutaneous use
    Dosage and administration details
    Dulaglutide 1.5 mg SC QW for 24 weeks.

    Arm title
    		 0.75 mg Dulaglutide
    Arm description
    		 Dulaglutide 0.75 mg given SC QW for 24 weeks.
    Arm type
    		 Experimental

    Investigational medicinal product name
    0.75 mg Dulaglutide
    Investigational medicinal product code
    Other name
    LY2189265
    Pharmaceutical forms
    Injection
    Routes of administration
    Subcutaneous use
    Dosage and administration details
    Dulaglutide 0.75 mg SC QW for 24 weeks.

    Arm title
    		 Placebo
    Arm description
    		 Placebo given SC QW for 24 weeks.
    Arm type
    		 Placebo

    Investigational medicinal product name
    Placebo
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Injection
    Routes of administration
    Subcutaneous use
    Dosage and administration details
    Placebo given SC QW for 24 weeks.

    Number of subjects in period 1
    		1.5 mg Dulaglutide 0.75 mg Dulaglutide Placebo
    Started
    142
    142
    140
    Received at least one dose of study drug
    142
    141
    140
    Completed
    142
    141
    140
    Not completed
    0
    1
    0
         Consent withdrawn by subject
    -
    1
    -
    Period 2
    Period 2 title
    Period 2
    Is this the baseline period?
    		 Yes [1]
    Allocation method
    Randomised - controlled
    Blinding used
    		 Double blind
    Roles blinded
    		 Subject, Investigator

    Arms
    Are arms mutually exclusive
    Yes

    Arm title
    		 1.5 mg Dulaglutide
    Arm description
    		 Dulaglutide 1.5 milligrams (mg) given SC QW for 24 weeks.
    Arm type
    		 Experimental

    Investigational medicinal product name
    Dulaglutide
    Investigational medicinal product code
    Other name
    LY2189265
    Pharmaceutical forms
    Injection
    Routes of administration
    Subcutaneous use
    Dosage and administration details
    Dulaglutide 1.5 milligrams (mg) given subcutaneously (SC) once a week (QW) for 24 weeks.

    Arm title
    		 0.75 mg Dulaglutide
    Arm description
    		 Dulaglutide 0.75 mg given subcutaneously (SC) once a week (QW) for 24 weeks.
    Arm type
    		 Experimental

    Investigational medicinal product name
    0.75 mg Dulaglutide
    Investigational medicinal product code
    Other name
    LY2189265
    Pharmaceutical forms
    Injection
    Routes of administration
    Subcutaneous use
    Dosage and administration details
    Dulaglutide 0.75 mg SC QW for 24 weeks.

    Arm title
    		 Placebo
    Arm description
    		 Placebo given SC QW for 24 weeks.
    Arm type
    		 Placebo

    Investigational medicinal product name
    Placebo
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Injection
    Routes of administration
    Subcutaneous use
    Dosage and administration details
    Placebo given SC QW for 24 weeks.

    Notes
    [1] - Period 1 is not the baseline period. It is expected that period 1 will be the baseline period.
    Justification: Of the 424 participants who started the study and were randomized, one participant was withdrawn from treatment prior to dosing. The participant continued study participation and completed the study without study drug. This participant is not included in the overall number of baseline participants [intent-to-treat (ITT) population] for the Dulaglutide 0.75 mg reporting group.
    Number of subjects in period 2 [2]
    		1.5 mg Dulaglutide 0.75 mg Dulaglutide Placebo
    Started
    142
    141
    140
    Completed
    135
    137
    137
    Not completed
    7
    4
    3
         Consent withdrawn by subject
    2
    1
    1
         Adverse event, non-fatal
    2
    -
    -
         Death
    2
    -
    -
         Lost to follow-up
    -
    3
    2
         Noncompliant with study visits
    1
    -
    -
    Notes
    [2] - The number of subjects reported to be in the baseline period are not the same as the worldwide number enrolled in the trial. It is expected that these numbers will be the same.
    Justification: The worldwide number enrolled is represented in Period 1, however one participant was randomized into the study did not receive injectable study drug at the discretion of the investigator. This participant was not included in the efficacy or safety analysis; however, the participant continued participation in the study and completed all study activities.

    Baseline characteristics

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    Baseline characteristics reporting groups
    Reporting group title
    1.5 mg Dulaglutide
    Reporting group description
    		 Dulaglutide 1.5 milligrams (mg) given SC QW for 24 weeks.

    Reporting group title
    0.75 mg Dulaglutide
    Reporting group description
    		 Dulaglutide 0.75 mg given subcutaneously (SC) once a week (QW) for 24 weeks.

    Reporting group title
    Placebo
    Reporting group description
    		 Placebo given SC QW for 24 weeks.

    Reporting group values
    		 1.5 mg Dulaglutide 0.75 mg Dulaglutide Placebo Total
    Number of subjects
    		 142 141 140 423
    Age categorical
    Units: Subjects
    Age Continuous
    Units: years
        arithmetic mean (standard deviation)
    		 56.17 ± 9.26 58.55 ± 9.14 57.10 ± 9.59 -
    Gender categorical
    Units: Subjects
        Female
    		 65 72 74 211
        Male
    		 77 69 66 212
    Ethnicity (NIH/OMB)
    Units: Subjects
        Hispanic or Latino
    		 51 44 44 139
        Not Hispanic or Latino
    		 90 97 94 281
        Unknown or Not Reported
    		 1 0 2 3
    Race (NIH/OMB)
    Units: Subjects
        American Indian or Alaska Native
    		 1 2 4 7
        Asian
    		 0 1 0 1
        Native Hawaiian or Other Pacific Islander
    		 0 0 0 0
        Black or African American
    		 3 3 6 12
        White
    		 127 127 124 378
        More than one race
    		 11 8 6 25
        Unknown or Not Reported
    		 0 0 0 0
    Region of Enrollment
    Units: Subjects
        Austria
    		 9 11 9 29
        Hungary
    		 19 19 19 57
        United States
    		 30 30 28 88
        Czechia
    		 25 23 25 73
        Mexico
    		 27 28 28 83
        Israel
    		 6 6 6 18
        Germany
    		 12 11 10 33
        Spain
    		 14 13 15 42
    Mean Hemoglobin A1c (HbA1c)
    Units: percentage of HbA1c
        arithmetic mean (standard deviation)
    		 8.04 ± 0.65 8.04 ± 0.61 8.05 ± 0.61 -
    Mean A1c Efficacy Estimand
    Units: percentage of A1c
        arithmetic mean (standard deviation)
    		 1.00 ± 0.1 1.1 ± 0.2 1.2 ± 0.3 -

    End points

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    End points reporting groups
    Reporting group title
    1.5 mg Dulaglutide
    Reporting group description
    		 Dulaglutide 1.5 milligrams (mg) given subcutaneously (SC) once a week (QW) for 24 weeks.

    Reporting group title
    0.75 mg Dulaglutide
    Reporting group description
    		 Dulaglutide 0.75 mg given SC QW for 24 weeks.

    Reporting group title
    Placebo
    Reporting group description
    		 Placebo given SC QW for 24 weeks.
    Reporting group title
    1.5 mg Dulaglutide
    Reporting group description
    		 Dulaglutide 1.5 milligrams (mg) given SC QW for 24 weeks.

    Reporting group title
    0.75 mg Dulaglutide
    Reporting group description
    		 Dulaglutide 0.75 mg given subcutaneously (SC) once a week (QW) for 24 weeks.

    Reporting group title
    Placebo
    Reporting group description
    		 Placebo given SC QW for 24 weeks.

    Primary: Change from Baseline in Hemoglobin A1c (HbA1c) at 24 Weeks (Treatment-regimen Estimand)

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    End point title
    		 Change from Baseline in Hemoglobin A1c (HbA1c) at 24 Weeks (Treatment-regimen Estimand)
    End point description
    Least Squares mean (LS) of the HbA1c change from baseline to primary endpoint at week 24 was adjusted by treatment, country, SGLT2 inhibitor dose, metformin use, treatment-by-visit interactions as fixed effects, and baseline HbA1c as a covariate and participant as a random effect, via a mixed-model repeated measure (MMRM) analysis. The intent-to-treat (ITT) estimand [treatment(Tx)-regimen estimand] used all data including post-rescue data and compared the benefit of treatment regimens as they were actually taken. Analysis Population Description (APD): All randomized participants who received at least one dose of study medication and had post-rescue data.
    End point type
    Primary
    End point timeframe
    Baseline, Week 24
    End point values
    		 1.5 mg Dulaglutide 0.75 mg Dulaglutide Placebo
    Number of subjects analysed
    132
    134
    133
    Units: percentage of HbA1c
        least squares mean (standard error)
    -1.34 ± 0.064
    -1.21 ± 0.064
    -0.54 ± 0.064
    Statistical analysis title
    		 1.5 mg Dulaglutide, Placebo Tx-regimen Estimand
    Comparison groups
    1.5 mg Dulaglutide v Placebo
    Number of subjects included in analysis
    265
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 < 0.001
    Method
    		 Mixed models analysis
    Parameter type
    		 Mean difference (final values)
    Point estimate
    -0.79
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -0.94
         upper limit
    		 -0.63
    Statistical analysis title
    		 0.75 mg Dulaglutide, Placebo Tx-regimen Estimand
    Comparison groups
    0.75 mg Dulaglutide v Placebo
    Number of subjects included in analysis
    267
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 < 0.001
    Method
    		 Mixed models analysis
    Parameter type
    		 Mean difference (final values)
    Point estimate
    -0.66
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -0.84
         upper limit
    		 -0.49

    Primary: Change from Baseline in the HbA1c at 24 Weeks (Efficacy Estimand)

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    End point title
    		 Change from Baseline in the HbA1c at 24 Weeks (Efficacy Estimand)
    End point description
    LS mean of the HbA1c change from baseline to primary endpoint at week 24 was adjusted by treatment, country, SGLT2 inhibitor dose, metformin use, treatment-by-visit interactions as fixed effects, and baseline HbA1c as a covariate and participant as a random effect, via a MMRM analysis. The efficacy estimand excluded post-rescue data and compared the benefit of randomized treatments as they were assigned. Analysis Population Description: All randomized participants who received at least one dose of study drug and did not require additional or alternative antihyperglycemic medications.
    End point type
    Primary
    End point timeframe
    Baseline, Week 24
    End point values
    		 1.5 mg Dulaglutide 0.75 mg Dulaglutide Placebo
    Number of subjects analysed
    140
    138
    134
    Units: percentage of HbA1c
        least squares mean (standard error)
    -1.30 ± 0.062
    -1.19 ± 0.062
    -0.49 ± 0.063
    Statistical analysis title
    		 1.5 mg Dulaglutide, Placebo Efficacy Estimand
    Comparison groups
    1.5 mg Dulaglutide v Placebo
    Number of subjects included in analysis
    274
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 < 0.001
    Method
    		 Mixed models analysis
    Parameter type
    		 Mean difference (final values)
    Point estimate
    -0.81
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -0.98
         upper limit
    		 -0.63
    Statistical analysis title
    		 0.75 mg Dulaglutide, Placebo Efficacy Estimand
    Comparison groups
    0.75 mg Dulaglutide v Placebo
    Number of subjects included in analysis
    272
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 < 0.001
    Method
    		 Mixed models analysis
    Parameter type
    		 Mean difference (final values)
    Point estimate
    -0.69
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -0.87
         upper limit
    		 -0.52

    Secondary: Percentage of Participants with HbA1c <7%

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    End point title
    		 Percentage of Participants with HbA1c <7%
    End point description
    Number of participants with an HbA1c value of <7% at Week 24 is measured using longitudinal logistic regression with repeated measurements will. The model will include independent variables of treatment, country, SGLT2 inhibitor dose, metformin use, visit, baseline HbA1c-by-visit interaction, treatment-by-visit, and baseline HbA1c as a covariate.
    End point type
    Secondary
    End point timeframe
    24 Weeks
    End point values
    		 1.5 mg Dulaglutide 0.75 mg Dulaglutide Placebo
    Number of subjects analysed
    140 [1]
    139 [2]
    137 [3]
    Units: percentage of participants
    number (not applicable)
        Tx-regimen Estimand (132, 134, 133)
    71.21
    60.45
    31.58
        Efficacy Estimand (130, 131, 123)
    71.54
    61.83
    32.52
    Notes
    [1] - All participants who received at least one dose of Dulaglutide with HBA1c at Week 24.
    [2] - All participants who received at least one dose of Dulaglutide with HBA1c at Week 24
    [3] - All participants who received at least one dose of Dulaglutide with HBA1c at Week 24
    Statistical analysis title
    		 1.5 mg Dulaglutide, Placebo Tx-regimen Estimand
    Statistical analysis description
    Tx-regimen Estimand
    Comparison groups
    1.5 mg Dulaglutide v Placebo
    Number of subjects included in analysis
    277
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 < 0.001
    Method
    		 Regression, Logistic
    Parameter type
    		 Odds ratio (OR)
    Point estimate
    11.53
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 5.69
         upper limit
    		 23.37
    Statistical analysis title
    		 0.75 mg Dulaglutide, Placebo Tx-regimen Estimand
    Statistical analysis description
    Tx-regimen Estimand
    Comparison groups
    0.75 mg Dulaglutide v Placebo
    Number of subjects included in analysis
    276
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 < 0.001
    Method
    		 Regression, Logistic
    Parameter type
    		 Odds ratio (OR)
    Point estimate
    6.85
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 3.56
         upper limit
    		 13.16
    Statistical analysis title
    		 1.5 mg Dulaglutide, Placebo Efficacy Estimand
    Statistical analysis description
    Efficacy Estimand
    Comparison groups
    1.5 mg Dulaglutide v Placebo
    Number of subjects included in analysis
    277
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 < 0.001
    Method
    		 Regression, Logistic
    Parameter type
    		 Odds ratio (OR)
    Point estimate
    12.06
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 5.86
         upper limit
    		 24.79
    Statistical analysis title
    		 0.75 mg Dulaglutide, Placebo Efficacy Estimand
    Statistical analysis description
    Efficacy Estimand
    Comparison groups
    0.75 mg Dulaglutide v Placebo
    Number of subjects included in analysis
    276
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 < 0.001
    Method
    		 Regression, Logistic
    Parameter type
    		 Odds ratio (OR)
    Point estimate
    7.13
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 3.67
         upper limit
    		 13.86

    Secondary: Change from Baseline in Body Weight at 24 Weeks

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    End point title
    		 Change from Baseline in Body Weight at 24 Weeks
    End point description
    LS mean of the body weight change from baseline to primary endpoint at week 24 was adjusted by treatment, country, SGLT2 inhibitor dose, metformin use, baseline HbA1c strata, treatment-by-visit interactions as fixed effects, and baseline body weight as a covariate and participant as a random effect, via a MMRM analysis.
    End point type
    Secondary
    End point timeframe
    Baseline, Week 24
    End point values
    		 1.5 mg Dulaglutide 0.75 mg Dulaglutide Placebo
    Number of subjects analysed
    142 [4]
    141 [5]
    140 [6]
    Units: kilograms (kg)
    least squares mean (standard error)
        Tx-regimen Estimand (135, 136, 137)
    -3.1 ± 0.30
    -2.6 ± 0.30
    -2.1 ± 0.30
        Efficacy Estimand (133, 133, 127)
    -3.1 ± 0.30
    -2.6 ± 0.30
    -2.3 ± 0.31
    Notes
    [4] - All participants who received at least one dose of study drug.
    [5] - All participants who received at least one dose of study drug.
    [6] - All participants who received at least one dose of study drug.
    Statistical analysis title
    		 1.5 mg Dulaglutide, Placebo Tx-regimen Estimand
    Statistical analysis description
    Tx-regimen Estimand
    Comparison groups
    1.5 mg Dulaglutide v Placebo
    Number of subjects included in analysis
    282
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.027
    Method
    		 Mixed models analysis
    Parameter type
    		 Mean difference (final values)
    Point estimate
    -0.9
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -1.8
         upper limit
    		 -0.1
    Statistical analysis title
    		 0.75 mg Dulaglutide, Placebo Tx-regimen Estimand
    Statistical analysis description
    Tx-regimen Estimand
    Comparison groups
    0.75 mg Dulaglutide v Placebo
    Number of subjects included in analysis
    281
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.264
    Method
    		 Mixed models analysis
    Parameter type
    		 Mean difference (final values)
    Point estimate
    -0.5
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -1.3
         upper limit
    		 0.4
    Statistical analysis title
    		 1.5 mg Dulaglutide, Placebo Efficacy Estimand
    Statistical analysis description
    Efficacy Estimand
    Comparison groups
    1.5 mg Dulaglutide v Placebo
    Number of subjects included in analysis
    282
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.034
    Method
    		 Mixed models analysis
    Parameter type
    		 Mean difference (final values)
    Point estimate
    -0.9
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -1.6
         upper limit
    		 -0.1
    Statistical analysis title
    		 0.75 mg Dulaglutide, Placebo Efficacy Estimand
    Statistical analysis description
    Efficacy Estimand
    Comparison groups
    0.75 mg Dulaglutide v Placebo
    Number of subjects included in analysis
    281
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.321
    Method
    		 Mixed models analysis
    Parameter type
    		 Mean difference (final values)
    Point estimate
    -0.4
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -1.2
         upper limit
    		 0.4

    Secondary: Change from Baseline in Fasting Serum Glucose (Central Laboratory) at 24 Weeks

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    End point title
    		 Change from Baseline in Fasting Serum Glucose (Central Laboratory) at 24 Weeks
    End point description
    LS mean of change from baseline was calculated using last observation carried forward (LOCF) by treatment group, analysis of covariance (ANCOVA), and the intent-to-treat population [(ITT) those participants who were randomized and received at least one dose of study drug]. Analysis Population Description: All participants who received at least one dose of study drug and had baseline and at least one post-baseline value.
    End point type
    Secondary
    End point timeframe
    Baseline, Week 24
    End point values
    		 1.5 mg Dulaglutide 0.75 mg Dulaglutide Placebo
    Number of subjects analysed
    142
    141
    140
    Units: milligram/deciliter (mg/dL)
    least squares mean (standard error)
        Tx-regimen Estimand (134, 133, 132)
    -31.6 ± 2.17
    -26.5 ± 2.18
    -6.9 ± 2.21
        Efficacy Estimand Data (132, 130, 122)
    -31.9 ± 2.11
    -26.0 ± 2.12
    -5.3 ± 2.21
    Statistical analysis title
    		 1.5 mg Dulaglutide, Placebo Tx-regimen Estimand
    Statistical analysis description
    Tx-regimen Estimand
    Comparison groups
    1.5 mg Dulaglutide v Placebo
    Number of subjects included in analysis
    282
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 < 0.001
    Method
    		 Regression, Linear
    Parameter type
    		 Mean difference (final values)
    Point estimate
    -24.7
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -30.8
         upper limit
    		 -18.6
    Statistical analysis title
    		 0.75 mg Dulaglutide, Placebo Tx-regimen Estimand
    Statistical analysis description
    Tx-regimen Estimand
    Comparison groups
    0.75 mg Dulaglutide v Placebo
    Number of subjects included in analysis
    281
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 < 0.001
    Method
    		 Regression, Linear
    Parameter type
    		 Mean difference (final values)
    Point estimate
    -19.6
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -25.7
         upper limit
    		 -13.6
    Statistical analysis title
    		 1.5 mg Dulaglutide, Placebo Efficacy Estimand
    Statistical analysis description
    Efficacy Estimand
    Comparison groups
    1.5 mg Dulaglutide v Placebo
    Number of subjects included in analysis
    282
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 < 0.001
    Method
    		 Regression, Linear
    Parameter type
    		 Mean difference (final values)
    Point estimate
    -26.6
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -32.7
         upper limit
    		 -20.6
    Statistical analysis title
    		 0.75 mg Dulaglutide, Placebo Efficacy Estimand
    Statistical analysis description
    Efficacy Estimand
    Comparison groups
    0.75 mg Dulaglutide v Placebo
    Number of subjects included in analysis
    281
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 < 0.001
    Method
    		 Regression, Linear
    Parameter type
    		 Mean difference (final values)
    Point estimate
    -20.7
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -26.7
         upper limit
    		 -14.6

    Secondary: Change from Baseline in 6-Point Self-Monitored Plasma Glucose (SMPG) Profile at 24 Weeks

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    End point title
    		 Change from Baseline in 6-Point Self-Monitored Plasma Glucose (SMPG) Profile at 24 Weeks
    End point description
    The self-monitored plasma glucose (SMPG) data were collected at the following 6 time points: pre-morning meal; 2 hours post-morning meal; pre-midday meal; 2 hours post-midday meal; pre-evening meal; 2 hours post-evening meal. Least Squares (LS) means of change from baseline were calculated using a mixed-effects model for repeated measures (MMRM) with treatment, metformin, country, SGLT2i dose, baseline HbA1c strata, visit, and treatment-by-visit interaction as fixed effects and baseline as a covariate. Analysis Population Description: All participants who received at least one dose of study drug and had baseline SMPG value and at least one post-baseline SMPG value.
    End point type
    Secondary
    End point timeframe
    Baseline, Week 24
    End point values
    		 1.5 mg Dulaglutide 0.75 mg Dulaglutide Placebo
    Number of subjects analysed
    142
    141
    140
    Units: mg/dL
    least squares mean (standard error)
        Pre-morning Morning Meal (128, 124, 128)
    -27.8 ± 2.13
    -23.2 ± 2.17
    -8.1 ± 2.14
        2-Hour Postprandial Morning Meal (121, 121, 119)
    -44.6 ± 3.31
    -41.1 ± 3.30
    -20.1 ± 3.33
        Pre-Mid Day Meal (127, 124, 126)
    -26.0 ± 2.91
    -22.0 ± 2.94
    -7.7 ± 2.93
        2-Hour Postprandial Mid Day Meal (122, 121, 118)
    -31.8 ± 3.47
    -25.5 ± 3.47
    -12.8 ± 3.63
        Pre-Evening Meal (128, 121, 124)
    -30.3 ± 2.85
    -30.1 ± 2.93
    -7.5 ± 2.91
        2-Hour Postprandial Evening Meal (122, 121, 117)
    -36.0 ± 3.30
    -30.6 ± 3.31
    -13.9 ± 3.38
    Statistical analysis title
    		 1.5 mg Dulaglutide, Placebo Pre-Morning
    Statistical analysis description
    Pre-morning meal.
    Comparison groups
    1.5 mg Dulaglutide v Placebo
    Number of subjects included in analysis
    282
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 < 0.001
    Method
    		 Mixed models analysis
    Parameter type
    		 Mean difference (final values)
    Point estimate
    -19.7
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -25.7
         upper limit
    		 -13.8
    Statistical analysis title
    		 0.75 mg Dulaglutide, Placebo Pre-Morning
    Statistical analysis description
    Pre-morning meal
    Comparison groups
    0.75 mg Dulaglutide v Placebo
    Number of subjects included in analysis
    281
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 < 0.001
    Method
    		 Mixed models analysis
    Parameter type
    		 Mean difference (final values)
    Point estimate
    -15.2
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -21.2
         upper limit
    		 -9.2
    Statistical analysis title
    		 1.5 mg Dulaglutide, Placebo 2-hour Post Morning
    Statistical analysis description
    2-hour postprandial morning meal
    Comparison groups
    1.5 mg Dulaglutide v Placebo
    Number of subjects included in analysis
    282
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 < 0.001
    Method
    		 Mixed models analysis
    Parameter type
    		 Mean difference (final values)
    Point estimate
    -24.5
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -33.8
         upper limit
    		 -15.3
    Statistical analysis title
    		 0.75 mg Dulaglutide, Placebo 2-hour Post Morning
    Statistical analysis description
    2-hour postprandial morning meal
    Comparison groups
    0.75 mg Dulaglutide v Placebo
    Number of subjects included in analysis
    281
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 < 0.001
    Method
    		 Mixed models analysis
    Parameter type
    		 Mean difference (final values)
    Point estimate
    -21.1
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -30.3
         upper limit
    		 -11.8
    Statistical analysis title
    		 1.5 mg Dulaglutide, Placebo Pre-Mid Day
    Statistical analysis description
    Pre-mid day meal
    Comparison groups
    1.5 mg Dulaglutide v Placebo
    Number of subjects included in analysis
    282
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 < 0.001
    Method
    		 Mixed models analysis
    Parameter type
    		 Mean difference (final values)
    Point estimate
    -18.3
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -26.4
         upper limit
    		 -10.2
    Statistical analysis title
    		 1.5 mg Dulaglutide, Placebo Pre-Mid Day
    Statistical analysis description
    Pre-midday meal
    Comparison groups
    0.75 mg Dulaglutide v Placebo
    Number of subjects included in analysis
    281
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 < 0.001
    Method
    		 Mixed models analysis
    Parameter type
    		 Mean difference (final values)
    Point estimate
    -18.3
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -22.5
         upper limit
    		 -6.2
    Statistical analysis title
    		 1.5 mg Dulaglutide, Placebo 2-hour Post Mid Day
    Statistical analysis description
    2-hour postprandial after mid day meal
    Comparison groups
    1.5 mg Dulaglutide v Placebo
    Number of subjects included in analysis
    282
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 < 0.001
    Method
    		 Mixed models analysis
    Parameter type
    		 Mean difference (final values)
    Point estimate
    -19
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -28.8
         upper limit
    		 -9.3
    Statistical analysis title
    		 0.75 mg Dulaglutide, Placebo 2-hour Post Mid Day
    Statistical analysis description
    2-hour postprandial after midday meal
    Comparison groups
    0.75 mg Dulaglutide v Placebo
    Number of subjects included in analysis
    281
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.01
    Method
    		 Mixed models analysis
    Parameter type
    		 Mean difference (final values)
    Point estimate
    -12.8
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -22.5
         upper limit
    		 -3.1
    Statistical analysis title
    		 1.5 mg Dulaglutide, Placebo Pre-Evening
    Statistical analysis description
    Pre-evening meal
    Comparison groups
    1.5 mg Dulaglutide v Placebo
    Number of subjects included in analysis
    282
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 < 0.001
    Method
    		 Mixed models analysis
    Parameter type
    		 Mean difference (final values)
    Point estimate
    -22.7
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -30.7
         upper limit
    		 -14.7
    Statistical analysis title
    		 0.75 mg, Placebo Pre-Evening
    Statistical analysis description
    Pre-evening meal
    Comparison groups
    0.75 mg Dulaglutide v Placebo
    Number of subjects included in analysis
    281
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 < 0.001
    Method
    		 Mixed models analysis
    Parameter type
    		 Mean difference (final values)
    Point estimate
    -22.5
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -30.7
         upper limit
    		 -14.4
    Statistical analysis title
    		 1.5 mg Dulaglutide, Placebo 2-hour Post Evening
    Statistical analysis description
    2-hour postprandial after evening meal
    Comparison groups
    1.5 mg Dulaglutide v Placebo
    Number of subjects included in analysis
    282
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 < 0.001
    Method
    		 Mixed models analysis
    Parameter type
    		 Mean difference (final values)
    Point estimate
    -22.1
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -31.4
         upper limit
    		 -12.9
    Statistical analysis title
    		 0.75 mg, Placebo 2-hour Post Evening
    Statistical analysis description
    2-hour postprandial after evening meal
    Comparison groups
    0.75 mg Dulaglutide v Placebo
    Number of subjects included in analysis
    281
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 < 0.001
    Method
    		 Mixed models analysis
    Parameter type
    		 Mean difference (final values)
    Point estimate
    -16.7
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -26
         upper limit
    		 -7.4

    Secondary: Change from Baseline in Fasting Glucagon at 24 Weeks

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    End point title
    		 Change from Baseline in Fasting Glucagon at 24 Weeks
    End point description
    Change from baseline in fasting glucagon was analyzed using an ANCOVA model with last observation carried forward (LOCF) included in treatment, country, SGLT2i dose, metformin use, and baseline HbA1c strata as fixed effects and baseline fasting glucagon as a covariate (with and without post rescue data). Analysis Population Description: All participants who received at least one dose of study drug and with non-missing baseline values and at least one post-baseline value at the specified time point.
    End point type
    Secondary
    End point timeframe
    Baseline, Week 24
    End point values
    		 1.5 mg Dulaglutide 0.75 mg Dulaglutide Placebo
    Number of subjects analysed
    134
    132
    128
    Units: picomole per liter (pmol/L)
    least squares mean (standard error)
        Tx-regimen Estimand (134, 132, 128)
    -2.1 ± 0.39
    -1.5 ± 0.39
    -0.9 ± 0.40
        Efficacy Estimand (133, 129, 118)
    -2.2 ± 0.39
    -1.4 ± 0.39
    -0.9 ± 0.41
    Statistical analysis title
    		 1.5 mg Dulaglutide, Placebo Tx-regimen Estimand
    Statistical analysis description
    Tx-regimen Estimand
    Comparison groups
    1.5 mg Dulaglutide v Placebo
    Number of subjects included in analysis
    262
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.032
    Method
    		 Regression, Linear
    Parameter type
    		 Mean difference (final values)
    Point estimate
    -1.2
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -2.3
         upper limit
    		 -0.1
    Statistical analysis title
    		 0.75 mg Dulaglutide, Placebo Tx-regimen Estimand
    Statistical analysis description
    Tx-regimen Estimand
    Comparison groups
    0.75 mg Dulaglutide v Placebo
    Number of subjects included in analysis
    260
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.273
    Method
    		 Regression, Linear
    Parameter type
    		 Mean difference (final values)
    Point estimate
    -0.6
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -1.7
         upper limit
    		 0.5
    Statistical analysis title
    		 1.5 mg Dulaglutide, Placebo Efficacy Estimand
    Statistical analysis description
    Efficacy Estimand
    Comparison groups
    1.5 mg Dulaglutide v Placebo
    Number of subjects included in analysis
    262
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.023
    Method
    		 Regression, Linear
    Parameter type
    		 Mean difference (final values)
    Point estimate
    -1.3
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -2.4
         upper limit
    		 -0.2
    Statistical analysis title
    		 0.75 mg Dulaglutide, Placebo Efficacy Estimand
    Statistical analysis description
    Efficacy Estimand
    Comparison groups
    0.75 mg Dulaglutide v Placebo
    Number of subjects included in analysis
    260
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.32
    Method
    		 Regression, Linear
    Parameter type
    		 Mean difference (final values)
    Point estimate
    -0.6
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -1.7
         upper limit
    		 0.6

    Secondary: Rate of Hypoglycemic Events Adjusted Per 30 Days

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    End point title
    		 Rate of Hypoglycemic Events Adjusted Per 30 Days
    End point description
    A hypoglycemic event is defined as any time a participant feels that he/she is experiencing symptoms and/or signs associated with hypoglycemia, and has a PG level of ≤70 mg/dL [≤3.9 millimole per liter(mmol/L)].
    End point type
    Secondary
    End point timeframe
    Baseline through 24 Weeks
    End point values
    		 1.5 mg Dulaglutide 0.75 mg Dulaglutide Placebo
    Number of subjects analysed
    142 [7]
    141 [8]
    140 [9]
    Units: Number of events/participant/30 days
    arithmetic mean (standard deviation)
        Total Hypoglycemia
    0.026 ± 0.1827
    0.022 ± 0.1375
    0.017 ± 0.1320
        Documented Symptomatic Hypoglycemia
    0.013 ± 0.1406
    0.013 ± 0.1030
    0.010 ± 0.0893
        Asymptomatic Hypoglycemia
    0.013 ± 0.1180
    0.008 ± 0.0639
    0.006 ± 0.0540
        Probable Symptomatic
    0.000 ± 0.0000
    0.001 ± 0.0152
    0.001 ± 0.0147
        Relative Hypoglycemia
    0.003 ± 0.0311
    0.001 ± 0.0150
    0.005 ± 0.0493
        Nocturnal Hypoglycemia
    0.002 ± 0.0288
    0.009 ± 0.0821
    0.000 ± 0.0000
    Notes
    [7] - All participants who received at least one dose of study drug.
    [8] - All participants who received at least one dose of study drug.
    [9] - All participants who received at least one dose of study drug.
    Statistical analysis title
    		 1.5 mg Dulaglutide, Placebo Total Hypoglycemia
    Statistical analysis description
    Total hypoglycemia with glucose <= 70 mg/dL
    Comparison groups
    1.5 mg Dulaglutide v Placebo
    Number of subjects included in analysis
    282
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 1
    Method
    		 Wilcoxon (Mann-Whitney)
    Confidence interval
    Statistical analysis title
    		 0.75 mg Dulaglutide, Placebo Total Hypoglycemia
    Statistical analysis description
    Total hypoglycemia glucose with <= 70 mg/dL
    Comparison groups
    0.75 mg Dulaglutide v Placebo
    Number of subjects included in analysis
    281
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 1
    Method
    		 Wilcoxon (Mann-Whitney)
    Confidence interval
    Statistical analysis title
    		 1.5 mg Dulaglutide, Placebo Symptomatic
    Statistical analysis description
    Documented symptomatic hypoglycemia glucose with <= 70 mg/dL
    Comparison groups
    1.5 mg Dulaglutide v Placebo
    Number of subjects included in analysis
    282
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.683
    Method
    		 Wilcoxon (Mann-Whitney)
    Confidence interval
    Statistical analysis title
    		 0.75 mg Dulaglutide, Placebo Symptomatic
    Statistical analysis description
    Documented symptomatic hypoglycemia glucose with <= 70 mg/dL
    Comparison groups
    0.75 mg Dulaglutide v Placebo
    Number of subjects included in analysis
    281
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 1
    Method
    		 Wilcoxon (Mann-Whitney)
    Confidence interval
    Statistical analysis title
    		 1.5 mg Dulaglutide, Placebo Asymptomatic
    Statistical analysis description
    Asymptomatic hypoglycemia with glucose <= 70 mg/dL
    Comparison groups
    1.5 mg Dulaglutide v Placebo
    Number of subjects included in analysis
    282
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 1
    Method
    		 Wilcoxon (Mann-Whitney)
    Confidence interval
    Statistical analysis title
    		 0.75 mg Dulaglutide, Placebo Asymptomatic
    Statistical analysis description
    Asymptomatic hypoglycemia with glucose <= 70 mg/dL
    Comparison groups
    0.75 mg Dulaglutide v Placebo
    Number of subjects included in analysis
    281
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 1
    Method
    		 Wilcoxon (Mann-Whitney)
    Confidence interval
    Statistical analysis title
    		 1.5 mg , Placebo Probable Symptomatic
    Statistical analysis description
    Probable symptomatic hypoglycemia with glucose <= 70 mg/dL
    Comparison groups
    1.5 mg Dulaglutide v Placebo
    Number of subjects included in analysis
    282
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.496
    Method
    		 Wilcoxon (Mann-Whitney)
    Confidence interval
    Statistical analysis title
    		 0.75 mg , Placebo Probable Symptomatic
    Statistical analysis description
    Probable symptomatic hypoglycemia with glucose <= 70 mg/dL
    Comparison groups
    0.75 mg Dulaglutide v Placebo
    Number of subjects included in analysis
    281
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 1
    Method
    		 Wilcoxon (Mann-Whitney)
    Confidence interval
    Statistical analysis title
    		 1.5 mg Dulaglutide, Placebo Relative
    Statistical analysis description
    Relative hypoglycemia with glucose <= 70 mg/dL
    Comparison groups
    1.5 mg Dulaglutide v Placebo
    Number of subjects included in analysis
    282
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.621
    Method
    		 Wilcoxon (Mann-Whitney)
    Confidence interval
    Statistical analysis title
    		 0.75 mg Dulaglutide, Placebo Relative
    Statistical analysis description
    Relative hypoglycemia with glucose <= 70 mg/dL
    Comparison groups
    0.75 mg Dulaglutide v Placebo
    Number of subjects included in analysis
    281
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.622
    Method
    		 Wilcoxon (Mann-Whitney)
    Confidence interval
    Statistical analysis title
    		 1.5 mg Dulaglutide, Placebo Nocturnal
    Statistical analysis description
    Nocturnal hypoglycemia with glucose <= 70 mg/dL
    Comparison groups
    1.5 mg Dulaglutide v Placebo
    Number of subjects included in analysis
    282
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 1
    Method
    		 Wilcoxon (Mann-Whitney)
    Confidence interval
    Statistical analysis title
    		 0.75 mg Dulaglutide, Placebo Nocturnal
    Statistical analysis description
    Nocturnal hypoglycemia with glucose <= 70 mg/dL
    Comparison groups
    0.75 mg Dulaglutide v Placebo
    Number of subjects included in analysis
    281
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.498
    Method
    		 Wilcoxon (Mann-Whitney)
    Confidence interval

    Secondary: Number of Participants Requiring Rescue Therapy Due to Severe Persistent Hyperglycemia

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    End point title
    		 Number of Participants Requiring Rescue Therapy Due to Severe Persistent Hyperglycemia
    End point description
    Rescue therapy was defined as any additional therapeutic intervention in participants who developed persistent, severe hyperglycemia despite full compliance with the assigned therapeutic regimen, or initiation of an alternative antihyperglycemic medication following study drug discontinuation.
    End point type
    Secondary
    End point timeframe
    Baseline through 24 Weeks
    End point values
    		 1.5 mg Dulaglutide 0.75 mg Dulaglutide Placebo
    Number of subjects analysed
    142 [10]
    141 [11]
    140 [12]
    Units: Participants
        number (not applicable)
    0
    3
    2
    Notes
    [10] - All participants who had at least one dose of study drug.
    [11] - All participants who had at least one dose of study drug.
    [12] - All participants who had at least one dose of study drug.
    No statistical analyses for this end point

    Secondary: Number of Participants With Adjudicated Acute Pancreatitis Events

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    End point title
    		 Number of Participants With Adjudicated Acute Pancreatitis Events
    End point description
    The number of participants with events of pancreatitis confirmed by adjudication were summarized cumulatively at 24 weeks. Pancreatitis events were adjudicated by a committee of physicians external to the Sponsor. A summary of serious and other non-serious events regardless of causality is located in the Reported Adverse Events module.
    End point type
    Secondary
    End point timeframe
    Baseline through 24 Weeks
    End point values
    		 1.5 mg Dulaglutide 0.75 mg Dulaglutide Placebo
    Number of subjects analysed
    142 [13]
    141 [14]
    140 [15]
    Units: Participants
        number (not applicable)
    0
    0
    0
    Notes
    [13] - All participants who had at least one dose of study drug.
    [14] - All participants who had at least one dose of study drug.
    [15] - All participants who had at least one dose of study drug.
    No statistical analyses for this end point

    Secondary: Number of Participants With Adjudicated Cardiovascular (CV) Events

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    End point title
    		 Number of Participants With Adjudicated Cardiovascular (CV) Events
    End point description
    Death and selected nonfatal CV adverse events (AEs) were adjudicated by an independent committee of physicians with cardiology expertise external to the Sponsor. Nonfatal CV events that were to be adjudicated were myocardial infarction (MI); hospitalization for unstable angina; hospitalization for heart failure; coronary interventions such as coronary artery bypass graft (CABG) or ( percutaneous coronary intervention (PCI); and cerebrovascular events, including cerebrovascular accident (stroke) and transient ischemic attack (TIA).
    End point type
    Secondary
    End point timeframe
    Baseline through 24 Weeks
    End point values
    		 1.5 mg Dulaglutide 0.75 mg Dulaglutide Placebo
    Number of subjects analysed
    142 [16]
    141 [17]
    140 [18]
    Units: Participants
    number (not applicable)
        Any CV Event
    0
    0
    3
        Fatal CV Event
    0
    0
    0
        Non-fatal CV Event
    0
    0
    3
    Notes
    [16] - All participants who had at least one dose of study drug.
    [17] - All participants who had at least one dose of study drug.
    [18] - All participants who had at least one dose of study drug.
    No statistical analyses for this end point

    Adverse events

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    Adverse events information
    Timeframe for reporting adverse events
    Baseline to end of study (up to 24 weeks)
    Adverse event reporting additional description
    H9X-MC-GBGE
    Assessment type
    		 Systematic
    Dictionary used for adverse event reporting
    Dictionary name
    		 MedDRA
    Dictionary version
    20.0
    Reporting groups
    Reporting group title
    1.5 mg Dulaglutide
    Reporting group description
    		 -

    Reporting group title
    0.75 mg Dulaglutide
    Reporting group description
    		 -

    Reporting group title
    Placebo
    Reporting group description
    		 -

    Serious adverse events
    		 1.5 mg Dulaglutide 0.75 mg Dulaglutide Placebo
    Total subjects affected by serious adverse events
         subjects affected / exposed
    5 / 142 (3.52%)
    3 / 141 (2.13%)
    5 / 140 (3.57%)
         number of deaths (all causes)
    2
    0
    0
         number of deaths resulting from adverse events
    0
    0
    0
    Neoplasms benign, malignant and unspecified (incl cysts and polyps)
    endometrial cancer
    alternative dictionary used: MedDRA 20.0
         subjects affected / exposed [1]
    1 / 65 (1.54%)
    0 / 72 (0.00%)
    0 / 74 (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
    endometrial sarcoma
    alternative dictionary used: MedDRA 20.0
         subjects affected / exposed [2]
    1 / 65 (1.54%)
    0 / 72 (0.00%)
    0 / 74 (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
    malignant neoplasm of conjunctiva
    alternative dictionary used: MedDRA 20.0
         subjects affected / exposed
    1 / 142 (0.70%)
    0 / 141 (0.00%)
    0 / 140 (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
    prostate cancer
    alternative dictionary used: MedDRA 20.0
         subjects affected / exposed [3]
    1 / 77 (1.30%)
    0 / 69 (0.00%)
    0 / 66 (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
    hip fracture
    alternative dictionary used: MedDRA 20.0
         subjects affected / exposed
    0 / 142 (0.00%)
    1 / 141 (0.71%)
    0 / 140 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    injury
    alternative dictionary used: MedDRA 20.0
         subjects affected / exposed
    0 / 142 (0.00%)
    0 / 141 (0.00%)
    1 / 140 (0.71%)
         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 cord injury lumbar
    alternative dictionary used: MedDRA 20.0
         subjects affected / exposed
    1 / 142 (0.70%)
    0 / 141 (0.00%)
    0 / 140 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Cardiac disorders
    angina unstable
    alternative dictionary used: MedDRA 20.0
         subjects affected / exposed
    0 / 142 (0.00%)
    0 / 141 (0.00%)
    2 / 140 (1.43%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    atrial fibrillation
    alternative dictionary used: MedDRA 20.0
         subjects affected / exposed
    0 / 142 (0.00%)
    0 / 141 (0.00%)
    1 / 140 (0.71%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    atrial tachycardia
    alternative dictionary used: MedDRA 20.0
         subjects affected / exposed
    0 / 142 (0.00%)
    0 / 141 (0.00%)
    1 / 140 (0.71%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    myocardial infarction
    alternative dictionary used: MedDRA 20.0
         subjects affected / exposed
    0 / 142 (0.00%)
    0 / 141 (0.00%)
    1 / 140 (0.71%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Gastrointestinal disorders
    gastrointestinal haemorrhage
    alternative dictionary used: MedDRA 20.0
         subjects affected / exposed
    0 / 142 (0.00%)
    1 / 141 (0.71%)
    0 / 140 (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
    dyspnoea
    alternative dictionary used: MedDRA 20.0
         subjects affected / exposed
    0 / 142 (0.00%)
    1 / 141 (0.71%)
    0 / 140 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Infections and infestations
    clostridium difficile colitis
    alternative dictionary used: MedDRA 20.0
         subjects affected / exposed
    1 / 142 (0.70%)
    0 / 141 (0.00%)
    0 / 140 (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
    erysipelas
    alternative dictionary used: MedDRA 20.0
         subjects affected / exposed
    1 / 142 (0.70%)
    0 / 141 (0.00%)
    0 / 140 (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
    alternative dictionary used: MedDRA 20.0
         subjects affected / exposed
    1 / 142 (0.70%)
    0 / 141 (0.00%)
    0 / 140 (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
    sepsis
    alternative dictionary used: MedDRA 20.0
         subjects affected / exposed
    0 / 142 (0.00%)
    0 / 141 (0.00%)
    1 / 140 (0.71%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Notes
    [1] - The number of subjects exposed to this adverse event is less than the total number of subjects exposed to this adverse event. These numbers are expected to be equal.
    Justification: This event is gender specific, only occurring in male or female subjects. The number of subjects exposed has been adjusted accordingly.
    [2] - The number of subjects exposed to this adverse event is less than the total number of subjects exposed to this adverse event. These numbers are expected to be equal.
    Justification: This event is gender specific, only occurring in male or female subjects. The number of subjects exposed has been adjusted accordingly.
    [3] - The number of subjects exposed to this adverse event is less than the total number of subjects exposed to this adverse event. These numbers are expected to be equal.
    Justification: This event is gender specific, only occurring in male or female subjects. The number of subjects exposed has been adjusted accordingly.
    Frequency threshold for reporting non-serious adverse events: 5%
    Non-serious adverse events
    		 1.5 mg Dulaglutide 0.75 mg Dulaglutide Placebo
    Total subjects affected by non serious adverse events
         subjects affected / exposed
    43 / 142 (30.28%)
    34 / 141 (24.11%)
    29 / 140 (20.71%)
    Nervous system disorders
    headache
    alternative dictionary used: MedDRA 20.0
         subjects affected / exposed
    8 / 142 (5.63%)
    5 / 141 (3.55%)
    13 / 140 (9.29%)
         occurrences all number
    13
    8
    16
    Gastrointestinal disorders
    diarrhoea
    alternative dictionary used: MedDRA 20.0
         subjects affected / exposed
    8 / 142 (5.63%)
    14 / 141 (9.93%)
    4 / 140 (2.86%)
         occurrences all number
    10
    16
    5
    nausea
    alternative dictionary used: MedDRA 20.0
         subjects affected / exposed
    21 / 142 (14.79%)
    7 / 141 (4.96%)
    5 / 140 (3.57%)
         occurrences all number
    32
    13
    6
    Musculoskeletal and connective tissue disorders
    back pain
    alternative dictionary used: MedDRA 20.0
         subjects affected / exposed
    13 / 142 (9.15%)
    12 / 141 (8.51%)
    10 / 140 (7.14%)
         occurrences all number
    15
    14
    14
    Infections and infestations
    viral upper respiratory tract infection
    alternative dictionary used: MedDRA 20.0
         subjects affected / exposed
    9 / 142 (6.34%)
    8 / 141 (5.67%)
    11 / 140 (7.86%)
         occurrences all number
    12
    10
    12

    More information

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    Substantial protocol amendments (globally)
    Were there any global substantial amendments to the protocol? Yes
    Date
    Amendment
    21 Aug 2015
    Protocol A - All available data for the primary analysis, up to 24 weeks, will be included, except those collected after initiation of glucose-lowering rescue therapy. - If study drug is permanently discontinued for acute pancreatitis or for a severe or serious allergic reaction, the participant will continue in the study on another glucose-lowering regimen. - For participants diagnosed with acute pancreatitis or experience a severe or serious allergic reaction, the participant will continue in the study on another glucose-lowering regimen.
    28 Mar 2016
    Protocol B - Two primary estimands to compare the placebo and the dulaglutide arms in terms of the primary measure the change from baseline to 24 weeks for HbA1c. One primary estimand will be an efficacy estimand which will not use post-rescue data and the other will be an intent-to-treat (ITT) estimand which will use post-rescue data (treatment-regimen estimand). - Analysis of the key secondary efficacy outcome measures will include datasets with and without post-rescue data. - The primary analysis for primary and key secondary efficacy measures will be mixed-model repeated measure (MMRM) analysis using restricted maximum likelihood (REML).

    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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