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    Clinical Trial Results:
    A Phase 2, Double-Blind, Placebo-Controlled, 18-Week Trial of Investigational Dulaglutide Doses versus Placebo in Patients with Type 2 Diabetes on Metformin Monotherapy

    Summary
    EudraCT number
    		 2016-002494-34
    Trial protocol
    		 PL   CZ  
    Global end of trial date
    14 Aug 2017

    Results information
    Results version number
    		 v1(current)
    This version publication date
    30 Jul 2018
    First version publication date
    30 Jul 2018
    Other versions

    Trial information

    		 Close Top of page
    Trial identification
    Sponsor protocol code
    H9X-MC-GBGJ
    Additional study identifiers
    ISRCTN number
    		 -
    US NCT number
    		 NCT02973100
    WHO universal trial number (UTN)
    		 -
    Other trial identifiers
    		 Trial Number: 16568
    Sponsors
    Sponsor organisation name
    Eli Lilly and Company
    Sponsor organisation address
    Lilly Corporate Center, Indianapolis, IN, United States, 46285
    Public contact
    Available Mon ‐ Fri 9 AM ‐ 5 PM EST, Eli Lilly and Company, 1 877‐CTLilly, EU_Lilly_Clinical_Trials@lilly.com
    Scientific contact
    Available Mon ‐ Fri 9 AM ‐ 5 PM EST, Eli Lilly and Company, 1 877‐285‐4559, EU_Lilly_Clinical_Trials@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
    14 Aug 2017
    Is this the analysis of the primary completion data?
    No
    Global end of trial reached?
    Yes
    Global end of trial date
    14 Aug 2017
    Was the trial ended prematurely?
    No
    General information about the trial
    Main objective of the trial
    The purpose of this study is to evaluate the efficacy and safety of investigational doses of dulaglutide in participants with type 2 diabetes on metformin monotherapy.
    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
    01 Dec 2016
    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
    Romania: 21
    Country: Number of subjects enrolled
    United States: 174
    Country: Number of subjects enrolled
    Czech Republic: 37
    Country: Number of subjects enrolled
    Poland: 44
    Country: Number of subjects enrolled
    Mexico: 41
    Worldwide total number of subjects
    317
    EEA total number of subjects
    102
    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)
    245
    From 65 to 84 years
    72
    85 years and over
    0

    Subject disposition

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    Recruitment
    Recruitment details
    		 The study consisted of 3 periods: an approximately 2-week lead-in period, followed by an 18-week treatment period, and a 4-week safety follow-up period.

    Pre-assignment
    Screening details
    		 Not applicable

    Period 1
    Period 1 title
    Overall Study
    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
    		 Placebo
    Arm description
    		 Participants received placebo once weekly (QW) by subcutaneous (SC) injection.
    Arm type
    		 Placebo

    Investigational medicinal product name
    Placebo
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Solution for injection in pre-filled syringe
    Routes of administration
    Subcutaneous use
    Dosage and administration details
    Placebo was administered through subcutaneous injection.

    Arm title
    		 Dulaglutide 1.5 milligrams (mg)
    Arm description
    		 Participants received 1.5mg of dulaglutide QW by SC injection.
    Arm type
    		 Active comparator

    Investigational medicinal product name
    Dulaglutide
    Investigational medicinal product code
    LY2189265
    Other name
    Trulicity
    Pharmaceutical forms
    Solution for injection/infusion in pre-filled syringe
    Routes of administration
    Subcutaneous use
    Dosage and administration details
    1.5mg of Dulaglutide administered SC

    Arm title
    		 Dulaglutide 3.0 milligrams (mg)
    Arm description
    		 Participants received 3.0mg of dulaglutide QW by SC injection.
    Arm type
    		 Experimental

    Investigational medicinal product name
    Dulaglutide
    Investigational medicinal product code
    LY2189265
    Other name
    Trulicity
    Pharmaceutical forms
    Solution for injection/infusion in pre-filled syringe
    Routes of administration
    Subcutaneous use
    Dosage and administration details
    3.0mg of Dulaglutide administered SC

    Arm title
    		 Dulaglutide 4.5 milligrams (mg)
    Arm description
    		 Participants received 4.5mg of dulaglutide QW by SC injection.
    Arm type
    		 Experimental

    Investigational medicinal product name
    Dulaglutide
    Investigational medicinal product code
    LY2189265
    Other name
    Trulicity
    Pharmaceutical forms
    Solution for injection/infusion in pre-filled syringe
    Routes of administration
    Subcutaneous use
    Dosage and administration details
    4.5mg of Dulaglutide administered SC

    Number of subjects in period 1
    		Placebo Dulaglutide 1.5 milligrams (mg) Dulaglutide 3.0 milligrams (mg) Dulaglutide 4.5 milligrams (mg)
    Started
    82
    81
    79
    76
    Received at Least 1 Dose of Study Drug
    81
    81
    79
    76
    Completed
    75
    73
    75
    69
    Not completed
    7
    8
    4
    7
         Consent withdrawn by subject
    3
    5
    1
    4
         Failed to attend Safety followup period
    -
    -
    1
    -
         Adverse event, non-fatal
    1
    2
    1
    2
         Notification of change in address
    -
    -
    -
    1
         Lost to follow-up
    3
    1
    1
    -
    Period 2
    Period 2 title
    Received at Least One Dose
    Is this the baseline period?
    		 Yes [1]
    Allocation method
    Randomised - controlled
    Blinding used
    		 Double blind
    Roles blinded
    		 Subject, Investigator

    Arms
    Are arms mutually exclusive
    No

    Arm title
    		 Placebo
    Arm description
    		 Participants received placebo once weekly (QW) by subcutaneous (SC) injection.
    Arm type
    		 Placebo

    Investigational medicinal product name
    Placebo
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Solution for injection in pre-filled syringe
    Routes of administration
    Subcutaneous use
    Dosage and administration details
    Placebo was administered through subcutaneous injection.

    Arm title
    		 Dulaglutide 1.5 milligrams (mg)
    Arm description
    		 Participants received 1.5mg of dulaglutide QW by SC injection.
    Arm type
    		 Active comparator

    Investigational medicinal product name
    Dulaglutide
    Investigational medicinal product code
    LY2189265
    Other name
    Trulicity
    Pharmaceutical forms
    Solution for injection/infusion in pre-filled syringe
    Routes of administration
    Subcutaneous use
    Dosage and administration details
    1.5mg of Dulaglutide administered SC

    Arm title
    		 Dulaglutide 3.0 milligrams (mg)
    Arm description
    		 Participants received 3.0mg of dulaglutide QW by SC injection.
    Arm type
    		 Experimental

    Investigational medicinal product name
    Dulaglutide
    Investigational medicinal product code
    LY2189265
    Other name
    Trulicity
    Pharmaceutical forms
    Solution for injection/infusion in pre-filled syringe
    Routes of administration
    Subcutaneous use
    Dosage and administration details
    3.0mg of Dulaglutide administered SC

    Arm title
    		 Dulaglutide 4.5 milligrams (mg)
    Arm description
    		 Participants received 4.5mg of dulaglutide QW by SC injection.
    Arm type
    		 Experimental

    Investigational medicinal product name
    Dulaglutide
    Investigational medicinal product code
    LY2189265
    Other name
    Trulicity
    Pharmaceutical forms
    Solution for injection/infusion in pre-filled syringe
    Routes of administration
    Subcutaneous use
    Dosage and administration details
    4.5mg of Dulaglutide administered SC

    Notes
    [1] - Period 1 is not the baseline period. It is expected that period 1 will be the baseline period.
    Justification: The baseline characteristics are calculated for participants who received at least one dose of study drug as per SAP.
    Number of subjects in period 2
    		Placebo Dulaglutide 1.5 milligrams (mg) Dulaglutide 3.0 milligrams (mg) Dulaglutide 4.5 milligrams (mg)
    Started
    81
    81
    79
    76
    Completed
    75
    73
    75
    69
    Not completed
    6
    8
    4
    7
         Consent withdrawn by subject
    2
    5
    1
    4
         Failed to attend Safety followup period
    -
    -
    1
    -
         Adverse event, non-fatal
    1
    2
    1
    2
         Notification of change in address
    -
    -
    -
    1
         Lost to follow-up
    3
    1
    1
    -

    Baseline characteristics

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    Baseline characteristics reporting groups
    Reporting group title
    Placebo
    Reporting group description
    		 Participants received placebo once weekly (QW) by subcutaneous (SC) injection.

    Reporting group title
    Dulaglutide 1.5 milligrams (mg)
    Reporting group description
    		 Participants received 1.5mg of dulaglutide QW by SC injection.

    Reporting group title
    Dulaglutide 3.0 milligrams (mg)
    Reporting group description
    		 Participants received 3.0mg of dulaglutide QW by SC injection.

    Reporting group title
    Dulaglutide 4.5 milligrams (mg)
    Reporting group description
    		 Participants received 4.5mg of dulaglutide QW by SC injection.

    Reporting group values
    		 Placebo Dulaglutide 1.5 milligrams (mg) Dulaglutide 3.0 milligrams (mg) Dulaglutide 4.5 milligrams (mg) Total
    Number of subjects
    		 81 81 79 76 317
    Age categorical
    Units: Subjects
        In utero
    		 0 0 0 0 0
        Preterm newborn infants (gestational age < 37 wks)
    		 0 0 0 0 0
        Newborns (0-27 days)
    		 0 0 0 0 0
        Infants and toddlers (28 days-23 months)
    		 0 0 0 0 0
        Children (2-11 years)
    		 0 0 0 0 0
        Adolescents (12-17 years)
    		 0 0 0 0 0
        Adults (18-64 years)
    		 65 59 62 59 245
        From 65-84 years
    		 16 22 17 17 72
        85 years and over
    		 0 0 0 0 0
    Age Continuous
    Units: Years
        arithmetic mean (standard deviation)
    		 56.52 ± 8.93 57.65 ± 9.79 55.90 ± 10.74 57.13 ± 9.63 -
    Gender categorical
    Units: Subjects
        Female
    		 33 42 44 40 159
        Male
    		 48 39 35 36 158
    Ethnicity (NIH/OMB)
    Units: Subjects
        Hispanic or Latino
    		 35 32 38 30 135
        Not Hispanic or Latino
    		 46 49 40 45 180
        Unknown or Not Reported
    		 0 0 1 1 2
    Race (NIH/OMB)
    Units: Subjects
        American Indian or Alaska Native
    		 10 6 9 6 31
        Asian
    		 0 0 1 3 4
        Native Hawaiian or Other Pacific Islander
    		 1 0 0 0 1
        Black or African American
    		 6 6 6 6 24
        White
    		 59 68 58 59 244
        More than one race
    		 5 1 4 2 12
        Unknown or Not Reported
    		 0 0 1 0 1
    Region of Enrollment
    Units: Subjects
        Romania
    		 6 6 5 4 21
        United States
    		 42 45 44 43 174
        Czech Republic
    		 10 9 10 8 37
        Poland
    		 13 11 10 10 44
        Mexico
    		 10 10 10 11 41
    Baseline Hemoglobin A1c (HbA1c)
    Units: Percentage of glycosylated hemoglobin
        arithmetic mean (standard deviation)
    		 8.08 ± 0.79 8.02 ± 0.80 8.16 ± 0.92 8.12 ± 0.81 -

    End points

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    End points reporting groups
    Reporting group title
    Placebo
    Reporting group description
    		 Participants received placebo once weekly (QW) by subcutaneous (SC) injection.

    Reporting group title
    Dulaglutide 1.5 milligrams (mg)
    Reporting group description
    		 Participants received 1.5mg of dulaglutide QW by SC injection.

    Reporting group title
    Dulaglutide 3.0 milligrams (mg)
    Reporting group description
    		 Participants received 3.0mg of dulaglutide QW by SC injection.

    Reporting group title
    Dulaglutide 4.5 milligrams (mg)
    Reporting group description
    		 Participants received 4.5mg of dulaglutide QW by SC injection.
    Reporting group title
    Placebo
    Reporting group description
    		 Participants received placebo once weekly (QW) by subcutaneous (SC) injection.

    Reporting group title
    Dulaglutide 1.5 milligrams (mg)
    Reporting group description
    		 Participants received 1.5mg of dulaglutide QW by SC injection.

    Reporting group title
    Dulaglutide 3.0 milligrams (mg)
    Reporting group description
    		 Participants received 3.0mg of dulaglutide QW by SC injection.

    Reporting group title
    Dulaglutide 4.5 milligrams (mg)
    Reporting group description
    		 Participants received 4.5mg of dulaglutide QW by SC injection.

    Primary: Change from Baseline in Hemoglobin A1c (HbA1c)

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    End point title
    		 Change from Baseline in Hemoglobin A1c (HbA1c)
    End point description
    HbA1c is the glycosylated fraction of hemoglobin A. HbA1c is measured to identify average plasma glucose concentration over prolonged periods of time. Least Squares (LS) mean was determined by mixed-model repeated measures (MMRM) model with baseline as a covariate, pooled country, treatment, time, treatment*time as fixed effects. Analysis Population Description (APD): All randomized participants who received at least one dose of study drug and had postbaseline values, excluding post rescue data for Hemoglobin A1c.
    End point type
    Primary
    End point timeframe
    Baseline, Week 18
    End point values
    		 Placebo Dulaglutide 1.5 milligrams (mg) Dulaglutide 3.0 milligrams (mg) Dulaglutide 4.5 milligrams (mg)
    Number of subjects analysed
    70
    73
    73
    66
    Units: Percentage of glycosylated hemoglobin
        least squares mean (standard error)
    -0.44 ± 0.101
    -1.23 ± 0.099
    -1.31 ± 0.099
    -1.40 ± 0.103
    Statistical analysis title
    		 Change from Baseline in HbA1c
    Comparison groups
    Placebo v Dulaglutide 1.5 milligrams (mg)
    Number of subjects included in analysis
    143
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 < 0.001
    Method
    		 Mixed models analysis
    Parameter type
    		 Mean difference (final values)
    Point estimate
    -0.8
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -1.07
         upper limit
    		 -0.53
    Statistical analysis title
    		 Change from Baseline in HbA1c
    Comparison groups
    Placebo v Dulaglutide 3.0 milligrams (mg)
    Number of subjects included in analysis
    143
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 < 0.001
    Method
    		 Mixed models analysis
    Parameter type
    		 Mean difference (final values)
    Point estimate
    -0.87
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -1.14
         upper limit
    		 -0.6
    Statistical analysis title
    		 Change from Baseline in HbA1c
    Comparison groups
    Placebo v Dulaglutide 4.5 milligrams (mg)
    Number of subjects included in analysis
    136
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 < 0.001
    Method
    		 Mixed models analysis
    Parameter type
    		 Mean difference (final values)
    Point estimate
    -0.96
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -1.24
         upper limit
    		 -0.69

    Secondary: Percentage of Participants with HbA1c of <7.0%

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    End point title
    		 Percentage of Participants with HbA1c of <7.0%
    End point description
    Hemoglobin A1c (HbA1c) is the glycosylated fraction of hemoglobin A. HbA1c is measured primarily to identify average plasma glucose concentration over prolonged periods of time. Analysis Population Description: All randomized participants who received at least one dose of study drug and had postbaseline values, excluding post rescue data for Hemoglobin A1c.
    End point type
    Secondary
    End point timeframe
    Week 18
    End point values
    		 Placebo Dulaglutide 1.5 milligrams (mg) Dulaglutide 3.0 milligrams (mg) Dulaglutide 4.5 milligrams (mg)
    Number of subjects analysed
    70
    73
    73
    66
    Units: Percentage of Participants
        number (not applicable)
    20
    71.2
    71.2
    68.2
    Statistical analysis title
    		 Percentage of Participants with HbA1c of <7.0%
    Comparison groups
    Placebo v Dulaglutide 1.5 milligrams (mg)
    Number of subjects included in analysis
    143
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 < 0.001
    Method
    		 Regression, Logistic
    Parameter type
    		 Odds ratio (OR)
    Point estimate
    24.489
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 8.368
         upper limit
    		 71.667
    Statistical analysis title
    		 Percentage of Participants with HbA1c of <7.0%
    Comparison groups
    Placebo v Dulaglutide 3.0 milligrams (mg)
    Number of subjects included in analysis
    143
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 < 0.001
    Method
    		 Regression, Logistic
    Parameter type
    		 Odds ratio (OR)
    Point estimate
    27.906
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 9.238
         upper limit
    		 84.3
    Statistical analysis title
    		 Percentage of Participants with HbA1c of <7.0%
    Comparison groups
    Placebo v Dulaglutide 4.5 milligrams (mg)
    Number of subjects included in analysis
    136
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 < 0.001
    Method
    		 Regression, Logistic
    Parameter type
    		 Odds ratio (OR)
    Point estimate
    21.852
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 7.672
         upper limit
    		 62.242

    Secondary: Change from Baseline in Fasting Serum Glucose (FSG)

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    End point title
    		 Change from Baseline in Fasting Serum Glucose (FSG)
    End point description
    Fasting serum glucose (FSG) is a test to determine how much glucose (sugar) is in a serum sample after an overnight fast. Least Squares (LS) means was determined by MMRM methodology with baseline as a covariate, pooled country, baseline HbA1c strata using >=8% as cutoff, treatment, time, treatment*time as fixed effects. Analysis Population Description: All randomized participants who received at least one dose of study drug and had postbaseline values, excluding post rescue data for FSG.
    End point type
    Secondary
    End point timeframe
    Baseline, Week 18
    End point values
    		 Placebo Dulaglutide 1.5 milligrams (mg) Dulaglutide 3.0 milligrams (mg) Dulaglutide 4.5 milligrams (mg)
    Number of subjects analysed
    63
    62
    67
    61
    Units: millimole/liter (mmol/L)
        least squares mean (standard error)
    -0.69 ± 0.257
    -2.01 ± 0.261
    -1.92 ± 0.250
    -2.11 ± 0.263
    Statistical analysis title
    		 Change from Baseline in FSG
    Comparison groups
    Placebo v Dulaglutide 1.5 milligrams (mg)
    Number of subjects included in analysis
    125
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 < 0.001
    Method
    		 Mixed models analysis
    Parameter type
    		 Mean difference (final values)
    Point estimate
    -1.32
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -2.02
         upper limit
    		 -0.62
    Statistical analysis title
    		 Change from Baseline in FSG
    Comparison groups
    Placebo v Dulaglutide 3.0 milligrams (mg)
    Number of subjects included in analysis
    130
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 < 0.001
    Method
    		 Mixed models analysis
    Parameter type
    		 Mean difference (final values)
    Point estimate
    -1.23
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -1.91
         upper limit
    		 -0.54
    Statistical analysis title
    		 Change from Baseline in FSG
    Comparison groups
    Placebo v Dulaglutide 4.5 milligrams (mg)
    Number of subjects included in analysis
    124
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 < 0.001
    Method
    		 Mixed models analysis
    Parameter type
    		 Mean difference (final values)
    Point estimate
    -1.42
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -2.12
         upper limit
    		 -0.72

    Secondary: Change from Baseline in Body Weight

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    End point title
    		 Change from Baseline in Body Weight
    End point description
    Least Squares (LS) mean was determined by mixed-model repeated measures (MMRM) model with baseline as a covariate, pooled country, baseline HbA1c strata using >=8% as cutoff, treatment, time, treatment*time as fixed effects. Analysis Population Description: All randomized participants who received at least one dose of study drug and had postbaseline values, excluding post rescue data for body weight.
    End point type
    Secondary
    End point timeframe
    Baseline, Week 18
    End point values
    		 Placebo Dulaglutide 1.5 milligrams (mg) Dulaglutide 3.0 milligrams (mg) Dulaglutide 4.5 milligrams (mg)
    Number of subjects analysed
    70
    72
    74
    67
    Units: Kilograms (Kg)
        least squares mean (standard error)
    -1.6 ± 0.39
    -2.8 ± 0.39
    -3.9 ± 0.39
    -4.1 ± 0.41
    Statistical analysis title
    		 Change from Baseline in Body Weight
    Comparison groups
    Placebo v Dulaglutide 1.5 milligrams (mg)
    Number of subjects included in analysis
    142
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.025
    Method
    		 Mixed models analysis
    Parameter type
    		 Mean difference (final values)
    Point estimate
    -1.2
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -2.3
         upper limit
    		 -0.2
    Statistical analysis title
    		 Change from Baseline in Body Weight
    Comparison groups
    Placebo v Dulaglutide 3.0 milligrams (mg)
    Number of subjects included in analysis
    144
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 < 0.001
    Method
    		 Mixed models analysis
    Parameter type
    		 Mean difference (final values)
    Point estimate
    -2.4
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -3.4
         upper limit
    		 -1.3
    Statistical analysis title
    		 Change from Baseline in Body Weight
    Comparison groups
    Placebo v Dulaglutide 4.5 milligrams (mg)
    Number of subjects included in analysis
    137
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 < 0.001
    Method
    		 Mixed models analysis
    Parameter type
    		 Mean difference (final values)
    Point estimate
    -2.6
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -3.7
         upper limit
    		 -1.5

    Secondary: Percentage of Participants Discontinuing Study Drug Due to Adverse Events

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    End point title
    		 Percentage of Participants Discontinuing Study Drug Due to Adverse Events
    End point description
    Adverse event (AE) defined as any unfavorable medical event, newly emerged or a deterioration of a preexisting condition, in other words any untoward medical occurrence in a patient administered a pharmaceutical product, without regard to the possibility of a causal relationship, that occurred after the visit for informed consent and up to the visit for completion of administration, or discontinuation. Analysis Population Description: All randomized participants who received study drug and had postbaseline data for safety analyses.
    End point type
    Secondary
    End point timeframe
    Baseline through Week 18
    End point values
    		 Placebo Dulaglutide 1.5 milligrams (mg) Dulaglutide 3.0 milligrams (mg) Dulaglutide 4.5 milligrams (mg)
    Number of subjects analysed
    82
    81
    79
    76
    Units: Percentage of Participants
        number (not applicable)
    4.9
    6.2
    10.1
    13.2
    No statistical analyses for this end point

    Secondary: Rate of Documented Symptomatic Hypoglycemia

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    End point title
    		 Rate of Documented Symptomatic Hypoglycemia
    End point description
    Hypoglycemic events (HE) were classified as severe, documented symptomatic (defined as an HE with typical symptoms of hypoglycemia and a blood glucose level of ≤3.9 millimoles per liter [mmol/L]). Hypoglycemia rate per 30 days was summarized at each visit by treatment group. The rate of hypoglycemia was analyzed using a generalized estimation equations model with a negative binomial distribution and a Log link. LS mean was determined by MMRM methodology with baseline hypoglycemia rate, pooled country, HbA1c at Baseline, treatment, with log of exposure in days divided by 365.25 as the offset. APD: All randomized participants who received at least one dose of study drug and had postbaseline values, excluding post rescue values for hypoglycemic Episodes.
    End point type
    Secondary
    End point timeframe
    Week 18
    End point values
    		 Placebo Dulaglutide 1.5 milligrams (mg) Dulaglutide 3.0 milligrams (mg) Dulaglutide 4.5 milligrams (mg)
    Number of subjects analysed
    81
    81
    79
    76
    Units: Episodes/participant/365.25 days
        least squares mean (standard error)
    0.00 ± 0.000
    0.00 ± 0.000
    0.00 ± 0.000
    0.00 ± 0.001
    No statistical analyses for this end point

    Secondary: Pharmacokinetics (PK): The Maximum Drug Concentration at Steady State (Cmax,ss) of Dulaglutide

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    End point title
    		 Pharmacokinetics (PK): The Maximum Drug Concentration at Steady State (Cmax,ss) of Dulaglutide
    End point description
    Plasma samples for PK analysis were combined measure obtained from 0, 2, 4, 6, 10, 18, 22 weeks and until early termination of the visit. Cmax takes all time points post dose into account and one value was reported. Analysis Population Description: All randomized participants who received at least one dose of the study drug and have evaluable PK data.
    End point type
    Secondary
    End point timeframe
    Predose, 0, 2, 4, 6, 10, 18, 22 weeks and early termination
    End point values
    		 Dulaglutide 1.5 milligrams (mg) Dulaglutide 3.0 milligrams (mg) Dulaglutide 4.5 milligrams (mg)
    Number of subjects analysed
    81
    79
    76
    Units: nanogram per milliliter (ng/mL)
        arithmetic mean (confidence interval 90%)
    90.4 (38.9 to 170)
    151 (64.3 to 277)
    204 (87.2 to 377)
    No statistical analyses for this end point

    Secondary: Pharmacokinetics: Area Under the Concentration-Time Curve at Steady State From Time Zero to 168 Hours (AUC[0-168], ss) of Dulaglutide

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    End point title
    		 Pharmacokinetics: Area Under the Concentration-Time Curve at Steady State From Time Zero to 168 Hours (AUC[0-168], ss) of Dulaglutide
    End point description
    AUC[0-168h] is a combined measure obtained from 0, 2, 4, 6, 10, 18, 22 weeks and until early termination of the visit. Analysis Population Description: All randomized participants who received at least one dose of the study drug and have evaluable PK data.
    End point type
    Secondary
    End point timeframe
    Predose, 0, 2, 4, 6, 10, 18, 22 weeks and early termination
    End point values
    		 Dulaglutide 1.5 milligrams (mg) Dulaglutide 3.0 milligrams (mg) Dulaglutide 4.5 milligrams (mg)
    Number of subjects analysed
    81
    79
    76
    Units: nanogram*hour per milliliter (ng*h/mL)
        arithmetic mean (confidence interval 90%)
    11800 (5300 to 21300)
    26700 (15300 to 41400)
    36600 (21100 to 56500)
    No statistical analyses for this end point

    Adverse events

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    Adverse events information
    Timeframe for reporting adverse events
    Entire Study
    Adverse event reporting additional description
    H9X-MC-GBGJ
    Assessment type
    		 Systematic
    Dictionary used for adverse event reporting
    Dictionary name
    		 MedDRA
    Dictionary version
    20.0
    Reporting groups
    Reporting group title
    Dulaglutide 4.5 milligrams (mg)
    Reporting group description
    		 -

    Reporting group title
    Dulaglutide 3.0 milligrams (mg)
    Reporting group description
    		 -

    Reporting group title
    Dulaglutide 1.5 milligrams (mg)
    Reporting group description
    		 -

    Reporting group title
    Placebo
    Reporting group description
    		 -

    Serious adverse events
    		 Dulaglutide 4.5 milligrams (mg) Dulaglutide 3.0 milligrams (mg) Dulaglutide 1.5 milligrams (mg) Placebo
    Total subjects affected by serious adverse events
         subjects affected / exposed
    3 / 76 (3.95%)
    7 / 79 (8.86%)
    3 / 81 (3.70%)
    4 / 81 (4.94%)
         number of deaths (all causes)
    0
    0
    0
    0
         number of deaths resulting from adverse events
    0
    0
    0
    0
    Neoplasms benign, malignant and unspecified (incl cysts and polyps)
    invasive ductal breast carcinoma
    alternative dictionary used: MedDRA 20.0
         subjects affected / exposed
    0 / 76 (0.00%)
    1 / 79 (1.27%)
    0 / 81 (0.00%)
    0 / 81 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Injury, poisoning and procedural complications
    traumatic intracranial haemorrhage
    alternative dictionary used: MedDRA 20.0
         subjects affected / exposed
    0 / 76 (0.00%)
    0 / 79 (0.00%)
    0 / 81 (0.00%)
    1 / 81 (1.23%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Vascular disorders
    hypotension
    alternative dictionary used: MedDRA 20.0
         subjects affected / exposed
    0 / 76 (0.00%)
    1 / 79 (1.27%)
    0 / 81 (0.00%)
    0 / 81 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Cardiac disorders
    acute myocardial infarction
    alternative dictionary used: MedDRA 20.0
         subjects affected / exposed
    0 / 76 (0.00%)
    0 / 79 (0.00%)
    0 / 81 (0.00%)
    1 / 81 (1.23%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    atrioventricular block second degree
    alternative dictionary used: MedDRA 20.0
         subjects affected / exposed
    0 / 76 (0.00%)
    1 / 79 (1.27%)
    0 / 81 (0.00%)
    0 / 81 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Myocardial infarction
    alternative dictionary used: MedDRA 20.0
         subjects affected / exposed
    0 / 76 (0.00%)
    0 / 79 (0.00%)
    1 / 81 (1.23%)
    0 / 81 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    pericarditis
    alternative dictionary used: MedDRA 20.0
         subjects affected / exposed
    0 / 76 (0.00%)
    0 / 79 (0.00%)
    1 / 81 (1.23%)
    0 / 81 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Gastrointestinal disorders
    abdominal pain upper
    alternative dictionary used: MedDRA 20.0
         subjects affected / exposed
    1 / 76 (1.32%)
    0 / 79 (0.00%)
    0 / 81 (0.00%)
    0 / 81 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    pancreatitis
    alternative dictionary used: MedDRA 20.0
         subjects affected / exposed
    1 / 76 (1.32%)
    0 / 79 (0.00%)
    0 / 81 (0.00%)
    0 / 81 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    vomiting
    alternative dictionary used: MedDRA 20.0
         subjects affected / exposed
    0 / 76 (0.00%)
    1 / 79 (1.27%)
    0 / 81 (0.00%)
    0 / 81 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Hepatobiliary disorders
    cholecystitis
    alternative dictionary used: MedDRA 20.0
         subjects affected / exposed
    1 / 76 (1.32%)
    0 / 79 (0.00%)
    0 / 81 (0.00%)
    0 / 81 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    cholecystitis acute
    alternative dictionary used: MedDRA 20.0
         subjects affected / exposed
    1 / 76 (1.32%)
    0 / 79 (0.00%)
    0 / 81 (0.00%)
    0 / 81 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    cholelithiasis
    alternative dictionary used: MedDRA 20.0
         subjects affected / exposed
    0 / 76 (0.00%)
    0 / 79 (0.00%)
    1 / 81 (1.23%)
    0 / 81 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Respiratory, thoracic and mediastinal disorders
    pulmonary oedema
    alternative dictionary used: MedDRA 20.0
         subjects affected / exposed
    0 / 76 (0.00%)
    1 / 79 (1.27%)
    0 / 81 (0.00%)
    0 / 81 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Renal and urinary disorders
    renal failure
    alternative dictionary used: MedDRA 20.0
         subjects affected / exposed
    0 / 76 (0.00%)
    1 / 79 (1.27%)
    0 / 81 (0.00%)
    0 / 81 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Musculoskeletal and connective tissue disorders
    spinal pain
    alternative dictionary used: MedDRA 20.0
         subjects affected / exposed
    0 / 76 (0.00%)
    0 / 79 (0.00%)
    0 / 81 (0.00%)
    1 / 81 (1.23%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Infections and infestations
    bronchitis
    alternative dictionary used: MedDRA 20.0
         subjects affected / exposed
    1 / 76 (1.32%)
    0 / 79 (0.00%)
    0 / 81 (0.00%)
    0 / 81 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    cholecystitis infective
    alternative dictionary used: MedDRA 20.0
         subjects affected / exposed
    0 / 76 (0.00%)
    1 / 79 (1.27%)
    0 / 81 (0.00%)
    0 / 81 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    fungal oesophagitis
    alternative dictionary used: MedDRA 20.0
         subjects affected / exposed
    0 / 76 (0.00%)
    1 / 79 (1.27%)
    0 / 81 (0.00%)
    0 / 81 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    peritonsillar abscess
    alternative dictionary used: MedDRA 20.0
         subjects affected / exposed
    0 / 76 (0.00%)
    1 / 79 (1.27%)
    0 / 81 (0.00%)
    0 / 81 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Metabolism and nutrition disorders
    hyperglycaemic hyperosmolar nonketotic syndrome
    alternative dictionary used: MedDRA 20.0
         subjects affected / exposed
    0 / 76 (0.00%)
    0 / 79 (0.00%)
    0 / 81 (0.00%)
    1 / 81 (1.23%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    hyponatraemia
    alternative dictionary used: MedDRA 20.0
         subjects affected / exposed
    0 / 76 (0.00%)
    1 / 79 (1.27%)
    0 / 81 (0.00%)
    0 / 81 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    hypovolaemia
    alternative dictionary used: MedDRA 20.0
         subjects affected / exposed
    0 / 76 (0.00%)
    1 / 79 (1.27%)
    0 / 81 (0.00%)
    0 / 81 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Frequency threshold for reporting non-serious adverse events: 5%
    Non-serious adverse events
    		 Dulaglutide 4.5 milligrams (mg) Dulaglutide 3.0 milligrams (mg) Dulaglutide 1.5 milligrams (mg) Placebo
    Total subjects affected by non serious adverse events
         subjects affected / exposed
    39 / 76 (51.32%)
    49 / 79 (62.03%)
    36 / 81 (44.44%)
    29 / 81 (35.80%)
    Investigations
    weight decreased
    alternative dictionary used: MedDRA 20.0
         subjects affected / exposed
    2 / 76 (2.63%)
    5 / 79 (6.33%)
    3 / 81 (3.70%)
    0 / 81 (0.00%)
         occurrences all number
    2
    6
    6
    0
    Vascular disorders
    hypertension
    alternative dictionary used: MedDRA 20.0
         subjects affected / exposed
    0 / 76 (0.00%)
    4 / 79 (5.06%)
    1 / 81 (1.23%)
    1 / 81 (1.23%)
         occurrences all number
    0
    4
    1
    1
    Nervous system disorders
    dizziness
    alternative dictionary used: MedDRA 20.0
         subjects affected / exposed
    4 / 76 (5.26%)
    5 / 79 (6.33%)
    4 / 81 (4.94%)
    4 / 81 (4.94%)
         occurrences all number
    5
    6
    6
    6
    headache
    alternative dictionary used: MedDRA 20.0
         subjects affected / exposed
    5 / 76 (6.58%)
    10 / 79 (12.66%)
    4 / 81 (4.94%)
    7 / 81 (8.64%)
         occurrences all number
    8
    13
    4
    11
    General disorders and administration site conditions
    fatigue
    alternative dictionary used: MedDRA 20.0
         subjects affected / exposed
    7 / 76 (9.21%)
    4 / 79 (5.06%)
    1 / 81 (1.23%)
    2 / 81 (2.47%)
         occurrences all number
    7
    4
    1
    3
    Gastrointestinal disorders
    abdominal discomfort
    alternative dictionary used: MedDRA 20.0
         subjects affected / exposed
    4 / 76 (5.26%)
    2 / 79 (2.53%)
    0 / 81 (0.00%)
    0 / 81 (0.00%)
         occurrences all number
    10
    2
    0
    0
    abdominal pain
    alternative dictionary used: MedDRA 20.0
         subjects affected / exposed
    7 / 76 (9.21%)
    1 / 79 (1.27%)
    3 / 81 (3.70%)
    1 / 81 (1.23%)
         occurrences all number
    7
    1
    4
    1
    constipation
    alternative dictionary used: MedDRA 20.0
         subjects affected / exposed
    6 / 76 (7.89%)
    4 / 79 (5.06%)
    5 / 81 (6.17%)
    0 / 81 (0.00%)
         occurrences all number
    6
    4
    5
    0
    diarrhoea
    alternative dictionary used: MedDRA 20.0
         subjects affected / exposed
    16 / 76 (21.05%)
    18 / 79 (22.78%)
    9 / 81 (11.11%)
    9 / 81 (11.11%)
         occurrences all number
    32
    34
    17
    10
    dyspepsia
    alternative dictionary used: MedDRA 20.0
         subjects affected / exposed
    8 / 76 (10.53%)
    5 / 79 (6.33%)
    6 / 81 (7.41%)
    0 / 81 (0.00%)
         occurrences all number
    13
    5
    10
    0
    eructation
    alternative dictionary used: MedDRA 20.0
         subjects affected / exposed
    6 / 76 (7.89%)
    1 / 79 (1.27%)
    3 / 81 (3.70%)
    0 / 81 (0.00%)
         occurrences all number
    6
    1
    3
    0
    gastrooesophageal reflux disease
    alternative dictionary used: MedDRA 20.0
         subjects affected / exposed
    0 / 76 (0.00%)
    1 / 79 (1.27%)
    5 / 81 (6.17%)
    0 / 81 (0.00%)
         occurrences all number
    0
    1
    5
    0
    nausea
    alternative dictionary used: MedDRA 20.0
         subjects affected / exposed
    23 / 76 (30.26%)
    20 / 79 (25.32%)
    18 / 81 (22.22%)
    4 / 81 (4.94%)
         occurrences all number
    40
    32
    45
    5
    vomiting
    alternative dictionary used: MedDRA 20.0
         subjects affected / exposed
    10 / 76 (13.16%)
    9 / 79 (11.39%)
    9 / 81 (11.11%)
    4 / 81 (4.94%)
         occurrences all number
    16
    15
    20
    6
    Musculoskeletal and connective tissue disorders
    back pain
    alternative dictionary used: MedDRA 20.0
         subjects affected / exposed
    4 / 76 (5.26%)
    1 / 79 (1.27%)
    0 / 81 (0.00%)
    1 / 81 (1.23%)
         occurrences all number
    4
    2
    0
    1
    Infections and infestations
    influenza
    alternative dictionary used: MedDRA 20.0
         subjects affected / exposed
    1 / 76 (1.32%)
    4 / 79 (5.06%)
    1 / 81 (1.23%)
    0 / 81 (0.00%)
         occurrences all number
    1
    4
    1
    0
    upper respiratory tract infection
    alternative dictionary used: MedDRA 20.0
         subjects affected / exposed
    1 / 76 (1.32%)
    5 / 79 (6.33%)
    1 / 81 (1.23%)
    3 / 81 (3.70%)
         occurrences all number
    1
    5
    1
    5
    viral upper respiratory tract infection
    alternative dictionary used: MedDRA 20.0
         subjects affected / exposed
    3 / 76 (3.95%)
    6 / 79 (7.59%)
    2 / 81 (2.47%)
    5 / 81 (6.17%)
         occurrences all number
    4
    6
    2
    7
    Metabolism and nutrition disorders
    decreased appetite
    alternative dictionary used: MedDRA 20.0
         subjects affected / exposed
    6 / 76 (7.89%)
    13 / 79 (16.46%)
    3 / 81 (3.70%)
    1 / 81 (1.23%)
         occurrences all number
    6
    17
    3
    1

    More information

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    Substantial protocol amendments (globally)
    Were there any global substantial amendments to the protocol? Yes
    Date
    Amendment
    19 Aug 2016
    Amendment (a): Supraventricular arrhythmias and cardiac conduction disorders were added as adverse events of special interest.

    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
    For support, Contact us.
    The status and protocol content of GB trials is no longer updated since 1 January 2021. For the UK, as of 31 January 2021, EU Law applies only to the territory of Northern Ireland (NI) to the extent foreseen in the Protocol on Ireland/NI. Legal notice
    As of 31 January 2023, all EU/EEA initial clinical trial applications must be submitted through CTIS . Updated EudraCT trials information and information on PIP/Art 46 trials conducted exclusively in third countries continues to be submitted through EudraCT and published on this website.

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