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    Clinical Trial Results:
    A Randomized, Double-Blind Trial Comparing the Effect of Dulaglutide 1.5 mg with Placebo on Glycemic Control in Patients with Type 2 Diabetes on Basal Insulin Glargine

    Summary
    EudraCT number
    		 2012-004229-25
    Trial protocol
    		 IT   HU   CZ   ES   GB  
    Global end of trial date
    15 Oct 2015

    Results information
    Results version number
    		 v1(current)
    This version publication date
    28 Oct 2016
    First version publication date
    28 Oct 2016
    Other versions

    Trial information

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    Trial identification
    Sponsor protocol code
    13195
    Additional study identifiers
    ISRCTN number
    		 -
    US NCT number
    		 NCT02152371
    WHO universal trial number (UTN)
    		 -
    Other trial identifiers
    		 Trial Alias: H9X-MC-GBDI, Trial ID : 13195
    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,
    Scientific contact
    Available Mon - Fri 9 AM - 5 PM EST, Eli Lilly and Company, 1 877-285-4559,
    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
    15 Oct 2015
    Is this the analysis of the primary completion data?
    No
    Global end of trial reached?
    Yes
    Global end of trial date
    15 Oct 2015
    Was the trial ended prematurely?
    No
    General information about the trial
    Main objective of the trial
    The main purpose of this study is to evaluate the use of the study drug known as dulaglutide in participants with type II diabetes who are taking once-daily insulin glargine. The study will last about 31 weeks for each participant.
    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
    28 May 2014
    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
    Czech Republic: 52
    Country: Number of subjects enrolled
    Puerto Rico: 28
    Country: Number of subjects enrolled
    Hungary: 72
    Country: Number of subjects enrolled
    United States: 61
    Country: Number of subjects enrolled
    Italy: 28
    Country: Number of subjects enrolled
    United Kingdom: 4
    Country: Number of subjects enrolled
    Spain: 55
    Worldwide total number of subjects
    300
    EEA total number of subjects
    211
    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)
    187
    From 65 to 84 years
    113
    85 years and over
    0

    Subject disposition

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    Recruitment
    Recruitment details
    		 -

    Pre-assignment
    Screening details
    		 Participants who met all inclusion criteria and none of the exclusion criteria entered a 2-week lead-in period. Only those participants who required further up-titration of the insulin glargine dose per treat-to-target (TTT) algorithm were randomized to one of two treatment groups.

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

    Arms
    Are arms mutually exclusive
    Yes

    Arm title
    		 Dulaglutide + Insulin Glargine
    Arm description
    		 1.5 milligrams (mg) dulaglutide administered subcutaneously (SQ) once weekly for 28 weeks. Titrated insulin glargine administered SQ once daily for 28 weeks. Participants who are taking metformin should remain on stable doses. Dulaglutide: Administered SQ Insulin Glargine: Administered SQ Metformin: Administered orally
    Arm type
    		 Experimental

    Investigational medicinal product name
    Dulaglutide
    Investigational medicinal product code
    LY2189265
    Other name
    Pharmaceutical forms
    Injection
    Routes of administration
    Subcutaneous use
    Dosage and administration details
    1.5 milligrams (mg) Dulaglutide administered subcutaneously (SQ) once weekly for 28 weeks.

    Investigational medicinal product name
    Metformin
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Tablet
    Routes of administration
    Oral use
    Dosage and administration details
    Metformin administered orally daily.

    Investigational medicinal product name
    Insulin Glargine
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Injection
    Routes of administration
    Subcutaneous use
    Dosage and administration details
    Titrated insulin glargine administered SQ once weekly for 28 weeks.

    Arm title
    		 Placebo + Insulin Glargine
    Arm description
    		 Placebo administered SQ once weekly for 28 weeks. Titrated insulin glargine administered SQ once daily for 28 weeks. Participants who are taking metformin should remain on stable doses. Placebo: Administered SQ Insulin Glargine: Administered SQ Metformin: Administered orally
    Arm type
    		 Placebo

    Investigational medicinal product name
    Insulin Glargine
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Injection
    Routes of administration
    Subcutaneous use
    Dosage and administration details
    Insulin Glargine administered subcutaneous once daily for 28 weeks.

    Investigational medicinal product name
    Placebo
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Injection
    Routes of administration
    Subcutaneous use
    Dosage and administration details
    Placebo administered SQ once weekly for 28 weeks.

    Investigational medicinal product name
    Metformin
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Tablet
    Routes of administration
    Oral use
    Dosage and administration details
    Metformin administered orally daily.

    Number of subjects in period 1
    		Dulaglutide + Insulin Glargine Placebo + Insulin Glargine
    Started
    150
    150
    Received at least 1 dose of study drug.
    150
    150
    Completed
    138
    134
    Not completed
    12
    16
         Consent withdrawn by subject
    3
    7
         Physician decision
    -
    2
         Adverse event, non-fatal
    6
    2
         Reason Not Given
    -
    1
         Lost to follow-up
    1
    -
         Protocol deviation
    2
    3
         Lack of efficacy
    -
    1

    Baseline characteristics

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    Baseline characteristics reporting groups
    Reporting group title
    Dulaglutide + Insulin Glargine
    Reporting group description
    		 1.5 milligrams (mg) dulaglutide administered subcutaneously (SQ) once weekly for 28 weeks. Titrated insulin glargine administered SQ once daily for 28 weeks. Participants who are taking metformin should remain on stable doses. Dulaglutide: Administered SQ Insulin Glargine: Administered SQ Metformin: Administered orally

    Reporting group title
    Placebo + Insulin Glargine
    Reporting group description
    		 Placebo administered SQ once weekly for 28 weeks. Titrated insulin glargine administered SQ once daily for 28 weeks. Participants who are taking metformin should remain on stable doses. Placebo: Administered SQ Insulin Glargine: Administered SQ Metformin: Administered orally

    Reporting group values
    		 Dulaglutide + Insulin Glargine Placebo + Insulin Glargine Total
    Number of subjects
    		 150 150 300
    Age categorical
    Units: Subjects
        In utero
    		 0 0 0
        Preterm newborn infants (gestational age < 37 wks)
    		 0 0 0
        Newborns (0-27 days)
    		 0 0 0
        Infants and toddlers (28 days-23 months)
    		 0 0 0
        Children (2-11 years)
    		 0 0 0
        Adolescents (12-17 years)
    		 0 0 0
        Adults (18-64 years)
    		 95 92 187
        From 65-84 years
    		 55 58 113
        85 years and over
    		 0 0 0
    Age Continuous
    Units: years
        arithmetic mean (standard deviation)
    		 60.2 ( 9.47 ) 60.6 ( 10.07 ) -
    Gender, Male/Female
    Units: participants
        Female
    		 65 62 127
        Male
    		 85 88 173
    Ethnicity (NIH/OMB)
    Units: Subjects
        Hispanic or Latino
    		 26 25 51
        Not Hispanic or Latino
    		 104 104 208
        Unknown or Not Reported
    		 20 21 41
    Race (NIH/OMB)
    Units: Subjects
        American Indian or Alaska Native
    		 0 0 0
        Asian
    		 0 1 1
        Native Hawaiian or Other Pacific Islander
    		 1 2 3
        Black or African American
    		 5 6 11
        White
    		 143 138 281
        More than one race
    		 1 3 4
        Unknown or Not Reported
    		 0 0 0
    Region of Enrollment
    Units: Subjects
        Czech Republic
    		 25 27 52
        Puerto Rico
    		 12 16 28
        Hungary
    		 37 35 72
        United States
    		 32 29 61
        Italy
    		 13 15 28
        United Kingdom
    		 2 2 4
        Spain
    		 29 26 55
    Metformin Use
    Number of participants with Metformin use at baseline
    Units: Subjects
        Metformin Use
    		 134 131 265
        No Metformin Use
    		 16 19 35
    Mean Insulin Glargine Dose
    Units: Units
        arithmetic mean (standard deviation)
    		 40.71 ( 23.12 ) 36.59 ( 21.46 ) -

    End points

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    End points reporting groups
    Reporting group title
    Dulaglutide + Insulin Glargine
    Reporting group description
    		 1.5 milligrams (mg) dulaglutide administered subcutaneously (SQ) once weekly for 28 weeks. Titrated insulin glargine administered SQ once daily for 28 weeks. Participants who are taking metformin should remain on stable doses. Dulaglutide: Administered SQ Insulin Glargine: Administered SQ Metformin: Administered orally

    Reporting group title
    Placebo + Insulin Glargine
    Reporting group description
    		 Placebo administered SQ once weekly for 28 weeks. Titrated insulin glargine administered SQ once daily for 28 weeks. Participants who are taking metformin should remain on stable doses. Placebo: Administered SQ Insulin Glargine: Administered SQ Metformin: Administered orally

    Primary: Change from Baseline to 28 Weeks in Hemoglobin A1c (HbA1c)

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    End point title
    		 Change from Baseline to 28 Weeks in Hemoglobin A1c (HbA1c)
    End point description
    HbA1c is a form of hemoglobin that is measured primarily to identify the average plasma glucose concentration over prolonged periods of time. Least-squares (LS) mean and standard error (SE) changes from baseline in HbA1c at 28 weeks were measured using mixed model regression and restricted maximum likelihood (REML) with treatment, pooled country, visit, and treatment-by -visit interaction as fixed effects, baseline as covariate, and participant as a random effect.
    End point type
    Primary
    End point timeframe
    Baseline, 28 Weeks
    End point values
    		 Dulaglutide + Insulin Glargine Placebo + Insulin Glargine
    Number of subjects analysed
    150
    150
    Units: percentage of change
        least squares mean (standard error)
    -1.44 ( 0.09 )
    -0.67 ( 0.09 )
    Statistical analysis title
    		 Change from Baseline to 28 Weeks HbA1c
    Comparison groups
    Dulaglutide + Insulin Glargine v Placebo + Insulin Glargine
    Number of subjects included in analysis
    300
    Analysis specification
    Pre-specified
    Analysis type
    P-value
    		 < 0.001
    Method
    		 Mixed-effect Model Repeated Measure
    Parameter type
    		 LS Means Diff
    Point estimate
    -0.77
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -0.97
         upper limit
    		 -0.56
    Variability estimate
    Standard error of the mean
    Dispersion value
    0.1

    Secondary: Change from Baseline to 28 Weeks in Fasting Serum Glucose (FSG)

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    End point title
    		 Change from Baseline to 28 Weeks in Fasting Serum Glucose (FSG)
    End point description
    FSG is a test to determine glucose levels after an overnight fast and prior to any meal. LS means of the FSG change from baseline to primary endpoint at wee 28 was adjusted by treatment, country, metformin use, week, treatment-by-week interaction, and baseline FSG as covariate, via a MMRM analysis.
    End point type
    Secondary
    End point timeframe
    Baseline, 28 Weeks
    End point values
    		 Dulaglutide + Insulin Glargine Placebo + Insulin Glargine
    Number of subjects analysed
    150
    150
    Units: milligram per deciliter (mg/dL)
        least squares mean (standard error)
    -44.63 ( 4.16 )
    -27.9 ( 4.08 )
    Statistical analysis title
    		 Change from Baseline to 28 Weeks in FSG
    Comparison groups
    Dulaglutide + Insulin Glargine v Placebo + Insulin Glargine
    Number of subjects included in analysis
    300
    Analysis specification
    Pre-specified
    Analysis type
    P-value
    		 < 0.001
    Method
    		 Mixed models analysis
    Parameter type
    		 LS Mean Diff
    Point estimate
    -16.73
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -26.02
         upper limit
    		 -7.44
    Variability estimate
    Standard error of the mean
    Dispersion value
    4.72

    Secondary: Change from Baseline to 28 Weeks in 7-Point Self Monitored Plasma Glucose (SMPG)

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    End point title
    		 Change from Baseline to 28 Weeks in 7-Point Self Monitored Plasma Glucose (SMPG)
    End point description
    The LS means of the 7-point SMPG change from baseline (BL) to primary endpoint at week 28 was measured using a MMRM analysis adjusted by treatment, country, metformin use, week, treatment-by-week interaction, and baseline SMPG as covariate.
    End point type
    Secondary
    End point timeframe
    Baseline, 28 Weeks
    End point values
    		 Dulaglutide + Insulin Glargine Placebo + Insulin Glargine
    Number of subjects analysed
    150
    150
    Units: mg/dL
    least squares mean (standard error)
        Pre-Morning Meal (n=133,129)
    -44.03 ( 2.71 )
    -35.97 ( 2.64 )
        Morning Meal 2-Hour Postprandial (n=123,119)
    -64.16 ( 4.31 )
    -46.97 ( 4.27 )
        Pre-Midday Meal (n=133,127)
    -40.89 ( 3.72 )
    -25.34 ( 3.62 )
        Midday Meal 2-Hour Post Prandial (n=123,117)
    -51.13 ( 4.4 )
    -32.98 ( 4.33 )
        Pre-Evening Meal (n=133,129)
    -43.68 ( 4.21 )
    -28.71 ( 4.07 )
        Evening Meal 2-Hour Postprandial (n=126,122)
    -48.63 ( 5.22 )
    -27.35 ( 5.16 )
        3:00 AM (n=124,117)
    -39.77 ( 4.27 )
    -20.3 ( 4.23 )
    Statistical analysis title
    		 Change from BL to 28 Weeks SMPG Pre-Morning Meal
    Comparison groups
    Dulaglutide + Insulin Glargine v Placebo + Insulin Glargine
    Number of subjects included in analysis
    300
    Analysis specification
    Pre-specified
    Analysis type
    P-value
    		 = 0.007
    Method
    		 Mixed models analysis
    Parameter type
    		 LS Mean Diff
    Point estimate
    -8.06
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -13.87
         upper limit
    		 -2.25
    Variability estimate
    Standard error of the mean
    Dispersion value
    2.95
    Statistical analysis title
    		 BL to 28 Wks SMPG Morning Meal 2hr Postprandial
    Statistical analysis description
    Change from Baseline to 28 Weeks SMPG Morning Meal 2-Hour Postprandial
    Comparison groups
    Dulaglutide + Insulin Glargine v Placebo + Insulin Glargine
    Number of subjects included in analysis
    300
    Analysis specification
    Pre-specified
    Analysis type
    P-value
    		 < 0.001
    Method
    		 Mixed models analysis
    Parameter type
    		 LS Mean Diff
    Point estimate
    -17.18
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -25.96
         upper limit
    		 -8.4
    Variability estimate
    Standard error of the mean
    Dispersion value
    4.45
    Statistical analysis title
    		 BL to 28 Weeks SMPG Pre-Midday Meal
    Statistical analysis description
    Change from Baseline to 28 Weeks SMPG Pre-Midday Meal
    Comparison groups
    Dulaglutide + Insulin Glargine v Placebo + Insulin Glargine
    Number of subjects included in analysis
    300
    Analysis specification
    Pre-specified
    Analysis type
    P-value
    		 < 0.001
    Method
    		 Mixed models analysis
    Parameter type
    		 LS Mean Diff
    Point estimate
    -15.55
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -23.58
         upper limit
    		 -7.52
    Variability estimate
    Standard error of the mean
    Dispersion value
    4.08
    Statistical analysis title
    		 BL to 28 Weeks SMPG Midday Meal 2-hr Postprandial
    Statistical analysis description
    Change from Baseline to 28 Weeks SMPG Midday Meal 2-Hour Postprandial
    Comparison groups
    Dulaglutide + Insulin Glargine v Placebo + Insulin Glargine
    Number of subjects included in analysis
    300
    Analysis specification
    Pre-specified
    Analysis type
    P-value
    		 < 0.001
    Method
    		 Mixed models analysis
    Parameter type
    		 LS Mean Diff
    Point estimate
    -18.15
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -27.18
         upper limit
    		 -9.12
    Variability estimate
    Standard error of the mean
    Dispersion value
    4.58
    Statistical analysis title
    		 BL to 28 Weeks SMPG Pre-Evening Meal
    Statistical analysis description
    Change from Baseline to 28 Weeks SMPG Pre-Evening Meal
    Comparison groups
    Dulaglutide + Insulin Glargine v Placebo + Insulin Glargine
    Number of subjects included in analysis
    300
    Analysis specification
    Pre-specified
    Analysis type
    P-value
    		 = 0.001
    Method
    		 Mixed models analysis
    Parameter type
    		 LS Mean Diff
    Point estimate
    -14.96
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -23.93
         upper limit
    		 -5.99
    Variability estimate
    Standard error of the mean
    Dispersion value
    4.55
    Statistical analysis title
    		 BL to 28 Weeks SMPG Evening Meal 2-hr Postprandial
    Statistical analysis description
    Change from Baseline to 28 Weeks SMPG Evening Meal 2-Hour Postprandial
    Comparison groups
    Dulaglutide + Insulin Glargine v Placebo + Insulin Glargine
    Number of subjects included in analysis
    300
    Analysis specification
    Pre-specified
    Analysis type
    P-value
    		 < 0.001
    Method
    		 Mixed models analysis
    Parameter type
    		 LS Mean Diff
    Point estimate
    -21.28
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -32.46
         upper limit
    		 -10.1
    Variability estimate
    Standard error of the mean
    Dispersion value
    5.68
    Statistical analysis title
    		 BL to 28 Weeks SMPG at 3:00AM
    Statistical analysis description
    Change from Baseline to 28 Weeks SMPG at 3:00AM
    Comparison groups
    Dulaglutide + Insulin Glargine v Placebo + Insulin Glargine
    Number of subjects included in analysis
    300
    Analysis specification
    Pre-specified
    Analysis type
    P-value
    		 < 0.001
    Method
    		 Mixed models analysis
    Parameter type
    		 LS Mean Diff
    Point estimate
    -19.48
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -28.77
         upper limit
    		 -10.18
    Variability estimate
    Standard error of the mean
    Dispersion value
    4.72

    Secondary: Change from Baseline to 28 Weeks in Body Weight

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    End point title
    		 Change from Baseline to 28 Weeks in Body Weight
    End point description
    LS means of the body weight change from baseline to primary endpoint at week 28 was adjusted by treatment, country, metformin use, week, treatment-by-week interaction, and baseline body weight as covariate, via a MMRM analysis.
    End point type
    Secondary
    End point timeframe
    Baseline, 28 Weeks
    End point values
    		 Dulaglutide + Insulin Glargine Placebo + Insulin Glargine
    Number of subjects analysed
    150
    150
    Units: kg
        least squares mean (standard error)
    -1.91 ( 0.3 )
    0.5 ( 0.3 )
    Statistical analysis title
    		 Change From Baseline to 28 Wks Body Weight MMRM
    Comparison groups
    Dulaglutide + Insulin Glargine v Placebo + Insulin Glargine
    Number of subjects included in analysis
    300
    Analysis specification
    Pre-specified
    Analysis type
    P-value
    		 < 0.001
    Method
    		 Mixed models analysis
    Parameter type
    		 LS Means Difference
    Point estimate
    -2.41
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -3.19
         upper limit
    		 -1.64
    Variability estimate
    Standard error of the mean
    Dispersion value
    0.39

    Secondary: Change from Baseline to 28 Weeks in Daily Mean Insulin Glargine Dose

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    End point title
    		 Change from Baseline to 28 Weeks in Daily Mean Insulin Glargine Dose
    End point description
    LS means of the insulin dose change from baseline to primary endpoint at week 28 was adjusted by treatment, country, metformin use, week, treatment-by-week interaction, and baseline insulin dose as covariate, via a MMRM analysis.
    End point type
    Secondary
    End point timeframe
    Baseline, 28 Weeks
    End point values
    		 Dulaglutide + Insulin Glargine Placebo + Insulin Glargine
    Number of subjects analysed
    150
    150
    Units: units (u)
    least squares mean (standard error)
        Units (U)
    12.75 ( 2.27 )
    25.94 ( 2.3 )
    Statistical analysis title
    		 Change From Baseline to 28 Wks Insulin Glargine
    Comparison groups
    Dulaglutide + Insulin Glargine v Placebo + Insulin Glargine
    Number of subjects included in analysis
    300
    Analysis specification
    Pre-specified
    Analysis type
    P-value
    		 < 0.001
    Method
    		 Mixed models analysis
    Parameter type
    		 LS Means Diff
    Point estimate
    -13.19
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -19.55
         upper limit
    		 -6.84
    Variability estimate
    Standard error of the mean
    Dispersion value
    3.21

    Secondary: Number of Participants with Investigator Reported and Adjudicated Cardiovascular Events

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    End point title
    		 Number of Participants with Investigator Reported and Adjudicated Cardiovascular Events
    End point description
    Cardiovascular (CV) adverse events (AEs) were adjudicated by an independent committee of physicians with cardiology expertise external to the sponsor. Deaths occurring during the study treatment period and nonfatal CV AEs were to be adjudicated. Nonfatal CV events that were to be adjudicated were myocardial infarction; 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 (CVA/stroke), and transient ischemic attack (TIA).
    End point type
    Secondary
    End point timeframe
    Baseline through 28 Weeks
    End point values
    		 Dulaglutide + Insulin Glargine Placebo + Insulin Glargine
    Number of subjects analysed
    150
    150
    Units: participants
        number (not applicable)
    3
    1
    No statistical analyses for this end point

    Secondary: Percentage of Participants with Self-Reported Events of Hypoglycemia

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    End point title
    		 Percentage of Participants with Self-Reported Events of Hypoglycemia
    End point description
    Hypoglycemic events (HE) were classified as severe (defined as episodes requiring the assistance of another person to actively administer resuscitative actions), documented symptomatic (defined as any time a participant feels that he/she is experiencing symptoms and/or signs associated with hypoglycemia, and has a plasma glucose level of =<3.9 mmol/L), asymptomatic (defined as events not accompanied by typical symptoms of hypoglycemia but with a measured plasma glucose of =<3.9 mmol/L), nocturnal (defined as any hypoglycemic event that occurred between bedtime and waking), or probable symptomatic (defined as events during which symptoms of hypoglycemia were not accompanied by a plasma glucose determination). The percentage of participants with self-reported hypoglycemic events is presented. The percentage of participants with self-reported hypoglycemic events is presented.
    End point type
    Secondary
    End point timeframe
    Baseline through 28 Weeks
    End point values
    		 Dulaglutide + Insulin Glargine Placebo + Insulin Glargine
    Number of subjects analysed
    150
    150
    Units: percentage of particpants
    number (not applicable)
        Symptomatic
    35.3
    30
        Asymptomatic
    42.7
    39.3
        Severe
    0.7
    0
        Nocturnal
    28
    28.7
        Probable Symptomatic
    2.7
    2
    No statistical analyses for this end point

    Secondary: Percentage of Participants Discontinuing the Study Due to Severe, Persistent Hyperglycemia

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    End point title
    		 Percentage of Participants Discontinuing the Study Due to Severe, Persistent Hyperglycemia
    End point description
    Percentage of participants who discontinued due to severe, persistent hyperglycemia are presented.
    End point type
    Secondary
    End point timeframe
    Baseline through 28 Weeks
    End point values
    		 Dulaglutide + Insulin Glargine Placebo + Insulin Glargine
    Number of subjects analysed
    150
    150
    Units: percentage of participants
        number (not applicable)
    0
    0
    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 cases of acute pancreatitis confirmed by adjudication. A summary of serious and other non-serious AEs, regardless of causality, is located in the Reported Adverse Events module.
    End point type
    Secondary
    End point timeframe
    Baseline through 28 Weeks
    End point values
    		 Dulaglutide + Insulin Glargine Placebo + Insulin Glargine
    Number of subjects analysed
    150
    150
    Units: participants
        number (not applicable)
    0
    0
    No statistical analyses for this end point

    Secondary: Number of Participants With Thyroid Tumors/Neoplasms (Including C-Cell Hyperplasia)

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    End point title
    		 Number of Participants With Thyroid Tumors/Neoplasms (Including C-Cell Hyperplasia)
    End point description
    Number of participants with one or more thyroid tumors/neoplasms of any type, including C-cell hyperplasia and thyroid cysts, is presented.
    End point type
    Secondary
    End point timeframe
    Baseline through 28 Weeks
    End point values
    		 Dulaglutide + Insulin Glargine Placebo + Insulin Glargine
    Number of subjects analysed
    150
    150
    Units: participants
        number (not applicable)
    1
    0
    No statistical analyses for this end point

    Secondary: Number of Participants with Dulaglutide Anti-Drug Antibodies

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    End point title
    		 Number of Participants with Dulaglutide Anti-Drug Antibodies
    End point description
    Dulaglutide anti-drug antibodies (ADA) were assessed at baseline, Weeks 12 and 28. A participant was considered to have treatment-emergent (TE) dulaglutide ADAs if the participant had at least 1 titer that was TE relative to baseline, defined as a 4-fold or greater increase in titer from baseline measurement.
    End point type
    Secondary
    End point timeframe
    Baseline, Week 12 and Week 28
    End point values
    		 Dulaglutide + Insulin Glargine Placebo + Insulin Glargine
    Number of subjects analysed
    149 [1]
    149 [2]
    Units: participants
        number (not applicable)
    0
    2
    Notes
    [1] - Participants receiving at least 1 dose of study drug and had at least 1 Dulaglutide ADA test result.
    [2] - Participants receiving at least 1 dose of study drug and had at least 1 Dulaglutide ADA test result.
    No statistical analyses for this end point

    Secondary: Percentage of Participants Achieving HbA1c Targets of <7.0% or ≤6.5%

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    End point title
    		 Percentage of Participants Achieving HbA1c Targets of <7.0% or ≤6.5%
    End point description
    Percentage of participants who achieved a target HbA1c target of <7%, without weight gain and without documented symptomatic hypoglycemia at 28 weeks were analyzed using regression model, controlling for treatment, pre-treatment, baseline HbA1c and country.
    End point type
    Secondary
    End point timeframe
    28 Weeks
    End point values
    		 Dulaglutide + Insulin Glargine Placebo + Insulin Glargine
    Number of subjects analysed
    150
    150
    Units: percentage of participants
    number (not applicable)
        HbA1c <= 6.5
    50.7
    16.7
        HbA1c < 7.0
    69.3
    35.3
    Statistical analysis title
    		 Participants Achieving HbA1c Targets ≤6.5%
    Comparison groups
    Dulaglutide + Insulin Glargine v Placebo + Insulin Glargine
    Number of subjects included in analysis
    300
    Analysis specification
    Pre-specified
    Analysis type
    P-value
    		 < 0.001
    Method
    		 Regression, Logistic
    Parameter type
    		 Odds ratio (OR)
    Point estimate
    6.66
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 3.7
         upper limit
    		 12
    Statistical analysis title
    		 Participants Achieving HbA1c Targets of <7.0%
    Comparison groups
    Dulaglutide + Insulin Glargine v Placebo + Insulin Glargine
    Number of subjects included in analysis
    300
    Analysis specification
    Pre-specified
    Analysis type
    P-value
    		 < 0.001
    Method
    		 Regression, Logistic
    Parameter type
    		 Log odds ratio
    Point estimate
    5.71
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 3.35
         upper limit
    		 9.73

    Secondary: Percentage of Participants Achieving HbA1c Target of <7.0% and Without Weight Gain (<0.1 kilograms [kg]) at 28 Weeks and Without Documented Symptomatic Hypoglycemia During the Maintenance Period (Weeks 12-28)

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    End point title
    		 Percentage of Participants Achieving HbA1c Target of <7.0% and Without Weight Gain (<0.1 kilograms [kg]) at 28 Weeks and Without Documented Symptomatic Hypoglycemia During the Maintenance Period (Weeks 12-28)
    End point description
    End point type
    Secondary
    End point timeframe
    28 Weeks
    End point values
    		 Dulaglutide + Insulin Glargine Placebo + Insulin Glargine
    Number of subjects analysed
    150
    150
    Units: percentage of participants
        number (not applicable)
    40.7
    16.7
    Statistical analysis title
    		 HbA1c Target <7.0% w/o Wt Gain and Hypoglycemia
    Comparison groups
    Dulaglutide + Insulin Glargine v Placebo + Insulin Glargine
    Number of subjects included in analysis
    300
    Analysis specification
    Pre-specified
    Analysis type
    P-value
    		 < 0.001
    Method
    		 Regression, Logistic
    Parameter type
    		 Odds ratio (OR)
    Point estimate
    4.17
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 2.32
         upper limit
    		 7.47

    Secondary: Percentage of Participants Achieving HbA1c Target of <7.0% at 28 Weeks and Without Documented Symptomatic Hypoglycemia during the Maintenance Period (Weeks 12-28)

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    End point title
    		 Percentage of Participants Achieving HbA1c Target of <7.0% at 28 Weeks and Without Documented Symptomatic Hypoglycemia during the Maintenance Period (Weeks 12-28)
    End point description
    Percentage of participants achieving target HbA1c of <7.0% at 28 weeks without documented symptomatic hypoglycemia are presented. Documented symptomatic hypoglycemia is defined as any time a participant experienced symptoms and or signs associated with hypoglycemia and had a plasma glucose of <=70 mg/dL.
    End point type
    Secondary
    End point timeframe
    28 Weeks
    End point values
    		 Dulaglutide + Insulin Glargine Placebo + Insulin Glargine
    Number of subjects analysed
    150
    150
    Units: percentage of participants
        number (not applicable)
    52
    28
    Statistical analysis title
    		 HbA1c Target of <7.0% w/o Symptom Hypoglycemia
    Comparison groups
    Dulaglutide + Insulin Glargine v Placebo + Insulin Glargine
    Number of subjects included in analysis
    300
    Analysis specification
    Pre-specified
    Analysis type
    P-value
    		 < 0.001
    Method
    		 Regression, Logistic
    Parameter type
    		 Odds ratio (OR)
    Point estimate
    3.61
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 2.09
         upper limit
    		 6.23

    Secondary: Percentage of Participants Achieving HbA1c Target of <7.0% and Without Weight Gain (<0.1 kg)

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    End point title
    		 Percentage of Participants Achieving HbA1c Target of <7.0% and Without Weight Gain (<0.1 kg)
    End point description
    The percentage of participants achieving a target HbA1c of <7.0% without weight gain is presented.
    End point type
    Secondary
    End point timeframe
    28 Weeks
    End point values
    		 Dulaglutide + Insulin Glargine Placebo + Insulin Glargine
    Number of subjects analysed
    150
    150
    Units: percentage of participants
        number (not applicable)
    52.7
    20
    Statistical analysis title
    		 Achieving HbA1c Target of <7.0% W/O Weight Gain
    Comparison groups
    Dulaglutide + Insulin Glargine v Placebo + Insulin Glargine
    Number of subjects included in analysis
    300
    Analysis specification
    Pre-specified
    Analysis type
    P-value
    		 < 0.001
    Method
    		 Regression, Logistic
    Parameter type
    		 Odds ratio (OR)
    Point estimate
    5.6
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 3.26
         upper limit
    		 9.62

    Secondary: Rate of Hypoglycemic Events up to 28 Weeks

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    End point title
    		 Rate of Hypoglycemic Events up to 28 Weeks
    End point description
    The rate of total hypoglycemic events any type per 30 days is presented. The hypoglycemia rate per 30 days during defined period is calculated by the number of hypoglycemia events within the period/number of days participant at risk within the period*30 days.
    End point type
    Secondary
    End point timeframe
    Baseline through 28 Weeks
    End point values
    		 Dulaglutide + Insulin Glargine Placebo + Insulin Glargine
    Number of subjects analysed
    150
    150
    Units: Rate
        arithmetic mean (standard deviation)
    0.63 ( 1.24 )
    0.7 ( 1.32 )
    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-GBDI
    Assessment type
    		 Systematic
    Dictionary used for adverse event reporting
    Dictionary name
    		 MedDRA
    Dictionary version
    18.1
    Reporting groups
    Reporting group title
    Dula_1.5
    Reporting group description
    		 -

    Reporting group title
    Placebo
    Reporting group description
    		 -

    Serious adverse events
    		 Dula_1.5 Placebo
    Total subjects affected by serious adverse events
         subjects affected / exposed
    9 / 150 (6.00%)
    7 / 150 (4.67%)
         number of deaths (all causes)
    0
    0
         number of deaths resulting from adverse events
    0
    0
    Neoplasms benign, malignant and unspecified (incl cysts and polyps)
    hepatic cancer
    alternative dictionary used: MedDRA 18.1
         subjects affected / exposed
    0 / 150 (0.00%)
    1 / 150 (0.67%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    Injury, poisoning and procedural complications
    lower limb fracture
    alternative dictionary used: MedDRA 18.1
         subjects affected / exposed
    1 / 150 (0.67%)
    0 / 150 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Cardiac disorders
    angina unstable
    alternative dictionary used: MedDRA 18.1
         subjects affected / exposed
    1 / 150 (0.67%)
    1 / 150 (0.67%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    atrial fibrillation
    alternative dictionary used: MedDRA 18.1
         subjects affected / exposed
    1 / 150 (0.67%)
    0 / 150 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    bradycardia
    alternative dictionary used: MedDRA 18.1
         subjects affected / exposed
    2 / 150 (1.33%)
    0 / 150 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    coronary artery disease
    alternative dictionary used: MedDRA 18.1
         subjects affected / exposed
    1 / 150 (0.67%)
    0 / 150 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    myocardial infarction
    alternative dictionary used: MedDRA 18.1
         subjects affected / exposed
    1 / 150 (0.67%)
    0 / 150 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Nervous system disorders
    carotid artery stenosis
    alternative dictionary used: MedDRA 18.1
         subjects affected / exposed
    1 / 150 (0.67%)
    0 / 150 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    cerebral infarction
    alternative dictionary used: MedDRA 18.1
         subjects affected / exposed
    1 / 150 (0.67%)
    0 / 150 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    transient ischaemic attack
    alternative dictionary used: MedDRA 18.1
         subjects affected / exposed
    2 / 150 (1.33%)
    0 / 150 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    General disorders and administration site conditions
    non-cardiac chest pain
    alternative dictionary used: MedDRA 18.1
         subjects affected / exposed
    0 / 150 (0.00%)
    1 / 150 (0.67%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Hepatobiliary disorders
    granulomatous liver disease
    alternative dictionary used: MedDRA 18.1
         subjects affected / exposed
    1 / 150 (0.67%)
    0 / 150 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Skin and subcutaneous tissue disorders
    skin ulcer
    alternative dictionary used: MedDRA 18.1
         subjects affected / exposed
    0 / 150 (0.00%)
    1 / 150 (0.67%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Musculoskeletal and connective tissue disorders
    intervertebral disc protrusion
    alternative dictionary used: MedDRA 18.1
         subjects affected / exposed
    0 / 150 (0.00%)
    1 / 150 (0.67%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    osteoarthritis
    alternative dictionary used: MedDRA 18.1
         subjects affected / exposed
    0 / 150 (0.00%)
    1 / 150 (0.67%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Infections and infestations
    gastroenteritis
    alternative dictionary used: MedDRA 18.1
         subjects affected / exposed
    1 / 150 (0.67%)
    0 / 150 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    viral infection
    alternative dictionary used: MedDRA 18.1
         subjects affected / exposed
    0 / 150 (0.00%)
    1 / 150 (0.67%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Metabolism and nutrition disorders
    hypoglycaemia
    alternative dictionary used: MedDRA 18.1
         subjects affected / exposed
    1 / 150 (0.67%)
    0 / 150 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Frequency threshold for reporting non-serious adverse events: 5%
    Non-serious adverse events
    		 Dula_1.5 Placebo
    Total subjects affected by non serious adverse events
         subjects affected / exposed
    51 / 150 (34.00%)
    29 / 150 (19.33%)
    Gastrointestinal disorders
    diarrhoea
    alternative dictionary used: MedDRA 18.1
         subjects affected / exposed
    17 / 150 (11.33%)
    6 / 150 (4.00%)
         occurrences all number
    19
    6
    dyspepsia
    alternative dictionary used: MedDRA 18.1
         subjects affected / exposed
    9 / 150 (6.00%)
    0 / 150 (0.00%)
         occurrences all number
    9
    0
    nausea
    alternative dictionary used: MedDRA 18.1
         subjects affected / exposed
    18 / 150 (12.00%)
    2 / 150 (1.33%)
         occurrences all number
    23
    3
    vomiting
    alternative dictionary used: MedDRA 18.1
         subjects affected / exposed
    9 / 150 (6.00%)
    0 / 150 (0.00%)
         occurrences all number
    11
    0
    Infections and infestations
    nasopharyngitis
    alternative dictionary used: MedDRA 18.1
         subjects affected / exposed
    6 / 150 (4.00%)
    14 / 150 (9.33%)
         occurrences all number
    7
    19
    upper respiratory tract infection
    alternative dictionary used: MedDRA 18.1
         subjects affected / exposed
    11 / 150 (7.33%)
    10 / 150 (6.67%)
         occurrences all number
    18
    10
    Metabolism and nutrition disorders
    decreased appetite
    alternative dictionary used: MedDRA 18.1
         subjects affected / exposed
    10 / 150 (6.67%)
    0 / 150 (0.00%)
         occurrences all number
    11
    0

    More information

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    Substantial protocol amendments (globally)
    Were there any global substantial amendments to the protocol? No

    Interruptions (globally)
    Were there any global interruptions to the trial? No

    Limitations and caveats
    Limitations of the trial such as small numbers of subjects analysed or technical problems leading to unreliable data.
    None reported
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