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    Clinical Trial Results:
    A Phase III, Multicenter, Randomized, Double-Blind, Placebo-Controlled Clinical Trial to Study the Efficacy and Safety of the Continuation of Sitagliptin Compared with the Withdrawal of Sitagliptin During Initiation and Titration of Insulin Glargine (LANTUS®) in Subjects with Type 2 Diabetes Mellitus

    Summary
    EudraCT number
    		 2015-004990-34
    Trial protocol
    		 EE   HU   LV   CZ   ES   DK   RO   PL  
    Global end of trial date
    30 Jan 2018

    Results information
    Results version number
    		 v1(current)
    This version publication date
    03 Feb 2019
    First version publication date
    03 Feb 2019
    Other versions

    Trial information

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    Trial identification
    Sponsor protocol code
    0431-845
    Additional study identifiers
    ISRCTN number
    		 -
    US NCT number
    		 NCT02738879
    WHO universal trial number (UTN)
    		 -
    Other trial identifiers
    		 MK-0431-845: Merck Protocol Number
    Sponsors
    Sponsor organisation name
    Merck Sharp & Dohme Corp.
    Sponsor organisation address
    2000 Galloping Hill Road, Kenilworth, NJ, United States, 07033
    Public contact
    Clinical Trials Disclosure, Merck Sharp & Dohme Corp., ClinicalTrialsDisclosure@merck.com
    Scientific contact
    Clinical Trials Disclosure, Merck Sharp & Dohme Corp., ClinicalTrialsDisclosure@merck.com
    Paediatric regulatory details
    Is trial part of an agreed paediatric investigation plan (PIP)
    No
    Does article 45 of REGULATION (EC) No 1901/2006 apply to this trial?
    No
    Does article 46 of REGULATION (EC) No 1901/2006 apply to this trial?
    No
    Results analysis stage
    Analysis stage
    Final
    Date of interim/final analysis
    30 Jan 2018
    Is this the analysis of the primary completion data?
    No
    Global end of trial reached?
    Yes
    Global end of trial date
    30 Jan 2018
    Was the trial ended prematurely?
    No
    General information about the trial
    Main objective of the trial
    This is a trial of continuing sitagliptin versus withdrawing sitagliptin in participants with type 2 diabetes mellitus (T2DM) and inadequate glycemic control who initiate and titrate insulin glargine (LANTUS®) based on a treat-to-target algorithm to achieve fasting glucose levels of 72-100 mg/dL (4-5.6 mmol/L). A primary hypothesis of this trial is that after 30 weeks, continuing sitagliptin results in a greater reduction of hemoglobin A1C (A1C) relative to withdrawing sitagliptin.
    Protection of trial subjects
    This study was conducted in conformance with Good Clinical Practice standards and applicable country and/or local statutes and regulations regarding ethical committee review, informed consent, and the protection of human subjects participating in biomedical research.
    Background therapy
    		 The following medications were given to all participants: Metformin: at least 1500 mg/day, oral, twice daily for participants entering the study on immediate-release metformin + sitagliptin or a fixed dose combination (FDC). Metformin XR: at least 1500 mg/day, oral, once daily for participants entering the study on extended-release metformin + sitagliptin or a FDC. Insulin glargine (LANTUS®) initiated at 10 units and titrated based on a treat-to-target algorithm to achieve fasting glucose levels of 72-100 mg/dL (4-5.6 mmol/L); administered once daily subcutaneously.
    Evidence for comparator
    		 -
    Actual start date of recruitment
    09 May 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
    Philippines: 52
    Country: Number of subjects enrolled
    Poland: 23
    Country: Number of subjects enrolled
    Romania: 30
    Country: Number of subjects enrolled
    Russian Federation: 59
    Country: Number of subjects enrolled
    Spain: 46
    Country: Number of subjects enrolled
    Turkey: 19
    Country: Number of subjects enrolled
    United States: 144
    Country: Number of subjects enrolled
    Argentina: 69
    Country: Number of subjects enrolled
    Australia: 9
    Country: Number of subjects enrolled
    Canada: 14
    Country: Number of subjects enrolled
    Czech Republic: 24
    Country: Number of subjects enrolled
    Denmark: 18
    Country: Number of subjects enrolled
    Estonia: 13
    Country: Number of subjects enrolled
    France: 4
    Country: Number of subjects enrolled
    Germany: 11
    Country: Number of subjects enrolled
    Guatemala: 58
    Country: Number of subjects enrolled
    Hungary: 37
    Country: Number of subjects enrolled
    Israel: 21
    Country: Number of subjects enrolled
    Korea, Republic of: 10
    Country: Number of subjects enrolled
    Latvia: 25
    Country: Number of subjects enrolled
    Mexico: 41
    Country: Number of subjects enrolled
    New Zealand: 19
    Worldwide total number of subjects
    746
    EEA total number of subjects
    231
    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)
    547
    From 65 to 84 years
    199
    85 years and over
    0

    Subject disposition

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    Recruitment
    Recruitment details
    		 A total of 746 participants were randomized across 149 study sites in 22 countries.

    Pre-assignment
    Screening details
    		 Male and female participants with Type 2 diabetes mellitus (T2DM) ≥18 years of age were enrolled in this trial.

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

    Arms
    Are arms mutually exclusive
    Yes

    Arm title
    		 Sitagliptin
    Arm description
    		 Sitagliptin 100 mg, oral, once daily for 30 weeks
    Arm type
    		 Experimental

    Investigational medicinal product name
    Sitagliptin
    Investigational medicinal product code
    Other name
    MK-0431 Januvia
    Pharmaceutical forms
    Tablet
    Routes of administration
    Oral use
    Dosage and administration details
    Sitagliptin 100 mg, oral, once daily for 30 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 as a background medication of at least 1500 mg/day, oral, twice daily for participants entering the study on immediate-release metformin + sitagliptin or a FDC.

    Investigational medicinal product name
    Metformin XR
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Tablet
    Routes of administration
    Oral use
    Dosage and administration details
    Metformin XR as a background medication of at least 1500 mg/day, oral, once daily for participants entering the study on extended-release metformin + sitagliptin or a FDC.

    Investigational medicinal product name
    Insulin glargine
    Investigational medicinal product code
    Other name
    LANTUS®
    Pharmaceutical forms
    Concentrate and solvent for solution for injection
    Routes of administration
    Intradermal use
    Dosage and administration details
    Basal insulin therapy of insulin glargine (LANTUS®) initiated at 10 units and titrated based on a treat-to-target algorithm to achieve fasting glucose levels of 72-100 mg/dL (4-5.6 mmol/L); administered once daily subcutaneously.

    Arm title
    		 Placebo
    Arm description
    		 Placebo to sitagliptin, 100 mg, oral, once daily for 30 weeks
    Arm type
    		 Placebo

    Investigational medicinal product name
    Placebo to sitagliptin
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Tablet
    Routes of administration
    Oral use
    Dosage and administration details
    Placebo to sitagliptin 100 mg, oral, once daily for 30 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 as a background medication of at least 1500 mg/day, oral, twice daily for participants entering the study on immediate-release metformin + sitagliptin or a FDC.

    Investigational medicinal product name
    Metformin XR
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Tablet
    Routes of administration
    Oral use
    Dosage and administration details
    Metformin XR as a background medication of at least 1500 mg/day, oral, once daily for participants entering the study on extended-release metformin + sitagliptin or a FDC.

    Investigational medicinal product name
    Insulin glargine
    Investigational medicinal product code
    Other name
    LANTUS®
    Pharmaceutical forms
    Concentrate and solvent for solution for injection
    Routes of administration
    Intradermal use
    Dosage and administration details
    Basal insulin therapy of insulin glargine (LANTUS®) initiated at 10 units and titrated based on a treat-to-target algorithm to achieve fasting glucose levels of 72-100 mg/dL (4-5.6 mmol/L); administered once daily subcutaneously.

    Number of subjects in period 1
    		Sitagliptin Placebo
    Started
    374
    372
    Treated
    373
    370
    Completed
    361
    347
    Not completed
    13
    25
         Consent withdrawn by subject
    5
    7
         Physician decision
    3
    4
         Screen Failure
    1
    2
         Adverse event, non-fatal
    1
    1
         Death
    -
    2
         Site Discontinued Study Participation
    1
    -
         Pregnancy
    -
    1
         Lost to follow-up
    1
    5
         Protocol deviation
    1
    3

    Baseline characteristics

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    Baseline characteristics reporting groups
    Reporting group title
    Sitagliptin
    Reporting group description
    		 Sitagliptin 100 mg, oral, once daily for 30 weeks

    Reporting group title
    Placebo
    Reporting group description
    		 Placebo to sitagliptin, 100 mg, oral, once daily for 30 weeks

    Reporting group values
    		 Sitagliptin Placebo Total
    Number of subjects
    		 374 372 746
    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)
    		 275 272 547
        From 65-84 years
    		 99 100 199
        85 years and over
    		 0 0 0
    Age Continuous
    Units: years
        arithmetic mean (standard deviation)
    		 58.5 ± 9.5 58.1 ± 9.7 -
    Gender Categorical
    Units: Subjects
        Female
    		 204 181 385
        Male
    		 170 191 361
    Race
    Units: Subjects
        American Indian Or Alaska
    		 19 18 37
        Asian
    		 42 37 79
        Black Or African American
    		 12 12 24
        Multiple
    		 34 34 68
        Native Hawaiian Or Other
    		 6 1 7
        White
    		 259 270 529
        Missing
    		 2 0 2
    Anti-Hyperglycemic Agent
    Background Anti-Hyperglycemic Agent (AHA) at Screening metformin = Met dipeptidyl peptidase 4 inhibitor = DPP-4i
    Units: Subjects
        Met + DPP-4i
    		 184 184 368
        Met + DPP-4i + sulfonylurea (SU)
    		 87 86 173
        Met + SU
    		 103 102 205
    Geographic Region
    Units: Subjects
        Asia
    		 36 26 62
        Europe
    		 158 172 330
        Latin America
    		 85 83 168
        North America
    		 80 78 158
        Other
    		 15 13 28
    Hemoglobin A1C (A1C)
    Percent A1C= Glycated hemoglobin/total hemoglobin x 100 (N= 373; 370)
    Units: Percent A1C
        arithmetic mean (standard deviation)
    		 8.8 ± 0.9 8.8 ± 1.0 -
    Fasting Plasma Glucose (FPG)
    Fasting plasma glucose level after a 10-hour overnight fast. (N= 373; 370)
    Units: mg/dL
        arithmetic mean (standard deviation)
    		 199.0 ± 50.8 201.2 ± 51.8 -
    Estimated Glomercular Filtration Rate
    Estimated Glomercular Filtration Rate (eGFR) is a test of renal function. (N= 373; 370)
    Units: mL/min/1.73 m^2
        arithmetic mean (standard deviation)
    		 103.7 ± 30.3 106.4 ± 28.1 -
    Body Weight
    (N= 373; 370)
    Units: Kilograms
        arithmetic mean (standard deviation)
    		 84.8 ± 19.8 85.6 ± 18.9 -

    End points

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    End points reporting groups
    Reporting group title
    Sitagliptin
    Reporting group description
    		 Sitagliptin 100 mg, oral, once daily for 30 weeks

    Reporting group title
    Placebo
    Reporting group description
    		 Placebo to sitagliptin, 100 mg, oral, once daily for 30 weeks

    Primary: Change from Baseline in A1C at Week 30

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    End point title
    		 Change from Baseline in A1C at Week 30
    End point description
    A1C is blood marker used to report average blood glucose levels over prolonged periods of time. Percentage A1C is the ratio of glycated hemoglobin to total hemoglobin x 100. Thus, this change from baseline reflects the Week 30 A1C minus the Week 0 A1C. The analysis population consisted of all randomized participants who received at least one dose of study treatment and had at least one measurement of the respective endpoint (baseline or post-baseline).
    End point type
    Primary
    End point timeframe
    Baseline and Week 30
    End point values
    		 Sitagliptin Placebo
    Number of subjects analysed
    373
    370
    Units: Pecent A1C
        least squares mean (confidence interval 95%)
    -1.88 (-1.98 to -1.78)
    -1.42 (-1.52 to -1.32)
    Statistical analysis title
    		 A1C Non-inferiority Analysis
    Statistical analysis description
    A longitudinal data analysis (LDA) model included terms for treatment, AHA treatment at screening (Met + DPP-4i, Met + DPP-4i + SU, Met + SU), time, and the interactions of time by treatment and of time by AHA treatment at screening. Least Squares Means = LSM
    Comparison groups
    Sitagliptin v Placebo
    Number of subjects included in analysis
    743
    Analysis specification
    Pre-specified
    Analysis type
    		 non-inferiority [1]
    Method
    		 LDA
    Parameter type
    		 Between Group Difference in the LSM
    Point estimate
    -0.46
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -0.58
         upper limit
    		 -0.34
    Notes
    [1] - Hypothesis A: After 30 weeks, continuing sitagliptin is non-inferior relative to withdrawing sitagliptin on the change from baseline in A1C. Non-inferiority is declared if the upper bound of the two-sided 95% CI for the difference is less than 0.3%.
    Statistical analysis title
    		 A1C Superiority Analysis
    Statistical analysis description
    A LDA model included terms for treatment, AHA treatment at screening (Met + DPP-4i, Met + DPP-4i + SU, Met + SU), time, and the interactions of time by treatment and of time by AHA treatment at screening.
    Comparison groups
    Sitagliptin v Placebo
    Number of subjects included in analysis
    743
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority [2]
    P-value
    		 < 0.001
    Method
    		 LDA
    Parameter type
    		 Between Group Difference in the LSM
    Point estimate
    -0.46
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -0.58
         upper limit
    		 -0.34
    Notes
    [2] - Hypothesis B: After 30 weeks, continuing sitagliptin results in a greater reduction of A1C relative to withdrawing sitagliptin.

    Primary: Event Rate of Documented Symptomatic Hypoglycemia with Blood Glucose ≤70 mg/dL (≤3.9 mmol/L)

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    End point title
    		 Event Rate of Documented Symptomatic Hypoglycemia with Blood Glucose ≤70 mg/dL (≤3.9 mmol/L)
    End point description
    Documented symptomatic hypoglycemia is defined as an event during which typical symptoms of hypoglycemia are accompanied by a measured (e.g., by fingerstick) plasma glucose concentration ≤70 mg/dL (≤3.9 mmol/L). The event rate was the number of events divided by follow-up time (participant-years). The analysis population consisted of all randomized participants who received at least one dose of study treatment. Two participants in the sitagliptin group were not included in the primary analysis due to a missing value of a model covariate (race).
    End point type
    Primary
    End point timeframe
    Up to 30 weeks
    End point values
    		 Sitagliptin Placebo
    Number of subjects analysed
    371
    370
    Units: Total Number of Events/Participant-Years
        number (confidence interval 95%)
    1.55 (1.22 to 1.96)
    2.12 (1.70 to 2.66)
    Statistical analysis title
    		 Event Rate Ratio (Sitagliptin vs. Placebo)
    Statistical analysis description
    Calculated via the Negative Binomial Model including terms for treatment, race (i.e., White and Other), region (i.e., Europe, North America, and Other), AHA treatment at screening, baseline A1C value and baseline body weight and an offset for follow-up time (on the natural log scale).
    Comparison groups
    Sitagliptin v Placebo
    Number of subjects included in analysis
    741
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.039
    Method
    		 Negative Binomial Model
    Parameter type
    		 Event Rate Ratio
    Point estimate
    0.73
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.54
         upper limit
    		 0.98

    Primary: Percentage of Participants Who Experienced One or More Adverse Events (AEs)

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    End point title
    		 Percentage of Participants Who Experienced One or More Adverse Events (AEs)
    End point description
    An AE is defined as any unfavorable and unintended sign including an abnormal laboratory finding, symptom or disease associated with the use of a medical treatment or procedure, regardless of whether it is considered related to the medical treatment or procedure, that occurs during the course of the study. The analysis population consisted all randomized participants who received at least one dose of study treatment.
    End point type
    Primary
    End point timeframe
    Up to 32 weeks
    End point values
    		 Sitagliptin Placebo
    Number of subjects analysed
    373
    370
    Units: Percentage of participants
        number (not applicable)
    57.9
    60.0
    Statistical analysis title
    		 Between Group Difference in Percentages
    Comparison groups
    Sitagliptin v Placebo
    Number of subjects included in analysis
    743
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    Method
    		 Miettinen & Nurminen
    Parameter type
    		 Between Group Difference in Percentages
    Point estimate
    -2.1
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -9.1
         upper limit
    		 5

    Primary: Percentage of Participants Who Discontinued Study Drug Due to an AE

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    End point title
    		 Percentage of Participants Who Discontinued Study Drug Due to an AE
    End point description
    An AE is defined as any unfavorable and unintended sign including an abnormal laboratory finding, symptom or disease associated with the use of a medical treatment or procedure, regardless of whether it is considered related to the medical treatment or procedure, that occurs during the course of the study. The analysis population consisted all randomized participants who received at least one dose of study treatment.
    End point type
    Primary
    End point timeframe
    Up to 30 weeks
    End point values
    		 Sitagliptin Placebo
    Number of subjects analysed
    373
    370
    Units: Percentage of participants
        number (not applicable)
    1.3
    1.6
    Statistical analysis title
    		 Between Group Difference in Percentages
    Comparison groups
    Sitagliptin v Placebo
    Number of subjects included in analysis
    743
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    Method
    		 Miettinen & Nurminen
    Parameter type
    		 Between Group Difference in Percentages
    Point estimate
    -0.3
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -2.3
         upper limit
    		 1.7

    Secondary: Percentage of Participants with Events of Documented Symptomatic Hypoglycemia with Blood Glucose ≤70 mg/dL (≤3.9 mmol/L)

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    End point title
    		 Percentage of Participants with Events of Documented Symptomatic Hypoglycemia with Blood Glucose ≤70 mg/dL (≤3.9 mmol/L)
    End point description
    Documented symptomatic hypoglycemia is defined as an event during which typical symptoms of hypoglycemia are accompanied by a measured (e.g., by fingerstick) plasma glucose concentration ≤70 mg/dL (≤3.9 mmol/L). The incidence (number of participants with ≥1 event divided by number of participants) of documented symptomatic hypoglycemia was determined. The analysis population consisted of all randomized participants who received at least one dose of study treatment.
    End point type
    Secondary
    End point timeframe
    Up to 30 weeks
    End point values
    		 Sitagliptin Placebo
    Number of subjects analysed
    373
    370
    Units: Percentage of participants
        number (confidence interval 95%)
    33.5 (28.5 to 38.6)
    37.7 (32.7 to 42.6)
    Statistical analysis title
    		 Between Group Difference in Percentages
    Comparison groups
    Sitagliptin v Placebo
    Number of subjects included in analysis
    743
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.25
    Method
    		 Miettinen and Nurminen
    Parameter type
    		 Between Group Difference in Percentages
    Point estimate
    -4.1
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -11.2
         upper limit
    		 2.9

    Secondary: Event Rate of Documented Symptomatic Hypoglycemia with Blood Glucose <56 mg/dL (≤3.1 mmol/L)

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    End point title
    		 Event Rate of Documented Symptomatic Hypoglycemia with Blood Glucose <56 mg/dL (≤3.1 mmol/L)
    End point description
    Documented symptomatic hypoglycemia is defined as an event during which typical symptoms of hypoglycemia are accompanied by a measured (e.g., by fingerstick) plasma glucose concentration <56 mg/dL (≤3.1 mmol/L). The event rate was the number of events divided by follow-up time (participant-years). The analysis population consisted of all randomized participants who received at least one dose of study treatment. Two participants in the sitagliptin group were not included in the primary analysis due to a missing value of a model covariate (race).
    End point type
    Secondary
    End point timeframe
    Up to 30 weeks
    End point values
    		 Sitagliptin Placebo
    Number of subjects analysed
    371
    370
    Units: Total Number of Events/Participant-Years
        number (confidence interval 95%)
    0.17 (0.10 to 0.28)
    0.22 (0.14 to 0.36)
    Statistical analysis title
    		 Event Rate Ratio
    Statistical analysis description
    The analysis was calculated via the Negative Binomial Model including terms for treatment, race (i.e., White and Other), region (i.e., Europe, North America, and Other), AHA treatment at screening, baseline A1C value and baseline body weight and an offset for follow-up time (on the natural log scale).
    Comparison groups
    Sitagliptin v Placebo
    Number of subjects included in analysis
    741
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.394
    Method
    		 Negative Binomial Model
    Parameter type
    		 Event Rate Ratio
    Point estimate
    0.76
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.4
         upper limit
    		 1.44

    Secondary: Percentage of Participants with Documented Hypoglycemia with Blood Glucose ≤70 mg/dL (≤3.9 mmol/L)

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    End point title
    		 Percentage of Participants with Documented Hypoglycemia with Blood Glucose ≤70 mg/dL (≤3.9 mmol/L)
    End point description
    Documented hypoglycemia is defined by a measured (e.g., by fingerstick) plasma glucose concentration ≤70 mg/dL (≤3.9 mmol/L). The analysis population consisted of all randomized participants who received at least one dose of study treatment.
    End point type
    Secondary
    End point timeframe
    Up to 30 weeks
    End point values
    		 Sitagliptin Placebo
    Number of subjects analysed
    373
    370
    Units: Percentage of participants
        number (confidence interval 95%)
    66.8 (61.9 to 71.7)
    68.0 (63.2 to 72.9)
    Statistical analysis title
    		 Between Group Difference in Percentages
    Statistical analysis description
    The analysis included imputed events after participants discontinued from the study medication, using a Gamma frailty model. Proportions and difference in proportions were calculated via the Miettinen and Nurminen stratified by AHA treatment at screening. The bootstrap method was used to obtain the CI and p-value.
    Comparison groups
    Sitagliptin v Placebo
    Number of subjects included in analysis
    743
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.74
    Method
    		 Miettinen and Nurminen
    Parameter type
    		 Between Group Difference in Percentages
    Point estimate
    -1.2
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -8.2
         upper limit
    		 5.8

    Secondary: Percentage of Participants with Documented Symptomatic Hypoglycemia with Blood Glucose <56 mg/dL (≤3.1 mmol/L)

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    End point title
    		 Percentage of Participants with Documented Symptomatic Hypoglycemia with Blood Glucose <56 mg/dL (≤3.1 mmol/L)
    End point description
    Documented symptomatic hypoglycemia is defined as an event during which typical symptoms of hypoglycemia are accompanied by a measured (e.g., by fingerstick) plasma glucose concentration <56 mg/dL (≤3.1 mmol/L). The analysis population consisted of all randomized participants who received at least one dose of study treatment.
    End point type
    Secondary
    End point timeframe
    Up to 30 weeks
    End point values
    		 Sitagliptin Placebo
    Number of subjects analysed
    373
    370
    Units: Percentage of participants
        number (confidence interval 95%)
    7.6 (4.9 to 10.3)
    8.3 (5.4 to 11.2)
    Statistical analysis title
    		 Between Group Difference in Percentages
    Statistical analysis description
    Percentages and difference in percentages were calculated via the Miettinen and Nurminen stratified by AHA treatment at screening. The analysis included imputed events after subjects discontinued from the study medication, using a Gamma frailty model. The bootstrap method was used to obtain the CI and p-value.
    Comparison groups
    Sitagliptin v Placebo
    Number of subjects included in analysis
    743
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.712
    Method
    		 Miettinen and Nurminen
    Parameter type
    		 Between Group Difference in Percentages
    Point estimate
    -0.7
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -4.7
         upper limit
    		 3.2

    Secondary: Change from Baseline in Total Daily Insulin Dose (Units) at Week 30

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    End point title
    		 Change from Baseline in Total Daily Insulin Dose (Units) at Week 30
    End point description
    Change from baseline reflects the Week 30 total daily insulin dose minus the Week 0 total daily insulin dose. The Week 0 total daily insulin dose was 0, by definition, because insulin was not administered at baseline. The analysis population consisted of all randomized participants who received at least one dose of study treatment and had at least one measurement of the respective endpoint (baseline or post-baseline).
    End point type
    Secondary
    End point timeframe
    Baseline and Week 30
    End point values
    		 Sitagliptin Placebo
    Number of subjects analysed
    365
    367
    Units: Insulin Units
        least squares mean (confidence interval 95%)
    53.2 (48.5 to 58.0)
    61.3 (56.5 to 66.0)
    Statistical analysis title
    		 Between Group Difference in the LSM
    Statistical analysis description
    The analysis is based on a LDA model including terms for treatment, AHA treatment at screening (Met + DPP-4i, Met + DPP-4i + SU, Met + SU), time, and the interactions of time by treatment and of time by AHA treatment at screening.
    Comparison groups
    Sitagliptin v Placebo
    Number of subjects included in analysis
    732
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.016
    Method
    		 LDA model
    Parameter type
    		 Between Group Difference in the LSM
    Point estimate
    -8
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -14.6
         upper limit
    		 -1.5

    Secondary: Event Rate of Documented Hypoglycemia with Blood Glucose ≤70 mg/dL (≤3.9 mmol/L)

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    End point title
    		 Event Rate of Documented Hypoglycemia with Blood Glucose ≤70 mg/dL (≤3.9 mmol/L)
    End point description
    Documented hypoglycemia is defined by a measured (e.g., by fingerstick) plasma glucose concentration ≤70 mg/dL (≤3.9 mmol/L). The event rate was the number of events divided by follow-up time (participant-years). The analysis population consisted of all randomized participants who received at least one dose of study treatment and had at least one measurement of the respective endpoint (baseline or post-baseline). Two participants (both in the sitagliptin group) were not included in the analysis due to a missing value of a model covariate (race).
    End point type
    Secondary
    End point timeframe
    Up to 30 weeks
    End point values
    		 Sitagliptin Placebo
    Number of subjects analysed
    371
    370
    Units: Total Number of Events/Participant-Years
        number (confidence interval 95%)
    5.05 (4.34 to 5.88)
    6.21 (5.33 to 7.24)
    Statistical analysis title
    		 Event Rate Ratio
    Statistical analysis description
    Negative Binomial Model including terms for treatment, race (i.e., White and Other), region (i.e., Europe, North America, and Other), AHA treatment at screening, baseline A1C value and baseline body weight and an offset for follow-up time (on the natural log scale).
    Comparison groups
    Sitagliptin v Placebo
    Number of subjects included in analysis
    741
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.041
    Method
    		 Negative Binomial Model
    Parameter type
    		 Event Rate Ratio
    Point estimate
    0.81
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.67
         upper limit
    		 0.99

    Secondary: Event Rate of Documented Hypoglycemia with Blood Glucose <56 mg/dL (≤3.1 mmol/L)

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    End point title
    		 Event Rate of Documented Hypoglycemia with Blood Glucose <56 mg/dL (≤3.1 mmol/L)
    End point description
    Documented hypoglycemia is defined by a measured (e.g., by fingerstick) plasma glucose concentration <56 mg/dL (≤3.1 mmol/L). The event rate was the number of events divided by follow-up time (participant-years). The analysis population consisted of all randomized participants who received at least one dose of study treatment and had at least one measurement of the respective endpoint (baseline or post-baseline). Two participants (both in the sitagliptin group) were not included in the analysis due to a missing value of a model covariate (race).
    End point type
    Secondary
    End point timeframe
    Up to 30 weeks
    End point values
    		 Sitagliptin Placebo
    Number of subjects analysed
    371
    370
    Units: Total Number of Events/Participant-Years
        number (confidence interval 95%)
    0.30 (0.20 to 0.45)
    0.36 (0.25 to 0.53)
    Statistical analysis title
    		 Event Rate Ratio
    Statistical analysis description
    Negative Binomial Model including terms for treatment, race (i.e., White and Other), region (i.e., Europe, North America, and Other), AHA treatment at screening, baseline A1C value and baseline body weight and an offset for follow-up time (on the natural log scale).
    Comparison groups
    Sitagliptin v Placebo
    Number of subjects included in analysis
    741
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.473
    Method
    		 Negative Binomial Model
    Parameter type
    		 Event Rate Ratio
    Point estimate
    0.83
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.51
         upper limit
    		 1.37

    Secondary: Percentage of Participants with Documented Hypoglycemia with Blood Glucose <56 mg/dL (≤3.1 mmol/L)

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    End point title
    		 Percentage of Participants with Documented Hypoglycemia with Blood Glucose <56 mg/dL (≤3.1 mmol/L)
    End point description
    Documented hypoglycemia is defined by a measured (e.g., by fingerstick) plasma glucose concentration <56 mg/dL (≤3.1 mmol/L). The analysis population consisted of all randomized participants who received at least one dose of study treatment.
    End point type
    Secondary
    End point timeframe
    Up to 30 weeks
    End point values
    		 Sitagliptin Placebo
    Number of subjects analysed
    373
    370
    Units: Percentage of Participants
        number (confidence interval 95%)
    12.4 (8.9 to 15.8)
    13.6 (10.0 to 17.2)
    Statistical analysis title
    		 Between Group Difference in Percentages
    Statistical analysis description
    Percentages and difference in percentages were calculated via the Miettinen and Nurminen stratified by AHA treatment at screening. Includes imputed events after participants discontinued from the study medication, using a Gamma frailty model. The bootstrap method was used to obtain the CI and p-value.
    Comparison groups
    Sitagliptin v Placebo
    Number of subjects included in analysis
    743
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.624
    Method
    		 Miettinen and Nurminen
    Parameter type
    		 Between Group Difference in Percentages
    Point estimate
    -1.2
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -6.2
         upper limit
    		 3.7

    Secondary: Percentage of Participants with A1C goal <7.0% (<53 mmol/mol) at Week 30

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    End point title
    		 Percentage of Participants with A1C goal <7.0% (<53 mmol/mol) at Week 30
    End point description
    A1C is blood marker used to report average blood glucose levels over prolonged periods of time. Percentage A1C is the ratio of glycated hemoglobin to total hemoglobin x 100. The analysis population consisted of all randomized participants who received at least one dose of study treatment.
    End point type
    Secondary
    End point timeframe
    Week 30
    End point values
    		 Sitagliptin Placebo
    Number of subjects analysed
    373
    370
    Units: Percentage of participants
        number (not applicable)
    54.2
    35.4
    Statistical analysis title
    		 Between Group Difference in Percentages
    Comparison groups
    Sitagliptin v Placebo
    Number of subjects included in analysis
    743
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 < 0.001
    Method
    		 Miettinen and Nurminen
    Parameter type
    		 Between Group Difference in Percentages
    Point estimate
    18.8
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 11.6
         upper limit
    		 25.7

    Secondary: Percentage of Participants with A1C goal <7.0% (<53 mmol/mol at Week 30 and No Documented Hypoglycemia with Blood Glucose ≤70 mg/dL (≤3.9 mmol/L) up to Week 30

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    End point title
    		 Percentage of Participants with A1C goal <7.0% (<53 mmol/mol at Week 30 and No Documented Hypoglycemia with Blood Glucose ≤70 mg/dL (≤3.9 mmol/L) up to Week 30
    End point description
    A1C is blood marker used to report average blood glucose levels over prolonged periods of time. Percentage A1C is the ratio of glycated hemoglobin to total hemoglobin x 100. The analysis population consisted of all randomized participants who received at least one dose of study treatment.
    End point type
    Secondary
    End point timeframe
    Week 30
    End point values
    		 Sitagliptin Placebo
    Number of subjects analysed
    373
    370
    Units: Percentage of participants
        number (not applicable)
    15.3
    10.0
    Statistical analysis title
    		 Between Group Difference in Percentages
    Comparison groups
    Sitagliptin v Placebo
    Number of subjects included in analysis
    743
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.03
    Method
    		 Miettinen and Nurminen
    Parameter type
    		 Between Group Difference in Percentages
    Point estimate
    5.3
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.5
         upper limit
    		 10.1

    Secondary: Change from Baseline in Fasting Plasma Glucose (FPG) at Week 30

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    End point title
    		 Change from Baseline in Fasting Plasma Glucose (FPG) at Week 30
    End point description
    Blood glucose was measured on a fasting basis. Blood was drawn at predose on Day 1 and after 30 weeks of treatment to determine change in plasma glucose levels (i.e., FPG at Week 30 minus FPG at Week 0). The analysis population consisted of all randomized participants who received at least one dose of study treatment and had at least one measurement of the respective endpoint (baseline or post-baseline).
    End point type
    Secondary
    End point timeframe
    Baseline and Week 30
    End point values
    		 Sitagliptin Placebo
    Number of subjects analysed
    373
    370
    Units: mg/dL
        least squares mean (confidence interval 95%)
    -84.8 (-90.0 to -79.6)
    -78.3 (-83.5 to -73.1)
    Statistical analysis title
    		 Between Group Difference in the LSM
    Statistical analysis description
    Analysis was based on a LDA model including terms for treatment, AHA treatment at screening (Met + DPP-4i, Met + DPP-4i + SU, Met + SU), time, and the interactions of time by treatment and of time by AHA treatment at screening.
    Comparison groups
    Sitagliptin v Placebo
    Number of subjects included in analysis
    743
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.02
    Method
    		 LDA
    Parameter type
    		 Between Group Difference in the LSM
    Point estimate
    -6.5
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -11.9
         upper limit
    		 -1

    Adverse events

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    Adverse events information
    Timeframe for reporting adverse events
    Up to 32 weeks
    Adverse event reporting additional description
    The analysis population consisted all randomized participants who received at least one dose of study treatment. Events of hypoglycemia of any type were collected as efficacy endpoints in this study. AEs of symptomatic hypoglycemia could also be reported by investigators.
    Assessment type
    		 Systematic
    Dictionary used for adverse event reporting
    Dictionary name
    		 MedDRA
    Dictionary version
    20.1
    Reporting groups
    Reporting group title
    Sitagliptin
    Reporting group description
    		 Sitagliptin 100 mg, oral, once daily for 30 weeks

    Reporting group title
    Placebo
    Reporting group description
    		 Placebo to sitagliptin, 100 mg, oral, once daily for 30 weeks

    Serious adverse events
    		 Sitagliptin Placebo
    Total subjects affected by serious adverse events
         subjects affected / exposed
    14 / 373 (3.75%)
    18 / 370 (4.86%)
         number of deaths (all causes)
    0
    2
         number of deaths resulting from adverse events
    0
    0
    Investigations
    Heart rate irregular
         subjects affected / exposed
    0 / 373 (0.00%)
    1 / 370 (0.27%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    1 / 1
    Neoplasms benign, malignant and unspecified (incl cysts and polyps)
    Endometrial adenocarcinoma
         subjects affected / exposed
    1 / 373 (0.27%)
    0 / 370 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Gastrointestinal tract adenoma
         subjects affected / exposed
    0 / 373 (0.00%)
    1 / 370 (0.27%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Non-Hodgkin's lymphoma
         subjects affected / exposed
    0 / 373 (0.00%)
    1 / 370 (0.27%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Prostate cancer
         subjects affected / exposed
    1 / 373 (0.27%)
    0 / 370 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Injury, poisoning and procedural complications
    Fibula fracture
         subjects affected / exposed
    1 / 373 (0.27%)
    0 / 370 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Ligament rupture
         subjects affected / exposed
    1 / 373 (0.27%)
    0 / 370 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Congenital, familial and genetic disorders
    Phimosis
         subjects affected / exposed
    0 / 373 (0.00%)
    1 / 370 (0.27%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Cardiac disorders
    Acute myocardial infarction
         subjects affected / exposed
    1 / 373 (0.27%)
    1 / 370 (0.27%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Atrial fibrillation
         subjects affected / exposed
    1 / 373 (0.27%)
    0 / 370 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Coronary artery disease
         subjects affected / exposed
    1 / 373 (0.27%)
    1 / 370 (0.27%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Myocardial infarction
         subjects affected / exposed
    0 / 373 (0.00%)
    1 / 370 (0.27%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    1 / 1
    Nervous system disorders
    Carotid artery stenosis
         subjects affected / exposed
    0 / 373 (0.00%)
    1 / 370 (0.27%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Cerebral ischaemia
         subjects affected / exposed
    0 / 373 (0.00%)
    1 / 370 (0.27%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Cerebrovascular accident
         subjects affected / exposed
    0 / 373 (0.00%)
    2 / 370 (0.54%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Ischaemic stroke
         subjects affected / exposed
    0 / 373 (0.00%)
    2 / 370 (0.54%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Lumbar radiculopathy
         subjects affected / exposed
    0 / 373 (0.00%)
    1 / 370 (0.27%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Neuralgia
         subjects affected / exposed
    0 / 373 (0.00%)
    1 / 370 (0.27%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Sciatica
         subjects affected / exposed
    1 / 373 (0.27%)
    0 / 370 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Gastrointestinal disorders
    Colitis
         subjects affected / exposed
    0 / 373 (0.00%)
    1 / 370 (0.27%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Strangulated umbilical hernia
         subjects affected / exposed
    1 / 373 (0.27%)
    0 / 370 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Hepatobiliary disorders
    Cholecystitis acute
         subjects affected / exposed
    1 / 373 (0.27%)
    0 / 370 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Respiratory, thoracic and mediastinal disorders
    Acute respiratory failure
         subjects affected / exposed
    1 / 373 (0.27%)
    0 / 370 (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
    Diabetic foot
         subjects affected / exposed
    0 / 373 (0.00%)
    1 / 370 (0.27%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Infections and infestations
    Bronchitis
         subjects affected / exposed
    0 / 373 (0.00%)
    1 / 370 (0.27%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Gastroenteritis
         subjects affected / exposed
    1 / 373 (0.27%)
    0 / 370 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Groin abscess
         subjects affected / exposed
    1 / 373 (0.27%)
    0 / 370 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pyelonephritis
         subjects affected / exposed
    0 / 373 (0.00%)
    1 / 370 (0.27%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Sialoadenitis
         subjects affected / exposed
    1 / 373 (0.27%)
    0 / 370 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Tracheitis
         subjects affected / exposed
    0 / 373 (0.00%)
    1 / 370 (0.27%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Urinary tract infection
         subjects affected / exposed
    1 / 373 (0.27%)
    0 / 370 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Metabolism and nutrition disorders
    Hyponatraemia
         subjects affected / exposed
    0 / 373 (0.00%)
    1 / 370 (0.27%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Frequency threshold for reporting non-serious adverse events: 5%
    Non-serious adverse events
    		 Sitagliptin Placebo
    Total subjects affected by non serious adverse events
         subjects affected / exposed
    79 / 373 (21.18%)
    72 / 370 (19.46%)
    Nervous system disorders
    Headache
         subjects affected / exposed
    25 / 373 (6.70%)
    19 / 370 (5.14%)
         occurrences all number
    36
    23
    Infections and infestations
    Nasopharyngitis
         subjects affected / exposed
    24 / 373 (6.43%)
    32 / 370 (8.65%)
         occurrences all number
    30
    35
    Metabolism and nutrition disorders
    Hypoglycaemia
         subjects affected / exposed
    35 / 373 (9.38%)
    24 / 370 (6.49%)
         occurrences all number
    96
    74

    More information

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    Substantial protocol amendments (globally)
    Were there any global substantial amendments to the protocol? Yes
    Date
    Amendment
    29 Apr 2016
    AM1: The participant population was expanded to include eligible patients on metformin and a sulfonylurea with an A1C of 7.5% to 11.0% at Screening in the study.
    11 Jul 2016
    AM2: 1. Metformin dosing was removed and the text was updated to allow the dose frequency to be defined by local labels or clinical practice guidelines. 2. Added text and footnote to state that participants participating in the continuous glucose monitoring (CGM) sub-study cannot use acetaminophen and/or medications containing acetaminophen for at least 24 hours prior to sensor insertion and while the sensor is being used.

    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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    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
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