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    Clinical Trial Results:
    A 52-week International, Multicenter, Randomized, Double-Blind, Active-Controlled, Parallel Group, Phase 3b Trial with a Blinded 104-week Long-term Extension Period to Evaluate the Efficacy and Safety of Saxagliptin Co-administered with Dapagliflozin in Combination with Metformin Compared to Glimepiride in Combination with Metformin in Adult Patients with Type 2 Diabetes Who Have Inadequate Glycemic Control on Metformin Therapy Alone

    Summary
    EudraCT number
    		 2014-003721-18
    Trial protocol
    		 CZ   DE   HU   SE   PL   RO  
    Global end of trial date
    18 Sep 2019

    Results information
    Results version number
    		 v1(current)
    This version publication date
    24 Jun 2020
    First version publication date
    24 Jun 2020
    Other versions

    Trial information

    		 Close Top of page
    Trial identification
    Sponsor protocol code
    CV181-365
    Additional study identifiers
    ISRCTN number
    		 -
    US NCT number
    		 NCT02419612
    WHO universal trial number (UTN)
    		 -
    Sponsors
    Sponsor organisation name
    AstraZeneca
    Sponsor organisation address
    Pepparedsleden 1, Mölndal, Sweden, SE-431 83
    Public contact
    Global Clinical Lead, AstraZeneca, +1 877-240-9479, information.center@astrazeneca.com
    Scientific contact
    Global Clinical Lead, AstraZeneca, +1 877-240-9479, information.center@astrazeneca.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
    18 Sep 2019
    Is this the analysis of the primary completion data?
    Yes
    Primary completion date
    29 Aug 2017
    Global end of trial reached?
    Yes
    Global end of trial date
    18 Sep 2019
    Was the trial ended prematurely?
    No
    General information about the trial
    Main objective of the trial
    The primary objective of this study was to compare the mean change from baseline in haemoglobin A1c (HbA1c) achieved with saxagliptin in co-administration with dapagliflozin added to current background therapy with metformin, compared with glimepiride added to current background therapy with metformin at Week 52.
    Protection of trial subjects
    This study was performed in accordance with the ethical principles that have their origin in the Declaration of Helsinki and that are consistent with International Council on Harmonisation/Good Clinical Practice, applicable regulatory requirements and the AstraZeneca policy on Bioethics. Subjects could discontinue the investigational product and assessments at any time at the discretion of the investigator(s). Subjects were also free to withdraw from the study at any time, without prejudice to further treatment.
    Background therapy
    		 Subjects should have been taking the same daily dose of metformin ≥1500 milligrams (mg) for at least 8 weeks prior to the enrollment visit and must not have taken any other antihyperglycemic therapy for more than 14 days (consecutive or not) during 12 weeks prior to screening.
    Evidence for comparator
    		 The active comparator was glimepiride plus background therapy with metformin. Glimepiride, a sulfonylurea (SU), is a widely used antidiabetic treatment. Glimepiride was prescribed according to its approved label. Data from clinical studies indicate that the overall incidence of AEs associated with glimepiride was generally lower compared with other SUs, including a lower risk of hypoglycaemia and weight gain. Key limitations of SU therapies, such as glimepiride, include weight gain and increased risk of hypoglycaemia. Saxagliptin and dapagliflozin have demonstrated a low propensity for hypoglycaemia and either demonstrated weight neutrality (saxagliptin) or moderate weight reduction (dapagliflozin).
    Actual start date of recruitment
    14 Aug 2015
    Long term follow-up planned
    Yes
    Long term follow-up rationale
    		 Safety, Efficacy
    Long term follow-up duration
    		 24 Months
    Independent data monitoring committee (IDMC) involvement?
    No
    Population of trial subjects
    Number of subjects enrolled per country
    Country: Number of subjects enrolled
    United States: 112
    Country: Number of subjects enrolled
    Mexico: 76
    Country: Number of subjects enrolled
    Russian Federation: 29
    Country: Number of subjects enrolled
    Germany: 1
    Country: Number of subjects enrolled
    Poland: 73
    Country: Number of subjects enrolled
    Sweden: 2
    Country: Number of subjects enrolled
    United Kingdom: 2
    Country: Number of subjects enrolled
    Czech Republic: 27
    Country: Number of subjects enrolled
    Hungary: 71
    Country: Number of subjects enrolled
    Romania: 51
    Worldwide total number of subjects
    444
    EEA total number of subjects
    227
    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)
    354
    From 65 to 84 years
    90
    85 years and over
    0

    Subject disposition

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    Recruitment
    Recruitment details
    		 A total of 444 subjects were randomized in this international, multi-center study which was conducted at 88 centers in 10 countries between 14 Aug 2015 and 18 September 2019.

    Pre-assignment
    Screening details
    		 The study duration was up to 160 weeks, consisting of a 2-week screening period, 2-week lead-in period, 52-week short-term treatment period, and 104-week long-term treatment period (156 week treatment period). One subject did not start the short-term treatment period and so only 443 subjects received treatment.

    Period 1
    Period 1 title
    Short-Term Treatment 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
    		 Dapagliflozin 10mg and Saxagliptin 5mg
    Arm description
    		 Subjects received dapagliflozin 10 mg, saxagliptin 5 mg plus placebo for glimepiride, each administered orally once daily. Subjects also continued to receive their metformin dose of at least 1500 mg per day.
    Arm type
    		 Experimental

    Investigational medicinal product name
    Dapagliflozin
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Film-coated tablet
    Routes of administration
    Oral use
    Dosage and administration details
    Dapagliflozin 10 mg, 1 tablet given orally once daily.

    Investigational medicinal product name
    Saxagliptin
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Film-coated tablet
    Routes of administration
    Oral use
    Dosage and administration details
    Saxagliptin 5 mg, 1 tablet given orally once daily.

    Investigational medicinal product name
    Placebo for glimepiride
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Capsule
    Routes of administration
    Oral use
    Dosage and administration details
    Placebo for glimepiride 1, 2, or 4 mg capsules, given orally once daily.

    Arm title
    		 Titrated Glimepiride
    Arm description
    		 Subjects received titrated glimepiride 1, 2, 3, 4, or 6 mg plus placebo for saxagliptin and placebo for dapagliflozin, administered orally once daily. Subjects also continued to receive their metformin dose of at least 1500 mg per day.
    Arm type
    		 Active comparator

    Investigational medicinal product name
    Glimepiride
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Capsule
    Routes of administration
    Oral use
    Dosage and administration details
    Glimepiride 1, 2, or 4 mg capsules, given orally once daily.

    Investigational medicinal product name
    Placebo for dapagliflozin
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Film-coated tablet
    Routes of administration
    Oral use
    Dosage and administration details
    Placebo for dapagliflozin 10 mg, 1 tablet given orally once daily.

    Investigational medicinal product name
    Placebo for saxagliptin
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Film-coated tablet
    Routes of administration
    Oral use
    Dosage and administration details
    Placebo for saxagliptin 5 mg, 1 tablet given orally once daily.

    Number of subjects in period 1 [1]
    		Dapagliflozin 10mg and Saxagliptin 5mg Titrated Glimepiride
    Started
    227
    216
    Completed
    210
    194
    Not completed
    17
    22
         Adverse event, serious fatal
    -
    2
         Consent withdrawn by subject
    9
    9
         Adverse event, non-fatal
    1
    1
         Unspecified
    1
    4
         Lost to follow-up
    6
    6
    Notes
    [1] - The number of subjects reported to be in the baseline period are not the same as the worldwide number enrolled in the trial. It is expected that these numbers will be the same.
    Justification: One subject that was randomized did not receive treatment and was not included in the baseline population.
    Period 2
    Period 2 title
    Long-Term Treatment Period
    Is this the baseline period?
    		 No
    Allocation method
    Randomised - controlled
    Blinding used
    		 Double blind
    Roles blinded
    		 Subject, Investigator

    Arms
    Are arms mutually exclusive
    Yes

    Arm title
    		 Dapagliflozin 10mg and Saxagliptin 5mg
    Arm description
    		 Subjects received dapagliflozin 10 mg, saxagliptin 5 mg plus placebo for glimepiride, each administered orally once daily. Subjects also continued to receive their metformin dose of at least 1500 mg per day.
    Arm type
    		 Experimental

    Investigational medicinal product name
    Dapagliflozin
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Film-coated tablet
    Routes of administration
    Oral use
    Dosage and administration details
    Dapagliflozin 10 mg, 1 tablet given orally once daily.

    Investigational medicinal product name
    Placebo for glimepiride
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Capsule
    Routes of administration
    Oral use
    Dosage and administration details
    Placebo for glimepiride 1, 2, or 4 mg capsules, given orally once daily.

    Investigational medicinal product name
    Saxagliptin
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Film-coated tablet
    Routes of administration
    Oral use
    Dosage and administration details
    Saxagliptin 5 mg, 1 tablet given orally once daily.

    Arm title
    		 Titrated Glimepiride
    Arm description
    		 Subjects received titrated glimepiride 1, 2, 3, 4, or 6 mg plus placebo for saxagliptin and placebo for dapagliflozin, administered orally once daily. Subjects also continued to receive their metformin dose of at least 1500 mg per day.
    Arm type
    		 Active comparator

    Investigational medicinal product name
    Glimepiride
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Capsule
    Routes of administration
    Oral use
    Dosage and administration details
    Glimepiride 1, 2, or 4 mg capsules, given orally once daily.

    Investigational medicinal product name
    Placebo for dapagliflozin
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Film-coated tablet
    Routes of administration
    Oral use
    Dosage and administration details
    Placebo for dapagliflozin 10 mg, 1 tablet given orally once daily.

    Investigational medicinal product name
    Placebo for saxagliptin
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Film-coated tablet
    Routes of administration
    Oral use
    Dosage and administration details
    Placebo for saxagliptin 5 mg, 1 tablet given orally once daily.

    Number of subjects in period 2 [2]
    		Dapagliflozin 10mg and Saxagliptin 5mg Titrated Glimepiride
    Started
    196
    186
    Recevied Treatment
    196
    183
    Completed
    174
    164
    Not completed
    22
    22
         Adverse event, serious fatal
    -
    1
         Non-compliance with Study Drug
    1
    1
         Consent withdrawn by subject
    8
    2
         Subject Decision
    2
    4
         Adverse event, non-fatal
    -
    5
         Unspecified
    4
    4
         Lost to follow-up
    6
    4
         Lack of efficacy
    1
    1
    Notes
    [2] - The number of subjects starting the period is not consistent with the number completing the preceding period. It is expected the number of subjects starting the subsequent period will be the same as the number completing the preceding period.
    Justification: Not all subjects that completed the previous short-term treatment period were eligible to enter the long-term treatment period. Subjects are included in the treatment group to which they were randomized at the start of the short-term double-blind treatment period.

    Baseline characteristics

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    Baseline characteristics reporting groups
    Reporting group title
    Dapagliflozin 10mg and Saxagliptin 5mg
    Reporting group description
    		 Subjects received dapagliflozin 10 mg, saxagliptin 5 mg plus placebo for glimepiride, each administered orally once daily. Subjects also continued to receive their metformin dose of at least 1500 mg per day.

    Reporting group title
    Titrated Glimepiride
    Reporting group description
    		 Subjects received titrated glimepiride 1, 2, 3, 4, or 6 mg plus placebo for saxagliptin and placebo for dapagliflozin, administered orally once daily. Subjects also continued to receive their metformin dose of at least 1500 mg per day.

    Reporting group values
    		 Dapagliflozin 10mg and Saxagliptin 5mg Titrated Glimepiride Total
    Number of subjects
    		 227 216 443
    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)
    		 182 171 353
        From 65-84 years
    		 45 45 90
        85 years and over
    		 0 0 0
    Age Continuous
    Units: Years
        arithmetic mean (standard deviation)
    		 56.1 ± 10.11 56.1 ± 9.23 -
    Gender, Male/Female
    Units:
        Female
    		 110 115 225
        Male
    		 117 101 218
    Race/Ethnicity, Customized
    Units: Subjects
        American Indian Or Alaska Native
    		 11 10 21
        Black Or African American
    		 4 5 9
        Native Hawaiian Or Other Pacific Islander
    		 0 1 1
        Other
    		 6 4 10
        White
    		 206 196 402

    End points

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    End points reporting groups
    Reporting group title
    Dapagliflozin 10mg and Saxagliptin 5mg
    Reporting group description
    		 Subjects received dapagliflozin 10 mg, saxagliptin 5 mg plus placebo for glimepiride, each administered orally once daily. Subjects also continued to receive their metformin dose of at least 1500 mg per day.

    Reporting group title
    Titrated Glimepiride
    Reporting group description
    		 Subjects received titrated glimepiride 1, 2, 3, 4, or 6 mg plus placebo for saxagliptin and placebo for dapagliflozin, administered orally once daily. Subjects also continued to receive their metformin dose of at least 1500 mg per day.
    Reporting group title
    Dapagliflozin 10mg and Saxagliptin 5mg
    Reporting group description
    		 Subjects received dapagliflozin 10 mg, saxagliptin 5 mg plus placebo for glimepiride, each administered orally once daily. Subjects also continued to receive their metformin dose of at least 1500 mg per day.

    Reporting group title
    Titrated Glimepiride
    Reporting group description
    		 Subjects received titrated glimepiride 1, 2, 3, 4, or 6 mg plus placebo for saxagliptin and placebo for dapagliflozin, administered orally once daily. Subjects also continued to receive their metformin dose of at least 1500 mg per day.

    Subject analysis set title
    Dapagliflozin 10mg and Saxagliptin 5mg
    Subject analysis set type
    		 Intention-to-treat
    Subject analysis set description
    Subjects received dapagliflozin 10 mg, saxagliptin 5 mg plus placebo for glimepiride, each administered orally once daily over the 156-week treatment period. Subjects also continued to receive their metformin dose of at least 1500 mg per day.

    Subject analysis set title
    Titrated Glimepiride
    Subject analysis set type
    		 Intention-to-treat
    Subject analysis set description
    Subjects received titrated glimepiride 1, 2, 3, 4, or 6 mg plus placebo for saxagliptin and placebo for dapagliflozin, administered orally once daily over the 156-week treatment period. Subjects also continued to receive their metformin dose of at least 1500 mg per day.

    Primary: Change from Baseline in HbA1c at Week 52

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    End point title
    		 Change from Baseline in HbA1c at Week 52
    End point description
    To examine whether the mean change from baseline in HbA1c with co-administered saxagliptin 5 mg and dapagliflozin 10 mg plus metformin is superior to titrated glimepiride plus metformin after 52 weeks of double-blind treatment.
    End point type
    Primary
    End point timeframe
    Baseline and Week 52
    End point values
    		 Dapagliflozin 10mg and Saxagliptin 5mg Titrated Glimepiride
    Number of subjects analysed
    218
    212
    Units: % HbA1c
        least squares mean (confidence interval 95%)
    -1.35 (-1.49 to -1.22)
    -0.98 (-1.12 to -0.84)
    Statistical analysis title
    		 Treatment Comparison
    Comparison groups
    Dapagliflozin 10mg and Saxagliptin 5mg v Titrated Glimepiride
    Number of subjects included in analysis
    430
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 < 0.001
    Method
    		 Mixed models analysis
    Parameter type
    		 Least Square (LS) Mean Difference
    Point estimate
    -0.37
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -0.57
         upper limit
    		 -0.18
    Variability estimate
    Standard error of the mean
    Dispersion value
    0.099

    Secondary: Change from Baseline in Total Body Weight at Week 52

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    End point title
    		 Change from Baseline in Total Body Weight at Week 52
    End point description
    To examine whether the mean change from baseline in total body weight with co-administered saxagliptin 5 mg and dapagliflozin 10 mg plus metformin is superior to titrated glimepiride plus metformin after 52 weeks of double-blind treatment.
    End point type
    Secondary
    End point timeframe
    Baseline and Week 52
    End point values
    		 Dapagliflozin 10mg and Saxagliptin 5mg Titrated Glimepiride
    Number of subjects analysed
    224
    214
    Units: kg
        least squares mean (confidence interval 95%)
    -3.11 (-3.65 to -2.57)
    0.95 (0.38 to 1.51)
    Statistical analysis title
    		 Treatment Comparison
    Comparison groups
    Dapagliflozin 10mg and Saxagliptin 5mg v Titrated Glimepiride
    Number of subjects included in analysis
    438
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 < 0.001
    Method
    		 Mixed models analysis
    Parameter type
    		 LS Mean Difference
    Point estimate
    -4.06
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -4.84
         upper limit
    		 -3.28
    Variability estimate
    Standard error of the mean
    Dispersion value
    0.397

    Secondary: Percentage of Subjects Achieving a Therapeutic Glycemic Response, Defined as HbA1c < 7.0%, at Week 52

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    End point title
    		 Percentage of Subjects Achieving a Therapeutic Glycemic Response, Defined as HbA1c < 7.0%, at Week 52
    End point description
    Therapeutic glycemic response was defined as HbA1c <7.0%. Subjects rescued or discontinued prior to, and subjects with missing measurement at Week 52 were treated as non-responders. The percentage of subjects with a therapeutic glycemic response is based on the logistic regression method with adjustment for baseline HbA1c.
    End point type
    Secondary
    End point timeframe
    At Week 52
    End point values
    		 Dapagliflozin 10mg and Saxagliptin 5mg Titrated Glimepiride
    Number of subjects analysed
    227
    216
    Units: Percentage of Subjects
        number (confidence interval 95%)
    44.3 (37.45 to 51.32)
    34.3 (27.87 to 41.33)
    Statistical analysis title
    		 Treatment Comparison
    Comparison groups
    Dapagliflozin 10mg and Saxagliptin 5mg v Titrated Glimepiride
    Number of subjects included in analysis
    443
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.044
    Method
    		 Regression, Logistic
    Parameter type
    		 Odds ratio (OR)
    Point estimate
    1.5
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 1.01
         upper limit
    		 2.29

    Secondary: Change from Baseline in Systolic Blood Pressure (SBP) at Week 52

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    End point title
    		 Change from Baseline in Systolic Blood Pressure (SBP) at Week 52
    End point description
    To examine whether the change from baseline in SBP with co-administered saxagliptin 5 mg and dapagliflozin 10 mg plus metformin is superior to titrated glimepiride plus metformin after 52 weeks of double-blind treatment.
    End point type
    Secondary
    End point timeframe
    Baseline and Week 52
    End point values
    		 Dapagliflozin 10mg and Saxagliptin 5mg Titrated Glimepiride
    Number of subjects analysed
    224
    214
    Units: mmHg
        least squares mean (confidence interval 95%)
    -2.6 (-4.4 to -0.8)
    1.0 (-0.9 to 2.9)
    Statistical analysis title
    		 Treatment Comparison
    Comparison groups
    Dapagliflozin 10mg and Saxagliptin 5mg v Titrated Glimepiride
    Number of subjects included in analysis
    438
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.007
    Method
    		 Mixed models analysis
    Parameter type
    		 LS Mean Difference
    Point estimate
    -3.6
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -6.3
         upper limit
    		 -1
    Variability estimate
    Standard error of the mean
    Dispersion value
    1.35

    Secondary: Percentage of Subjects with Treatment Intensification During the 52 Week Short-term Treatment Period

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    End point title
    		 Percentage of Subjects with Treatment Intensification During the 52 Week Short-term Treatment Period
    End point description
    Treatment intensification was defined as the addition of insulin or other glucose-lowering agent for rescue therapy or discontinuation for lack of glycemic control. Time to treatment intensification was censored at end of the 52-week treatment period if treatment intensification had not occurred by then. Subjects rescued at Week 52 were counted as having an event for the analysis. The values presented are the percentage of subjects requiring the addition of insulin or other glucose lowering agent for rescue therapy or discontinuation for lack of glycemic control during the 52-week short-term treatment period.
    End point type
    Secondary
    End point timeframe
    Up to Week 52
    End point values
    		 Dapagliflozin 10mg and Saxagliptin 5mg Titrated Glimepiride
    Number of subjects analysed
    227
    216
    Units: Percentage of Subjects
        number (not applicable)
    1.3
    8.8
    Statistical analysis title
    		 Treatment Comparison
    Statistical analysis description
    Time to treatment intensification was analyzed using a Cox proportional hazards model.
    Comparison groups
    Dapagliflozin 10mg and Saxagliptin 5mg v Titrated Glimepiride
    Number of subjects included in analysis
    443
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.002 [1]
    Method
    		 Regression, Cox Proportional Hazards
    Parameter type
    		 Hazard ratio (HR)
    Point estimate
    0.15
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.04
         upper limit
    		 0.5
    Notes
    [1] - This endpoint did not meet the required number of events (n=10) in each treatment arm, hence was excluded from sequential testing.

    Secondary: Percentage of Subjects with Treatment Intensification During the 156-Week Short-term plus Long-Term Treatment Period.

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    End point title
    		 Percentage of Subjects with Treatment Intensification During the 156-Week Short-term plus Long-Term Treatment Period.
    End point description
    Treatment intensification was defined as the addition of insulin or other glucose-lowering agent for rescue therapy or discontinuation for lack of glycemic control. Time to treatment intensification was censored at end of 156-week treatment period if treatment intensification had not occurred by then. Subjects rescued at Week 156 were counted as having an event for the analysis. The values presented are the percentage of subjects requiring the addition of insulin or other glucose lowering agent for rescue therapy or discontinuation for lack of glycemic control during the 156-week short-term plus long-term treatment period.
    End point type
    Secondary
    End point timeframe
    Up to Week 156
    End point values
    		 Dapagliflozin 10mg and Saxagliptin 5mg Titrated Glimepiride
    Number of subjects analysed
    227
    216
    Units: Percentage of Subjects
        number (not applicable)
    37.0
    55.6
    Statistical analysis title
    		 Treatment Comparison
    Statistical analysis description
    Time to treatment intensification was analyzed using a Cox proportional hazards model.
    Comparison groups
    Dapagliflozin 10mg and Saxagliptin 5mg v Titrated Glimepiride
    Number of subjects included in analysis
    443
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 < 0.001
    Method
    		 Regression, Cox Proportional Hazards
    Parameter type
    		 Hazard ratio (HR)
    Point estimate
    0.52
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.39
         upper limit
    		 0.68

    Secondary: Percentage of Subjects Achieving a Therapeutic Glycemic Response, Defined as HbA1c < 7.0%, at Week 156

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    End point title
    		 Percentage of Subjects Achieving a Therapeutic Glycemic Response, Defined as HbA1c < 7.0%, at Week 156
    End point description
    Therapeutic glycemic response was defined as HbA1c <7.0%. Subjects rescued or discontinued prior to, and subjects with missing measurement at Week 156 were treated as non-responders. The percentage of subjects with a therapeutic glycemic response is based on the logistic regression method with adjustment for baseline HbA1c.
    End point type
    Secondary
    End point timeframe
    At Week 156
    End point values
    		 Dapagliflozin 10mg and Saxagliptin 5mg Titrated Glimepiride
    Number of subjects analysed
    227
    216
    Units: Percentage of Subjects
        number (confidence interval 95%)
    21.4 (16.30 to 27.64)
    11.7 (8.03 to 16.82)
    Statistical analysis title
    		 Treatment Comparison
    Comparison groups
    Dapagliflozin 10mg and Saxagliptin 5mg v Titrated Glimepiride
    Number of subjects included in analysis
    443
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.006
    Method
    		 Regression, Logistic
    Parameter type
    		 Odds ratio (OR)
    Point estimate
    2.1
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 1.23
         upper limit
    		 3.42
    Variability estimate
    Standard error of the mean
    Dispersion value
    0.54

    Adverse events

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    Adverse events information
    Timeframe for reporting adverse events
    All adverse events (AEs), including serious adverse events (SAEs), were collected on or after the date of first dose of short-term study medication and up to and including 4 days (other AEs) or 30 days (SAEs) after last dose. Up to a total of 160 weeks.
    Adverse event reporting additional description
    The treated subjects data set for the short-tem plus long-term treatment period consisted of all subjects who received at least 1 dose of double-blind study medication during the short-term double-blind treatment period.
    Assessment type
    		 Systematic
    Dictionary used for adverse event reporting
    Dictionary name
    		 MedDRA
    Dictionary version
    22.0
    Reporting groups
    Reporting group title
    Dapagliflozin 10mg and Saxagliptin 5mg
    Reporting group description
    		 Subjects received dapagliflozin 10 mg, saxagliptin 5 mg plus placebo for glimepiride, each administered orally once daily. Subjects also continued to receive their metformin dose of at least 1500 mg per day.

    Reporting group title
    Titrated Glimepiride
    Reporting group description
    		 Subjects received titrated glimepiride 1, 2, 3, 4, or 6 mg plus placebo for saxagliptin and placebo for dapagliflozin, administered orally once daily. Subjects also continued to receive their metformin dose of at least 1500 mg per day.

    Serious adverse events
    		 Dapagliflozin 10mg and Saxagliptin 5mg Titrated Glimepiride
    Total subjects affected by serious adverse events
         subjects affected / exposed
    29 / 227 (12.78%)
    24 / 216 (11.11%)
         number of deaths (all causes)
    1
    3
         number of deaths resulting from adverse events
    1
    3
    Neoplasms benign, malignant and unspecified (incl cysts and polyps)
    Colorectal cancer
         subjects affected / exposed
    1 / 227 (0.44%)
    0 / 216 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Endometrial adenocarcinoma
         subjects affected / exposed
    1 / 227 (0.44%)
    2 / 216 (0.93%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pituitary tumour benign
         subjects affected / exposed
    1 / 227 (0.44%)
    0 / 216 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Adenocarcinoma gastric
         subjects affected / exposed
    0 / 227 (0.00%)
    1 / 216 (0.46%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Bladder cancer
         subjects affected / exposed
    0 / 227 (0.00%)
    1 / 216 (0.46%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Oesophageal adenocarcinoma
         subjects affected / exposed
    0 / 227 (0.00%)
    1 / 216 (0.46%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Squamous cell carcinoma of lung
         subjects affected / exposed
    0 / 227 (0.00%)
    1 / 216 (0.46%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    Vascular disorders
    Aortic stenosis
         subjects affected / exposed
    0 / 227 (0.00%)
    1 / 216 (0.46%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Hypertensive crisis
         subjects affected / exposed
    1 / 227 (0.44%)
    0 / 216 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Peripheral ischaemia
         subjects affected / exposed
    1 / 227 (0.44%)
    1 / 216 (0.46%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pregnancy, puerperium and perinatal conditions
    Abortion spontaneous
         subjects affected / exposed
    2 / 227 (0.88%)
    0 / 216 (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
         subjects affected / exposed
    0 / 227 (0.00%)
    1 / 216 (0.46%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Reproductive system and breast disorders
    Uterine haemorrhage
         subjects affected / exposed
    0 / 227 (0.00%)
    1 / 216 (0.46%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Investigations
    Hormone level abnormal
         subjects affected / exposed
    1 / 227 (0.44%)
    0 / 216 (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
    Overdose
         subjects affected / exposed
    1 / 227 (0.44%)
    1 / 216 (0.46%)
         occurrences causally related to treatment / all
    1 / 1
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Road traffic accident
         subjects affected / exposed
    0 / 227 (0.00%)
    1 / 216 (0.46%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    Limb traumatic amputation
         subjects affected / exposed
    1 / 227 (0.44%)
    0 / 216 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Tibia fracture
         subjects affected / exposed
    1 / 227 (0.44%)
    0 / 216 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Humerus fracture
         subjects affected / exposed
    1 / 227 (0.44%)
    0 / 216 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Cardiac disorders
    Coronary artery stenosis
         subjects affected / exposed
    1 / 227 (0.44%)
    0 / 216 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Acute myocardial infarction
         subjects affected / exposed
    0 / 227 (0.00%)
    1 / 216 (0.46%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Angina pectoris
         subjects affected / exposed
    0 / 227 (0.00%)
    1 / 216 (0.46%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Cardiac failure chronic
         subjects affected / exposed
    0 / 227 (0.00%)
    1 / 216 (0.46%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Cardiac failure congestive
         subjects affected / exposed
    0 / 227 (0.00%)
    1 / 216 (0.46%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Nervous system disorders
    Cerebrovascular accident
         subjects affected / exposed
    1 / 227 (0.44%)
    0 / 216 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Chronic inflammatory demyelinating polyradiculoneuropathy
         subjects affected / exposed
    1 / 227 (0.44%)
    0 / 216 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Generalised tonic-clonic seizure
         subjects affected / exposed
    1 / 227 (0.44%)
    0 / 216 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Guillain-Barre syndrome
         subjects affected / exposed
    1 / 227 (0.44%)
    0 / 216 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Ischaemic stroke
         subjects affected / exposed
    0 / 227 (0.00%)
    2 / 216 (0.93%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 3
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    Vertebrobasilar insufficiency
         subjects affected / exposed
    2 / 227 (0.88%)
    0 / 216 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Carotid artery occlusion
         subjects affected / exposed
    0 / 227 (0.00%)
    1 / 216 (0.46%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Cerebral infarction
         subjects affected / exposed
    0 / 227 (0.00%)
    1 / 216 (0.46%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Ear and labyrinth disorders
    Vertigo positional
         subjects affected / exposed
    0 / 227 (0.00%)
    1 / 216 (0.46%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Gastrointestinal disorders
    Obstructive pancreatitis
         subjects affected / exposed
    0 / 227 (0.00%)
    1 / 216 (0.46%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Endocrine disorders
    Thyroid mass
         subjects affected / exposed
    1 / 227 (0.44%)
    0 / 216 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Musculoskeletal and connective tissue disorders
    Spinal osteoarthritis
         subjects affected / exposed
    0 / 227 (0.00%)
    1 / 216 (0.46%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Back pain
         subjects affected / exposed
    0 / 227 (0.00%)
    1 / 216 (0.46%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Periarthritis
         subjects affected / exposed
    1 / 227 (0.44%)
    0 / 216 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Arthralgia
         subjects affected / exposed
    1 / 227 (0.44%)
    0 / 216 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Osteoarthritis
         subjects affected / exposed
    2 / 227 (0.88%)
    0 / 216 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Intervertebral disc protrusion
         subjects affected / exposed
    2 / 227 (0.88%)
    0 / 216 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Infections and infestations
    Cellulitis
         subjects affected / exposed
    0 / 227 (0.00%)
    1 / 216 (0.46%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Gangrene
         subjects affected / exposed
    1 / 227 (0.44%)
    0 / 216 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Laryngitis
         subjects affected / exposed
    1 / 227 (0.44%)
    0 / 216 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pneumonia
         subjects affected / exposed
    1 / 227 (0.44%)
    2 / 216 (0.93%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 2
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    Sepsis
         subjects affected / exposed
    1 / 227 (0.44%)
    0 / 216 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Sinusitis
         subjects affected / exposed
    0 / 227 (0.00%)
    1 / 216 (0.46%)
         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 / 227 (0.44%)
    0 / 216 (0.00%)
         occurrences causally related to treatment / all
    0 / 3
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Abdominal wall infection
         subjects affected / exposed
    0 / 227 (0.00%)
    1 / 216 (0.46%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Erysipelas
         subjects affected / exposed
    0 / 227 (0.00%)
    1 / 216 (0.46%)
         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
         subjects affected / exposed
    1 / 227 (0.44%)
    0 / 216 (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
    		 Dapagliflozin 10mg and Saxagliptin 5mg Titrated Glimepiride
    Total subjects affected by non serious adverse events
         subjects affected / exposed
    99 / 227 (43.61%)
    106 / 216 (49.07%)
    Vascular disorders
    Hypertension
         subjects affected / exposed
    7 / 227 (3.08%)
    18 / 216 (8.33%)
         occurrences all number
    7
    18
    Nervous system disorders
    Headache
         subjects affected / exposed
    18 / 227 (7.93%)
    16 / 216 (7.41%)
         occurrences all number
    21
    20
    Gastrointestinal disorders
    Diarrhoea
         subjects affected / exposed
    10 / 227 (4.41%)
    12 / 216 (5.56%)
         occurrences all number
    11
    13
    Musculoskeletal and connective tissue disorders
    Back pain
         subjects affected / exposed
    12 / 227 (5.29%)
    7 / 216 (3.24%)
         occurrences all number
    16
    8
    Infections and infestations
    Upper respiratory tract infection
         subjects affected / exposed
    23 / 227 (10.13%)
    21 / 216 (9.72%)
         occurrences all number
    29
    27
    Bronchitis
         subjects affected / exposed
    11 / 227 (4.85%)
    17 / 216 (7.87%)
         occurrences all number
    15
    21
    Influenza
         subjects affected / exposed
    9 / 227 (3.96%)
    12 / 216 (5.56%)
         occurrences all number
    10
    16
    Nasopharyngitis
         subjects affected / exposed
    14 / 227 (6.17%)
    19 / 216 (8.80%)
         occurrences all number
    20
    25
    Pharyngitis
         subjects affected / exposed
    6 / 227 (2.64%)
    12 / 216 (5.56%)
         occurrences all number
    9
    13
    Urinary tract infection
         subjects affected / exposed
    31 / 227 (13.66%)
    21 / 216 (9.72%)
         occurrences all number
    41
    28
    Metabolism and nutrition disorders
    Dyslipidaemia
         subjects affected / exposed
    2 / 227 (0.88%)
    13 / 216 (6.02%)
         occurrences all number
    2
    14

    More information

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    Substantial protocol amendments (globally)
    Were there any global substantial amendments to the protocol? Yes
    Date
    Amendment
    28 Jan 2015
    This amendment added a pharmacogenetics substudy, and amended exploratory pharmacogenetics objectives, informed consent, sample collection, and inclusion and exclusion criteria.
    11 Mar 2015
    This amendment clarified the use of glimepiride as the active comparator and that subjects with contraindications to glimepiride should be excluded. It also clarified that subjects could re-enroll in the study if they were a pretreatment failure and that a subject may not have taken any other investigational agent within 30 days prior to study entry. It also clarified that other glucose lowering agents should be considered for rescue therapy.
    12 Aug 2015
    This amendment changed discontinuation criterion for creatinine clearance to <60 mL/min and added language for confirmation test.
    27 May 2016
    This amendment added discontinuation guidelines for ketoacidosis. It also clarified length of time to use contraception, clarified hormonal and nonhormonal forms of contraception, and clarified requirements for vasectomy as a form of contraception. It also defined that subjects with unevaluable data would be removed from the substudies but retained in the base study.
    08 Feb 2018
    This amendment added details regarding the Diabetic Ketoacidosis Adjudication Committee and clarification around liver function test abnormalities, adverse events including those leading to lower limb amputation and those with potential risk factor for amputations, confirmed hypoglycemia, magnetic resonance imaging, pregnancy, blinding, investigational medicinal products, efficacy analyses, rescue therapies, and prohibited treatments. It also clarified the definition of the end of the study and incorporated administrative changes.

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

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