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    Clinical Trial Results:
    A 24-Week, Multicentre, Randomised, Double-blind, Parallel Group, Placebo-controlled Study to Investigate the Effects of Saxagliptin and Sitagliptin in Patients with Type 2 Diabetes Mellitus and Heart Failure

    Summary
    EudraCT number
    		 2015-004825-14
    Trial protocol
    		 ES   HU   BG   RO  
    Global end of trial date
    23 Aug 2019

    Results information
    Results version number
    		 v1(current)
    This version publication date
    19 Aug 2021
    First version publication date
    19 Aug 2021
    Other versions

    Trial information

    		 Close Top of page
    Trial identification
    Sponsor protocol code
    D1680C00016
    Additional study identifiers
    ISRCTN number
    		 -
    US NCT number
    		 NCT02917031
    WHO universal trial number (UTN)
    		 -
    Sponsors
    Sponsor organisation name
    AstraZeneca AB
    Sponsor organisation address
    Södertälje, Södertälje, Sweden, 151 85
    Public contact
    AstraZeneca AB, AstraZeneca AB, +46 766 346712, clinicaltrialtransparency@astrazeneca.com
    Scientific contact
    AstraZeneca R&D, AstraZeneca R&D, +46 766 346712, clinicaltrialtransparency@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
    24 Oct 2020
    Is this the analysis of the primary completion data?
    Yes
    Primary completion date
    23 Aug 2019
    Global end of trial reached?
    Yes
    Global end of trial date
    23 Aug 2019
    Was the trial ended prematurely?
    No
    General information about the trial
    Main objective of the trial
    To exclude an increase in left ventricular end diastolic volume (LVEDV) index of greater than 10% of the overall baseline value (non-inferiority margin) in patients with Type 2 Diabetes Mellitus (T2DM) and heart failure (HF) treated with saxagliptin for 24 weeks, compared to placebo
    Protection of trial subjects
    The study was performed in accordance with ethical principles that have their origin in the Declaration of Helsinki and are consistent with International Council for Harmonisation/Good Clinical Practice, applicable regulatory requirements and the AstraZeneca policy on Bioethics and Human Biological Samples.
    Background therapy
    		 -
    Evidence for comparator
    		 -
    Actual start date of recruitment
    10 Jan 2017
    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
    Bulgaria: 33
    Country: Number of subjects enrolled
    Chile: 33
    Country: Number of subjects enrolled
    Hungary: 54
    Country: Number of subjects enrolled
    Korea, Republic of: 25
    Country: Number of subjects enrolled
    Romania: 2
    Country: Number of subjects enrolled
    Russian Federation: 138
    Country: Number of subjects enrolled
    Thailand: 23
    Country: Number of subjects enrolled
    Ukraine: 29
    Country: Number of subjects enrolled
    United States: 10
    Worldwide total number of subjects
    347
    EEA total number of subjects
    89
    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)
    154
    From 65 to 84 years
    191
    85 years and over
    2

    Subject disposition

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    Recruitment
    Recruitment details
    		 Patients who met all the inclusion and exclusion criteria were enrolled in 9 countries.

    Pre-assignment
    Screening details
    		 Patients with documented Left Ventricular Ejection Fraction (LVEF) ≤ 45% and N-terminal prohormone of brain natriuretic peptide (NT-proBNP) > 300 pg/mL attended a Screening Visit within 28 days before receiving their first dose with saxagliptin, sitagliptin, or placebo.

    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, Carer

    Arms
    Are arms mutually exclusive
    Yes

    Arm title
    		 Saxagliptin
    Arm description
    		 Participants with an eGFR ≥50 mL/min/1.73m^2 received one saxagliptin 5 mg tablet and one sitaglipitin placebo capsule administered orally once daily for a 24-week treatment period. Participants with an eGFR ≥30 to <50 mL/min/1.73m^2, the dose of saxagliptin was adjusted to one 2.5 mg tablet.
    Arm type
    		 Active comparator

    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
    Patients received one saxagliptin 5 mg tablet administered orally once daily for a 24-week treatment period. Patients with an eGFR ≥30 to <50 mL/min/1.73m^2, the dose of saxagliptin was adjusted to one 2.5 mg tablet.

    Arm title
    		 Sitagliptin
    Arm description
    		 Patients with an eGFR ≥50 mL/min/1.73m^2 received one sitagliptin 100 mg capsule and one saxagliptin placebo tablet administered orally once daily for a 24-week treatment period. Patients with an eGFR ≥30 to <50 mL/min/1.73m^2, the dose of sitagliptin was adjusted to one 50 mg capsule.
    Arm type
    		 Active comparator

    Investigational medicinal product name
    Sitagliptin
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Capsule
    Routes of administration
    Oral use
    Dosage and administration details
    Patients received one sitagliptin 100 mg capsule administered orally once daily for a 24-week treatment period. Patients with an eGFR ≥30 to <50 mL/min/1.73m^2, the dose of sitagliptin was adjusted to one 50 mg capsule.

    Arm title
    		 Placebo
    Arm description
    		 Patients recieved one saxagliptin placebo tablet and one sitagliptin placebo capsule administered orally once daily for a 24-week treatment period as a control.
    Arm type
    		 Placebo

    Investigational medicinal product name
    Placebo for sitagliptin
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Tablet
    Routes of administration
    Oral use
    Dosage and administration details
    Patients received sitagliptin placebo capsule orally once daily for a 24-week treatment period as a control.

    Investigational medicinal product name
    Placebo for saxagliptin
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Capsule
    Routes of administration
    Oral use
    Dosage and administration details
    Patients received saxagliptin placebo tablet orally once daily for a 24-week treatment period as a control.

    Number of subjects in period 1
    		Saxagliptin Sitagliptin Placebo
    Started
    112
    115
    120
    Completed
    94
    102
    105
    Not completed
    18
    13
    15
         Adverse event, serious fatal
    2
    3
    4
         Consent withdrawn by subject
    3
    3
    -
         Physician decision
    1
    -
    -
         Adverse event, non-fatal
    4
    1
    5
         Development of study-specific withdrawal criteria
    1
    1
    -
         Reason not specifie
    7
    5
    6

    Baseline characteristics

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    Baseline characteristics reporting groups
    Reporting group title
    Saxagliptin
    Reporting group description
    		 Participants with an eGFR ≥50 mL/min/1.73m^2 received one saxagliptin 5 mg tablet and one sitaglipitin placebo capsule administered orally once daily for a 24-week treatment period. Participants with an eGFR ≥30 to <50 mL/min/1.73m^2, the dose of saxagliptin was adjusted to one 2.5 mg tablet.

    Reporting group title
    Sitagliptin
    Reporting group description
    		 Patients with an eGFR ≥50 mL/min/1.73m^2 received one sitagliptin 100 mg capsule and one saxagliptin placebo tablet administered orally once daily for a 24-week treatment period. Patients with an eGFR ≥30 to <50 mL/min/1.73m^2, the dose of sitagliptin was adjusted to one 50 mg capsule.

    Reporting group title
    Placebo
    Reporting group description
    		 Patients recieved one saxagliptin placebo tablet and one sitagliptin placebo capsule administered orally once daily for a 24-week treatment period as a control.

    Reporting group values
    		 Saxagliptin Sitagliptin Placebo Total
    Number of subjects
    		 112 115 120 347
    Age categorical
    Units: Subjects
        In utero
    		 0 0 0 0
        Preterm newborn infants (gestational age < 37 wks)
    		 0 0 0 0
        Newborns (0-27 days)
    		 0 0 0 0
        Infants and toddlers (28 days-23 months)
    		 0 0 0 0
        Children (2-11 years)
    		 0 0 0 0
        Adolescents (12-17 years)
    		 0 0 0 0
        Adults (18-64 years)
    		 54 47 53 154
        From 65-84 years
    		 58 68 67 193
        85 years and over
    		 0 0 0 0
    Age Continuous
    Units: Years
        arithmetic mean (standard deviation)
    		 64.6 ± 7.96 64.9 ± 9.85 66.5 ± 7.84 -
    Sex: Female, Male
    Units: Participants
        Female
    		 35 36 37 108
        Male
    		 77 79 83 239
    Race (NIH/OMB)
    Units: Subjects
        American Indian or Alaska Native
    		 0 0 0 0
        Asian
    		 17 17 15 49
        Native Hawaiian or Other Pacific Islander
    		 0 0 0 0
        Black or African American
    		 1 0 3 4
        White
    		 94 98 102 294
        More than one race
    		 0 0 0 0
        Unknown or Not Reported
    		 0 0 0 0
    Ethnicity (NIH/OMB)
    Units: Subjects
        Hispanic or Latino
    		 10 16 17 43
        Not Hispanic or Latino
    		 102 99 103 304
        Unknown or Not Reported
    		 0 0 0 0

    End points

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    End points reporting groups
    Reporting group title
    Saxagliptin
    Reporting group description
    		 Participants with an eGFR ≥50 mL/min/1.73m^2 received one saxagliptin 5 mg tablet and one sitaglipitin placebo capsule administered orally once daily for a 24-week treatment period. Participants with an eGFR ≥30 to <50 mL/min/1.73m^2, the dose of saxagliptin was adjusted to one 2.5 mg tablet.

    Reporting group title
    Sitagliptin
    Reporting group description
    		 Patients with an eGFR ≥50 mL/min/1.73m^2 received one sitagliptin 100 mg capsule and one saxagliptin placebo tablet administered orally once daily for a 24-week treatment period. Patients with an eGFR ≥30 to <50 mL/min/1.73m^2, the dose of sitagliptin was adjusted to one 50 mg capsule.

    Reporting group title
    Placebo
    Reporting group description
    		 Patients recieved one saxagliptin placebo tablet and one sitagliptin placebo capsule administered orally once daily for a 24-week treatment period as a control.

    Primary: Change from baseline in Left Ventricular End Diastolic Volume (LVEDV) index measured by Magnetic Resonance Imaging (MRI) at 24 weeks

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    End point title
    		 Change from baseline in Left Ventricular End Diastolic Volume (LVEDV) index measured by Magnetic Resonance Imaging (MRI) at 24 weeks [1]
    End point description
    MRI was performed to evaluate LVEDV at baseline and Visit 10 (Week 24). Evaluated to exclude an increase in left ventricular end diastolic volume (LVEDV) index of greater than 10% of the overall baseline value (noninferiority margin) in patients with T2DM and HF treated with saxagliptin for 24 weeks, compared to placebo. Baseline is last assessment on or before the date of first dose.
    End point type
    Primary
    End point timeframe
    Baseline to 24 weeks
    Notes
    [1] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
    Justification: Statistical analysis was done for Saxagliptin and Placebo as per objective.
    End point values
    		 Saxagliptin Placebo
    Number of subjects analysed
    96
    106
    Units: mL/m^2
        arithmetic mean (standard deviation)
    -3.395 ± 15.3412
    -0.716 ± 18.1178
    Statistical analysis title
    		 saxagliptin versus placebo.
    Statistical analysis description
    Change from baseline, saxagliptin versus placebo
    Comparison groups
    Saxagliptin v Placebo
    Number of subjects included in analysis
    202
    Analysis specification
    Pre-specified
    Analysis type
    P-value
    		 = 0.252
    Method
    		 ANCOVA
    Parameter type
    		 Mean difference (final values)
    Point estimate
    -2.595
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -7.04
         upper limit
    		 1.85

    Secondary: Change from baseline in left ventricular end systolic volume (LVESV) index measured by MRI at 24 weeks.

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    End point title
    		 Change from baseline in left ventricular end systolic volume (LVESV) index measured by MRI at 24 weeks. [2]
    End point description
    Evaluation of the effects of saxagliptin compared to placebo on left ventricular end systolic volume (LVESV) index, after 24 weeks in patients with T2DM and HF.
    End point type
    Secondary
    End point timeframe
    Baseline to week 24
    Notes
    [2] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
    Justification: Statistical analysis was done for Saxagliptin and Placebo as per objective.
    End point values
    		 Saxagliptin Placebo
    Number of subjects analysed
    96
    106
    Units: mL/m^2
        arithmetic mean (standard deviation)
    -2.555 ± 12.4136
    -0.839 ± 17.2458
    Statistical analysis title
    		 Saxagliptin versus Placebo
    Statistical analysis description
    Change from baseline, saxagliptin versus placebo
    Comparison groups
    Saxagliptin v Placebo
    Number of subjects included in analysis
    202
    Analysis specification
    Pre-specified
    Analysis type
    P-value
    		 = 0.425
    Method
    		 ANCOVA
    Parameter type
    		 Mean difference (final values)
    Point estimate
    -1.631
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -5.635
         upper limit
    		 2.373

    Secondary: Change from baseline in left ventricular ejection fraction (LVEF) measured by MRI at 24 weeks.

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    End point title
    		 Change from baseline in left ventricular ejection fraction (LVEF) measured by MRI at 24 weeks. [3]
    End point description
    Evaluation of the effects of saxagliptin compared to placebo on left ventricular ejection fraction (LVEF) after 24 weeks in patients with T2DM and HF.
    End point type
    Secondary
    End point timeframe
    Baseline to week 24
    Notes
    [3] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
    Justification: Statistical analysis was done for Saxagliptin and Placebo as per objective.
    End point values
    		 Saxagliptin Placebo
    Number of subjects analysed
    96
    106
    Units: Percentage
        arithmetic mean (standard deviation)
    0.533 ± 7.1971
    0.298 ± 7.2843
    Statistical analysis title
    		 Saxagliptin versus Placebo
    Statistical analysis description
    Change from baseline, saxagliptin versus placebo
    Comparison groups
    Saxagliptin v Placebo
    Number of subjects included in analysis
    202
    Analysis specification
    Pre-specified
    Analysis type
    P-value
    		 = 0.925
    Method
    		 ANCOVA
    Parameter type
    		 Mean difference (final values)
    Point estimate
    0.1
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -1.996
         upper limit
    		 2.197

    Secondary: Change from baseline in left ventricular mass (LVM) measured by MRI at 24 weeks.

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    End point title
    		 Change from baseline in left ventricular mass (LVM) measured by MRI at 24 weeks. [4]
    End point description
    Evaluation of the effects of saxagliptin compared to placebo on left ventricular mass (LVM) after 24 weeks in patients with T2DM and HF.
    End point type
    Secondary
    End point timeframe
    Baseline to week 24
    Notes
    [4] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
    Justification: Statistical analysis was done for Saxagliptin and Placebo as per objective.
    End point values
    		 Saxagliptin Placebo
    Number of subjects analysed
    96
    106
    Units: Gram
        arithmetic mean (standard deviation)
    -4.211 ± 16.6003
    -0.758 ± 16.1763
    Statistical analysis title
    		 Saxagliptin versus placebo
    Statistical analysis description
    Change from baseline, saxagliptin versus placebo
    Comparison groups
    Saxagliptin v Placebo
    Number of subjects included in analysis
    202
    Analysis specification
    Pre-specified
    Analysis type
    P-value
    		 = 0.105
    Method
    		 ANCOVA
    Parameter type
    		 Mean difference (final values)
    Point estimate
    -3.605
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -7.97
         upper limit
    		 0.76

    Secondary: Change from baseline in NT-proBNP after 24 weeks of treatment

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    End point title
    		 Change from baseline in NT-proBNP after 24 weeks of treatment [5]
    End point description
    Evaluation of the effects of saxagliptin compared to placebo on N-terminal prohormone of brain natriuretic peptide (NT-proBNP) after 24 weeks of treatment.
    End point type
    Secondary
    End point timeframe
    Baseline to Week 24
    Notes
    [5] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
    Justification: Statistical analysis was done for Saxagliptin and Placebo as per objective.
    End point values
    		 Saxagliptin Placebo
    Number of subjects analysed
    93
    104
    Units: pg/mL
        arithmetic mean (standard deviation)
    -277.525 ± 1324.7471
    -61.895 ± 3415.9525
    Statistical analysis title
    		 Saxagliptin versus placebo
    Statistical analysis description
    Change from baseline, saxagliptin versus placebo
    Comparison groups
    Saxagliptin v Placebo
    Number of subjects included in analysis
    197
    Analysis specification
    Pre-specified
    Analysis type
    P-value
    		 = 0.796
    Method
    		 ANCOVA
    Parameter type
    		 Ratio for relative change
    Point estimate
    0.971
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.777
         upper limit
    		 1.214

    Secondary: Number of participants with adverse events

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    End point title
    		 Number of participants with adverse events
    End point description
    Assessment of safety and tolerability of saxagliptin and sitagliptin treatment in patients with T2DM and HF
    End point type
    Secondary
    End point timeframe
    From screening (Days -28 to -1) until Week 28 (follow-up visit)
    End point values
    		 Saxagliptin Sitagliptin Placebo
    Number of subjects analysed
    112
    115
    120
    Units: Participants
        Any AE
    53
    51
    58
        Any severe AE
    9
    13
    14
        Any treatment related AE
    3
    4
    0
        Any AE with outcome Death
    2
    3
    4
        Any SAE
    17
    19
    29
        Any treatment related SAE
    0
    0
    0
        Any SAE leading to discontinuation
    1
    0
    4
        Any AE leading to discontinuation
    5
    3
    7
        Any Adverse event of special interest
    12
    15
    16
    No statistical analyses for this end point

    Adverse events

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    Adverse events information
    Timeframe for reporting adverse events
    From screening (Days -28 to -1) until Week 28 (follow-up visit)
    Adverse event reporting additional description
    An AEs is the development of an undesirable medical condition or the deterioration of a preexisting medical condition following or during exposure to a pharmaceutical product, whether or not considered causally related to the product.
    Assessment type
    		 Systematic
    Dictionary used for adverse event reporting
    Dictionary name
    		 MedDRA
    Dictionary version
    23.0
    Reporting groups
    Reporting group title
    Saxagliptin
    Reporting group description
    		 Participants with an eGFR ≥50 mL/min/1.73m^2 received one saxagliptin 5 mg tablet and one sitaglipitin placebo capsule administered orally once daily for a 24-week treatment period. Participants with an eGFR ≥30 to <50 mL/min/1.73m^2, the dose of saxagliptin was adjusted to one 2.5 mg tablet.

    Reporting group title
    Placebo
    Reporting group description
    		 Participants recieved one saxagliptin placebo tablet and one sitagliptin placebo capsule administered orally once daily for a 24-week treatment period as a control.

    Reporting group title
    Sitagliptin
    Reporting group description
    		 Participants with an eGFR ≥50 mL/min/1.73m^2 received one sitagliptin 100 mg capsule and one saxagliptin placebo tablet administered orally once daily for a 24-week treatment period. Participants with an eGFR ≥30 to <50 mL/min/1.73m^2, the dose of sitagliptin was adjusted to one 50 mg capsule.

    Serious adverse events
    		 Saxagliptin Placebo Sitagliptin
    Total subjects affected by serious adverse events
         subjects affected / exposed
    17 / 112 (15.18%)
    29 / 120 (24.17%)
    19 / 115 (16.52%)
         number of deaths (all causes)
    2
    4
    3
         number of deaths resulting from adverse events
    2
    4
    3
    Vascular disorders
    Hypertensive crisis
         subjects affected / exposed
    0 / 112 (0.00%)
    1 / 120 (0.83%)
    0 / 115 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Peripheral arterial occlusive disease
         subjects affected / exposed
    0 / 112 (0.00%)
    1 / 120 (0.83%)
    0 / 115 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    General disorders and administration site conditions
    Sudden cardiac death
         subjects affected / exposed
    0 / 112 (0.00%)
    2 / 120 (1.67%)
    1 / 115 (0.87%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 2
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    2 / 2
    1 / 1
    Cardiac death
         subjects affected / exposed
    1 / 112 (0.89%)
    0 / 120 (0.00%)
    0 / 115 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    1 / 1
    0 / 0
    0 / 0
    Death
         subjects affected / exposed
    0 / 112 (0.00%)
    0 / 120 (0.00%)
    1 / 115 (0.87%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    1 / 1
    Respiratory, thoracic and mediastinal disorders
    Dyspnoea paroxysmal nocturnal
         subjects affected / exposed
    0 / 112 (0.00%)
    1 / 120 (0.83%)
    0 / 115 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Psychiatric disorders
    Depression
         subjects affected / exposed
    1 / 112 (0.89%)
    0 / 120 (0.00%)
    0 / 115 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Injury, poisoning and procedural complications
    Ankle fracture
         subjects affected / exposed
    0 / 112 (0.00%)
    1 / 120 (0.83%)
    0 / 115 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Craniocerebral injury
         subjects affected / exposed
    0 / 112 (0.00%)
    1 / 120 (0.83%)
    0 / 115 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Femur fracture
         subjects affected / exposed
    0 / 112 (0.00%)
    1 / 120 (0.83%)
    0 / 115 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Humerus fracture
         subjects affected / exposed
    0 / 112 (0.00%)
    1 / 120 (0.83%)
    0 / 115 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Lower limb fracture
         subjects affected / exposed
    1 / 112 (0.89%)
    0 / 120 (0.00%)
    0 / 115 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Pelvic fracture
         subjects affected / exposed
    0 / 112 (0.00%)
    0 / 120 (0.00%)
    1 / 115 (0.87%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Spinal compression fracture
         subjects affected / exposed
    1 / 112 (0.89%)
    0 / 120 (0.00%)
    0 / 115 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Cardiac disorders
    Cardiac failure
         subjects affected / exposed
    7 / 112 (6.25%)
    6 / 120 (5.00%)
    5 / 115 (4.35%)
         occurrences causally related to treatment / all
    0 / 9
    0 / 7
    0 / 5
         deaths causally related to treatment / all
    1 / 1
    1 / 1
    0 / 0
    Acute coronary syndrome
         subjects affected / exposed
    1 / 112 (0.89%)
    0 / 120 (0.00%)
    1 / 115 (0.87%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Angina unstable
         subjects affected / exposed
    0 / 112 (0.00%)
    2 / 120 (1.67%)
    0 / 115 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Atrial fibrillation
         subjects affected / exposed
    0 / 112 (0.00%)
    1 / 120 (0.83%)
    1 / 115 (0.87%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Acute left ventricular failure
         subjects affected / exposed
    0 / 112 (0.00%)
    0 / 120 (0.00%)
    1 / 115 (0.87%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Acute myocardial infarction
         subjects affected / exposed
    0 / 112 (0.00%)
    0 / 120 (0.00%)
    1 / 115 (0.87%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Angina pectoris
         subjects affected / exposed
    0 / 112 (0.00%)
    1 / 120 (0.83%)
    0 / 115 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Bradycardia
         subjects affected / exposed
    0 / 112 (0.00%)
    1 / 120 (0.83%)
    0 / 115 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Cardiac failure acute
         subjects affected / exposed
    0 / 112 (0.00%)
    0 / 120 (0.00%)
    1 / 115 (0.87%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    1 / 1
    Coronary artery disease
         subjects affected / exposed
    1 / 112 (0.89%)
    0 / 120 (0.00%)
    0 / 115 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Supraventricular tachycardia
         subjects affected / exposed
    1 / 112 (0.89%)
    0 / 120 (0.00%)
    0 / 115 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Ventricular tachycardia
         subjects affected / exposed
    0 / 112 (0.00%)
    0 / 120 (0.00%)
    1 / 115 (0.87%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Nervous system disorders
    Cerebrovascular accident
         subjects affected / exposed
    0 / 112 (0.00%)
    0 / 120 (0.00%)
    2 / 115 (1.74%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Cerebral arteriosclerosis
         subjects affected / exposed
    1 / 112 (0.89%)
    0 / 120 (0.00%)
    0 / 115 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Cerebrovascular insufficiency
         subjects affected / exposed
    0 / 112 (0.00%)
    0 / 120 (0.00%)
    1 / 115 (0.87%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Dizziness
         subjects affected / exposed
    0 / 112 (0.00%)
    1 / 120 (0.83%)
    0 / 115 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Ischaemic stroke
         subjects affected / exposed
    0 / 112 (0.00%)
    1 / 120 (0.83%)
    0 / 115 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Blood and lymphatic system disorders
    Anaemia
         subjects affected / exposed
    1 / 112 (0.89%)
    0 / 120 (0.00%)
    0 / 115 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Gastrointestinal disorders
    Enterocolitis
         subjects affected / exposed
    0 / 112 (0.00%)
    1 / 120 (0.83%)
    0 / 115 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    1 / 1
    0 / 0
    Hepatobiliary disorders
    Bile duct stone
         subjects affected / exposed
    0 / 112 (0.00%)
    1 / 120 (0.83%)
    0 / 115 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Cholelithiasis
         subjects affected / exposed
    0 / 112 (0.00%)
    0 / 120 (0.00%)
    1 / 115 (0.87%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Skin and subcutaneous tissue disorders
    Diabetic foot
         subjects affected / exposed
    1 / 112 (0.89%)
    1 / 120 (0.83%)
    1 / 115 (0.87%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Skin ulcer
         subjects affected / exposed
    1 / 112 (0.89%)
    0 / 120 (0.00%)
    0 / 115 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Renal and urinary disorders
    Acute kidney injury
         subjects affected / exposed
    0 / 112 (0.00%)
    1 / 120 (0.83%)
    0 / 115 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Cystitis haemorrhagic
         subjects affected / exposed
    0 / 112 (0.00%)
    0 / 120 (0.00%)
    1 / 115 (0.87%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Renal colic
         subjects affected / exposed
    0 / 112 (0.00%)
    0 / 120 (0.00%)
    1 / 115 (0.87%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Musculoskeletal and connective tissue disorders
    Back disorder
         subjects affected / exposed
    0 / 112 (0.00%)
    0 / 120 (0.00%)
    1 / 115 (0.87%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Infections and infestations
    Pneumonia
         subjects affected / exposed
    3 / 112 (2.68%)
    1 / 120 (0.83%)
    1 / 115 (0.87%)
         occurrences causally related to treatment / all
    0 / 3
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Acute hepatitis B
         subjects affected / exposed
    0 / 112 (0.00%)
    1 / 120 (0.83%)
    0 / 115 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Epididymitis
         subjects affected / exposed
    1 / 112 (0.89%)
    0 / 120 (0.00%)
    0 / 115 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Laryngitis
         subjects affected / exposed
    0 / 112 (0.00%)
    1 / 120 (0.83%)
    0 / 115 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Sepsis
         subjects affected / exposed
    0 / 112 (0.00%)
    1 / 120 (0.83%)
    0 / 115 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Metabolism and nutrition disorders
    Diabetes mellitus inadequate control
         subjects affected / exposed
    0 / 112 (0.00%)
    1 / 120 (0.83%)
    0 / 115 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Lactic acidosis
         subjects affected / exposed
    0 / 112 (0.00%)
    1 / 120 (0.83%)
    0 / 115 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Frequency threshold for reporting non-serious adverse events: 3%
    Non-serious adverse events
    		 Saxagliptin Placebo Sitagliptin
    Total subjects affected by non serious adverse events
         subjects affected / exposed
    8 / 112 (7.14%)
    8 / 120 (6.67%)
    9 / 115 (7.83%)
    Vascular disorders
    Hypertension
         subjects affected / exposed
    1 / 112 (0.89%)
    4 / 120 (3.33%)
    2 / 115 (1.74%)
         occurrences all number
    1
    4
    2
    Cardiac disorders
    Cardiac failure
         subjects affected / exposed
    2 / 112 (1.79%)
    4 / 120 (3.33%)
    5 / 115 (4.35%)
         occurrences all number
    2
    4
    5
    Metabolism and nutrition disorders
    Hyperglycaemia
         subjects affected / exposed
    5 / 112 (4.46%)
    1 / 120 (0.83%)
    3 / 115 (2.61%)
         occurrences all number
    5
    1
    3

    More information

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    Substantial protocol amendments (globally)
    Were there any global substantial amendments to the protocol? Yes
    Date
    Amendment
    15 Jul 2016
    Study Objectives and Methods of assigning treatment groups section was updated, SGLT2 stratification factor was added to reflect removal of saxagliptin/dapagliflozin treatment arm and all elements related to dapagliflozin component. PK sampling will no longer be performed for the full study cohort but in a subset of approximately 150 patients.
    12 Apr 2017
    Study design and relevant sections in eligibility criteria were updated to lower the NT-proBNP inclusion level lowered to > 400 pg/mL, expansion of HbA1c range to ≥6.5% and ≤10.5%, extension of pre-screening/screening period to 21 days, to allow re-pre-screening/re-screening, remove requirement of enrolment to screening not later than 7 days after pre-screening, and introduction of mandatory cMRI scan quality approval at baseline (before first dose of study medication) and before the visit at week 24.
    13 Jun 2018
    Inclusion criteria revised for definition of documented, controlled T2DM (criteria were added in Appendix C), updated for HF medications requirements; removal of normal sinus rhythm requirement on the qualifying ECG. Definitions of analysis sets, variables and statistical methods were updated.

    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.
    Last subject last visit for this study was on 23Aug2019. After the LSLV, protocol was amended on 14Feb2020. The last amendment did not introduce any changes in how study visits or assessments are done, only statistical analysis were updated.
    For support, Contact us.
    The status and protocol content of GB trials is no longer updated since 1 January 2021. For the UK, as of 31 January 2021, EU Law applies only to the territory of Northern Ireland (NI) to the extent foreseen in the Protocol on Ireland/NI. Legal notice
    As of 31 January 2023, all EU/EEA initial clinical trial applications must be submitted through CTIS . Updated EudraCT trials information and information on PIP/Art 46 trials conducted exclusively in third countries continues to be submitted through EudraCT and published on this website.

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