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    Clinical Trial Results:
    A randomized, double-blind, three arm, three treatment period, cross-over trial to investi-gate the effect of a SGLT-2 inhibitor, a DPP-4 inhibitor and a SGLT-2 inhibitor + DPP-4 inhibitor on glucagon levels, endogenous glucose production and lipolysis during hyper-, normo- and hypoglycaemia in subjects with type 2 diabetes using stable tracer technique.

    Summary
    EudraCT number
    		 2015-004637-27
    Trial protocol
    		 AT  
    Global end of trial date
    06 Oct 2016

    Results information
    Results version number
    		 v1(current)
    This version publication date
    02 Dec 2020
    First version publication date
    02 Dec 2020
    Other versions

    Trial information

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    Trial identification
    Sponsor protocol code
    AZ-01_SGLT-2
    Additional study identifiers
    ISRCTN number
    		 -
    US NCT number
    		 -
    WHO universal trial number (UTN)
    		 -
    Sponsors
    Sponsor organisation name
    Medical University of Graz, Department of Internal Medicine Division of Endocrinology and Metabolism
    Sponsor organisation address
    Auenbruggerplatz 15, Graz, Austria,
    Public contact
    Study Coordinator , Medical University of Graz, +43 31638572835, stefanie.sach-friedl@medunigraz.at
    Scientific contact
    Principal Investigator and Sponsor , Medical University of Graz, Univ. Prof. Dr. Thomas R. Pieber, +43 316 385 12383, thomas.pieber@medunigraz.at
    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
    23 Jan 2017
    Is this the analysis of the primary completion data?
    Yes
    Primary completion date
    06 Oct 2016
    Global end of trial reached?
    Yes
    Global end of trial date
    06 Oct 2016
    Was the trial ended prematurely?
    No
    General information about the trial
    Main objective of the trial
    To compare the glucagon response of a treatment with metformin monotherapy (baseline), a SGLT-2 inhibitor, a DPP-4 inhibitor and a combination of a SGLT-2 inhibitor and a DPP-4 inhibitor during normo-, hyper- and hypoglycaemia in a controlled clamp setting under stable metformin therapy.
    Protection of trial subjects
    This study was conducted in accordance with the ethical principles that have their origin in the Declaration of Helsinki and that are consistent with Good Clinical Practices and applicable regulatory requirements.
    Background therapy
    		 -
    Evidence for comparator
    		 -
    Actual start date of recruitment
    11 Jan 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
    Austria: 19
    Worldwide total number of subjects
    19
    EEA total number of subjects
    19
    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)
    19
    From 65 to 84 years
    0
    85 years and over
    0

    Subject disposition

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    Recruitment
    Recruitment details
    		 Single-Center Study - 1 site in Austria

    Pre-assignment
    Screening details
    		 33 Patients have been screened and in total 19 randomizations were performed. 17 subjects completed the study. There have been 2 drop-outs – not drug related

    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, Monitor, Data analyst
    Blinding implementation details
    The allocation of a treatment arm to a randomisation nr has been provided by an unblinded trial staff. The documentation on the allocation of the treatment arm sequences to the randomisation nr has beenstored only accessible for the unblinded trial staff. Dapaglifllozin, Saxagliptin, Placebo Dapaglifllozin orPlacebo Saxagliptin were packed and labelled to fulfil the requirements for double-blind procedures.Blinding was maintained for the whole study period

    Arms
    Are arms mutually exclusive
    No

    Arm title
    		 Dapagliflozin and Placebo Saxagliptin
    Arm description
    		 Each randomized subject was allocated to one of the three treatment sequences (seven days once daily dosing of either Dapagliflozin+placebo Saxagliptin, or Saxagliptin + placebo Dapagliflozin or the combination of Saxagliptin + Dapagliflozin). A wash-out period of 56-84 days between the first period and second period and one of 7-42 days between the second and third period has been carried out. 1 tablet of Dapagliflozin 10 mg and 1 tablet of matching placebo for Saxagliptin 5 mg has been administrated once daily in the morning for 7 days
    Arm type
    		 Experimental

    Investigational medicinal product name
    Dapagliflozin 10 mg
    Investigational medicinal product code
    Other name
    Forxiga™
    Pharmaceutical forms
    Tablet
    Routes of administration
    Oral use
    Dosage and administration details
    1 tablet of Dapagliflozin 10 mg together with 1 tablet of matching placebo for Saxagliptin 5 mg has been administrated once daily in the morning for 7 days

    Investigational medicinal product name
    Matching placebo for Saxagliptin 5 mg
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Tablet
    Routes of administration
    Oral use
    Dosage and administration details
    1 tablet of matching placebo for Saxagliptin 5 mg together with 1 tablet of Dapagliflozin 10 mg has been administrated once daily in the morning for 7 days

    Arm title
    		 Saxagliptin and Placebo Dapagliflozin
    Arm description
    		 Each randomized subject was allocated to one of the three treatment sequences (seven days once daily dosing of either Dapagliflozin+placebo Saxagliptin, or Saxagliptin + placebo Dapagliflozin or the combination of Saxagliptin + Dapagliflozin). A wash-out period of 56-84 days between the first period and second period and one of 7-42 days between the second and third period has been carried out. In this sequence 1 tablet of Saxagliptin 5 mg and 1 tablet of matching placebo for Dapagliflozin 10 mg has been administrated once daily in the morning for 7 days.
    Arm type
    		 Experimental

    Investigational medicinal product name
    Saxagliptin 5 mg
    Investigational medicinal product code
    Other name
    Onglyza®
    Pharmaceutical forms
    Tablet
    Routes of administration
    Oral use
    Dosage and administration details
    1 tablet of Saxagliptin 5 mg together with 1 tablet of matching placebo for Dapagliflozin 10 mg has been administrated once daily in the morning for 7 days

    Investigational medicinal product name
    Matching placebo for Dapagliflozin 10 mg
    Investigational medicinal product code
    o
    Other name
    Pharmaceutical forms
    Tablet
    Routes of administration
    Oral use
    Dosage and administration details
    1 tablet of matching placebo for Dapagliflozin 10 mg and 1 tablet of Saxagliptin 5 mg has been administrated once daily in the morning for 7 days

    Arm title
    		 Saxagliptin and Dapagliflozin
    Arm description
    		 Each randomized subject was allocated to one of the three treatment sequences (seven days once daily dosing of either Dapagliflozin+placebo Saxagliptin, or Saxagliptin + placebo Dapagliflozin or the combination of Saxagliptin + Dapagliflozin).A wash-out period of 56-84 days between the first period and second period and one of 7-42 days between the second and third period has been carried out. In this seuence 1 tablet of Saxagliptin 5 mg and 1 tablet of Dapagliflozin 10 mg has been administrated ce daily in the morning for 7 days
    Arm type
    		 Experimental

    Investigational medicinal product name
    Dapagliflozin 10 mg
    Investigational medicinal product code
    Other name
    Forxiga™
    Pharmaceutical forms
    Tablet
    Routes of administration
    Oral use
    Dosage and administration details
    1 tablet of Dapagliflozin 10 mg together with 1 tablet of Saxagliptin 5 mg has been administrated once daily in the morning for 7 days

    Investigational medicinal product name
    Saxagliptin 5 mg
    Investigational medicinal product code
    Other name
    Onglyza®
    Pharmaceutical forms
    Tablet
    Routes of administration
    Oral use
    Dosage and administration details
    1 tablet of Saxagliptin 5 mg together with 1 tablet of Dapagliflozin 10 mg has been administrated once daily in the morning for 7 days

    Arm title
    		 Pre - treatment
    Arm description
    		 All the results from all arms have been compared to the values before starting the treatment.
    Arm type
    		 No intervention

    Investigational medicinal product name
    No investigational medicinal product assigned in this arm
    Number of subjects in period 1
    		Dapagliflozin and Placebo Saxagliptin Saxagliptin and Placebo Dapagliflozin Saxagliptin and Dapagliflozin Pre - treatment
    Started
    17
    17
    17
    17
    Completed
    17
    17
    17
    17

    Baseline characteristics

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    Baseline characteristics reporting groups
    Reporting group title
    Overall Study (overall period)
    Reporting group description
    		 -

    Reporting group values
    		 Overall Study (overall period) Total
    Number of subjects
    		 19 19
    Age categorical
    Units: Subjects
        In utero
    		 0 0
        Preterm newborn infants (gestational age < 37 wks)
    		 0 0
        Newborns (0-27 days)
    		 0 0
        Infants and toddlers (28 days-23 months)
    		 0 0
        Children (2-11 years)
    		 0 0
        Adolescents (12-17 years)
    		 0 0
        Adults (18-64 years)
    		 19 19
        From 65-84 years
    		 0 0
        85 years and over
    		 0 0
    Age continuous
    Units: years
        arithmetic mean (standard deviation)
    		 53 ± 6 -
    Gender categorical
    Units: Subjects
        Female
    		 1 1
        Male
    		 18 18
    Diabetes duration
    Units: years
        arithmetic mean (standard deviation)
    		 7.6 ± 5.8 -
    BMI
    Units: kg/m²
        arithmetic mean (standard deviation)
    		 29.4 ± 3.5 -
    HbA1c
    Units: mmol/mol
        arithmetic mean (standard deviation)
    		 60.6 ± 10.3 -

    End points

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    End points reporting groups
    Reporting group title
    Dapagliflozin and Placebo Saxagliptin
    Reporting group description
    		 Each randomized subject was allocated to one of the three treatment sequences (seven days once daily dosing of either Dapagliflozin+placebo Saxagliptin, or Saxagliptin + placebo Dapagliflozin or the combination of Saxagliptin + Dapagliflozin). A wash-out period of 56-84 days between the first period and second period and one of 7-42 days between the second and third period has been carried out. 1 tablet of Dapagliflozin 10 mg and 1 tablet of matching placebo for Saxagliptin 5 mg has been administrated once daily in the morning for 7 days

    Reporting group title
    Saxagliptin and Placebo Dapagliflozin
    Reporting group description
    		 Each randomized subject was allocated to one of the three treatment sequences (seven days once daily dosing of either Dapagliflozin+placebo Saxagliptin, or Saxagliptin + placebo Dapagliflozin or the combination of Saxagliptin + Dapagliflozin). A wash-out period of 56-84 days between the first period and second period and one of 7-42 days between the second and third period has been carried out. In this sequence 1 tablet of Saxagliptin 5 mg and 1 tablet of matching placebo for Dapagliflozin 10 mg has been administrated once daily in the morning for 7 days.

    Reporting group title
    Saxagliptin and Dapagliflozin
    Reporting group description
    		 Each randomized subject was allocated to one of the three treatment sequences (seven days once daily dosing of either Dapagliflozin+placebo Saxagliptin, or Saxagliptin + placebo Dapagliflozin or the combination of Saxagliptin + Dapagliflozin).A wash-out period of 56-84 days between the first period and second period and one of 7-42 days between the second and third period has been carried out. In this seuence 1 tablet of Saxagliptin 5 mg and 1 tablet of Dapagliflozin 10 mg has been administrated ce daily in the morning for 7 days

    Reporting group title
    Pre - treatment
    Reporting group description
    		 All the results from all arms have been compared to the values before starting the treatment.

    Primary: Change in glucagon concentration from 5.5 mmol/L low insulin to 11.1 mmol/L: Glucagon11.1-Glucagon5.5.

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    End point title
    		 Change in glucagon concentration from 5.5 mmol/L low insulin to 11.1 mmol/L: Glucagon11.1-Glucagon5.5.
    End point description
    Dapagliflozin (+/- saxagliptin) did not increase glucagon during eu-, hyper-, and hypoglycaemia compared to no treatment (see attachment)
    End point type
    Primary
    End point timeframe
    During Clamp Procedure - comparison between treatments
    End point values
    		 Dapagliflozin and Placebo Saxagliptin Saxagliptin and Placebo Dapagliflozin Saxagliptin and Dapagliflozin Pre - treatment
    Number of subjects analysed
    17
    17
    17
    17
    Units: pmol/L
    arithmetic mean (standard deviation)
        5.5 mmol/L low insulin
    11.5 ± 6.0
    11.1 ± 6.2
    11.6 ± 5.3
    9.4 ± 4.1
        11.1 mmol/L
    7.0 ± 4.8
    6.3 ± 4.8
    5.9 ± 4.9
    6.2 ± 3.6
        5.5 mmol/L high insulin
    4.4 ± 3.6
    4.4 ± 4.1
    4.1 ± 3.2
    3.3 ± 3.4
        3.5 mmol/L
    6.5 ± 4.5
    7.2 ± 7.3
    7.9 ± 10.3
    6.6 ± 5.0
        2.5 mmol/L
    21.2 ± 12.6
    24.5 ± 18.9
    16.5 ± 12.0
    18.9 ± 14.0
    Attachments
    		 Untitled (Filename: Trial design.PNG)
    Untitled (Filename: Clamp Design.PNG)
    Statistical analysis title
    		 Mixed effects model
    Statistical analysis description
    Mixed effects model, using treatment (No treatment; SGLT-2; DPP-4; SGLT-2+DPP-4), sequence (No treatment -> SGLT-2 -> DPP-4 -> SGLT-2+DPP-4; No treatment -> SGLT-2 -> SGLT-2+DPP-4 -> DPP-4;…), and period (Baseline Period; Treatment Peri-od 1; Treatment period 2; Treatment Period 3) as fixed effects and patient (PATIENT) as random effect.
    Comparison groups
    Dapagliflozin and Placebo Saxagliptin v Saxagliptin and Placebo Dapagliflozin v Saxagliptin and Dapagliflozin
    Number of subjects included in analysis
    51
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority [1]
    P-value
    		 < 0.05
    Method
    		 Mixed models analysis
    Confidence interval
    Notes
    [1] - Not applicable

    Secondary: Ketone bodies during euglycaemia at ambient insulin levels and hyperglycaemia

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    End point title
    		 Ketone bodies during euglycaemia at ambient insulin levels and hyperglycaemia
    End point description
    Dapagliflozin did not significantly increase ketone bodies during euglycaemia at ambient insulin levels and hyperglycaemia compared to no treatment. Saxagliptin significantly decreased ketone body concentrations compared to no treatment during hyperglycaemia and compared to dapagliflozin and the combination of saxagliptin and dapagliflozin during eu- and hypoglycaemia at high insulin levels
    End point type
    Secondary
    End point timeframe
    During Clamp Procedure - comparison between treatments
    End point values
    		 Dapagliflozin and Placebo Saxagliptin Saxagliptin and Placebo Dapagliflozin Saxagliptin and Dapagliflozin Pre - treatment
    Number of subjects analysed
    17
    17
    17
    17
    Units: µmol/L
    arithmetic mean (standard deviation)
        5.5 mmol/L low insulin
    51.8 ± 25.0
    37.6 ± 28.1
    157 ± 268
    63.8 ± 64.6
        11.1 mmol/L
    125 ± 156
    35.1 ± 26.1
    111 ± 152
    119 ± 142
        5.5 mmol/L high insulin
    12.2 ± 7.9
    8.2 ± 4.2
    11.1 ± 6.7
    9.6 ± 5.8
        3.5 mmol/L
    10.4 ± 5.2
    7.4 ± 3.7
    9.5 ± 5.4
    8.0 ± 4.2
        2.5 mmol/L
    13.3 ± 7.6
    9.3 ± 5.9
    0.1 ± 0.2
    13.3 ± 15.1
    No statistical analyses for this end point

    Secondary: NEFA concentrations

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    End point title
    		 NEFA concentrations
    End point description
    NEFA concentrations were significantly reduced during hyperglycaemia in saxagliptin and dapagliflozin + saxagliptin treatment compared to no treatment
    End point type
    Secondary
    End point timeframe
    During Clamp Procedure - comparison between treatments
    End point values
    		 Dapagliflozin and Placebo Saxagliptin Saxagliptin and Placebo Dapagliflozin Saxagliptin and Dapagliflozin Pre - treatment
    Number of subjects analysed
    17
    17
    17
    17
    Units: mmol/L
    arithmetic mean (standard deviation)
        5.5 mmol/L low insulin
    0.4 ± 0.2
    0.3 ± 0.2
    0.4 ± 0.3
    0.4 ± 0.2
        11.1 mmol/L
    0.5 ± 0.3
    0.4 ± 0.2
    0.4 ± 0.2
    0.5 ± 0.3
        5.5 mmol/L high insulin
    0.02 ± 0.03
    0.02 ± 0.03
    0.01 ± 0.03
    0.02 ± 0.04
        3.5 mmol/L
    0.02 ± 0.05
    0.02 ± 0.03
    0.02 ± 0.04
    0.02 ± 0.1
        2.5 mmol/L
    0.1 ± 0.1
    0.1 ± 0.2
    0.1 ± 0.1
    0.1 ± 0.2
    No statistical analyses for this end point

    Secondary: C-Peptide

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    End point title
    		 C-Peptide
    End point description
    C-Peptide was significantly higher during hyper- and hypoglycaemia for dapagliflozin + saxagliptin compared to no treatment
    End point type
    Secondary
    End point timeframe
    During Clamp Procedure - comparison between treatments
    End point values
    		 Dapagliflozin and Placebo Saxagliptin Saxagliptin and Placebo Dapagliflozin Saxagliptin and Dapagliflozin Pre - treatment
    Number of subjects analysed
    17
    17
    17
    17
    Units: ng/mL
    arithmetic mean (standard deviation)
        5.5 mmol/L low insulin
    0.8 ± 0.5
    0.9 ± 0.4
    1.0 ± 0.5
    0.8 ± 0.5
        11.1 mmol/L
    2.7 ± 1.4
    2.5 ± 1.0
    3.2 ± 1.3
    2.3 ± 1.3
        5.5 mmol/L high insulin
    1.5 ± 0.9
    1.4 ± 0.6
    1.9 ± 1.1
    1.3 ± 0.9
        3.5 mmol/L
    1.0 ± 6.0
    1.0 ± 0.4
    1.3 ± 0.7
    0.9 ± 0.6
        2.5 mmol/L
    0.6 ± 0.3
    0.6 ± 0.3
    0.8 ± 0.4
    0.6 ± 0.4
    No statistical analyses for this end point

    Secondary: Noradrenalin concentration

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    End point title
    		 Noradrenalin concentration
    End point description
    Saxagliptin reduced noradrenalin concentration significantly during euglycaemia at ambient insulin levels compared to no treatment and dapagliflozin and euglycaemia at high insulin levels compared to dapagliflozin
    End point type
    Secondary
    End point timeframe
    During Clamp Procedure - comparison between treatments
    End point values
    		 Dapagliflozin and Placebo Saxagliptin Saxagliptin and Placebo Dapagliflozin Saxagliptin and Dapagliflozin Pre - treatment
    Number of subjects analysed
    17
    17
    17
    17
    Units: pg/mL
    arithmetic mean (standard deviation)
        5.5 mmol/L low insulin
    143 ± 89
    79 ± 70
    132 ± 77
    127 ± 64
        11.1 mmol/L
    131 ± 81
    95 ± 81
    132 ± 88
    150 ± 184
        5.5 mmol/L high insulin
    169 ± 99
    117 ± 84
    141 ± 73
    115 ± 63
        3.5 mmol/L
    185 ± 111
    122 ± 94
    160 ± 100
    155 ± 81
        2.5 mmol/L
    283 ± 206
    202 ± 167
    276 ± 164
    246 ± 97
    No statistical analyses for this end point

    Secondary: Endogenous Glucose Production

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    End point title
    		 Endogenous Glucose Production
    End point description
    All three treatments significantly reduced EGP during hyper-, but not during hypoglycaemia (see Figure )
    End point type
    Secondary
    End point timeframe
    During Clamp Procedure - comparison between treatments
    End point values
    		 Dapagliflozin and Placebo Saxagliptin Saxagliptin and Placebo Dapagliflozin Saxagliptin and Dapagliflozin Pre - treatment
    Number of subjects analysed
    17
    17
    17
    17
    Units: mg/kg/min
    arithmetic mean (standard deviation)
        5.5 mmol/L low insulin
    2.23 ± 0.46
    2.46 ± 0.47
    2.36 ± 0.42
    2.25 ± 0.46
        11.1 mmol/L
    1.46 ± 0.41
    1.55 ± 0.62
    1.43 ± 0.55
    1.77 ± 0.45
        5.5 mmol/L high insulin
    0.57 ± 0.42
    0.42 ± 0.39
    0.41 ± 0.33
    0.79 ± 0.77
        3.5 mmol/L
    0.64 ± 0.22
    0.59 ± 0.33
    0.48 ± 0.33
    0.80 ± 0.48
        2.5 mmol/L
    0.91 ± 0.25
    0.89 ± 0.36
    0.76 ± 0.32
    0.94 ± 0.40
    Attachments
    		 Untitled (Filename: Endogenous Glucose Production.PNG)
    No statistical analyses for this end point

    Secondary: Insulin

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    End point title
    		 Insulin
    End point description
    Insulin level was comparable for all treatment groups
    End point type
    Secondary
    End point timeframe
    During Clamp Procedure - comparison between treatments
    End point values
    		 Dapagliflozin and Placebo Saxagliptin Saxagliptin and Placebo Dapagliflozin Saxagliptin and Dapagliflozin Pre - treatment
    Number of subjects analysed
    17
    17
    17
    17
    Units: mU/L
    arithmetic mean (standard deviation)
        5.5 mmol/L low insulin
    14.2 ± 5.6
    18.5 ± 7.1
    15.0 ± 7.6
    28.7 ± 48.3
        11.1 mmol/L
    20.8 ± 18.6
    20.3 ± 14.8
    27.3 ± 19.5
    30.8 ± 38.4
        5.5 mmol/L high insulin
    230.2 ± 43.9
    237.8 ± 44.4
    238.8 ± 51.9
    230.2 ± 43.6
        3.5 mmol/L
    224.7 ± 40.1
    235.1 ± 45.0
    236.9 ± 49.2
    228.5 ± 42.0
        2.5 mmol/L
    201.8 ± 60.4
    201.0 ± 67.2
    195.0 ± 67.1
    204.0 ± 53.7
    No statistical analyses for this end point

    Secondary: Ra Glycerol

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    End point title
    		 Ra Glycerol
    End point description
    End point type
    Secondary
    End point timeframe
    During Clamp Procedure - comparison between treatments
    End point values
    		 Dapagliflozin and Placebo Saxagliptin Saxagliptin and Placebo Dapagliflozin Saxagliptin and Dapagliflozin Pre - treatment
    Number of subjects analysed
    17
    17
    17
    17
    Units: μmol/kg/min
    arithmetic mean (standard deviation)
        5.5 mmol/L low insulin
    1.36 ± 0.43
    1.69 ± 0.55
    1.71 ± 0.71
    2.01 ± 0.93
        11.1 mmol/L
    1.56 ± 0.61
    1.78 ± 0.85
    1.60 ± 0.52
    2.23 ± 0.85
        5.5 mmol/L high insulin
    0.70 ± 0.24
    0.80 ± 0.33
    0.81 ± 0.40
    1.21 ± 0.41
        3.5 mmol/L
    0.66 ± 0.23
    0.80 ± 0.38
    0.79 ± 0.37
    1.28 ± 0.44
        2.5 mmol/L
    1.10 ± 0.46
    1.40 ± 0.92
    1.40 ± 1.02
    1.83 ± 0.81
    Attachments
    		 Untitled (Filename: Ra Glycerol.PNG)
    No statistical analyses for this end point

    Adverse events

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    Adverse events information
    Timeframe for reporting adverse events
    Overall period of study
    Assessment type
    		 Systematic
    Dictionary used for adverse event reporting
    Dictionary name
    		 MedDRA
    Dictionary version
    23
    Reporting groups
    Reporting group title
    Saxagliptin
    Reporting group description
    		 -

    Reporting group title
    Dapagliflozin
    Reporting group description
    		 -

    Reporting group title
    Dapagliflozin and Saxagliptin
    Reporting group description
    		 -

    Reporting group title
    Before first treatment
    Reporting group description
    		 -

    Reporting group title
    After last treatment
    Reporting group description
    		 -

    Serious adverse events
    		 Saxagliptin Dapagliflozin Dapagliflozin and Saxagliptin Before first treatment After last treatment
    Total subjects affected by serious adverse events
         subjects affected / exposed
    0 / 17 (0.00%)
    0 / 17 (0.00%)
    0 / 17 (0.00%)
    0 / 17 (0.00%)
    0 / 17 (0.00%)
         number of deaths (all causes)
    0
    0
    0
    0
    0
         number of deaths resulting from adverse events
    Frequency threshold for reporting non-serious adverse events: 0%
    Non-serious adverse events
    		 Saxagliptin Dapagliflozin Dapagliflozin and Saxagliptin Before first treatment After last treatment
    Total subjects affected by non serious adverse events
         subjects affected / exposed
    4 / 17 (23.53%)
    2 / 17 (11.76%)
    4 / 17 (23.53%)
    3 / 17 (17.65%)
    2 / 17 (11.76%)
    Investigations
    Maculopapular, pruritic rash on both lower arms
         subjects affected / exposed
    0 / 17 (0.00%)
    0 / 17 (0.00%)
    1 / 17 (5.88%)
    0 / 17 (0.00%)
    0 / 17 (0.00%)
         occurrences all number
    1
    1
    1
    1
    1
    Cardiac disorders
    Common Cold
         subjects affected / exposed
    1 / 17 (5.88%)
    0 / 17 (0.00%)
    0 / 17 (0.00%)
    0 / 17 (0.00%)
    0 / 17 (0.00%)
         occurrences all number
    1
    1
    1
    1
    1
    Palpitations
         subjects affected / exposed
    1 / 17 (5.88%)
    0 / 17 (0.00%)
    0 / 17 (0.00%)
    0 / 17 (0.00%)
    1 / 17 (5.88%)
         occurrences all number
    2
    2
    2
    2
    2
    Nervous system disorders
    Headache
         subjects affected / exposed
    1 / 17 (5.88%)
    0 / 17 (0.00%)
    1 / 17 (5.88%)
    2 / 17 (11.76%)
    1 / 17 (5.88%)
         occurrences all number
    5
    5
    5
    5
    5
    Pain in the left jaw
         subjects affected / exposed
    1 / 17 (5.88%)
    0 / 17 (0.00%)
    0 / 17 (0.00%)
    0 / 17 (0.00%)
    0 / 17 (0.00%)
         occurrences all number
    1
    1
    1
    1
    1
    Increased neuropathic pain in the feet
         subjects affected / exposed
    0 / 17 (0.00%)
    1 / 17 (5.88%)
    0 / 17 (0.00%)
    0 / 17 (0.00%)
    0 / 17 (0.00%)
         occurrences all number
    1
    1
    1
    1
    1
    Retrograde amnesia
    Additional description: Retrogade amnesia on the time of hypoglycaemic clamp
         subjects affected / exposed
    0 / 17 (0.00%)
    0 / 17 (0.00%)
    0 / 17 (0.00%)
    1 / 17 (5.88%)
    0 / 17 (0.00%)
         occurrences all number
    1
    1
    1
    1
    1
    Dizzyness
         subjects affected / exposed
    1 / 17 (5.88%)
    0 / 17 (0.00%)
    0 / 17 (0.00%)
    0 / 17 (0.00%)
    0 / 17 (0.00%)
         occurrences all number
    1
    1
    1
    1
    1
    Eye disorders
    Fever
         subjects affected / exposed
    0 / 17 (0.00%)
    0 / 17 (0.00%)
    1 / 17 (5.88%)
    0 / 17 (0.00%)
    0 / 17 (0.00%)
         occurrences all number
    1
    1
    1
    1
    1
    Gastrointestinal disorders
    Diarrhea
    Additional description: 1 Diarrhea was bright colored
         subjects affected / exposed
    2 / 17 (11.76%)
    1 / 17 (5.88%)
    1 / 17 (5.88%)
    1 / 17 (5.88%)
    1 / 17 (5.88%)
         occurrences all number
    6
    6
    6
    6
    6
    Nausea
         subjects affected / exposed
    0 / 17 (0.00%)
    0 / 17 (0.00%)
    1 / 17 (5.88%)
    1 / 17 (5.88%)
    0 / 17 (0.00%)
         occurrences all number
    2
    2
    2
    2
    2
    Hepatobiliary disorders
    Hypertensive episodes
    Additional description: Multiple not clinically significant hypertensive episodes during the clamp visit
         subjects affected / exposed
    0 / 17 (0.00%)
    1 / 17 (5.88%)
    0 / 17 (0.00%)
    0 / 17 (0.00%)
    0 / 17 (0.00%)
         occurrences all number
    1
    1
    1
    1
    1
    Renal and urinary disorders
    Urinary retention (temporary)
         subjects affected / exposed
    0 / 17 (0.00%)
    0 / 17 (0.00%)
    0 / 17 (0.00%)
    1 / 17 (5.88%)
    0 / 17 (0.00%)
         occurrences all number
    1
    1
    1
    1
    1
    Endocrine disorders
    Pain in the epigastric region
         subjects affected / exposed
    1 / 17 (5.88%)
    0 / 17 (0.00%)
    0 / 17 (0.00%)
    0 / 17 (0.00%)
    1 / 17 (5.88%)
         occurrences all number
    1
    1
    1
    1
    1
    Musculoskeletal and connective tissue disorders
    Lower back pain
         subjects affected / exposed
    0 / 17 (0.00%)
    0 / 17 (0.00%)
    0 / 17 (0.00%)
    1 / 17 (5.88%)
    0 / 17 (0.00%)
         occurrences all number
    1
    1
    1
    1
    1

    More information

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    Substantial protocol amendments (globally)
    Were there any global substantial amendments to the protocol? Yes
    Date
    Amendment
    21 Jun 2016
    The study protocol was amended regarding Primary Objective, Primary and Secondary Endpoints and Study Duration per patient

    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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