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    Clinical Trial Results:
    A 26-WEEK INTERNATIONAL, MULTICENTER, RANDOMIZED, DOUBLE-BLIND, ACTIVE-CONTROLLED, PARALLEL GROUP, PHASE 3B TRIAL WITH A BLINDED 26-WEEK LONG-TERM EXTENSION PERIOD TO EVALUATE THE EFFICACY AND SAFETY OF SAXAGLIPTIN CO-ADMINISTERED WITH DAPAGLIFLOZIN IN COMBINATION WITH METFORMIN COMPARED TO SITAGLIPTIN IN COMBINATION WITH METFORMIN IN ADULT PATIENTS WITH TYPE 2 DIABETES WHO HAVE INADEQUATE GLYCEMIC CONTROL ON METFORMIN THERAPY ALONE

    Summary
    EudraCT number
    2014-001102-17
    Trial protocol
    HU   PL  
    Global end of trial date
    26 Oct 2016

    Results information
    Results version number
    v1(current)
    This version publication date
    23 Nov 2017
    First version publication date
    23 Nov 2017
    Other versions

    Trial information

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    Trial identification
    Sponsor protocol code
    CV181-363
    Additional study identifiers
    ISRCTN number
    -
    US NCT number
    -
    WHO universal trial number (UTN)
    -
    Sponsors
    Sponsor organisation name
    AstraZeneca
    Sponsor organisation address
    Pepparedsleden 1, Mölndal, Sweden, 431 53
    Public contact
    Eva Johnsson, AstraZeneca, +46 (0) 31 7762484, eva.johnsson@astrazeneca.com
    Scientific contact
    Eva Johnsson, AstraZeneca, +46 (0) 31 7762484, eva.johnsson@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
    31 Jul 2017
    Is this the analysis of the primary completion data?
    Yes
    Primary completion date
    26 Oct 2016
    Global end of trial reached?
    Yes
    Global end of trial date
    26 Oct 2016
    Was the trial ended prematurely?
    No
    General information about the trial
    Main objective of the trial
    To compare the mean change from baseline in glycated hemoglobin (HbA1c) achieved with saxagliptin in co-administration with dapagliflozin added to current background therapy with metformin compared to sitagliptin added to current background therapy with metformin at week 26.
    Protection of trial subjects
    The laws and regulatory requirements of all countries that had sites participating in this study were adhered to. This study was conducted in accordance with Good Clinical Practice, as defined by the International Council for Harmonisation and in accordance with the ethical principles underlying European Union (EU) Directive 2001/20/EC and the United States Code of Federal Regulations, Title 21, Part 50 (21CFR50). This study was conducted in accordance with the ethical principles that have their origin in the Declaration of Helsinki. The rights, safety, and well-being of the study subjects were the most important consideration and prevailed over the interests of science and society.
    Background therapy
    Subjects received metformin (≥ 1,500 mg/day) in accordance with the product label for their respective countries. Dose adjustment of metformin was not allowed. Metformin background therapy was not provided by the Sponsor.
    Evidence for comparator
    -
    Actual start date of recruitment
    22 Dec 2014
    Long term follow-up planned
    No
    Independent data monitoring committee (IDMC) involvement?
    No
    Population of trial subjects
    Number of subjects enrolled per country
    Country: Number of subjects enrolled
    United States: 227
    Country: Number of subjects enrolled
    Romania: 41
    Country: Number of subjects enrolled
    Hungary: 25
    Country: Number of subjects enrolled
    Mexico: 88
    Country: Number of subjects enrolled
    Poland: 36
    Country: Number of subjects enrolled
    South Africa: 44
    Worldwide total number of subjects
    461
    EEA total number of subjects
    102
    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)
    381
    From 65 to 84 years
    80
    85 years and over
    0

    Subject disposition

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    Recruitment
    Recruitment details
    -

    Pre-assignment
    Screening details
    461 Patients were Randomized and treated, during the 26-week, Double-blind Treatment Period. 411 patients completed. 402 Patients were Randomized and treated, during the 52-week, Double-blind Treatment Period. 378 patients completed.?

    Period 1
    Period 1 title
    26 week (short term)
    Is this the baseline period?
    Yes
    Allocation method
    Randomised - controlled
    Blinding used
    Double blind
    Roles blinded
    Subject, Investigator, Monitor, Carer, Data analyst, Assessor

    Arms
    Are arms mutually exclusive
    Yes

    Arm title
    SAXA + DAPA + MET
    Arm description
    Saxagliptin 5-mg tablet+Dapagliflozin 10-mg tablet+Placebo capsules matching the sitagliptin 100-mg capsules+Metformin background therapy
    Arm type
    Experimental

    Investigational medicinal product name
    saxagliptin and dapagliflozin
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Coated tablet
    Routes of administration
    Oral use
    Dosage and administration details
    5mg saxagliptin and 10 mg dapagliflozin

    Arm title
    SITA + MET
    Arm description
    Placebo tablet matching the saxagliptin 5-mg tablet +Placebo tablet matching the dapagliflozin 10-mg table+Sitagliptin 100-mg capsules +Metformin background therapy
    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
    100 mg

    Number of subjects in period 1
    SAXA + DAPA + MET SITA + MET
    Started
    232
    229
    Completed
    213
    198
    Not completed
    19
    31
         Withrawal of the consent by the subject
             7
             10
         Subject no longer meets study criteria
             5
             8
         Adverse event, non-fatal
             1
             9
         Discontinuation by the subject
             2
             2
         other
             1
             1
         Lost to follow-up
             3
             1
    Period 2
    Period 2 title
    52 week (long term)
    Is this the baseline period?
    No
    Allocation method
    Randomised - controlled
    Blinding used
    Double blind
    Roles blinded
    Subject, Investigator, Monitor, Carer, Data analyst, Assessor

    Arms
    Are arms mutually exclusive
    Yes

    Arm title
    SAXA + DAPA + MET
    Arm description
    Saxagliptin 5-mg tablet+Dapagliflozin 10-mg tablet+Placebo capsules matching the sitagliptin 100-mg capsules+Metformin background therapy
    Arm type
    Experimental

    Investigational medicinal product name
    saxagliptin and dapgliflozin tablets
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Film-coated tablet
    Routes of administration
    Oral use
    Dosage and administration details
    5 mg saxagliptin and 10 mg dapagliflozin

    Arm title
    SITA + MET
    Arm description
    Placebo tablet matching the saxagliptin 5-mg tablet +Placebo tablet matching the dapagliflozin 10-mg table+Sitagliptin 100-mg capsules +Metformin background therapy
    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
    100 mg

    Number of subjects in period 2 [1]
    SAXA + DAPA + MET SITA + MET
    Started
    209
    193
    Completed
    198
    180
    Not completed
    11
    13
         Withrawal of the consent by the subject
             4
             6
         Subject no longer meets study criteria
             -
             1
         Non-Compliance
             2
             3
         Adverse event, non-fatal
             3
             1
         Lost to follow-up
             2
             2
    Notes
    [1] - 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: Subjects discontinued the study prematurely

    Baseline characteristics

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    Baseline characteristics reporting groups
    Reporting group title
    SAXA + DAPA + MET
    Reporting group description
    Saxagliptin 5-mg tablet+Dapagliflozin 10-mg tablet+Placebo capsules matching the sitagliptin 100-mg capsules+Metformin background therapy

    Reporting group title
    SITA + MET
    Reporting group description
    Placebo tablet matching the saxagliptin 5-mg tablet +Placebo tablet matching the dapagliflozin 10-mg table+Sitagliptin 100-mg capsules +Metformin background therapy

    Reporting group values
    SAXA + DAPA + MET SITA + MET Total
    Number of subjects
    232 229 461
    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)
    197 184 381
        From 65-84 years
    35 45 80
        85 years and over
    0 0 0
    Gender Categorical
    Units: Subjects
        Female
    132 119 251
        Male
    100 110 210
    Geographic Region
    Units: Subjects
    The America
    Units: Subjects
    Geographic Region
    Units: Subjects
    xx
    Units: Subjects
    Subject analysis sets

    Subject analysis set title
    SAXA+DAPA+MET
    Subject analysis set type
    Full analysis
    Subject analysis set description
    Saxagliptin 5-mg tablet +Dapagliflozin 10-mg tablet+Placebo capsules matching the sitagliptin 100-mg capsules+Metformin background therapy

    Subject analysis set title
    SITA+MET
    Subject analysis set type
    Full analysis
    Subject analysis set description
    Placebo tablet matching the saxagliptin 5-mg tablet+Placebo tablet matching the dapagliflozin 10-mg tablet+Sitagliptin 100-mg capsules+Metformin background therapy

    Subject analysis sets values
    SAXA+DAPA+MET SITA+MET
    Number of subjects
    232
    229
    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)
    197
    184
        From 65-84 years
    35
    45
        85 years and over
    0
    0
    Age Continuous
    Units:
        
    ±
    ±
    Gender Categorical
    Units: Subjects
        Female
    132
    119
        Male
    100
    110
    Geographic Region
    Units: Subjects
    The America
    Units: Subjects
    Geographic Region
    Units: Subjects
    xx
    Units: Subjects

    End points

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    End points reporting groups
    Reporting group title
    SAXA + DAPA + MET
    Reporting group description
    Saxagliptin 5-mg tablet+Dapagliflozin 10-mg tablet+Placebo capsules matching the sitagliptin 100-mg capsules+Metformin background therapy

    Reporting group title
    SITA + MET
    Reporting group description
    Placebo tablet matching the saxagliptin 5-mg tablet +Placebo tablet matching the dapagliflozin 10-mg table+Sitagliptin 100-mg capsules +Metformin background therapy
    Reporting group title
    SAXA + DAPA + MET
    Reporting group description
    Saxagliptin 5-mg tablet+Dapagliflozin 10-mg tablet+Placebo capsules matching the sitagliptin 100-mg capsules+Metformin background therapy

    Reporting group title
    SITA + MET
    Reporting group description
    Placebo tablet matching the saxagliptin 5-mg tablet +Placebo tablet matching the dapagliflozin 10-mg table+Sitagliptin 100-mg capsules +Metformin background therapy

    Subject analysis set title
    SAXA+DAPA+MET
    Subject analysis set type
    Full analysis
    Subject analysis set description
    Saxagliptin 5-mg tablet +Dapagliflozin 10-mg tablet+Placebo capsules matching the sitagliptin 100-mg capsules+Metformin background therapy

    Subject analysis set title
    SITA+MET
    Subject analysis set type
    Full analysis
    Subject analysis set description
    Placebo tablet matching the saxagliptin 5-mg tablet+Placebo tablet matching the dapagliflozin 10-mg tablet+Sitagliptin 100-mg capsules+Metformin background therapy

    Primary: Mean change in HbA1c

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    End point title
    Mean change in HbA1c
    End point description
    End point type
    Primary
    End point timeframe
    From baseline to week 26
    End point values
    SAXA+DAPA+MET SITA+MET
    Number of subjects analysed
    224
    219
    Units: Percentage (%)
        least squares mean (standard error)
    -1.41 ± 0.0696
    -1.07 ± 0.0719
    Statistical analysis title
    SAXA + DAPA + MET VS. SITA + MET
    Comparison groups
    SAXA+DAPA+MET v SITA+MET
    Number of subjects included in analysis
    443
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    P-value
    = 0.0008
    Method
    Mixed models analysis
    Parameter type
    Mean difference (final values)
    Point estimate
    -0.34
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    -0.53
         upper limit
    -0.14
    Variability estimate
    Standard error of the mean
    Dispersion value
    0.1001

    Secondary: Percent of subjects achieving a therapeutic glycemic response, defined as HbA1c < 7.0%

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    End point title
    Percent of subjects achieving a therapeutic glycemic response, defined as HbA1c < 7.0%
    End point description
    End point type
    Secondary
    End point timeframe
    week 26
    End point values
    SAXA+DAPA+MET SITA+MET
    Number of subjects analysed
    224
    219
    Units: Percentage
        least squares mean (standard error)
    37.3 ± 3.150
    25.1 ± 2.871
    Statistical analysis title
    SAXA + DAPA + MET VS. SITA + MET
    Comparison groups
    SAXA+DAPA+MET v SITA+MET
    Number of subjects included in analysis
    443
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    P-value
    = 0.0034
    Method
    Regression, Logistic
    Parameter type
    Mean difference (final values)
    Point estimate
    12.2
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    4
         upper limit
    20.4
    Variability estimate
    Standard error of the mean
    Dispersion value
    4.175

    Secondary: Mean change in total body weight

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    End point title
    Mean change in total body weight
    End point description
    End point type
    Secondary
    End point timeframe
    from baseline to week 26
    End point values
    SAXA+DAPA+MET SITA+MET
    Number of subjects analysed
    224
    219
    Units: kg
        least squares mean (standard error)
    -1.86 ± 0.2010
    -0.51 ± 0.2078
    Statistical analysis title
    SAXA + DAPA + MET VS. SITA + MET
    Comparison groups
    SAXA+DAPA+MET v SITA+MET
    Number of subjects included in analysis
    443
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    P-value
    < 0.0001
    Method
    Mixed models analysis
    Parameter type
    Mean difference (final values)
    Point estimate
    -1.35
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    -1.92
         upper limit
    -0.79
    Variability estimate
    Standard error of the mean
    Dispersion value
    0.2891

    Secondary: Mean change in FPG

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    End point title
    Mean change in FPG
    End point description
    End point type
    Secondary
    End point timeframe
    from baseline to week 26
    End point values
    SAXA+DAPA+MET SITA+MET
    Number of subjects analysed
    224
    219
    Units: mg/dl
        least squares mean (standard error)
    -31.9 ± 2.538
    -11.0 ± 2.668
    Statistical analysis title
    SAXA + DAPA + MET VS. SITA + MET
    Comparison groups
    SAXA+DAPA+MET v SITA+MET
    Number of subjects included in analysis
    443
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    P-value
    < 0.0001
    Method
    Mixed models analysis
    Parameter type
    Mean difference (final values)
    Point estimate
    -20.9
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    -28.2
         upper limit
    -13.7
    Variability estimate
    Standard error of the mean
    Dispersion value
    3.682

    Adverse events

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    Adverse events information
    Timeframe for reporting adverse events
    52 weeks
    Adverse event reporting additional description
    including Data After Rescue Treated Subjects (The Treated Subjects data set consists of all subjects who received at least 1 dose of double-blind study drug)
    Assessment type
    Systematic
    Dictionary used for adverse event reporting
    Dictionary name
    MedDRA
    Dictionary version
    19.1
    Reporting groups
    Reporting group title
    SITA + MET
    Reporting group description
    Placebo tablet matching the saxagliptin 5-mg tablet+Placebo tablet matching the dapagliflozin 10-mg tablet+Sitagliptin 100-mg capsules+Metformin background therapy

    Reporting group title
    SAXA + DAPA + MET
    Reporting group description
    Saxagliptin 5-mg tablet +Dapagliflozin 10-mg tablet+Placebo capsules matching the sitagliptin 100-mg capsules+Metformin background therapy

    Serious adverse events
    SITA + MET SAXA + DAPA + MET
    Total subjects affected by serious adverse events
         subjects affected / exposed
    13 / 229 (5.68%)
    9 / 232 (3.88%)
         number of deaths (all causes)
    0
    0
         number of deaths resulting from adverse events
    0
    0
    Vascular disorders
    Deep vein thrombosis
    Additional description: Deep vein thrombosis
         subjects affected / exposed
    1 / 229 (0.44%)
    0 / 232 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Peripheral vasoconstriction, necrosis and vascular insufficiency
    Additional description: Peripheral Arterial Occlusive Disease
         subjects affected / exposed
    0 / 229 (0.00%)
    1 / 232 (0.43%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Injury, poisoning and procedural complications
    Laceration of leg
    Additional description: Laceration
         subjects affected / exposed
    1 / 229 (0.44%)
    0 / 232 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Lower limb motor deficit
    Additional description: Lower limb fracture
         subjects affected / exposed
    1 / 229 (0.44%)
    0 / 232 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Neoplasms benign, malignant and unspecified (incl cysts and polyps)
    Adenocarcinoma of colon
         subjects affected / exposed
    0 / 229 (0.00%)
    1 / 232 (0.43%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Neoplasm
    Additional description: Meningioma
         subjects affected / exposed
    0 / 229 (0.00%)
    1 / 232 (0.43%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Cardiac disorders
    Atrial fibrillation
         subjects affected / exposed
    1 / 229 (0.44%)
    0 / 232 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Cardiac failure chronic aggravated
         subjects affected / exposed
    1 / 229 (0.44%)
    0 / 232 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Cardiac failure (NOS)
    Additional description: Cardiac Failure Congestive
         subjects affected / exposed
    1 / 229 (0.44%)
    0 / 232 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Cardiomyopathy primary
    Additional description: congestive cardiomyopathy
         subjects affected / exposed
    1 / 229 (0.44%)
    0 / 232 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Coronary artery disease NOS
         subjects affected / exposed
    0 / 229 (0.00%)
    1 / 232 (0.43%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Mitral valve disease NOS
    Additional description: Mitral valve Prolapse
         subjects affected / exposed
    1 / 229 (0.44%)
    0 / 232 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Heart rate increased
    Additional description: Palpitations
         subjects affected / exposed
    0 / 229 (0.00%)
    1 / 232 (0.43%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Tachycardia NOS
    Additional description: Tachycardia
         subjects affected / exposed
    1 / 229 (0.44%)
    0 / 232 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Respiratory, thoracic and mediastinal disorders
    Respiratory failures (excl neonatal)
    Additional description: Acute Respiratory Failure
         subjects affected / exposed
    1 / 229 (0.44%)
    0 / 232 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Dysponesis
    Additional description: Dyspnoea
         subjects affected / exposed
    1 / 229 (0.44%)
    0 / 232 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Immune system disorders
    Hypersensitivity NOS
    Additional description: Drug hypersnsitivity
         subjects affected / exposed
    1 / 229 (0.44%)
    0 / 232 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Nervous system disorders
    Headache
         subjects affected / exposed
    1 / 229 (0.44%)
    0 / 232 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Lumbar nerve decompression
    Additional description: Lumbar Radiculopathy
         subjects affected / exposed
    0 / 229 (0.00%)
    1 / 232 (0.43%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Gastrointestinal disorders
    Abdominal wall disorder
    Additional description: Abdominal Pain
         subjects affected / exposed
    1 / 229 (0.44%)
    0 / 232 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Anal exam abnormal
    Additional description: Anal Fissure
         subjects affected / exposed
    1 / 229 (0.44%)
    0 / 232 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Gastrooesophageal junction ulcer
    Additional description: Garstrooesophageal Reflux Disease
         subjects affected / exposed
    0 / 229 (0.00%)
    1 / 232 (0.43%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Vomiting alone
    Additional description: Vomiting
         subjects affected / exposed
    0 / 229 (0.00%)
    1 / 232 (0.43%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Psychiatric disorders
    Mental status changes
         subjects affected / exposed
    0 / 229 (0.00%)
    1 / 232 (0.43%)
         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
    Dysfunctional uterine haemorrhage
    Additional description: Dysfunctional Uterine Bleeding
         subjects affected / exposed
    0 / 229 (0.00%)
    1 / 232 (0.43%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Endometriosis ablation
    Additional description: Endometriosis
         subjects affected / exposed
    2 / 229 (0.87%)
    0 / 232 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Musculoskeletal and connective tissue disorders
    Osteoarthritis aggravated
    Additional description: Osteoarthritis
         subjects affected / exposed
    2 / 229 (0.87%)
    0 / 232 (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
    Pneumonia viral
    Additional description: Pneumonia
         subjects affected / exposed
    2 / 229 (0.87%)
    0 / 232 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Sepsis
         subjects affected / exposed
    1 / 229 (0.44%)
    0 / 232 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Frequency threshold for reporting non-serious adverse events: 2%
    Non-serious adverse events
    SITA + MET SAXA + DAPA + MET
    Total subjects affected by non serious adverse events
         subjects affected / exposed
    131 / 229 (57.21%)
    132 / 232 (56.90%)
    Vascular disorders
    hypertension
         subjects affected / exposed
    8 / 229 (3.49%)
    3 / 232 (1.29%)
         occurrences all number
    10
    3
    Cardiac disorders
    Atrial flutter/ fibrillation
         subjects affected / exposed
    5 / 229 (2.18%)
    1 / 232 (0.43%)
         occurrences all number
    5
    1
    Congenital, familial and genetic disorders
    Lipid metabolism disorder
    Additional description: dyslipidaemia
         subjects affected / exposed
    3 / 229 (1.31%)
    5 / 232 (2.16%)
         occurrences all number
    3
    5
    Respiratory, thoracic and mediastinal disorders
    Cough aggravated
    Additional description: cough
         subjects affected / exposed
    7 / 229 (3.06%)
    3 / 232 (1.29%)
         occurrences all number
    7
    3
    Blood and lymphatic system disorders
    Anaemia
         subjects affected / exposed
    7 / 229 (3.06%)
    1 / 232 (0.43%)
         occurrences all number
    8
    1
    Nervous system disorders
    Headache
         subjects affected / exposed
    10 / 229 (4.37%)
    13 / 232 (5.60%)
         occurrences all number
    11
    16
    Gastrointestinal disorders
    Diarrhea NOS
         subjects affected / exposed
    6 / 229 (2.62%)
    2 / 232 (0.86%)
         occurrences all number
    7
    2
    Gastritis
         subjects affected / exposed
    5 / 229 (2.18%)
    1 / 232 (0.43%)
         occurrences all number
    5
    1
    Gastrooesophageal junction ulcer
    Additional description: Gastrooesophageal Reflux Disease
         subjects affected / exposed
    1 / 229 (0.44%)
    5 / 232 (2.16%)
         occurrences all number
    1
    5
    Renal and urinary disorders
    Urinary tract infection
         subjects affected / exposed
    7 / 229 (3.06%)
    10 / 232 (4.31%)
         occurrences all number
    8
    12
    Musculoskeletal and connective tissue disorders
    Joint destruction
    Additional description: Arthralgia
         subjects affected / exposed
    2 / 229 (0.87%)
    5 / 232 (2.16%)
         occurrences all number
    2
    6
    Backache
    Additional description: back pain
         subjects affected / exposed
    9 / 229 (3.93%)
    5 / 232 (2.16%)
         occurrences all number
    9
    5
    Pain
    Additional description: Pain in extremity
         subjects affected / exposed
    6 / 229 (2.62%)
    3 / 232 (1.29%)
         occurrences all number
    6
    3
    Endocrine disorders
    Hyperglyceridemia
    Additional description: Hyperglycaemia
         subjects affected / exposed
    5 / 229 (2.18%)
    0 / 232 (0.00%)
         occurrences all number
    5
    0
    Infections and infestations
    Bronchitis NOS
         subjects affected / exposed
    2 / 229 (0.87%)
    8 / 232 (3.45%)
         occurrences all number
    2
    9
    Influenza with other manifestations
    Additional description: Influenza
         subjects affected / exposed
    11 / 229 (4.80%)
    8 / 232 (3.45%)
         occurrences all number
    12
    8
    Gastroenteritis
         subjects affected / exposed
    5 / 229 (2.18%)
    4 / 232 (1.72%)
         occurrences all number
    5
    5
    Nasopharyngeal disorder
    Additional description: Nasopharygitis
         subjects affected / exposed
    12 / 229 (5.24%)
    18 / 232 (7.76%)
         occurrences all number
    12
    20
    Sinus disorder
    Additional description: Sinusitis
         subjects affected / exposed
    2 / 229 (0.87%)
    5 / 232 (2.16%)
         occurrences all number
    2
    6
    Upper respiratory infection
    Additional description: Upper respiratory tract infection
         subjects affected / exposed
    8 / 229 (3.49%)
    7 / 232 (3.02%)
         occurrences all number
    9
    8
    Vulvovaginal mycotic infection
         subjects affected / exposed
    2 / 229 (0.87%)
    5 / 232 (2.16%)
         occurrences all number
    2
    7

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    Substantial protocol amendments (globally)

    Were there any global substantial amendments to the protocol? No

    Interruptions (globally)

    Were there any global interruptions to the trial? No

    Limitations and caveats

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