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    Clinical Trial Results:
    A Multicenter, Randomized, Double-Blind, Placebo-Controlled, Parallel Group, Phase 3 Trial to Evaluate the Safety and Efficacy of Therapy with Dapagliflozin added to Saxagliptin in Combination with Metformin compared to Therapy with Placebo added to Saxagliptin in Combination with Metformin in Subjects with Type 2 Diabetes who have Inadequate Glycemic Control on Metformin and Saxagliptin

    Summary
    EudraCT number
    2011-006324-20
    Trial protocol
    GB   CZ   PL  
    Global end of trial date
    19 Feb 2015

    Results information
    Results version number
    v1(current)
    This version publication date
    29 Jul 2016
    First version publication date
    29 Jul 2016
    Other versions

    Trial information

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    Trial identification
    Sponsor protocol code
    MB102-129
    Additional study identifiers
    ISRCTN number
    -
    US NCT number
    NCT01646320
    WHO universal trial number (UTN)
    -
    Sponsors
    Sponsor organisation name
    AstraZeneca Pharmaceuticals
    Sponsor organisation address
    Västra Mälarehamnen 9, Södertälje, Sweden, S-151851170
    Public contact
    Eva.Johnsson@astrazeneca.com, AstraZeneca Pharmaceuticals, +46 31 7762484 x 762 484,
    Scientific contact
    Eva Johnsson, Clinical Science Lead, AstraZeneca Pharmaceuticals, +46 31 7762484 x 762 484, 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
    10 Jul 2015
    Is this the analysis of the primary completion data?
    Yes
    Primary completion date
    19 Feb 2015
    Global end of trial reached?
    Yes
    Global end of trial date
    19 Feb 2015
    Was the trial ended prematurely?
    No
    General information about the trial
    Main objective of the trial
    The purpose of this study is to learn if BMS-512148 (dapagliflozin) as part of a triple combination therapy can improve (decrease) hemoglobin A1c in patients with type 2 diabetes after 24 weeks of treatment compared to a 2 drug oral antidiabetic therapy. The safety of this treatment will also be studied.
    Protection of trial subjects
    Prior to the beginning of the study, the investigator must have had the IRB/IEC’s written approval/favorable opinion of the written informed consent form and any other information to be provided to the subjects. Freely given written informed consent was obtained from each subject or, in those situations where consent could not be given by the subject, their legally acceptable representatives, prior to study participation, including informed consent for any screening procedures conducted to establish subject eligibility in the study.
    Background therapy
    Stable metformin therapy alone for at least 8 weeks prior to screening visit at a dose ≥ 1500 mg per day. Saxagliptin 5 mg was added during the open label treatment period of 8-16 weeks.
    Evidence for comparator
    -
    Actual start date of recruitment
    21 Sep 2012
    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: 148
    Country: Number of subjects enrolled
    Czech Republic: 13
    Country: Number of subjects enrolled
    Mexico: 166
    Country: Number of subjects enrolled
    Poland: 17
    Country: Number of subjects enrolled
    Puerto Rico: 6
    Country: Number of subjects enrolled
    Romania: 25
    Country: Number of subjects enrolled
    Russian Federation: 89
    Country: Number of subjects enrolled
    United Kingdom: 19
    Worldwide total number of subjects
    483
    EEA total number of subjects
    74
    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)
    415
    From 65 to 84 years
    68
    85 years and over
    0

    Subject disposition

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    Recruitment
    Recruitment details
    Multicenter, Randomized, Double-Blind, Placebo-Controlled, Parallel Group, Phase 3 Trial with Dapagliflozin 10 mg added to Saxagliptin 5 mg in Combination with Metformin ≥ 1500 mg compared to placebo added to Saxagliptin in combination with Metformin in Subjects with Type 2 Diabetes who have Inadequate Glycemic Control on Metformin and Saxagliptin

    Pre-assignment
    Screening details
    Arm1: Dapagliflozin (10 mg) + Saxagliptin (5 mg) + Metformin ≥ 1500 mg IR Arm 2: Placebo + Saxagliptin (5 mg) + Metformin IR

    Period 1
    Period 1 title
    Short-term period (Day 1 to Week 24)
    Is this the baseline period?
    Yes
    Allocation method
    Randomised - controlled
    Blinding used
    Double blind
    Roles blinded
    Subject, Investigator, Monitor, Data analyst, Carer, Assessor

    Arms
    Are arms mutually exclusive
    Yes

    Arm title
    Dapa+Saxa+Met
    Arm description
    Participants received dapagliflozin, 10 mg, and open-label saxagliptin 5 mg and metformin ≥1500 mg per day for up to 52 weeks
    Arm type
    Experimental

    Investigational medicinal product name
    Dapagliflozin (10 mg) + Saxagliptin (5 mg) + Metformin IR
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Tablet
    Routes of administration
    Oral use
    Dosage and administration details
    Saxagliptin Tablets, Oral, 5mg , Once daily, 24 weeks: Metformin XR Tablets, Oral, ≥ 1500mg/≤ 2000mg, Once daily, 24 weeks Other Names: Glucophage XR Drug: Dapagliflozin Tablet, Oral, 10mg, Once daily, 24 weeks

    Arm title
    Pla+Saxa+Met
    Arm description
    Participants received dapagliflozin matching placebo and open-label saxagliptin 5 mg and metformin ≥1500 mg per day for up to 52 weeks
    Arm type
    Placebo

    Investigational medicinal product name
    Placebo + Saxagliptin (5 mg) + Metformin IR
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Tablet
    Routes of administration
    Oral use
    Dosage and administration details
    Saxagliptin Tablets, Oral, 5mg , Once daily, 24 weeks: Metformin XR Tablets, Oral, ≥ 1500mg/≤ 2000mg, Once daily, 24 weeks Other Names: Glucophage XR: Placebo matching with Dapagliflozin Tablets, Oral, 0mg, Once daily, 24 weeks

    Number of subjects in period 1 [1]
    Dapa+Saxa+Met Pla+Saxa+Met
    Started
    160
    160
    Completed
    148
    153
    Not completed
    12
    7
         No longer meets study criteria
    -
    1
         Not specified
    1
    -
         Not reported
    2
    2
         Adverse event, non-fatal
    3
    -
         Consent withdrawn by subject
    2
    -
         Lost to follow-up
    4
    4
    Notes
    [1] - The number of subjects reported to be in the baseline period are not the same as the worldwide number enrolled in the trial. It is expected that these numbers will be the same.
    Justification: Of 320 participants randomized, 301 completed Short-Term (ST) treatment period. Of 294 participants entered Long-Term (LT) treatment period, 281 completed
    Period 2
    Period 2 title
    Long-term Period (Weeks 24 to 52)
    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
    Dapa+Saxa+Met
    Arm description
    Participants received dapagliflozin, 10 mg, and open-label saxagliptin 5 mg and metformin ≥1500 mg per day for up to 52 weeks
    Arm type
    Experimental

    Investigational medicinal product name
    Dapagliflozin (10 mg) + Saxagliptin (5 mg) + Metformin IR
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Tablet
    Routes of administration
    Oral use
    Dosage and administration details
    Saxagliptin Tablets, Oral, 5mg , Once daily, 52 weeks: Metformin XR Tablets, Oral, ≥ 1500mg/≤ 2000mg, Once daily, 52 weeks Other Names: Glucophage XR Drug: Dapagliflozin Tablet, Oral, 10mg, Once daily, 52 weeks

    Arm title
    Pla+Saxa+Met
    Arm description
    Participants received dapagliflozin matching placebo and open-label saxagliptin 5 mg and metformin ≥1500 mg per day for up to 52 weeks
    Arm type
    Placebo

    Investigational medicinal product name
    Placebo + Saxagliptin (5 mg) + Metformin IR
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Tablet
    Routes of administration
    Oral use
    Dosage and administration details
    Saxagliptin Tablets, Oral, 5mg , Once daily, 52 weeks: Metformin XR Tablets, Oral, ≥ 1500mg/≤ 2000mg, Once daily, 52 weeks Other Names: Glucophage XR: Placebo matching with Dapagliflozin Tablets, Oral, 0mg, Once daily, 52 weeks

    Number of subjects in period 2 [2]
    Dapa+Saxa+Met Pla+Saxa+Met
    Started
    147
    147
    Completed
    141
    140
    Not completed
    6
    7
         Subject no longer meets study criteria
    2
    -
         Lack of efficacy
    -
    1
         Adverse event, non-fatal
    4
    2
         Consent withdrawn by subject
    -
    2
         Lost to follow-up
    -
    2
    Notes
    [2] - The number of subjects starting the period is not consistent with the number completing the preceding period. It is expected the number of subjects starting the subsequent period will be the same as the number completing the preceding period.
    Justification: Of 320 participants randomized, 301 completed Short-Term (ST) treatment period. Of 294 participants entered Long-Term (LT) treatment period, 281 completed

    Baseline characteristics

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    Baseline characteristics reporting groups
    Reporting group title
    Dapa+Saxa+Met
    Reporting group description
    Participants received dapagliflozin, 10 mg, and open-label saxagliptin 5 mg and metformin ≥1500 mg per day for up to 52 weeks

    Reporting group title
    Pla+Saxa+Met
    Reporting group description
    Participants received dapagliflozin matching placebo and open-label saxagliptin 5 mg and metformin ≥1500 mg per day for up to 52 weeks

    Reporting group values
    Dapa+Saxa+Met Pla+Saxa+Met Total
    Number of subjects
    160 160 320
    Age categorical
    Units: Subjects
        Adults (18-64 years)
    137 132 269
        Greater than or equal to 65 years
    23 28 51
    Age Continuous |
    Units: YEARS
        arithmetic mean (standard deviation)
    55.2 ± 8.61 55 ± 9.6 -
    Gender, Male/Female
    Units: Participants
        FEMALE
    90 84 174
        MALE
    70 76 146
    Age, Customized
    Units: Subjects
        < 65
    137 132 269
        >= 65
    23 28 51

    End points

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    End points reporting groups
    Reporting group title
    Dapa+Saxa+Met
    Reporting group description
    Participants received dapagliflozin, 10 mg, and open-label saxagliptin 5 mg and metformin ≥1500 mg per day for up to 52 weeks

    Reporting group title
    Pla+Saxa+Met
    Reporting group description
    Participants received dapagliflozin matching placebo and open-label saxagliptin 5 mg and metformin ≥1500 mg per day for up to 52 weeks
    Reporting group title
    Dapa+Saxa+Met
    Reporting group description
    Participants received dapagliflozin, 10 mg, and open-label saxagliptin 5 mg and metformin ≥1500 mg per day for up to 52 weeks

    Reporting group title
    Pla+Saxa+Met
    Reporting group description
    Participants received dapagliflozin matching placebo and open-label saxagliptin 5 mg and metformin ≥1500 mg per day for up to 52 weeks

    Primary: Adjusted mean change from baseline in Hemoglobin A1C (HbA1c) at Week 24

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    End point title
    Adjusted mean change from baseline in Hemoglobin A1C (HbA1c) at Week 24
    End point description
    HbA1c was measured as percent of hemoglobin by a central laboratory. HbA1c values recorded after rescue treatment or recorded more than 8 days after last dose date were excluded from this analysis. Baseline was defined as the last assessment prior to the start date and time of the first dose of the double-blind study medication. In cases where time of the first dose or time of the assessment was not available, baseline was defined as the last assessment on or prior to the date of the first dose of the double-blind study medication. HbA1c measurements were obtained during the qualification and lead-in periods and on Day 1 and Weeks 6, 12, 18, and 24 in the double-blind period.
    End point type
    Primary
    End point timeframe
    From Baseline to Week 24
    End point values
    Dapa+Saxa+Met Pla+Saxa+Met
    Number of subjects analysed
    158
    158
    Units: Percentage
        least squares mean (standard error)
    -0.82 ± 0.0686
    -0.1 ± 0.0704
    Statistical analysis title
    Primary Analysis
    Statistical analysis description
    Longitudinal repeated measures analysis
    Comparison groups
    Dapa+Saxa+Met v Pla+Saxa+Met
    Number of subjects included in analysis
    316
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    P-value
    < 0.0001 [1]
    Method
    Longitudinal Repeated Measures Analysis
    Parameter type
    Mean difference (final values)
    Point estimate
    -0.72
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    -0.91
         upper limit
    -0.53
    Variability estimate
    Standard error of the mean
    Dispersion value
    0.0964
    Notes
    [1] - Tested at alpha=0.05

    Secondary: Adjusted Mean Change From Baseline in Fasting Plasma Glucose at Week 24

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    End point title
    Adjusted Mean Change From Baseline in Fasting Plasma Glucose at Week 24
    End point description
    Data after rescue medication was excluded from this analysis. Baseline was defined as the last assessment prior to the start date and time of the first dose of the double-blind study medication. In cases where time of the first dose or time of the assessment was not available, baseline was defined as the last assessment on or prior to the date of the first dose of the double-blind study medication. FPG measurements were obtained during the qualification and lead-in periods and on Day 1 and Weeks 6, 12, 18, and 24 in the double-blind period
    End point type
    Secondary
    End point timeframe
    From Baseline to Week 24
    End point values
    Dapa+Saxa+Met Pla+Saxa+Met
    Number of subjects analysed
    158
    157
    Units: mg/dL
        least squares mean (standard error)
    -32.7 ± 2.821
    -5.3 ± 2.968
    Statistical analysis title
    Secondary Analysis
    Statistical analysis description
    Longitudinal repeated measures analysis of FPG
    Comparison groups
    Dapa+Saxa+Met v Pla+Saxa+Met
    Number of subjects included in analysis
    315
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    P-value
    < 0.0001 [2]
    Method
    Longitudinal Repeated Measures Analysis
    Parameter type
    Mean difference (final values)
    Point estimate
    -27.5
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    -35.4
         upper limit
    -19.6
    Variability estimate
    Standard error of the mean
    Dispersion value
    4.015
    Notes
    [2] - Secondary end points are tested following a sequential testing procedure at alpha=0.05

    Secondary: Adjusted mean change from baseline in 120-minute postprandial glucose (PPG) at Week 24

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    End point title
    Adjusted mean change from baseline in 120-minute postprandial glucose (PPG) at Week 24
    End point description
    2-hour postprandial glucose (PPG) from a liquid meal tolerance test (2-h MTT) Subject must be fasted for at least 8 hrs prior to the MTT.
    End point type
    Secondary
    End point timeframe
    From Baseline to Week 24
    End point values
    Dapa+Saxa+Met Pla+Saxa+Met
    Number of subjects analysed
    134
    132
    Units: mg/dL
        least squares mean (standard error)
    -73.5 ± 4.055
    -38 ± 4.104
    Statistical analysis title
    Secondary analysis
    Statistical analysis description
    ANCOVA analysis of change from baseline in 2-hour postprandial glucose during a MTT at Week 24
    Comparison groups
    Dapa+Saxa+Met v Pla+Saxa+Met
    Number of subjects included in analysis
    266
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    P-value
    < 0.0001 [3]
    Method
    Longitudinal Repeated Measures Analysis
    Parameter type
    Mean difference (final values)
    Point estimate
    -35.5
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    -46.3
         upper limit
    -24.7
    Variability estimate
    Standard error of the mean
    Dispersion value
    5.493
    Notes
    [3] - Secondary end points are tested following a sequential testing procedure at alpha=0.05

    Secondary: Adjusted mean change from baseline in body weight at week 24

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    End point title
    Adjusted mean change from baseline in body weight at week 24
    End point description
    Data after rescue medication was excluded from this analysis. Baseline was defined as the last assessment prior to the start date and time of the first dose of the double-blind study medication. In cases where time of the first dose or time of the assessment was not available, baseline was defined as the last assessment on or prior to the date of the first dose of the double-blind study medication. Body weights were measured during the qualification and lead-in periods and on Day 1 and Weeks 6, 12, 18, and 24 in the double-blind period.
    End point type
    Secondary
    End point timeframe
    From baseline to Week 24
    End point values
    Dapa+Saxa+Met Pla+Saxa+Met
    Number of subjects analysed
    158
    158
    Units: kg
        least squares mean (standard error)
    -1.91 ± 0.2191
    -0.41 ± 0.227
    Statistical analysis title
    Secondary analysis
    Statistical analysis description
    Longitudinal repeated measures model analysis of change from baseline in Total body weight at week 24
    Comparison groups
    Dapa+Saxa+Met v Pla+Saxa+Met
    Number of subjects included in analysis
    316
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    P-value
    < 0.0001 [4]
    Method
    Longitudinal Repeated Measures Analysis
    Parameter type
    Mean difference (final values)
    Point estimate
    -1.5
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    -2.12
         upper limit
    -0.89
    Variability estimate
    Standard error of the mean
    Dispersion value
    0.3126
    Notes
    [4] - Secondary endpoints are tested following a sequential testing procedure at alpha=0.05

    Secondary: Percentage of Subjects Achieving a Therapeutic Glycemic Response (Hemoglobin A1c [HbA1C]) <7.0% at Week 24 (Last Observation Carried Forward [LOCF])

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    End point title
    Percentage of Subjects Achieving a Therapeutic Glycemic Response (Hemoglobin A1c [HbA1C]) <7.0% at Week 24 (Last Observation Carried Forward [LOCF])
    End point description
    Percent adjusted for baseline HbA1c. Therapeutic glycemic response is defined as HbA1c <7.0%. Data after rescue medication was excluded from this analysis.
    End point type
    Secondary
    End point timeframe
    From baseline to week 24
    End point values
    Dapa+Saxa+Met Pla+Saxa+Met
    Number of subjects analysed
    158
    158
    Units: Percentage
        number (not applicable)
    36.7
    13.3
    Statistical analysis title
    Secondary analysis
    Statistical analysis description
    Analysis of the proportion of subjects achieving a therapeutic glycemic response (defined as HbA1c < 7.0%) at Week 24 (LOCF) using a logistic regression based on the methodology of Zhang, Tsiatis and Davidian and Tsiatis, Davidian, Zhang and Lu, with the adjustment for baseline HbA1c and stratum.
    Comparison groups
    Dapa+Saxa+Met v Pla+Saxa+Met
    Number of subjects included in analysis
    316
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    P-value
    < 0.0001 [5]
    Method
    Modified logistic regression
    Parameter type
    Mean difference (final values)
    Point estimate
    25.5
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    16.7
         upper limit
    34.4
    Notes
    [5] - Secondary end points are tested following a sequential testing procedure at alpha=0.05

    Adverse events

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    Adverse events information
    Timeframe for reporting adverse events
    From baseline to week 52
    Assessment type
    Systematic
    Dictionary used for adverse event reporting
    Dictionary name
    MedDRA
    Dictionary version
    17.1
    Reporting groups
    Reporting group title
    PLA + SAXA + MET
    Reporting group description
    Participants received dapagliflozin matching placebo and open-label saxagliptin 5 mg and metformin ≥1500 mg per day for up to 52 weeks

    Reporting group title
    DAPA + SAXA + MET
    Reporting group description
    Participants received dapagliflozin, 10 mg, and open-label saxagliptin 5 mg and metformin ≥1500 mg per day for up to 52 weeks

    Serious adverse events
    PLA + SAXA + MET DAPA + SAXA + MET
    Total subjects affected by serious adverse events
         subjects affected / exposed
    4 / 160 (2.50%)
    7 / 160 (4.38%)
         number of deaths (all causes)
    0
    1
         number of deaths resulting from adverse events
    Injury, poisoning and procedural complications
    ANKLE FRACTURE
         subjects affected / exposed
    1 / 160 (0.63%)
    0 / 160 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Investigations
    LIVER FUNCTION TEST ABNORMAL
         subjects affected / exposed
    1 / 160 (0.63%)
    0 / 160 (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)
    INVASIVE DUCTAL BREAST CARCINOMA
         subjects affected / exposed
    0 / 160 (0.00%)
    1 / 160 (0.63%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Cardiac disorders
    ANGINA UNSTABLE
         subjects affected / exposed
    0 / 160 (0.00%)
    1 / 160 (0.63%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    ACUTE MYOCARDIAL INFARCTION
         subjects affected / exposed
    0 / 160 (0.00%)
    1 / 160 (0.63%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    ATRIAL FIBRILLATION
         subjects affected / exposed
    0 / 160 (0.00%)
    1 / 160 (0.63%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    CARDIAC FAILURE
         subjects affected / exposed
    0 / 160 (0.00%)
    1 / 160 (0.63%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    CARDIAC FAILURE ACUTE
         subjects affected / exposed
    0 / 160 (0.00%)
    1 / 160 (0.63%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    VENTRICULAR TACHYCARDIA
         subjects affected / exposed
    0 / 160 (0.00%)
    1 / 160 (0.63%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Respiratory, thoracic and mediastinal disorders
    CHRONIC OBSTRUCTIVE PULMONARY DISEASE
         subjects affected / exposed
    0 / 160 (0.00%)
    1 / 160 (0.63%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Blood and lymphatic system disorders
    THROMBOCYTOPENIA
         subjects affected / exposed
    0 / 160 (0.00%)
    1 / 160 (0.63%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Gastrointestinal disorders
    GASTRIC ULCER
         subjects affected / exposed
    1 / 160 (0.63%)
    0 / 160 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Infections and infestations
    ABSCESS LIMB
         subjects affected / exposed
    1 / 160 (0.63%)
    0 / 160 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    APPENDICITIS
         subjects affected / exposed
    0 / 160 (0.00%)
    1 / 160 (0.63%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    GANGRENE
         subjects affected / exposed
    1 / 160 (0.63%)
    0 / 160 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    POSTOPERATIVE WOUND INFECTION
         subjects affected / exposed
    0 / 160 (0.00%)
    1 / 160 (0.63%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Frequency threshold for reporting non-serious adverse events: 2%
    Non-serious adverse events
    PLA + SAXA + MET DAPA + SAXA + MET
    Total subjects affected by non serious adverse events
         subjects affected / exposed
    112 / 160 (70.00%)
    103 / 160 (64.38%)
    Injury, poisoning and procedural complications
    CONTUSION
         subjects affected / exposed
    4 / 160 (2.50%)
    1 / 160 (0.63%)
         occurrences all number
    4
    1
    Respiratory, thoracic and mediastinal disorders
    COUGH
         subjects affected / exposed
    3 / 160 (1.88%)
    5 / 160 (3.13%)
         occurrences all number
    3
    5
    Nervous system disorders
    DIZZINESS
         subjects affected / exposed
    0 / 160 (0.00%)
    6 / 160 (3.75%)
         occurrences all number
    0
    6
    HEADACHE
         subjects affected / exposed
    13 / 160 (8.13%)
    11 / 160 (6.88%)
         occurrences all number
    15
    16
    General disorders and administration site conditions
    CHEST PAIN
         subjects affected / exposed
    4 / 160 (2.50%)
    1 / 160 (0.63%)
         occurrences all number
    5
    1
    Psychiatric disorders
    DEPRESSION
         subjects affected / exposed
    5 / 160 (3.13%)
    0 / 160 (0.00%)
         occurrences all number
    5
    0
    Gastrointestinal disorders
    DIARRHOEA
         subjects affected / exposed
    9 / 160 (5.63%)
    7 / 160 (4.38%)
         occurrences all number
    11
    7
    ABDOMINAL PAIN
         subjects affected / exposed
    3 / 160 (1.88%)
    4 / 160 (2.50%)
         occurrences all number
    3
    4
    DYSPEPSIA
         subjects affected / exposed
    4 / 160 (2.50%)
    2 / 160 (1.25%)
         occurrences all number
    4
    2
    NAUSEA
         subjects affected / exposed
    8 / 160 (5.00%)
    4 / 160 (2.50%)
         occurrences all number
    9
    4
    Hepatobiliary disorders
    HEPATIC STEATOSIS
         subjects affected / exposed
    4 / 160 (2.50%)
    1 / 160 (0.63%)
         occurrences all number
    4
    1
    Skin and subcutaneous tissue disorders
    RASH
         subjects affected / exposed
    4 / 160 (2.50%)
    0 / 160 (0.00%)
         occurrences all number
    4
    0
    Musculoskeletal and connective tissue disorders
    ARTHRALGIA
         subjects affected / exposed
    2 / 160 (1.25%)
    4 / 160 (2.50%)
         occurrences all number
    2
    4
    MUSCLE SPASMS
         subjects affected / exposed
    6 / 160 (3.75%)
    2 / 160 (1.25%)
         occurrences all number
    6
    2
    BACK PAIN
         subjects affected / exposed
    10 / 160 (6.25%)
    5 / 160 (3.13%)
         occurrences all number
    10
    5
    MUSCULOSKELETAL PAIN
         subjects affected / exposed
    4 / 160 (2.50%)
    3 / 160 (1.88%)
         occurrences all number
    4
    4
    PAIN IN EXTREMITY
         subjects affected / exposed
    6 / 160 (3.75%)
    3 / 160 (1.88%)
         occurrences all number
    6
    3
    Metabolism and nutrition disorders
    DYSLIPIDAEMIA
         subjects affected / exposed
    3 / 160 (1.88%)
    7 / 160 (4.38%)
         occurrences all number
    3
    7
    HYPERTRIGLYCERIDAEMIA
         subjects affected / exposed
    9 / 160 (5.63%)
    5 / 160 (3.13%)
         occurrences all number
    10
    5
    Infections and infestations
    INFLUENZA
         subjects affected / exposed
    12 / 160 (7.50%)
    12 / 160 (7.50%)
         occurrences all number
    14
    14
    NASOPHARYNGITIS
         subjects affected / exposed
    8 / 160 (5.00%)
    5 / 160 (3.13%)
         occurrences all number
    9
    5
    URINARY TRACT INFECTION
         subjects affected / exposed
    16 / 160 (10.00%)
    15 / 160 (9.38%)
         occurrences all number
    19
    19
    PHARYNGITIS
         subjects affected / exposed
    3 / 160 (1.88%)
    6 / 160 (3.75%)
         occurrences all number
    3
    6
    VULVOVAGINAL MYCOTIC INFECTION
         subjects affected / exposed
    1 / 160 (0.63%)
    7 / 160 (4.38%)
         occurrences all number
    1
    9

    More information

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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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