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    Clinical Trial Results:
    Efficacy and safety of semaglutide versus canagliflozin as add-on to metformin in subjects with type 2 diabetes

    Summary
    EudraCT number
    		 2016-000989-35
    Trial protocol
    		 SE   IE   GB  
    Global end of trial date
    16 Nov 2018

    Results information
    Results version number
    		 v1(current)
    This version publication date
    03 Dec 2019
    First version publication date
    03 Dec 2019
    Other versions

    Trial information

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    Trial identification
    Sponsor protocol code
    NN9535-4270
    Additional study identifiers
    ISRCTN number
    		 -
    US NCT number
    		 NCT03136484
    WHO universal trial number (UTN)
    		 U1111-1180-3651
    Sponsors
    Sponsor organisation name
    Novo Nordisk A/S
    Sponsor organisation address
    Novo Allé, Bagsvaerd, Denmark, 2880
    Public contact
    Clinical Reporting Anchor and Disclosure (1452), Novo Nordisk A/S, +1 866 8677178, clinicaltrials@novonordisk.com
    Scientific contact
    Clinical Reporting Anchor and Disclosure (1452), Novo Nordisk A/S, +1 866 8677178, clinicaltrials@novonordisk.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
    05 Jun 2019
    Is this the analysis of the primary completion data?
    Yes
    Primary completion date
    16 Oct 2018
    Global end of trial reached?
    Yes
    Global end of trial date
    16 Nov 2018
    Was the trial ended prematurely?
    No
    General information about the trial
    Main objective of the trial
    To compare the effect of once-weekly dosing of semaglutide subcutaneous (s.c.) 1.0 milligrams (mg) versus once-daily dosing of oral canagliflozin 300 mg on glycaemic control in subjects with type 2 diabetes (T2D) on a background treatment of metformin.
    Protection of trial subjects
    The trial was conducted in accordance with the Declaration of Helsinki (2013) and ICH Good Clinical Practice, including archiving of essential documents, (1996) and FDA 21 CFR 312.120.
    Background therapy
    		 Subjects were to be on a stable treatment for at least 90 days prior to screening with metformin (≥1500 mg or maximum tolerated dose) and the medication was to be maintained at the stable, pre-trial dose and frequency during the whole treatment period unless rescue medication was needed.
    Evidence for comparator
    		 -
    Actual start date of recruitment
    23 Jan 2017
    Long term follow-up planned
    No
    Independent data monitoring committee (IDMC) involvement?
    No
    Population of trial subjects
    Number of subjects enrolled per country
    Country: Number of subjects enrolled
    Argentina: 74
    Country: Number of subjects enrolled
    Brazil: 42
    Country: Number of subjects enrolled
    Canada: 50
    Country: Number of subjects enrolled
    United Kingdom: 91
    Country: Number of subjects enrolled
    India: 50
    Country: Number of subjects enrolled
    Ireland: 29
    Country: Number of subjects enrolled
    Lebanon: 29
    Country: Number of subjects enrolled
    Mexico: 56
    Country: Number of subjects enrolled
    Malaysia: 33
    Country: Number of subjects enrolled
    Sweden: 34
    Country: Number of subjects enrolled
    United States: 300
    Worldwide total number of subjects
    788
    EEA total number of subjects
    154
    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)
    595
    From 65 to 84 years
    193
    85 years and over
    0

    Subject disposition

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    Recruitment
    Recruitment details
    		 The trial was conducted at 115 sites in 11 countries as follows: Argentina (5), Brazil (2), Canada (8), India (10), Ireland (4), Lebanon (5), Malaysia (5), Mexico (2), Sweden (5), United Kingdom (11) and United States (58).

    Pre-assignment
    Screening details
    		 Study design: Body composition (sub-study) was measured using dual x-ray absorptiometry (DXA) scans in a planned subset of randomised subjects.

    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
    Blinding implementation details
    For semaglutide and canagliflozin, the active trial product and the corresponding placebo solutions or tablets were visually identical. The clinical study group and the investigator remained blinded throughout the trial. The blinding was maintained until the database had been released for statistical analysis after database lock (DBL).

    Arms
    Are arms mutually exclusive
    Yes

    Arm title
    		 Semaglutide + canagliflozin placebo
    Arm description
    		 Subjects received subcutaneous (s.c.) injection of semaglutide once-weekly for 52 weeks. Subjects also received placebo matched to canagliflozin tablet once-daily for 52 weeks.
    Arm type
    		 Experimental

    Investigational medicinal product name
    Canagliflozin placebo
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Film-coated tablet
    Routes of administration
    Oral use
    Dosage and administration details
    Subjects received placebo matched to canagliflozin tablet once-daily for 52 weeks. Canagliflozin placebo tablets were to be taken orally once daily, swallowed whole, preferably before the first meal of the day.

    Investigational medicinal product name
    Semaglutide
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Solution for injection
    Routes of administration
    Subcutaneous use
    Dosage and administration details
    Subjects received s.c. injection of semaglutide once-weekly for 52 weeks: 0.25 mg during weeks 0-4 followed by 0.5 mg during weeks 5-8 and then 1.0 mg during weeks 9-52. Semaglutide 1.5 mL prefilled PDS290 pen-injectors were to be administered s.c. in the thigh, abdomen or upper arm, once-weekly on the same day of the week and at any time of the day irrespective of meals.

    Arm title
    		 Canagliflozin + semaglutide placebo
    Arm description
    		 Subjects received canagliflozin tablet once-daily orally for 52 weeks. Subjects also received placebo matched to semaglutide s.c. injection once-weekly for 52 weeks.
    Arm type
    		 Active comparator

    Investigational medicinal product name
    Canagliflozin
    Investigational medicinal product code
    Other name
    Invokana 100 mg
    Pharmaceutical forms
    Film-coated tablet
    Routes of administration
    Oral use
    Dosage and administration details
    Subjects received canagliflozin tablet once-daily orally for 52 weeks: 100 mg tablet during weeks 0-8 followed by 300 mg tablet during weeks 9-52. Canagliflozin tablets were to be taken orally once daily, swallowed whole, preferably before the first meal of the day.

    Investigational medicinal product name
    Semaglutide placebo
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Solution for injection
    Routes of administration
    Subcutaneous use
    Dosage and administration details
    Subjects received placebo matched to semaglutide s.c. injection once-weekly for 52 weeks. Semaglutide placebo in 1.5 mL prefilled PDS290 pen-injectors were to be administered s.c. in the thigh, abdomen or upper arm, once-weekly on the same day of the week and at any time of the day irrespective of meals.

    Number of subjects in period 1
    		Semaglutide + canagliflozin placebo Canagliflozin + semaglutide placebo
    Started
    394
    394
    Completed
    367
    372
    Not completed
    27
    22
         Death
    1
    -
         Withdrawal by Subject
    19
    14
         Lost to follow-up
    7
    8

    Baseline characteristics

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    Baseline characteristics reporting groups
    Reporting group title
    Semaglutide + canagliflozin placebo
    Reporting group description
    		 Subjects received subcutaneous (s.c.) injection of semaglutide once-weekly for 52 weeks. Subjects also received placebo matched to canagliflozin tablet once-daily for 52 weeks.

    Reporting group title
    Canagliflozin + semaglutide placebo
    Reporting group description
    		 Subjects received canagliflozin tablet once-daily orally for 52 weeks. Subjects also received placebo matched to semaglutide s.c. injection once-weekly for 52 weeks.

    Reporting group values
    		 Semaglutide + canagliflozin placebo Canagliflozin + semaglutide placebo Total
    Number of subjects
    		 394 394 788
    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)
    		 312 283 595
        From 65-84 years
    		 82 111 193
        85 years and over
    		 0 0 0
    Age Continuous
    Units: years
        arithmetic mean (standard deviation)
    		 55.7 ( 11.1 ) 57.5 ( 10.7 ) -
    Gender Categorical
    Units: Subjects
        Female
    		 171 193 364
        Male
    		 223 201 424
    HbA1c
    Units: Percentage (%) of HbA1c
        arithmetic mean (standard deviation)
    		 8.3 ( 1.0 ) 8.2 ( 1.0 ) -

    End points

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    End points reporting groups
    Reporting group title
    Semaglutide + canagliflozin placebo
    Reporting group description
    		 Subjects received subcutaneous (s.c.) injection of semaglutide once-weekly for 52 weeks. Subjects also received placebo matched to canagliflozin tablet once-daily for 52 weeks.

    Reporting group title
    Canagliflozin + semaglutide placebo
    Reporting group description
    		 Subjects received canagliflozin tablet once-daily orally for 52 weeks. Subjects also received placebo matched to semaglutide s.c. injection once-weekly for 52 weeks.

    Primary: Change in HbA1c

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    End point title
    		 Change in HbA1c
    End point description
    Change from baseline (week 0) to week 52 in glycosylated haemoglobin (HbA1c) was evaluated for full analysis set which comprised of all randomised subjects. Results are based on the 'on-treatment without rescue medication' observation period, which started at the date of first dose to either the day of last dose plus 7 days or first initiation of rescue medication, whichever came first; and 'In-trial' observation period which started at the date of randomisation and include the period after initiation of rescue medication and/or premature trial product discontinuation, if any and ended at the last contact, withdrawal of consent or death, whichever came first. 'n' is the number of subjects (subjects with available data) analysed for the respective reporting group.
    End point type
    Primary
    End point timeframe
    From baseline to week 52
    End point values
    		 Semaglutide + canagliflozin placebo Canagliflozin + semaglutide placebo
    Number of subjects analysed
    394
    394
    Units: Percentage (%) of HbA1c
    arithmetic mean (standard deviation)
        On-treatment without rescue medication (n=293,313)
    -1.7 ( 1.1 )
    -1.0 ( 1.0 )
        In-trial (n=361,362)
    -1.5 ( 1.3 )
    -1.0 ( 1.1 )
    Statistical analysis title
    		 Primary non-inferiority analysis
    Statistical analysis description
    The responses were analysed using an analysis of covariance (ANCOVA) with treatment, region and stratification factor as fixed factors and baseline value as covariate. Before analysis, missing data were multiple imputed using observed data from participants within the same group defined by randomised treatment, using a regression model including region and stratification factor as categorical effects and data from baseline and all previous visits as covariates.
    Comparison groups
    Canagliflozin + semaglutide placebo v Semaglutide + canagliflozin placebo
    Number of subjects included in analysis
    788
    Analysis specification
    Pre-specified
    Analysis type
    		 non-inferiority [1]
    P-value
    		 < 0.0001 [2]
    Method
    		 ANCOVA
    Parameter type
    		 Treatment difference
    Point estimate
    -0.49
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -0.65
         upper limit
    		 -0.33
    Notes
    [1] - "Number of subjects in this analysis" is being erroneously shown as '788'. Actual number of subjects contributed to the analysis and with measurement at week 52 = 606.
    [2] - The non-inferiority p-value was calculated as two times the one-sided p-value from a t-distributed test statistic comparing the treatment contrast with 0.3 rather than zero as in a superiority test.
    Statistical analysis title
    		 Primary superiority analysis
    Statistical analysis description
    The responses were analysed using an ANCOVA with treatment, region and stratification factor as fixed factors and baseline value as covariate. Before analysis, missing data were multiple imputed using observed data from participants within the same group defined by randomised treatment, using a regression model including region and stratification factor as categorical effects and data from baseline and all previous visits as covariates.
    Comparison groups
    Semaglutide + canagliflozin placebo v Canagliflozin + semaglutide placebo
    Number of subjects included in analysis
    788
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority [3]
    P-value
    		 < 0.0001
    Method
    		 ANCOVA
    Parameter type
    		 Treatment difference
    Point estimate
    -0.49
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -0.65
         upper limit
    		 -0.33
    Notes
    [3] - "Number of subjects in this analysis" is being erroneously shown as '788'. Actual number of subjects contributed to the analysis and with measurement at week 52 = 606.

    Secondary: Change in Fasting Plasma Glucose (FPG)

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    End point title
    		 Change in Fasting Plasma Glucose (FPG)
    End point description
    Change from baseline (week 0) to week 52 in FPG was evaluated for full analysis set which comprised of all randomised subjects. Results are based on the 'on-treatment without rescue medication' observation period, which started at the date of first dose to either the day of last dose plus 7 days or first initiation of rescue medication, whichever came first. "Number of subjects analyzed"= subjects with available data.
    End point type
    Secondary
    End point timeframe
    From baseline to week 52
    End point values
    		 Semaglutide + canagliflozin placebo Canagliflozin + semaglutide placebo
    Number of subjects analysed
    293
    305
    Units: Millimoles per liter (mmol/L)
        arithmetic mean (standard deviation)
    -2.54 ( 2.77 )
    -2.00 ( 2.53 )
    No statistical analyses for this end point

    Secondary: Change in systolic and diastolic blood pressure

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    End point title
    		 Change in systolic and diastolic blood pressure
    End point description
    Change from baseline (week 0) to week 52 in systolic blood pressure and diastolic blood pressure was evaluated for full analysis set which comprised of all randomised subjects. Results are based on the 'on-treatment without rescue medication' observation period, which started at the date of first dose to either the day of last dose plus 7 days or first initiation of rescue medication, whichever came first. 'n' is the number of subjects (subjects with available data) analysed for the respective reporting group.
    End point type
    Secondary
    End point timeframe
    From baseline to week 52
    End point values
    		 Semaglutide + canagliflozin placebo Canagliflozin + semaglutide placebo
    Number of subjects analysed
    298
    313
    Units: Millimeters of mercury (mmHg)
    arithmetic mean (standard deviation)
        Systolic blood pressure (n=298,313)
    -3.7 ( 14.0 )
    -5.8 ( 13.5 )
        Diastolic blood pressure (n=298,313)
    -1.2 ( 9.8 )
    -2.9 ( 9.0 )
    No statistical analyses for this end point

    Secondary: Change in Diabetes Treatment Satisfaction Questionnaire (DTSQ): Treatment satisfaction score (sum of 6 of 8 items) and the 8 items separately

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    End point title
    		 Change in Diabetes Treatment Satisfaction Questionnaire (DTSQ): Treatment satisfaction score (sum of 6 of 8 items) and the 8 items separately
    End point description
    Change from baseline (week 0) in DTSQ was evaluated for full analysis set comprised of all randomised subjects. The DTSQs items are scored on a 7-point graded response scale ranging from 6 to 0. Higher scores indicate higher levels of treatment satisfaction for DTSQs items 1, 4 -8. For items 2 and 3 a higher score indicate higher patient perceived experience of high blood sugars and low blood sugars, respectively. Thus, lower scores indicate a perception of blood glucose levels being “none of the time” unacceptably high (item 2) or low (item 3). The domain score of total treatment satisfaction (total treatment satisfaction score) was computed by adding the six items scores 1, 4-8. The score ranges 0-36. A higher treatment satisfaction score indicates a higher level of treatment satisfaction. Results are based on the 'on-treatment without rescue medication' observation period. 'n' is the number of subjects (subjects with available data) analysed for the respective reporting group.
    End point type
    Secondary
    End point timeframe
    From baseline to week 52
    End point values
    		 Semaglutide + canagliflozin placebo Canagliflozin + semaglutide placebo
    Number of subjects analysed
    263
    280
    Units: Score on a scale
    arithmetic mean (standard deviation)
        1)Satisfaction with treatment (n=263,280)
    1.4 ( 1.6 )
    1.0 ( 1.6 )
        2)Experienced high blood sugar (n=263,280)
    -2.0 ( 2.2 )
    -1.8 ( 2.2 )
        3)Experienced low blood sugar (n=263,280)
    0.1 ( 1.9 )
    0.1 ( 1.6 )
        4)Convenience of treatment (n=263,280)
    0.8 ( 1.8 )
    0.7 ( 1.8 )
        5)Flexibility of current treatment (n=263,280)
    0.8 ( 1.7 )
    0.7 ( 1.7 )
        6)Satisfied understanding diabetes (n=263,280)
    0.8 ( 1.5 )
    0.6 ( 1.3 )
        7)Recommending treatment to others (n=263,280)
    0.9 ( 1.5 )
    0.9 ( 1.5 )
        8)Satisfied to continue treatment (n=263,280)
    1.1 ( 1.8 )
    0.8 ( 1.8 )
        Total treatment satisfaction score (n=263,280)
    5.8 ( 7.0 )
    4.8 ( 7.2 )
    No statistical analyses for this end point

    Adverse events

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    Adverse events information
    Timeframe for reporting adverse events
    From the date of first dose of trial product (week 0) to end of treatment (week 52) + 42 days
    Adverse event reporting additional description
    Evaluation of safety was based on SAS which comprised of all randomised participants who received at least one dose of trial product. ‘Number of deaths causally related to treatment’ is the data considered to present under ‘total number of deaths resulting from adverse events’.
    Assessment type
    		 Systematic
    Dictionary used for adverse event reporting
    Dictionary name
    		 MedDRA
    Dictionary version
    21.0
    Reporting groups
    Reporting group title
    Canagliflozin + semaglutide placebo
    Reporting group description
    		 Subjects received canagliflozin tablet once-daily orally for 52 weeks. Subjects also received placebo matched to semaglutide s.c. injection once-weekly for 52 weeks.

    Reporting group title
    Semaglutide + canagliflozin placebo
    Reporting group description
    		 Subjects received s.c. injection of semaglutide once-weekly for 52 weeks. Subjects also received placebo matched to canagliflozin tablet once-daily for 52 weeks.

    Serious adverse events
    		 Canagliflozin + semaglutide placebo Semaglutide + canagliflozin placebo
    Total subjects affected by serious adverse events
         subjects affected / exposed
    21 / 394 (5.33%)
    18 / 392 (4.59%)
         number of deaths (all causes)
    0
    1
         number of deaths resulting from adverse events
    0
    0
    Neoplasms benign, malignant and unspecified (incl cysts and polyps)
    Prostate cancer metastatic
         subjects affected / exposed
    1 / 394 (0.25%)
    0 / 392 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Vascular disorders
    Arteriosclerosis
         subjects affected / exposed
    0 / 394 (0.00%)
    1 / 392 (0.26%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    Deep vein thrombosis
         subjects affected / exposed
    0 / 394 (0.00%)
    1 / 392 (0.26%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    General disorders and administration site conditions
    Chest pain
         subjects affected / exposed
    1 / 394 (0.25%)
    0 / 392 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Non-cardiac chest pain
         subjects affected / exposed
    1 / 394 (0.25%)
    1 / 392 (0.26%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pyrexia
         subjects affected / exposed
    2 / 394 (0.51%)
    0 / 392 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Reproductive system and breast disorders
    Bartholin's cyst
         subjects affected / exposed
    1 / 394 (0.25%)
    0 / 392 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Prostatism
         subjects affected / exposed
    1 / 394 (0.25%)
    0 / 392 (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
    Chronic obstructive pulmonary disease
         subjects affected / exposed
    0 / 394 (0.00%)
    1 / 392 (0.26%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pulmonary embolism
         subjects affected / exposed
    0 / 394 (0.00%)
    1 / 392 (0.26%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Psychiatric disorders
    Bipolar disorder
         subjects affected / exposed
    1 / 394 (0.25%)
    0 / 392 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Confusional state
         subjects affected / exposed
    0 / 394 (0.00%)
    1 / 392 (0.26%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Investigations
    Glomerular filtration rate decreased
         subjects affected / exposed
    0 / 394 (0.00%)
    1 / 392 (0.26%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Transaminases increased
         subjects affected / exposed
    1 / 394 (0.25%)
    0 / 392 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Injury, poisoning and procedural complications
    Airway complication of anaesthesia
         subjects affected / exposed
    0 / 394 (0.00%)
    1 / 392 (0.26%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Ankle fracture
         subjects affected / exposed
    1 / 394 (0.25%)
    0 / 392 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Femur fracture
         subjects affected / exposed
    1 / 394 (0.25%)
    0 / 392 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Patella fracture
         subjects affected / exposed
    0 / 394 (0.00%)
    1 / 392 (0.26%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Post procedural haematuria
         subjects affected / exposed
    0 / 394 (0.00%)
    1 / 392 (0.26%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Prescribed overdose
         subjects affected / exposed
    1 / 394 (0.25%)
    0 / 392 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Road traffic accident
         subjects affected / exposed
    0 / 394 (0.00%)
    1 / 392 (0.26%)
         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
    1 / 394 (0.25%)
    0 / 392 (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
         subjects affected / exposed
    1 / 394 (0.25%)
    0 / 392 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Coronary artery stenosis
         subjects affected / exposed
    1 / 394 (0.25%)
    0 / 392 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Myocardial ischaemia
         subjects affected / exposed
    0 / 394 (0.00%)
    1 / 392 (0.26%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Nervous system disorders
    Aphasia
         subjects affected / exposed
    0 / 394 (0.00%)
    1 / 392 (0.26%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Basal ganglia haemorrhage
         subjects affected / exposed
    1 / 394 (0.25%)
    0 / 392 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Ischaemic stroke
         subjects affected / exposed
    0 / 394 (0.00%)
    1 / 392 (0.26%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Transient ischaemic attack
         subjects affected / exposed
    1 / 394 (0.25%)
    0 / 392 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Blood and lymphatic system disorders
    Splenomegaly
         subjects affected / exposed
    1 / 394 (0.25%)
    0 / 392 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Ear and labyrinth disorders
    Vertigo
         subjects affected / exposed
    1 / 394 (0.25%)
    0 / 392 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Eye disorders
    Cataract
         subjects affected / exposed
    0 / 394 (0.00%)
    1 / 392 (0.26%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Retinal infarction
         subjects affected / exposed
    0 / 394 (0.00%)
    1 / 392 (0.26%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Gastrointestinal disorders
    Abdominal pain upper
         subjects affected / exposed
    0 / 394 (0.00%)
    1 / 392 (0.26%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Ascites
         subjects affected / exposed
    1 / 394 (0.25%)
    0 / 392 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Diarrhoea
         subjects affected / exposed
    0 / 394 (0.00%)
    1 / 392 (0.26%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Gastritis
         subjects affected / exposed
    1 / 394 (0.25%)
    0 / 392 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Haemorrhoids thrombosed
         subjects affected / exposed
    1 / 394 (0.25%)
    0 / 392 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Small intestinal obstruction
         subjects affected / exposed
    1 / 394 (0.25%)
    0 / 392 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Hepatobiliary disorders
    Cholecystitis chronic
         subjects affected / exposed
    1 / 394 (0.25%)
    0 / 392 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Cholelithiasis
         subjects affected / exposed
    3 / 394 (0.76%)
    0 / 392 (0.00%)
         occurrences causally related to treatment / all
    0 / 3
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Hepatic cirrhosis
         subjects affected / exposed
    1 / 394 (0.25%)
    0 / 392 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Renal and urinary disorders
    Hydronephrosis
         subjects affected / exposed
    0 / 394 (0.00%)
    1 / 392 (0.26%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Nephrolithiasis
         subjects affected / exposed
    0 / 394 (0.00%)
    2 / 392 (0.51%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Ureterolithiasis
         subjects affected / exposed
    0 / 394 (0.00%)
    1 / 392 (0.26%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Infections and infestations
    Cellulitis gangrenous
         subjects affected / exposed
    1 / 394 (0.25%)
    0 / 392 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Cellulitis staphylococcal
         subjects affected / exposed
    1 / 394 (0.25%)
    0 / 392 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Lower respiratory tract infection
         subjects affected / exposed
    1 / 394 (0.25%)
    0 / 392 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Perirectal abscess
         subjects affected / exposed
    1 / 394 (0.25%)
    0 / 392 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pneumonia
         subjects affected / exposed
    1 / 394 (0.25%)
    1 / 392 (0.26%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Respiratory tract infection viral
         subjects affected / exposed
    1 / 394 (0.25%)
    0 / 392 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Urinary tract infection
         subjects affected / exposed
    0 / 394 (0.00%)
    3 / 392 (0.77%)
         occurrences causally related to treatment / all
    0 / 0
    3 / 3
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Urosepsis
         subjects affected / exposed
    0 / 394 (0.00%)
    1 / 392 (0.26%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Vulval abscess
         subjects affected / exposed
    1 / 394 (0.25%)
    0 / 392 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Metabolism and nutrition disorders
    Hypokalaemia
         subjects affected / exposed
    0 / 394 (0.00%)
    1 / 392 (0.26%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Hypomagnesaemia
         subjects affected / exposed
    0 / 394 (0.00%)
    1 / 392 (0.26%)
         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: 5%
    Non-serious adverse events
    		 Canagliflozin + semaglutide placebo Semaglutide + canagliflozin placebo
    Total subjects affected by non serious adverse events
         subjects affected / exposed
    120 / 394 (30.46%)
    185 / 392 (47.19%)
    Nervous system disorders
    Headache
         subjects affected / exposed
    27 / 394 (6.85%)
    26 / 392 (6.63%)
         occurrences all number
    47
    48
    Gastrointestinal disorders
    Constipation
         subjects affected / exposed
    23 / 394 (5.84%)
    20 / 392 (5.10%)
         occurrences all number
    23
    20
    Diarrhoea
         subjects affected / exposed
    37 / 394 (9.39%)
    59 / 392 (15.05%)
         occurrences all number
    58
    94
    Dyspepsia
         subjects affected / exposed
    8 / 394 (2.03%)
    22 / 392 (5.61%)
         occurrences all number
    8
    23
    Nausea
         subjects affected / exposed
    26 / 394 (6.60%)
    89 / 392 (22.70%)
         occurrences all number
    30
    127
    Vomiting
         subjects affected / exposed
    9 / 394 (2.28%)
    50 / 392 (12.76%)
         occurrences all number
    9
    77
    Musculoskeletal and connective tissue disorders
    Back pain
         subjects affected / exposed
    21 / 394 (5.33%)
    11 / 392 (2.81%)
         occurrences all number
    21
    11
    Infections and infestations
    Nasopharyngitis
         subjects affected / exposed
    26 / 394 (6.60%)
    23 / 392 (5.87%)
         occurrences all number
    34
    25
    Metabolism and nutrition disorders
    Decreased appetite
         subjects affected / exposed
    6 / 394 (1.52%)
    26 / 392 (6.63%)
         occurrences all number
    6
    26

    More information

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    Substantial protocol amendments (globally)
    Were there any global substantial amendments to the protocol? Yes
    Date
    Amendment
    16 Dec 2016
    This protocol amendment introduced: 1. Risk-mitigation strategy for the risk of lower limb amputations potentially associated with canagliflozin. This strategy included additional exclusion and premature discontinuation criteria, physical examination of legs and feet at every site visits and description of this potential risk. 2. Updated identified risks for semaglutide. 3. Other minor corrections and clarifications.

    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

    Online references
    http://www.ncbi.nlm.nih.gov/pubmed/31540867
    For support, Contact us.
    The status and protocol content of GB trials is no longer updated since 1 January 2021. For the UK, as of 31 January 2021, EU Law applies only to the territory of Northern Ireland (NI) to the extent foreseen in the Protocol on Ireland/NI. Legal notice
    As of 31 January 2023, all EU/EEA initial clinical trial applications must be submitted through CTIS . Updated EudraCT trials information and information on PIP/Art 46 trials conducted exclusively in third countries continues to be submitted through EudraCT and published on this website.

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