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    Clinical Trial Results:
    A Randomized, Double-Blind, 5-Arm, Parallel-Group, 26-Week, Multicenter Study to Evaluate the Efficacy, Safety, and Tolerability of Canagliflozin in Combination With Metformin as Initial Combination Therapy in the Treatment of Subjects With Type 2 Diabetes Mellitus With Inadequate Glycemic Control With Diet and Exercise

    Due to the EudraCT – Results system being out of service between 31 July 2015 and 12 January 2016, these results have been published in compliance with revised timelines.
    Summary
    EudraCT number
    		 2011-000400-17
    Trial protocol
    		 HU   CZ   SK  
    Global end of trial date
    01 Dec 2014

    Results information
    Results version number
    		 v1(current)
    This version publication date
    30 Apr 2016
    First version publication date
    30 Apr 2016
    Other versions

    Trial information

    		 Close Top of page
    Trial identification
    Sponsor protocol code
    28431754DIA3011
    Additional study identifiers
    ISRCTN number
    		 -
    US NCT number
    		 NCT01809327
    WHO universal trial number (UTN)
    		 -
    Sponsors
    Sponsor organisation name
    Janssen Research & Development, LLC
    Sponsor organisation address
    Antwerpseweg 15-17, Beerse, Belgium, B-2340
    Public contact
    Clinical Registry Group-JB BV, Janssen Research and Development, ClinicalTrialsEU@its.jnj.com
    Scientific contact
    Clinical Registry Group-JB BV, Janssen Research and Development, ClinicalTrialsEU@its.jnj.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
    01 Dec 2014
    Is this the analysis of the primary completion data?
    No
    Global end of trial reached?
    Yes
    Global end of trial date
    01 Dec 2014
    Was the trial ended prematurely?
    No
    General information about the trial
    Main objective of the trial
    The purpose of this study to assess the effect of the co-administration of canagliflozin and metformin extended-release (XR) compared with canagliflozin alone on hemoglobin A1c (HbA1c). To assess the effect of the co-administration of canagliflozin and metformin XR compared with metformin XR alone on HbA1c. To assess the safety and tolerability of the co-administration of canagliflozin and metformin XR, canagliflozin alone, and metformin XR alone
    Protection of trial subjects
    Safety evaluations included the collection of adverse events, safety laboratory tests (including chemistry, hematology, and urinalysis), vital signs (blood pressures and pulse rates), body weight, physical examinations, self-monitored blood glucose (SMBG), and collection of potential hypoglycemic episodes.
    Background therapy
    		 -
    Evidence for comparator
    		 -
    Actual start date of recruitment
    16 May 2013
    Long term follow-up planned
    No
    Independent data monitoring committee (IDMC) involvement?
    Yes
    Population of trial subjects
    Number of subjects enrolled per country
    Country: Number of subjects enrolled
    Argentina: 89
    Country: Number of subjects enrolled
    Brazil: 4
    Country: Number of subjects enrolled
    Czech Republic: 34
    Country: Number of subjects enrolled
    Hungary: 28
    Country: Number of subjects enrolled
    Mexico: 159
    Country: Number of subjects enrolled
    Korea, Republic of: 12
    Country: Number of subjects enrolled
    Romania: 102
    Country: Number of subjects enrolled
    Russian Federation: 202
    Country: Number of subjects enrolled
    Slovakia: 69
    Country: Number of subjects enrolled
    South Africa: 22
    Country: Number of subjects enrolled
    Ukraine: 242
    Country: Number of subjects enrolled
    United States: 223
    Worldwide total number of subjects
    1186
    EEA total number of subjects
    233
    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)
    990
    From 65 to 84 years
    196
    85 years and over
    0

    Subject disposition

    		 Close Top of page
    Recruitment
    Recruitment details
    		 This study was conducted in 158 centers in 12 countries from 16 May 2013 to 01 December 2014.

    Pre-assignment
    Screening details
    		 A total of 2,000 subjects were screened and a total of 1,186 subjects were randomly assigned to study treatment.

    Period 1
    Period 1 title
    Overall Study (overall period)
    Is this the baseline period?
    		 Yes
    Allocation method
    Randomised - controlled
    Blinding used
    		 Double blind
    Roles blinded
    		 Subject, Investigator, Carer, Assessor

    Arms
    Are arms mutually exclusive
    Yes

    Arm title
    		 Metformin XR
    Arm description
    		 Subjects received metformin extended release (XR) tablets (in doses titrated over 9 weeks) once daily with the evening meal, plus one placebo capsule before the morning meal and one placebo capsule with the evening meal (to match the canagliflozin capsules administered in other treatment arms) for 26 weeks.
    Arm type
    		 Experimental

    Investigational medicinal product name
    Placebo Capsule
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Capsule
    Routes of administration
    Oral use
    Dosage and administration details
    One placebo capsule was taken before the morning meal and one placebo capsule was taken with evening meal for 26 weeks

    Investigational medicinal product name
    Metformin
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Film-coated tablet
    Routes of administration
    Oral use
    Dosage and administration details
    Subjects received metformin extended release (XR) tablets (in doses titrated over 9 weeks) once daily with the evening meal for 26 weeks.

    Arm title
    		 Canagliflozin 100 mg
    Arm description
    		 Subjects received one 100 milligram (mg) canagliflozin capsule before the morning meal and one matching placebo capsule with the evening meal plus placebo tablets with the evening meal (to match the metformin XR tablets administered in other treatment arms) for 26 weeks.
    Arm type
    		 Experimental

    Investigational medicinal product name
    Canagliflozin 100 mg
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Capsule
    Routes of administration
    Oral use
    Dosage and administration details
    One 100 mg capsule taken orally once daily before the morning meal

    Investigational medicinal product name
    Placebo Tablet
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Film-coated tablet
    Routes of administration
    Oral use
    Dosage and administration details
    One Placebo tablet with the evening meal.

    Investigational medicinal product name
    Placebo Capsule
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Capsule
    Routes of administration
    Oral use
    Dosage and administration details
    One matching placebo capsule with the evening meal.

    Arm title
    		 Canagliflozin 300 mg
    Arm description
    		 Subjects received one 300 mg canagliflozin capsule before the morning meal and one matching placebo capsule with the evening meal plus placebo tablets with the evening meal (to match the metformin XR tablets administered in other treatment arms) for 26 weeks.
    Arm type
    		 Experimental

    Investigational medicinal product name
    Canagliflozin 300 mg
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Capsule
    Routes of administration
    Oral use
    Dosage and administration details
    One 300 mg capsule taken orally (by mouth) once daily before the morning meal for 26 weeks.

    Investigational medicinal product name
    Placebo Tablet
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Film-coated tablet
    Routes of administration
    Oral use
    Dosage and administration details
    One Placebo tablet with the evening meal for 26 weeks

    Investigational medicinal product name
    Placebo Capsule
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Capsule
    Routes of administration
    Oral use
    Dosage and administration details
    One placebo capsule was taken before the morning meal and one placebo capsule was taken with evening meal.

    Arm title
    		 Canagliflozin 100 mg/Metformin XR
    Arm description
    		 Subjects received one 100 mg canagliflozin capsule with the evening meal and one matching placebo capsule before the morning meal plus metformin XR tablets (in doses titrated over 9 weeks) once daily with the evening meal for 26 weeks.
    Arm type
    		 Experimental

    Investigational medicinal product name
    Canagliflozin 100 mg
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Capsule
    Routes of administration
    Oral use
    Dosage and administration details
    One 100 mg capsule taken orally once daily before the morning meal

    Investigational medicinal product name
    Placebo Capsule
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Capsule
    Routes of administration
    Oral use
    Dosage and administration details
    One placebo capsule was taken before the morning meal and one placebo capsule was taken with evening meal.

    Investigational medicinal product name
    Metformin
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Film-coated tablet
    Routes of administration
    Oral use
    Dosage and administration details
    One 500 mg tablet was taken from Day 1 up to week 1 followed by two 500 mg tablets was taken from week 1 up to week 3 and three 500 mg tablets was taken from week 3 to week 6 followed by four 500 mg tablets from Week 6 to Week 9. Tablets was administered with the evening meal.

    Arm title
    		 Canagliflozin 300 mg/Metformin XR
    Arm description
    		 Subjects received one 300 mg canagliflozin capsule with the evening meal and one matching placebo capsule before the morning meal plus metformin XR tablets (in doses titrated over 9 weeks) once daily with the evening meal for 26 weeks.
    Arm type
    		 Experimental

    Investigational medicinal product name
    Canagliflozin 300 mg
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Capsule
    Routes of administration
    Oral use
    Dosage and administration details
    One 300 mg capsule taken orally (by mouth) once daily before the morning meal for 26 weeks.

    Investigational medicinal product name
    Placebo Capsule
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Capsule
    Routes of administration
    Oral use
    Dosage and administration details
    One placebo capsule was taken before the morning meal and one placebo capsule was taken with evening meal.

    Investigational medicinal product name
    Metformin
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Film-coated tablet
    Routes of administration
    Oral use
    Dosage and administration details
    One 500 mg tablet was taken from Day 1 up to week 1 followed by two 500 mg tablets was taken from week 1 up to week 3 and three 500 mg tablets was taken from week 3 to week 6 followed by four 500 mg tablets from Week 6 to Week 9. Tablets was administered with the evening meal.

    Number of subjects in period 1
    		Metformin XR Canagliflozin 100 mg Canagliflozin 300 mg Canagliflozin 100 mg/Metformin XR Canagliflozin 300 mg/Metformin XR
    Started
    237
    237
    238
    237
    237
    Completed
    205
    211
    216
    225
    212
    Not completed
    32
    26
    22
    12
    25
         Adverse event, serious fatal
    1
    -
    -
    -
    -
         Consent withdrawn by subject
    18
    11
    7
    5
    7
         Physician decision
    1
    1
    -
    -
    -
         Adverse event, non-fatal
    2
    2
    4
    2
    6
         Other
    1
    1
    2
    1
    2
         Pregnancy
    1
    -
    -
    -
    -
         Adverse event, serious non-fatal
    2
    1
    3
    2
    2
         Lost to follow-up
    5
    2
    4
    2
    3
         Lack of efficacy
    1
    6
    1
    -
    2
         Protocol deviation
    -
    2
    1
    -
    3

    Baseline characteristics

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    Baseline characteristics reporting groups
    Reporting group title
    Metformin XR
    Reporting group description
    		 Subjects received metformin extended release (XR) tablets (in doses titrated over 9 weeks) once daily with the evening meal, plus one placebo capsule before the morning meal and one placebo capsule with the evening meal (to match the canagliflozin capsules administered in other treatment arms) for 26 weeks.

    Reporting group title
    Canagliflozin 100 mg
    Reporting group description
    		 Subjects received one 100 milligram (mg) canagliflozin capsule before the morning meal and one matching placebo capsule with the evening meal plus placebo tablets with the evening meal (to match the metformin XR tablets administered in other treatment arms) for 26 weeks.

    Reporting group title
    Canagliflozin 300 mg
    Reporting group description
    		 Subjects received one 300 mg canagliflozin capsule before the morning meal and one matching placebo capsule with the evening meal plus placebo tablets with the evening meal (to match the metformin XR tablets administered in other treatment arms) for 26 weeks.

    Reporting group title
    Canagliflozin 100 mg/Metformin XR
    Reporting group description
    		 Subjects received one 100 mg canagliflozin capsule with the evening meal and one matching placebo capsule before the morning meal plus metformin XR tablets (in doses titrated over 9 weeks) once daily with the evening meal for 26 weeks.

    Reporting group title
    Canagliflozin 300 mg/Metformin XR
    Reporting group description
    		 Subjects received one 300 mg canagliflozin capsule with the evening meal and one matching placebo capsule before the morning meal plus metformin XR tablets (in doses titrated over 9 weeks) once daily with the evening meal for 26 weeks.

    Reporting group values
    		 Metformin XR Canagliflozin 100 mg Canagliflozin 300 mg Canagliflozin 100 mg/Metformin XR Canagliflozin 300 mg/Metformin XR Total
    Number of subjects
    		 237 237 238 237 237 1186
    Title for AgeCategorical
    Units: subjects
        Children(2-11 years)
    		 0 0 0 0 0 0
        Adolescents(12-17 years)
    		 0 0 0 0 0 0
        Adults (18-64 years)
    		 188 201 203 204 194 990
        From 65 to 84 years
    		 49 36 35 33 43 196
        85 years and over
    		 0 0 0 0 0 0
    Title for AgeContinuous
    Units: years
        arithmetic mean (standard deviation)
    		 55.2 ± 9.75 54 ± 10.7 55.8 ± 9.56 54.2 ± 9.58 55.4 ± 9.84 -
    Title for Gender
    Units: subjects
        Female
    		 121 132 113 129 122 617
        Male
    		 116 105 125 108 115 569

    End points

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    End points reporting groups
    Reporting group title
    Metformin XR
    Reporting group description
    		 Subjects received metformin extended release (XR) tablets (in doses titrated over 9 weeks) once daily with the evening meal, plus one placebo capsule before the morning meal and one placebo capsule with the evening meal (to match the canagliflozin capsules administered in other treatment arms) for 26 weeks.

    Reporting group title
    Canagliflozin 100 mg
    Reporting group description
    		 Subjects received one 100 milligram (mg) canagliflozin capsule before the morning meal and one matching placebo capsule with the evening meal plus placebo tablets with the evening meal (to match the metformin XR tablets administered in other treatment arms) for 26 weeks.

    Reporting group title
    Canagliflozin 300 mg
    Reporting group description
    		 Subjects received one 300 mg canagliflozin capsule before the morning meal and one matching placebo capsule with the evening meal plus placebo tablets with the evening meal (to match the metformin XR tablets administered in other treatment arms) for 26 weeks.

    Reporting group title
    Canagliflozin 100 mg/Metformin XR
    Reporting group description
    		 Subjects received one 100 mg canagliflozin capsule with the evening meal and one matching placebo capsule before the morning meal plus metformin XR tablets (in doses titrated over 9 weeks) once daily with the evening meal for 26 weeks.

    Reporting group title
    Canagliflozin 300 mg/Metformin XR
    Reporting group description
    		 Subjects received one 300 mg canagliflozin capsule with the evening meal and one matching placebo capsule before the morning meal plus metformin XR tablets (in doses titrated over 9 weeks) once daily with the evening meal for 26 weeks.

    Primary: Change in glycated hemoglobin (HbA1c) from baseline to Week 26

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    End point title
    		 Change in glycated hemoglobin (HbA1c) from baseline to Week 26
    End point description
    The change from baseline in HbA1c was compared at 26 week between the different treatment groups. Here 'N' signifies number of subjects who were analysed for this outcome measure.
    End point type
    Primary
    End point timeframe
    Day 1 (Baseline) and Week 26
    End point values
    		 Metformin XR Canagliflozin 100 mg Canagliflozin 300 mg Canagliflozin 100 mg/Metformin XR Canagliflozin 300 mg/Metformin XR
    Number of subjects analysed
    230
    230
    234
    235
    236
    Units: percentage of HbA1c
        least squares mean (standard error)
    -1.3 ± 0.071
    -1.37 ± 0.071
    -1.42 ± 0.07
    -1.77 ± 0.069
    -1.78 ± 0.07
    Statistical analysis title
    		 Statistical analysis 1
    Comparison groups
    Canagliflozin 100 mg/Metformin XR v Metformin XR
    Number of subjects included in analysis
    465
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.001
    Method
    		 Mixed models analysis
    Parameter type
    		 Least Square (LS) Mean Difference
    Point estimate
    -0.46
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -0.657
         upper limit
    		 -0.269
    Variability estimate
    Standard error of the mean
    Dispersion value
    0.099
    Statistical analysis title
    		 Statistical analysis 2
    Comparison groups
    Canagliflozin 300 mg/Metformin XR v Metformin XR
    Number of subjects included in analysis
    466
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.001
    Method
    		 Mixed models analysis
    Parameter type
    		 LS Mean Difference
    Point estimate
    -0.48
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -0.67
         upper limit
    		 -0.28
    Variability estimate
    Standard error of the mean
    Dispersion value
    0.099
    Statistical analysis title
    		 Statistical analysis 3
    Comparison groups
    Canagliflozin 100 mg/Metformin XR v Canagliflozin 100 mg
    Number of subjects included in analysis
    465
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.001
    Method
    		 Mixed models analysis
    Parameter type
    		 LS Mean Difference
    Point estimate
    -0.4
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -0.594
         upper limit
    		 -0.207
    Variability estimate
    Standard error of the mean
    Dispersion value
    0.099
    Statistical analysis title
    		 Statistical analysis 4
    Comparison groups
    Canagliflozin 300 mg/Metformin XR v Canagliflozin 300 mg
    Number of subjects included in analysis
    470
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.001
    Method
    		 Mixed models analysis
    Parameter type
    		 LS Mean Difference
    Point estimate
    -0.36
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -0.557
         upper limit
    		 -0.169
    Variability estimate
    Standard error of the mean
    Dispersion value
    0.099
    Statistical analysis title
    		 Statistical analysis 5
    Comparison groups
    Canagliflozin 100 mg v Metformin XR
    Number of subjects included in analysis
    460
    Analysis specification
    Pre-specified
    Analysis type
    		 non-inferiority
    P-value
    		 = 0.001
    Method
    		 Mixed models analysis
    Parameter type
    		 LS Mean Difference
    Point estimate
    -0.06
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -0.258
         upper limit
    		 0.133
    Variability estimate
    Standard error of the mean
    Dispersion value
    0.1
    Statistical analysis title
    		 Statistical analysis 6
    Comparison groups
    Canagliflozin 300 mg v Metformin XR
    Number of subjects included in analysis
    464
    Analysis specification
    Pre-specified
    Analysis type
    		 non-inferiority
    P-value
    		 = 0.001
    Method
    		 Mixed models analysis
    Parameter type
    		 LS Mean Difference
    Point estimate
    -0.11
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -0.307
         upper limit
    		 0.082
    Variability estimate
    Standard error of the mean
    Dispersion value
    0.099

    Secondary: Percent Change From Baseline in Body Weight at Week 26

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    End point title
    		 Percent Change From Baseline in Body Weight at Week 26
    End point description
    The percent change in body weight from baseline to week 26 was compared between the different treatment groups. Here 'N' signifies number of subjects who were analysed for this outcome measure.
    End point type
    Secondary
    End point timeframe
    Day 1 (Baseline) and Week 26
    End point values
    		 Metformin XR Canagliflozin 100 mg Canagliflozin 300 mg Canagliflozin 100 mg/Metformin XR Canagliflozin 300 mg/Metformin XR
    Number of subjects analysed
    237
    236
    236
    237
    236
    Units: percent change
        least squares mean (standard error)
    -2.1 ± 0.3
    -3 ± 0.3
    -3.9 ± 0.3
    -3.5 ± 0.3
    -4.2 ± 0.3
    Statistical analysis title
    		 Statistical analysis 1
    Comparison groups
    Canagliflozin 100 mg/Metformin XR v Metformin XR
    Number of subjects included in analysis
    474
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.001
    Method
    		 Mixed models analysis
    Parameter type
    		 LS Mean Difference
    Point estimate
    -1.4
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -2.1
         upper limit
    		 -0.6
    Variability estimate
    Standard error of the mean
    Dispersion value
    0.4
    Statistical analysis title
    		 Statistical analysis 2
    Comparison groups
    Canagliflozin 300 mg/Metformin XR v Metformin XR
    Number of subjects included in analysis
    473
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.001
    Method
    		 Mixed models analysis
    Parameter type
    		 LS Mean Difference
    Point estimate
    -2.1
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -2.9
         upper limit
    		 -1.4
    Variability estimate
    Standard error of the mean
    Dispersion value
    0.4
    Statistical analysis title
    		 Statistical analysis 3
    Comparison groups
    Canagliflozin 100 mg v Metformin XR
    Number of subjects included in analysis
    473
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.016
    Method
    		 Mixed models analysis
    Parameter type
    		 LS Mean Difference
    Point estimate
    -0.9
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -1.6
         upper limit
    		 -0.2
    Variability estimate
    Standard error of the mean
    Dispersion value
    0.4
    Statistical analysis title
    		 Statistical analysis 4
    Comparison groups
    Canagliflozin 300 mg v Metformin XR
    Number of subjects included in analysis
    473
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.002
    Method
    		 Mixed models analysis
    Parameter type
    		 LS Mean Difference
    Point estimate
    -1.8
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -2.6
         upper limit
    		 -1.1
    Variability estimate
    Standard error of the mean
    Dispersion value
    0.4

    Secondary: Percentage of Subjects With Glycated Hemoglobin (HbAIc) Less Than 7 Percent at Week 26

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    End point title
    		 Percentage of Subjects With Glycated Hemoglobin (HbAIc) Less Than 7 Percent at Week 26
    End point description
    The percentage of subjects achieved HbAIc less than 7 percent at Week 26 was compared between the different treatment groups. Here 'N' signifies number of subjects who were analysed for this outcome measure.
    End point type
    Secondary
    End point timeframe
    Week 26
    End point values
    		 Metformin XR Canagliflozin 100 mg Canagliflozin 300 mg Canagliflozin 100 mg/Metformin XR Canagliflozin 300 mg/Metformin XR
    Number of subjects analysed
    207 [1]
    206 [2]
    215 [3]
    224 [4]
    213 [5]
    Units: percentage of subjects
        number (not applicable)
    43
    38.8
    42.8
    49.6
    56.8
    Notes
    [1] - mITT population
    [2] - mITT population
    [3] - mITT population
    [4] - mITT population
    [5] - mITT population
    Statistical analysis title
    		 Statistical analysis 1
    Comparison groups
    Canagliflozin 100 mg/Metformin XR v Metformin XR
    Number of subjects included in analysis
    431
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.027
    Method
    		 generalized linear mixed model
    Parameter type
    		 Odds ratio (OR)
    Point estimate
    1.58
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 1.06
         upper limit
    		 2.37
    Statistical analysis title
    		 Statistical analysis 2
    Comparison groups
    Canagliflozin 300 mg/Metformin XR v Metformin XR
    Number of subjects included in analysis
    420
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.016
    Method
    		 generalized linear mixed model
    Parameter type
    		 Odds ratio (OR)
    Point estimate
    2.39
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 1.52
         upper limit
    		 3.77

    Secondary: Change in Systolic Blood Pressure From Baseline at Week 26

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    End point title
    		 Change in Systolic Blood Pressure From Baseline at Week 26
    End point description
    The change in systolic blood pressure from baseline at Week 26 was compared between the different treatment groups. Here 'N' signifies number of subjects who were analysed for this outcome measure.
    End point type
    Secondary
    End point timeframe
    Day 1 (Baseline) and Week 26
    End point values
    		 Metformin XR Canagliflozin 100 mg Canagliflozin 300 mg Canagliflozin 100 mg/Metformin XR Canagliflozin 300 mg/Metformin XR
    Number of subjects analysed
    237
    236
    236
    237
    236
    Units: percent Change
        least squares mean (standard error)
    -0.33 ± 0.633
    -2.24 ± 0.627
    -2.36 ± 0.622
    -2.24 ± 0.613
    -1.65 ± 0.624
    Statistical analysis title
    		 Statistical analysis 1
    Comparison groups
    Canagliflozin 100 mg/Metformin XR v Metformin XR
    Number of subjects included in analysis
    474
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.06
    Method
    		 Mixed models analysis
    Parameter type
    		 LS Mean Difference
    Point estimate
    -1.91
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -3.641
         upper limit
    		 -0.182
    Variability estimate
    Standard error of the mean
    Dispersion value
    0.882
    Statistical analysis title
    		 Statistical analysis 2
    Comparison groups
    Canagliflozin 300 mg/Metformin XR v Metformin XR
    Number of subjects included in analysis
    473
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.147
    Method
    		 Mixed models analysis
    Parameter type
    		 LS Mean Difference
    Point estimate
    -1.31
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -3.058
         upper limit
    		 0.431
    Variability estimate
    Standard error of the mean
    Dispersion value
    0.889

    Secondary: Percent Change in Fasting High-Density Lipoprotein Cholesterol (HDL-C) From Baseline to Week 26

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    End point title
    		 Percent Change in Fasting High-Density Lipoprotein Cholesterol (HDL-C) From Baseline to Week 26
    End point description
    The percentage change in Fasting High-Density Lipoprotein Cholesterol (HDL-C) from baseline to Week 26 was compared between the different treatment groups. Here 'N' signifies number of subjects who were analysed for this outcome measure.
    End point type
    Secondary
    End point timeframe
    Day 1 (Baseline) and Week 26
    End point values
    		 Metformin XR Canagliflozin 100 mg Canagliflozin 300 mg Canagliflozin 100 mg/Metformin XR Canagliflozin 300 mg/Metformin XR
    Number of subjects analysed
    222
    225
    228
    227
    225
    Units: Percent Change
        least squares mean (standard error)
    10.2 ± 1.5
    17.6 ± 1.5
    16.6 ± 1.5
    15.5 ± 1.5
    14.5 ± 1.5
    Statistical analysis title
    		 Statistical analysis 1
    Comparison groups
    Canagliflozin 100 mg/Metformin XR v Metformin XR
    Number of subjects included in analysis
    449
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.147
    Method
    		 ANCOVA
    Parameter type
    		 LS Mean Difference
    Point estimate
    5.3
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 1.2
         upper limit
    		 9.5
    Variability estimate
    Standard error of the mean
    Dispersion value
    2.1
    Statistical analysis title
    		 Statistical analysis 2
    Comparison groups
    Canagliflozin 300 mg/Metformin XR v Metformin XR
    Number of subjects included in analysis
    447
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.147
    Method
    		 ANCOVA
    Parameter type
    		 LS Mean Difference
    Point estimate
    4.3
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.2
         upper limit
    		 8.5
    Variability estimate
    Standard error of the mean
    Dispersion value
    2.1

    Secondary: Percent Change in Triglycerides From Baseline to Week 26

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    End point title
    		 Percent Change in Triglycerides From Baseline to Week 26
    End point description
    The percentage change in triglycerides from baseline to Week 26 was compared between the different treatment groups. Here 'N' signifies number of subjects who were analysed for this outcome measure.
    End point type
    Secondary
    End point timeframe
    Day 1 (Baseline) and Week 26
    End point values
    		 Metformin XR Canagliflozin 100 mg Canagliflozin 300 mg Canagliflozin 100 mg/Metformin XR Canagliflozin 300 mg/Metformin XR
    Number of subjects analysed
    223 [6]
    225 [7]
    229 [8]
    229 [9]
    225 [10]
    Units: percent change
        arithmetic mean (standard deviation)
    13.6 ± 51.8
    1.7 ± 50.5
    2.8 ± 60.3
    13 ± 81.9
    21.2 ± 71.1
    Notes
    [6] - mITT population
    [7] - mITT population
    [8] - mITT population
    [9] - mITT population
    [10] - mITT population
    Statistical analysis title
    		 Statistical analysis 1
    Comparison groups
    Canagliflozin 100 mg/Metformin XR v Metformin XR
    Number of subjects included in analysis
    452
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.608
    Method
    		 Wilcoxon rank sum test
    Parameter type
    		 Hodges-Lehman Estimate
    Point estimate
    -3.7
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -11.1
         upper limit
    		 3.4
    Statistical analysis title
    		 Statistical analysis 2
    Comparison groups
    Canagliflozin 300 mg/Metformin XR v Metformin XR
    Number of subjects included in analysis
    448
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.806
    Method
    		 Wilcoxon rank sum test
    Parameter type
    		 Hodges-Lehman Estimate
    Point estimate
    1.3
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -7.3
         upper limit
    		 10

    Secondary: Number of Subjects With Treatment Emergent Adverse Events (AEs)

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    End point title
    		 Number of Subjects With Treatment Emergent Adverse Events (AEs)
    End point description
    An adverse event (AE) was any untoward medical occurrence in a subject who received study drug without regard to possibility of causal relationship. A serious adverse event (SAE) was an AE resulting in any of the following outcomes or deemed significant for any other reason: death; initial or prolonged inpatient hospitalization; life-threatening experience (immediate risk of dying); persistent or significant disability/incapacity; congenital anomaly. Treatment-emergent were events between administration of study drug and up to 30 days after last dose of study drug that were absent before treatment or that worsened relative to pre-treatment state.
    End point type
    Secondary
    End point timeframe
    Up to 30 weeks of last study drug administration
    End point values
    		 Metformin XR Canagliflozin 100 mg Canagliflozin 300 mg Canagliflozin 100 mg/Metformin XR Canagliflozin 300 mg/Metformin XR
    Number of subjects analysed
    237 [11]
    237 [12]
    238 [13]
    237 [14]
    237 [15]
    Units: subjects
        number (not applicable)
    89
    88
    95
    99
    105
    Notes
    [11] - mITT population
    [12] - mITT population
    [13] - mITT population
    [14] - mITT population
    [15] - mITT population
    No statistical analyses for this end point

    Adverse events

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    Adverse events information
    Timeframe for reporting adverse events
    Up to 30 weeks of last study drug administration
    Assessment type
    		 Non-systematic
    Dictionary used for adverse event reporting
    Dictionary name
    		 MedDRA
    Dictionary version
    17.1
    Reporting groups
    Reporting group title
    Metformin XR
    Reporting group description
    		 One 500 mg tablet was taken from Day 1 up to week 1 followed by two 500 mg tablets was taken from week 1 up to week 3 and three 500 mg tablets was taken from week 3 to week 6 followed by four 500 mg tablets from Week 6 to Week 9. Tablets will be administered with the evening meal.

    Reporting group title
    Canagliflozin 100 mg
    Reporting group description
    		 Subjects received one 100 milligram (mg) canagliflozin capsule before the morning meal and one matching placebo capsule with the evening meal plus placebo tablets with the evening meal (to match the metformin XR tablets administered in other treatment arms) for 26 weeks.

    Reporting group title
    Canagliflozin 300 mg
    Reporting group description
    		 Subjects received one 300 mg canagliflozin capsule before the morning meal and one matching placebo capsule with the evening meal plus placebo tablets with the evening meal (to match the metformin XR tablets administered in other treatment arms) for 26 weeks.

    Reporting group title
    Canagliflozin 100 mg/Metformin XR
    Reporting group description
    		 Subjects received one 100 mg canagliflozin capsule with the evening meal and one matching placebo capsule before the morning meal plus metformin XR tablets (in doses titrated over 9 weeks) once daily with the evening meal for 26 weeks.

    Reporting group title
    Canagliflozin 300 mg/Metformin XR
    Reporting group description
    		 Co-administration of Canagliflozin 300 mg and Metformin XR

    Serious adverse events
    		 Metformin XR Canagliflozin 100 mg Canagliflozin 300 mg Canagliflozin 100 mg/Metformin XR Canagliflozin 300 mg/Metformin XR
    Total subjects affected by serious adverse events
         subjects affected / exposed
    7 / 237 (2.95%)
    4 / 237 (1.69%)
    7 / 238 (2.94%)
    7 / 237 (2.95%)
    4 / 237 (1.69%)
         number of deaths (all causes)
    1
    0
    0
    0
    0
         number of deaths resulting from adverse events
    Neoplasms benign, malignant and unspecified (incl cysts and polyps)
    Endometrial Adenocarcinoma
         subjects affected / exposed
    1 / 237 (0.42%)
    0 / 237 (0.00%)
    0 / 238 (0.00%)
    0 / 237 (0.00%)
    0 / 237 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Medullary Thyroid Cancer
         subjects affected / exposed
    0 / 237 (0.00%)
    0 / 237 (0.00%)
    0 / 238 (0.00%)
    0 / 237 (0.00%)
    1 / 237 (0.42%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Pancreatic Carcinoma
         subjects affected / exposed
    0 / 237 (0.00%)
    0 / 237 (0.00%)
    0 / 238 (0.00%)
    1 / 237 (0.42%)
    0 / 237 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Vascular disorders
    Arterial Occlusive Disease
         subjects affected / exposed
    1 / 237 (0.42%)
    0 / 237 (0.00%)
    0 / 238 (0.00%)
    0 / 237 (0.00%)
    0 / 237 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Deep Vein Thrombosis
         subjects affected / exposed
    0 / 237 (0.00%)
    0 / 237 (0.00%)
    1 / 238 (0.42%)
    0 / 237 (0.00%)
    0 / 237 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Peripheral Arterial Occlusive Disease
         subjects affected / exposed
    1 / 237 (0.42%)
    0 / 237 (0.00%)
    0 / 238 (0.00%)
    0 / 237 (0.00%)
    0 / 237 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    General disorders and administration site conditions
    Cardiac Death
         subjects affected / exposed
    1 / 237 (0.42%)
    0 / 237 (0.00%)
    0 / 238 (0.00%)
    0 / 237 (0.00%)
    0 / 237 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Respiratory, thoracic and mediastinal disorders
    Dyspnoea
         subjects affected / exposed
    0 / 237 (0.00%)
    1 / 237 (0.42%)
    0 / 238 (0.00%)
    0 / 237 (0.00%)
    0 / 237 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Injury, poisoning and procedural complications
    Extradural Haematoma
         subjects affected / exposed
    0 / 237 (0.00%)
    0 / 237 (0.00%)
    0 / 238 (0.00%)
    1 / 237 (0.42%)
    0 / 237 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Post Laminectomy Syndrome
         subjects affected / exposed
    0 / 237 (0.00%)
    0 / 237 (0.00%)
    0 / 238 (0.00%)
    1 / 237 (0.42%)
    0 / 237 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Cardiac disorders
    Angina Pectoris
         subjects affected / exposed
    0 / 237 (0.00%)
    0 / 237 (0.00%)
    2 / 238 (0.84%)
    0 / 237 (0.00%)
    0 / 237 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 2
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Angina Unstable
         subjects affected / exposed
    0 / 237 (0.00%)
    0 / 237 (0.00%)
    0 / 238 (0.00%)
    1 / 237 (0.42%)
    0 / 237 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Arrhythmia
         subjects affected / exposed
    0 / 237 (0.00%)
    1 / 237 (0.42%)
    0 / 238 (0.00%)
    0 / 237 (0.00%)
    0 / 237 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Atrial Fibrillation
         subjects affected / exposed
    0 / 237 (0.00%)
    0 / 237 (0.00%)
    1 / 238 (0.42%)
    0 / 237 (0.00%)
    0 / 237 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Coronary Artery Disease
         subjects affected / exposed
    0 / 237 (0.00%)
    1 / 237 (0.42%)
    0 / 238 (0.00%)
    1 / 237 (0.42%)
    0 / 237 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Nervous system disorders
    Cerebrovascular Accident
         subjects affected / exposed
    0 / 237 (0.00%)
    0 / 237 (0.00%)
    1 / 238 (0.42%)
    0 / 237 (0.00%)
    0 / 237 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Cervicobrachial Syndrome
         subjects affected / exposed
    0 / 237 (0.00%)
    0 / 237 (0.00%)
    0 / 238 (0.00%)
    1 / 237 (0.42%)
    0 / 237 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Ischaemic Stroke
         subjects affected / exposed
    0 / 237 (0.00%)
    0 / 237 (0.00%)
    0 / 238 (0.00%)
    0 / 237 (0.00%)
    1 / 237 (0.42%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Syncope
         subjects affected / exposed
    0 / 237 (0.00%)
    0 / 237 (0.00%)
    2 / 238 (0.84%)
    0 / 237 (0.00%)
    0 / 237 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 2
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Blood and lymphatic system disorders
    Anaemia
         subjects affected / exposed
    0 / 237 (0.00%)
    1 / 237 (0.42%)
    0 / 238 (0.00%)
    0 / 237 (0.00%)
    0 / 237 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Immune Thrombocytopenic Purpura
         subjects affected / exposed
    0 / 237 (0.00%)
    1 / 237 (0.42%)
    0 / 238 (0.00%)
    0 / 237 (0.00%)
    0 / 237 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Gastrointestinal disorders
    Diverticulum
         subjects affected / exposed
    1 / 237 (0.42%)
    0 / 237 (0.00%)
    0 / 238 (0.00%)
    0 / 237 (0.00%)
    0 / 237 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Epiploic Appendagitis
         subjects affected / exposed
    1 / 237 (0.42%)
    0 / 237 (0.00%)
    0 / 238 (0.00%)
    0 / 237 (0.00%)
    0 / 237 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Endocrine disorders
    Goitre
         subjects affected / exposed
    0 / 237 (0.00%)
    0 / 237 (0.00%)
    0 / 238 (0.00%)
    1 / 237 (0.42%)
    0 / 237 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Musculoskeletal and connective tissue disorders
    Osteoarthritis
         subjects affected / exposed
    1 / 237 (0.42%)
    0 / 237 (0.00%)
    0 / 238 (0.00%)
    0 / 237 (0.00%)
    0 / 237 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Infections and infestations
    Appendicitis
         subjects affected / exposed
    0 / 237 (0.00%)
    0 / 237 (0.00%)
    0 / 238 (0.00%)
    1 / 237 (0.42%)
    0 / 237 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Cellulitis
         subjects affected / exposed
    0 / 237 (0.00%)
    0 / 237 (0.00%)
    0 / 238 (0.00%)
    0 / 237 (0.00%)
    1 / 237 (0.42%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Lobar Pneumonia
         subjects affected / exposed
    0 / 237 (0.00%)
    1 / 237 (0.42%)
    0 / 238 (0.00%)
    0 / 237 (0.00%)
    0 / 237 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Ophthalmic Herpes Simplex
         subjects affected / exposed
    0 / 237 (0.00%)
    0 / 237 (0.00%)
    0 / 238 (0.00%)
    0 / 237 (0.00%)
    1 / 237 (0.42%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Urinary Tract Infection
         subjects affected / exposed
    0 / 237 (0.00%)
    0 / 237 (0.00%)
    1 / 238 (0.42%)
    0 / 237 (0.00%)
    0 / 237 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    1 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Metabolism and nutrition disorders
    Ketoacidosis
         subjects affected / exposed
    0 / 237 (0.00%)
    0 / 237 (0.00%)
    1 / 238 (0.42%)
    0 / 237 (0.00%)
    0 / 237 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    1 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Frequency threshold for reporting non-serious adverse events: 2%
    Non-serious adverse events
    		 Metformin XR Canagliflozin 100 mg Canagliflozin 300 mg Canagliflozin 100 mg/Metformin XR Canagliflozin 300 mg/Metformin XR
    Total subjects affected by non serious adverse events
         subjects affected / exposed
    37 / 237 (15.61%)
    38 / 237 (16.03%)
    38 / 238 (15.97%)
    42 / 237 (17.72%)
    43 / 237 (18.14%)
    Investigations
    Glomerular Filtration Rate Decreased
         subjects affected / exposed
    0 / 237 (0.00%)
    6 / 237 (2.53%)
    3 / 238 (1.26%)
    1 / 237 (0.42%)
    2 / 237 (0.84%)
         occurrences all number
    0
    7
    3
    1
    2
    Vascular disorders
    Hypertension
         subjects affected / exposed
    1 / 237 (0.42%)
    2 / 237 (0.84%)
    2 / 238 (0.84%)
    5 / 237 (2.11%)
    1 / 237 (0.42%)
         occurrences all number
    1
    2
    2
    5
    1
    Nervous system disorders
    Headache
         subjects affected / exposed
    8 / 237 (3.38%)
    4 / 237 (1.69%)
    4 / 238 (1.68%)
    9 / 237 (3.80%)
    7 / 237 (2.95%)
         occurrences all number
    10
    4
    4
    11
    9
    Gastrointestinal disorders
    Diarrhoea
         subjects affected / exposed
    3 / 237 (1.27%)
    3 / 237 (1.27%)
    4 / 238 (1.68%)
    10 / 237 (4.22%)
    10 / 237 (4.22%)
         occurrences all number
    7
    4
    4
    11
    13
    Nausea
         subjects affected / exposed
    6 / 237 (2.53%)
    1 / 237 (0.42%)
    2 / 238 (0.84%)
    1 / 237 (0.42%)
    2 / 237 (0.84%)
         occurrences all number
    6
    1
    2
    1
    2
    Vomiting
         subjects affected / exposed
    5 / 237 (2.11%)
    2 / 237 (0.84%)
    1 / 238 (0.42%)
    2 / 237 (0.84%)
    0 / 237 (0.00%)
         occurrences all number
    6
    3
    1
    2
    0
    Musculoskeletal and connective tissue disorders
    Back Pain
         subjects affected / exposed
    4 / 237 (1.69%)
    3 / 237 (1.27%)
    5 / 238 (2.10%)
    6 / 237 (2.53%)
    5 / 237 (2.11%)
         occurrences all number
    6
    4
    5
    7
    5
    Infections and infestations
    Gastroenteritis
         subjects affected / exposed
    3 / 237 (1.27%)
    0 / 237 (0.00%)
    1 / 238 (0.42%)
    1 / 237 (0.42%)
    5 / 237 (2.11%)
         occurrences all number
    3
    0
    1
    1
    6
    Influenza
         subjects affected / exposed
    5 / 237 (2.11%)
    6 / 237 (2.53%)
    5 / 238 (2.10%)
    8 / 237 (3.38%)
    7 / 237 (2.95%)
         occurrences all number
    5
    6
    6
    9
    7
    Nasopharyngitis
         subjects affected / exposed
    3 / 237 (1.27%)
    9 / 237 (3.80%)
    9 / 238 (3.78%)
    6 / 237 (2.53%)
    3 / 237 (1.27%)
         occurrences all number
    3
    9
    9
    8
    3
    Upper Respiratory Tract Infection
         subjects affected / exposed
    6 / 237 (2.53%)
    2 / 237 (0.84%)
    6 / 238 (2.52%)
    3 / 237 (1.27%)
    4 / 237 (1.69%)
         occurrences all number
    7
    2
    10
    3
    4
    Urinary Tract Infection
         subjects affected / exposed
    3 / 237 (1.27%)
    3 / 237 (1.27%)
    3 / 238 (1.26%)
    2 / 237 (0.84%)
    7 / 237 (2.95%)
         occurrences all number
    3
    3
    3
    2
    10
    Metabolism and nutrition disorders
    Hyperglycaemia
         subjects affected / exposed
    6 / 237 (2.53%)
    5 / 237 (2.11%)
    1 / 238 (0.42%)
    0 / 237 (0.00%)
    2 / 237 (0.84%)
         occurrences all number
    6
    5
    1
    0
    2

    More information

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    Substantial protocol amendments (globally)
    Were there any global substantial amendments to the protocol? Yes
    Date
    Amendment
    11 Feb 2013
    Changes was implemented before the start of any study-related procedures and the overall reason was to update the study based on the results from completed studies in the Phase 3 program and feedback obtained from Health Authority review
    04 Feb 2014
    The overall reason was to remove adjudication of cardiovascular (CV) and renal events (as dedicated studies were conducted and designed to assess the effects of canagliflozin on CV and renal and outcomes)

    Interruptions (globally)
    Were there any global interruptions to the trial? No

    Limitations and caveats
    Limitations of the trial such as small numbers of subjects analysed or technical problems leading to unreliable data.
    None reported
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    The status and protocol content of GB trials is no longer updated since 1 January 2021. For the UK, as of 31 January 2021, EU Law applies only to the territory of Northern Ireland (NI) to the extent foreseen in the Protocol on Ireland/NI. Legal notice
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