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    Clinical Trial Results:
    A Randomized, Multicenter, Double-Blind, Parallel-Group, Placebo-Controlled Study to Investigate the Efficacy and Safety of Canagliflozin in Children and Adolescents (>=10 to <18 years) with Type 2 Diabetes Mellitus

    Summary
    EudraCT number
    		 2016-005223-88
    Trial protocol
    		 GR   PL   Outside EU/EEA  
    Global end of trial date
    20 Sep 2023

    Results information
    Results version number
    		 v1(current)
    This version publication date
    31 Mar 2024
    First version publication date
    31 Mar 2024
    Other versions

    Trial information

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    Trial identification
    Sponsor protocol code
    28431754DIA3018
    Additional study identifiers
    ISRCTN number
    		 -
    US NCT number
    		 NCT03170518
    WHO universal trial number (UTN)
    		 -
    Sponsors
    Sponsor organisation name
    Janssen Research & Development, LLC
    Sponsor organisation address
    920 Route 202, Raritan, NJ 08869, United States, 300
    Public contact
    Clinical Registry Group, Janssen Research & Development, LLC, ClinicalTrialsEU@its.jnj.com
    Scientific contact
    Clinical Registry Group, Janssen Research & Development, LLC, ClinicalTrialsEU@its.jnj.com
    Paediatric regulatory details
    Is trial part of an agreed paediatric investigation plan (PIP)
    Yes
    EMA paediatric investigation plan number(s)
    		 EMEA-001030-PIP01-10
    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?
    Yes
    Results analysis stage
    Analysis stage
    Final
    Date of interim/final analysis
    20 Sep 2023
    Is this the analysis of the primary completion data?
    No
    Global end of trial reached?
    Yes
    Global end of trial date
    20 Sep 2023
    Was the trial ended prematurely?
    No
    General information about the trial
    Main objective of the trial
    The main objective of this trial was to assess the effect of canagliflozin relative to placebo on glycated hemoglobin (HbA1c) after 26 weeks of treatment, and to assess the overall safety and tolerability of canagliflozin.
    Protection of trial subjects
    This study was conducted in accordance with the ethical principles that have their origin in the Declaration of Helsinki and that are consistent with Good Clinical Practice and applicable regulatory requirements.
    Background therapy
    		 -
    Evidence for comparator
    		 -
    Actual start date of recruitment
    28 Jul 2017
    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
    Brazil: 12
    Country: Number of subjects enrolled
    China: 4
    Country: Number of subjects enrolled
    India: 9
    Country: Number of subjects enrolled
    Mexico: 36
    Country: Number of subjects enrolled
    Malaysia: 30
    Country: Number of subjects enrolled
    Philippines: 23
    Country: Number of subjects enrolled
    Poland: 6
    Country: Number of subjects enrolled
    Russian Federation: 10
    Country: Number of subjects enrolled
    United States: 41
    Worldwide total number of subjects
    171
    EEA total number of subjects
    6
    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)
    19
    Adolescents (12-17 years)
    152
    Adults (18-64 years)
    0
    From 65 to 84 years
    0
    85 years and over
    0

    Subject disposition

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    Recruitment
    Recruitment details
    		 A total of 171 subjects (87 received placebo and 84 received Canagliflozin) were enrolled. Of the 84 subjects on canagliflozin, 33 subjects were re-randomised (1:1 ratio) at Week 13 based on Week 12 HbA1c (>=7%) and eGFR (>=60 mL/min/1.73 m^2): 16 subjects remained on 100 milligrams (mg) and 17 subjects were up-titrated to receive 300 mg.

    Pre-assignment
    Screening details
    		 Randomisation was stratified by antihyperglycemic agent (AHA) background (that is, diet and exercise only; metformin monotherapy; insulin monotherapy; or combination of insulin and metformin) and age group (greater than or equal to [>=]10 to less than [<]15 years old; >=15 to <18 years old).

    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

    Arms
    Are arms mutually exclusive
    Yes

    Arm title
    		 Placebo
    Arm description
    		 Subjects received orally 1 placebo tablet matching to canagliflozin 100/300 milligrams (mg) once-daily from Day 1 till Week 52. At Week 13, subjects who met re-randomisation criteria (glycated hemoglobin [HbA1c] of >=7.0 percent [%], estimated glomerular filtration rate [eGFR] >=60 millilitre per minute per 1.73 metre square [mL/min/1.73 m^2]) at Week 12 were alone re-randomized to receive orally 1 tablet of placebo matching canagliflozin 100 mg and 1 tablet of placebo matching canagliflozin 300 mg once daily till Week 52. Subjects who did not meet the re-randomisation criteria continued to receive orally 1 tablet of placebo matching to canagliflozin 100 mg once daily till Week 52.
    Arm type
    		 Placebo

    Investigational medicinal product name
    Placebo
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Tablet
    Routes of administration
    Oral use
    Dosage and administration details
    Subjects received 1 placebo matching to canagliflozin 100/300 milligrams (mg) once-daily from Day 1 till Week 52. At Week 13, subjects who met re-randomisation criteria (HbA1c] of >=7.0%, eGFR >=60 mL/min/1.73 m^2) at Week 12 were alone re-randomised to receive orally 1 placebo matching canagliflozin 100 mg and 1 placebo matching canagliflozin 300 mg once daily till Week 52.

    Arm title
    		 Canagliflozin 100 mg
    Arm description
    		 Subjects received orally canagliflozin 100 mg tablet once daily from Day 1 till Week 12. At Week 13, subjects who met re-randomisation criteria (HbA1c of >=7.0%, estimated eGFR >=60 mL/min/1.73 m^2) at Week 12 were alone re-randomised at 1:1 ratio to receive orally 1 tablet of canagliflozin 100 mg tablet and 1 tablet of placebo matching canagliflozin 300 mg once daily till Week 52. Subjects who did not meet the re-randomisation criteria continued to receive orally 1 tablet of canagliflozin 100 mg once daily till Week 52.
    Arm type
    		 Experimental

    Investigational medicinal product name
    Canagliflozin
    Investigational medicinal product code
    Other name
    JNJ-28431754
    Pharmaceutical forms
    Tablet
    Routes of administration
    Oral use
    Dosage and administration details
    Subjects received canagliflozin 100 mg once daily from Day 1 till Week 12. At week 13, subjects who had HbA1c of >=7.0%, estimated eGFR >=60 mL/min/1.73 m^2 were re-randomised at 1:1 ratio to continue receiving canagliflozin 100 mg and 1 added placebo matching to canagliflozin 300 mg once daily for the remainder of the double-blind treatment period till Week 52.

    Arm title
    		 Canagliflozin 300 mg
    Arm description
    		 Subjects received orally canagliflozin 100 mg tablet once daily from Day 1 till Week 12. At Week 13, subjects who met re-randomisation criteria (HbA1c of >=7.0%, estimated eGFR >=60 mL/min/1.73 m^2) at Week 12 were alone re-randomised at 1:1 ratio to receive orally 1 tablet of canagliflozin 300 mg tablet and 1 tablet of placebo matching canagliflozin 100 mg once daily till Week 52. Subjects who did not meet the re-randomisation criteria continued to receive orally 1 tablet of canagliflozin 100 mg once daily till Week 52.
    Arm type
    		 Experimental

    Investigational medicinal product name
    Canagliflozin
    Investigational medicinal product code
    Other name
    JNJ-28431754
    Pharmaceutical forms
    Tablet
    Routes of administration
    Oral use
    Dosage and administration details
    At Week 13, subjects who met re-randomisation criteria (HbA1c of >=7.0%, estimated eGFR >=60 mL/min/1.73 m^2) at Week 12 were alone re-randomised at 1:1 ratio to receive 1 canagliflozin 300 mg and 1 placebo matching canagliflozin 100 mg once daily till Week 52.

    Number of subjects in period 1
    		Placebo Canagliflozin 100 mg Canagliflozin 300 mg
    Started
    87
    67
    17
    Subjects not re-randomized at Week 13
    27 [1]
    51 [2]
    0 [3]
    Subjects Re-randomized at Week 13
    60 [4]
    16 [5]
    17
    Subjects treated from Week13 till Week52
    87
    67
    17
    Completed
    75
    60
    14
    Not completed
    12
    7
    3
         Physician decision
    1
    -
    -
         Site terminated by sponsor
    -
    1
    -
         Non-compliance with study drug
    1
    -
    1
         Lost to follow-up
    4
    1
    -
         Withdrawal by parent/guardian
    2
    -
    -
         Withdrawal by subject
    4
    5
    2
    Notes
    [1] - The number of subjects at this milestone seems inconsistent with the number of subjects in the arm. It is expected that the number of subjects will be greater than, or equal to the number that completed, minus those who left.
    Justification: Only reported subjects were planned to be included in the respective milestone.
    [2] - The number of subjects at this milestone seems inconsistent with the number of subjects in the arm. It is expected that the number of subjects will be greater than, or equal to the number that completed, minus those who left.
    Justification: Only reported subjects were planned to be included in the respective milestone.
    [3] - The number of subjects at this milestone seems inconsistent with the number of subjects in the arm. It is expected that the number of subjects will be greater than, or equal to the number that completed, minus those who left.
    Justification: Only reported subjects were planned to be included in the respective milestone.
    [4] - The number of subjects at this milestone seems inconsistent with the number of subjects in the arm. It is expected that the number of subjects will be greater than, or equal to the number that completed, minus those who left.
    Justification: Only reported subjects were planned to be included in the respective milestone.
    [5] - The number of subjects at this milestone seems inconsistent with the number of subjects in the arm. It is expected that the number of subjects will be greater than, or equal to the number that completed, minus those who left.
    Justification: Only reported subjects were planned to be included in the respective milestone.

    Baseline characteristics

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    Baseline characteristics reporting groups
    Reporting group title
    Placebo
    Reporting group description
    		 Subjects received orally 1 placebo tablet matching to canagliflozin 100/300 milligrams (mg) once-daily from Day 1 till Week 52. At Week 13, subjects who met re-randomisation criteria (glycated hemoglobin [HbA1c] of >=7.0 percent [%], estimated glomerular filtration rate [eGFR] >=60 millilitre per minute per 1.73 metre square [mL/min/1.73 m^2]) at Week 12 were alone re-randomized to receive orally 1 tablet of placebo matching canagliflozin 100 mg and 1 tablet of placebo matching canagliflozin 300 mg once daily till Week 52. Subjects who did not meet the re-randomisation criteria continued to receive orally 1 tablet of placebo matching to canagliflozin 100 mg once daily till Week 52.

    Reporting group title
    Canagliflozin 100 mg
    Reporting group description
    		 Subjects received orally canagliflozin 100 mg tablet once daily from Day 1 till Week 12. At Week 13, subjects who met re-randomisation criteria (HbA1c of >=7.0%, estimated eGFR >=60 mL/min/1.73 m^2) at Week 12 were alone re-randomised at 1:1 ratio to receive orally 1 tablet of canagliflozin 100 mg tablet and 1 tablet of placebo matching canagliflozin 300 mg once daily till Week 52. Subjects who did not meet the re-randomisation criteria continued to receive orally 1 tablet of canagliflozin 100 mg once daily till Week 52.

    Reporting group title
    Canagliflozin 300 mg
    Reporting group description
    		 Subjects received orally canagliflozin 100 mg tablet once daily from Day 1 till Week 12. At Week 13, subjects who met re-randomisation criteria (HbA1c of >=7.0%, estimated eGFR >=60 mL/min/1.73 m^2) at Week 12 were alone re-randomised at 1:1 ratio to receive orally 1 tablet of canagliflozin 300 mg tablet and 1 tablet of placebo matching canagliflozin 100 mg once daily till Week 52. Subjects who did not meet the re-randomisation criteria continued to receive orally 1 tablet of canagliflozin 100 mg once daily till Week 52.

    Reporting group values
    		 Placebo Canagliflozin 100 mg Canagliflozin 300 mg Total
    Number of subjects
    		 87 67 17 171
    Title for AgeCategorical
    Units: subjects
        Children (2-11 years)
    		 10 7 2 19
        Adolescents (12-17 years)
    		 77 60 15 152
        Adults (18-64 years)
    		 0 0 0 0
        From 65 to 84 years
    		 0 0 0 0
        85 years and over
    		 0 0 0 0
    Title for AgeContinuous
    Units: years
        arithmetic mean (standard deviation)
    		 14.4 ( 2.04 ) 14.2 ( 2 ) 14.5 ( 2.07 ) -
    Title for Gender
    Units: subjects
        Female
    		 60 49 8 117
        Male
    		 27 18 9 54

    End points

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    End points reporting groups
    Reporting group title
    Placebo
    Reporting group description
    		 Subjects received orally 1 placebo tablet matching to canagliflozin 100/300 milligrams (mg) once-daily from Day 1 till Week 52. At Week 13, subjects who met re-randomisation criteria (glycated hemoglobin [HbA1c] of >=7.0 percent [%], estimated glomerular filtration rate [eGFR] >=60 millilitre per minute per 1.73 metre square [mL/min/1.73 m^2]) at Week 12 were alone re-randomized to receive orally 1 tablet of placebo matching canagliflozin 100 mg and 1 tablet of placebo matching canagliflozin 300 mg once daily till Week 52. Subjects who did not meet the re-randomisation criteria continued to receive orally 1 tablet of placebo matching to canagliflozin 100 mg once daily till Week 52.

    Reporting group title
    Canagliflozin 100 mg
    Reporting group description
    		 Subjects received orally canagliflozin 100 mg tablet once daily from Day 1 till Week 12. At Week 13, subjects who met re-randomisation criteria (HbA1c of >=7.0%, estimated eGFR >=60 mL/min/1.73 m^2) at Week 12 were alone re-randomised at 1:1 ratio to receive orally 1 tablet of canagliflozin 100 mg tablet and 1 tablet of placebo matching canagliflozin 300 mg once daily till Week 52. Subjects who did not meet the re-randomisation criteria continued to receive orally 1 tablet of canagliflozin 100 mg once daily till Week 52.

    Reporting group title
    Canagliflozin 300 mg
    Reporting group description
    		 Subjects received orally canagliflozin 100 mg tablet once daily from Day 1 till Week 12. At Week 13, subjects who met re-randomisation criteria (HbA1c of >=7.0%, estimated eGFR >=60 mL/min/1.73 m^2) at Week 12 were alone re-randomised at 1:1 ratio to receive orally 1 tablet of canagliflozin 300 mg tablet and 1 tablet of placebo matching canagliflozin 100 mg once daily till Week 52. Subjects who did not meet the re-randomisation criteria continued to receive orally 1 tablet of canagliflozin 100 mg once daily till Week 52.

    Subject analysis set title
    Placebo
    Subject analysis set type
    		 Full analysis
    Subject analysis set description
    Subjects received orally 1 placebo tablet matching to canagliflozin 100/300 milligrams (mg) once-daily from Day 1 till Week 52. At Week 13, subjects who met re-randomisation criteria (glycated hemoglobin [HbA1c] of >=7.0%, estimated glomerular filtration rate [eGFR] >=60 mL/min/1.73 m^2) at Week 12 were alone re-randomised to receive orally 1 tablet of placebo matching canagliflozin 100 mg and 1 tablet of placebo matching canagliflozin 300 mg once daily till Week 52. Subjects who did not meet the re-randomisation criteria continued to receive orally 1 tablet of placebo matching to canagliflozin 100 mg once daily till Week 52.

    Subject analysis set title
    Canagliflozin
    Subject analysis set type
    		 Full analysis
    Subject analysis set description
    Subjects received orally canagliflozin 100 mg tablet once daily from Day 1 till Week 12. At Week 13, subjects who met re-randomisation criteria (HbA1c of >=7.0%, estimated eGFR >=60 mL/min/1.73 m^2) at Week 12 were alone re-randomised (1:1 ratio) to receive orally 1 tablet of canagliflozin 100 mg tablet and 1 tablet of placebo matching canagliflozin 300 mg or canagliflozin 300 mg tablet and 1 tablet of placebo matching canagliflozin 100 mg once daily till Week 52. Subjects who did not meet the re-randomisation criteria continued to receive orally 1 tablet of canagliflozin 100 mg once daily till Week 52.

    Primary: Change From Baseline in Glycated Hemoglobin (HbA1c) at Week 26

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    End point title
    		 Change From Baseline in Glycated Hemoglobin (HbA1c) at Week 26
    End point description
    Change from baseline in HbA1c at Week 26 was analysed using a pattern mixture model with multiple imputation. Data for this endpoint was planned to be collected and analysed for the combined population of arm Canagliflozin 100 mg and Canagliflozin 300 mg. Full analysis set (FAS) included all subjects who were randomly assigned to a treatment group, received at least one dose of study agent and had a baseline HbA1c measurement. Here, N (number of subjects analysed) signifies subjects evaluable for this endpoint.
    End point type
    Primary
    End point timeframe
    Baseline (Day 1), Week 26
    End point values
    		 Placebo Canagliflozin
    Number of subjects analysed
    87
    84
    Units: Percent (%) of HbA1c
        least squares mean (standard error)
    0.39 ( 0.191 )
    -0.37 ( 0.194 )
    Statistical analysis title
    		 Canagliflozin Vs Placebo
    Comparison groups
    Placebo v Canagliflozin
    Number of subjects included in analysis
    171
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority [1]
    P-value
    		 = 0.002
    Method
    		 ANCOVA
    Parameter type
    		 Least square mean difference
    Point estimate
    -0.76
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -1.25
         upper limit
    		 -0.27
    Notes
    [1] - Imputed datasets were analyzed using analysis of covariance (ANCOVA) with terms for treatment, stratification factors (AHA background and age group), and baseline HbA1c.

    Primary: Percentage of Subjects with Treatment-emergent Adverse Events (TEAEs)

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    End point title
    		 Percentage of Subjects with Treatment-emergent Adverse Events (TEAEs) [2]
    End point description
    AE was any untoward medical occurrence in a clinical study subject administered a pharmaceutical (investigational or non investigational) product. An AE did not necessarily have a causal relationship with the pharmaceutical/biological agent under study. TEAE was defined as the AEs occurring after first administration of study intervention (or worsened since then) up to 30 days post last dose of study intervention. Safety analysis set included all randomised subjects who received at least 1 dose of study drug.
    End point type
    Primary
    End point timeframe
    Baseline (Day 1) up to 30 days post last dose (up to Week 56)
    Notes
    [2] - No statistical analyses have been specified for this primary end point. It is expected there is at least one statistical analysis for each primary end point.
    Justification: Descriptive statistics was done, no inferential statistical analysis was performed.
    End point values
    		 Placebo Canagliflozin 100 mg Canagliflozin 300 mg
    Number of subjects analysed
    87
    67
    17
    Units: Percentage of subjects
        number (not applicable)
    74.7
    76.1
    82.4
    No statistical analyses for this end point

    Secondary: Change From Baseline in Fasting Plasma Glucose (FPG) at Weeks 26 and 52

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    End point title
    		 Change From Baseline in Fasting Plasma Glucose (FPG) at Weeks 26 and 52
    End point description
    Change from baseline in FPG at Weeks 26 and Week 52 was reported. Data for this endpoint was planned to be collected and analysed for the combined population of arm Canagliflozin 100 mg and Canagliflozin 300 mg. FAS included all subjects who were randomly assigned to a treatment group, received at least one dose of study agent and had a baseline HbA1c measurement. Here, 'N' (number of subjects analysed) signifies subjects evaluable for this endpoint and 'n' (number analysed) signifies number of subjects analysed at each specified timepoints.
    End point type
    Secondary
    End point timeframe
    Baseline (Day 1), Weeks 26 and 52
    End point values
    		 Placebo Canagliflozin
    Number of subjects analysed
    83
    79
    Units: milligrams per deciliter (mg/dL)
    least squares mean (standard error)
        Week 26 (n=82, 76)
    15.3 ( 6.68 )
    -11.5 ( 6.86 )
        Week 52 (n=83, 79)
    19.2 ( 6.90 )
    -16.4 ( 6.98 )
    No statistical analyses for this end point

    Secondary: Percentage of Subjects With HbA1c Less Than (<)7.5 Percent (%), <7%, and <6.5% at Weeks 26 and 52

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    End point title
    		 Percentage of Subjects With HbA1c Less Than (<)7.5 Percent (%), <7%, and <6.5% at Weeks 26 and 52
    End point description
    The percentage of subjects achieving HbA1c <7.5%, <7.0%, and <6.0% at Weeks 26 and 52 was reported. Data for this endpoint was planned to be collected and analysed for the combined population of arm Canagliflozin 100 mg and Canagliflozin 300 mg. FAS included all subjects who were randomly assigned to a treatment group, received at least one dose of study agent and had a baseline HbA1c measurement.
    End point type
    Secondary
    End point timeframe
    Weeks 26 and 52
    End point values
    		 Placebo Canagliflozin
    Number of subjects analysed
    87
    84
    Units: Percentage of subjects
    number (not applicable)
        Week 26: HbA1c <7.5%
    40.0
    64.9
        Week 52: HbA1c <7.5%
    29.3
    69.0
        Week 26: HbA1c <7%
    27.5
    51.9
        Week 52: HbA1c <7%
    22.7
    54.9
        Week 26: HbA1c <6.5%
    11.3
    41.6
        Week 52: HbA1c <6.5%
    12.0
    36.6
    No statistical analyses for this end point

    Secondary: Percent Change From Baseline in Body Weight at Weeks 26 and 52

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    End point title
    		 Percent Change From Baseline in Body Weight at Weeks 26 and 52
    End point description
    The percent change in body weight from baseline to Weeks 26 and 52 were reported. Data for this endpoint was planned to be collected and analysed for the combined population of arm Canagliflozin 100 mg and Canagliflozin 300 mg. FAS included all subjects who were randomly assigned to a treatment group, received at least one dose of study agent and had a baseline HbA1c measurement. N (number of subjects analysed) were defined subjects who were evaluable for this outcome measure.
    End point type
    Secondary
    End point timeframe
    Baseline (Day 1), Weeks 26 and 52
    End point values
    		 Placebo Canagliflozin
    Number of subjects analysed
    85
    84
    Units: Percent change
    least squares mean (standard error)
        Week 26
    -0.0 ( 0.51 )
    -1.6 ( 0.51 )
        Week 52
    0.4 ( 0.69 )
    -0.5 ( 0.69 )
    No statistical analyses for this end point

    Secondary: Percentage of Subjects Who Received Rescue Therapy

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    End point title
    		 Percentage of Subjects Who Received Rescue Therapy
    End point description
    Percentage of subjects who received rescue therapy were reported. Data for this endpoint was planned to be collected and analysed for the combined population of arm Canagliflozin 100 mg and Canagliflozin 300 mg. FAS included all subjects who were randomly assigned to a treatment group, received at least one dose of study agent and had a baseline HbA1c measurement.
    End point type
    Secondary
    End point timeframe
    Baseline (Day 1) up to Week 52
    End point values
    		 Placebo Canagliflozin
    Number of subjects analysed
    87
    84
    Units: Percentage of subjects
        number (not applicable)
    46.0
    11.9
    No statistical analyses for this end point

    Secondary: Change From Baseline in Body Mass Index (BMI) at Weeks 26 and 52

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    End point title
    		 Change From Baseline in Body Mass Index (BMI) at Weeks 26 and 52
    End point description
    Change from baseline in BMI at Weeks 26 and 52 were reported. Data for this endpoint was planned to be collected and analysed for the combined population of arm Canagliflozin 100 mg and Canagliflozin 300 mg. FAS included all subjects who were randomly assigned to a treatment group, received at least one dose of study agent and had a baseline HbA1c measurement. Here, 'N' (number of subjects analysed) signifies subjects evaluable for this endpoint.
    End point type
    Secondary
    End point timeframe
    Baseline (Day 1), Weeks 26, and 52
    End point values
    		 Placebo Canagliflozin
    Number of subjects analysed
    85
    84
    Units: kilograms per meter square (kg/m^2)
    least squares mean (standard error)
        Week 26
    -0.4 ( 0.15 )
    -0.8 ( 0.15 )
        Week 52
    -0.5 ( 0.19 )
    -0.7 ( 0.19 )
    No statistical analyses for this end point

    Secondary: Percent Change From Baseline in Fasting Plasma Lipids Levels at Weeks 26 and 52

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    End point title
    		 Percent Change From Baseline in Fasting Plasma Lipids Levels at Weeks 26 and 52
    End point description
    The percentage change from baseline in fasting plasma lipids (low-density lipoprotein-cholesterol [LDL-C], high-density lipoprotein-cholesterol [HDL-C], total cholesterol, non-HDL-C, and triglycerides) at Weeks 26 and 52 were reported. Data for this endpoint was planned to be collected and analysed for the combined population of arm Canagliflozin 100 mg and Canagliflozin 300 mg. FAS included all subjects who were randomly assigned to a treatment group, received at least one dose of study agent and had a baseline HbA1c measurement. Here, 'N' (number of subjects analysed) signifies subjects evaluable for this endpoint and 'n' (number analysed) signifies number of subjects analysed at each specified timepoints.
    End point type
    Secondary
    End point timeframe
    Baseline (Day 1), Weeks 26, and 52
    End point values
    		 Placebo Canagliflozin
    Number of subjects analysed
    78
    76
    Units: Percent change
    least squares mean (standard error)
        Week 26: Total cholesterol (n-76,72)
    1.2 ( 2.22 )
    8.2 ( 2.22 )
        Week 52: Total cholesterol (n-78,76)
    5.6 ( 2.16 )
    5.1 ( 2.13 )
        Week 26: LDL-C (n=67,67)
    3.3 ( 3.73 )
    12.4 ( 3.58 )
        Week 52: LDL-C (n=72,74)
    7.5 ( 3.57 )
    8.3 ( 3.44 )
        Week 26: HDL-C (n=68,68)
    1.5 ( 2.40 )
    6.4 ( 2.33 )
        Week 52: HDL-C (n=73,74)
    1.0 ( 2.58 )
    7.9 ( 2.52 )
        Week 26: non-HDL-C (n=66,66)
    1.7 ( 2.69 )
    6.8 ( 2.62 )
        Week 52: non-HDL-C (n=71,74)
    7.7 ( 3.02 )
    5.0 ( 2.95 )
        Week 26: Triglyceride (n=76,72)
    8.6 ( 6.32 )
    4.6 ( 6.28 )
        Week 52: Triglyceride (n=78,76)
    18.2 ( 7.17 )
    3.4 ( 7.05 )
    No statistical analyses for this end point

    Secondary: Percent Change From Baseline in LDL-C to HDL-C Ratio and Non-HDL-C to LDL-C Ratio at Weeks 26 and 52

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    End point title
    		 Percent Change From Baseline in LDL-C to HDL-C Ratio and Non-HDL-C to LDL-C Ratio at Weeks 26 and 52
    End point description
    The percentage change from baseline of LDL-C to HDL-C ratio and non-HDL-C to LDL-C ratio at Weeks 26 and 52 were reported. Data for this endpoint was planned to be collected and analysed for the combined population of arm Canagliflozin 100 mg and Canagliflozin 300 mg. FAS included all subjects who were randomly assigned to a treatment group, received at least one dose of study agent and had a baseline HbA1c measurement. Here, 'N' (number of subjects analysed) signifies subjects evaluable for this endpoint and 'n' (number analysed) signifies number of subjects analysed at each specified timepoints.
    End point type
    Secondary
    End point timeframe
    Baseline (Day 1), Weeks 26, and 52
    End point values
    		 Placebo Canagliflozin
    Number of subjects analysed
    71
    74
    Units: Percent change
    least squares mean (standard error)
        Week 26: LDL-C/HDL-C (n=66,66)
    0.5 ( 4.05 )
    2.5 ( 4.03 )
        Week 52: LDL-C/HDL-C (n=71,74)
    -1.5 ( 3.20 )
    4.0 ( 3.13 )
        Week 26: non HDL-C/LDL-C (n=63,60)
    1.1 ( 3.42 )
    3.3 ( 3.47 )
        Week 52: non HDL-C/LDL-C (n=68,69)
    -1.5 ( 3.20 )
    4.0 ( 3.13 )
    No statistical analyses for this end point

    Secondary: Change From Baseline in Systolic Blood Pressure at Weeks 26 and 52

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    End point title
    		 Change From Baseline in Systolic Blood Pressure at Weeks 26 and 52
    End point description
    Change from baseline in systolic blood pressure at Weeks 26 and 52 was reported. Data for this endpoint was planned to be collected and analysed for the combined population of arm Canagliflozin 100 mg and Canagliflozin 300 mg. FAS included all subjects who were randomly assigned to a treatment group, received at least one dose of study agent and had a baseline HbA1c measurement. Here, 'N' (number of subjects analysed) signifies subjects evaluable for this endpoint and 'n' (number analysed) signifies number of subjects analysed at each specified timepoints.
    End point type
    Secondary
    End point timeframe
    Baseline (Day 1), Weeks 26 and 52
    End point values
    		 Placebo Canagliflozin
    Number of subjects analysed
    81
    80
    Units: millimetre of mercury (mmHg)
    least squares mean (standard error)
        Week 26 (n=81,80)
    1.4 ( 1.04 )
    0.7 ( 1.04 )
        Week 52 (n=75,74)
    1.5 ( 1.06 )
    0.0 ( 1.05 )
    No statistical analyses for this end point

    Secondary: Change From Baseline in Diastolic Blood Pressure at Weeks 26 and 52

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    End point title
    		 Change From Baseline in Diastolic Blood Pressure at Weeks 26 and 52
    End point description
    Change from baseline in diastolic blood pressure at Weeks 26 and 52 were reported. Data for this endpoint was planned to be collected and analysed for the combined population of arm Canagliflozin 100 mg and Canagliflozin 300 mg. FAS included all subjects who were randomly assigned to a treatment group, received at least one dose of study agent and had a baseline HbA1c measurement. Here, 'N' (number of subjects analysed) signifies subjects evaluable for this endpoint and 'n' (number analysed) signifies number of subjects analysed at each specified timepoints.
    End point type
    Secondary
    End point timeframe
    Baseline (Day 1), Weeks 26, and 52
    End point values
    		 Placebo Canagliflozin
    Number of subjects analysed
    81
    80
    Units: mmHg
    least squares mean (standard error)
        Week 26 (n=81,80)
    -0.1 ( 0.78 )
    -0.1 ( 0.78 )
        Week 52 (n=75,74)
    0.7 ( 0.83 )
    -0.2 ( 0.83 )
    No statistical analyses for this end point

    Secondary: Change From Baseline in HbA1c at Weeks 12 and 52

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    End point title
    		 Change From Baseline in HbA1c at Weeks 12 and 52
    End point description
    Change from baseline in HbA1c at Weeks 12 and 52 were reported. Data for this endpoint was planned to be collected and analysed for the combined population of arm Canagliflozin 100 mg and Canagliflozin 300 mg. FAS included all subjects who were randomly assigned to a treatment group, received at least one dose of study agent and had a baseline HbA1c measurement. Here, 'N' (number of subjects analysed) signifies subjects evaluable for this endpoint and 'n' (number analysed) signifies number of subjects analysed at each specified timepoints.
    End point type
    Secondary
    End point timeframe
    Baseline (Day 1), Weeks 12, and 52
    End point values
    		 Placebo Canagliflozin
    Number of subjects analysed
    83
    84
    Units: Percent (%) of HbA1c
    least squares mean (standard error)
        Week 12 (n=83,84)
    0.10 ( 0.138 )
    -0.59 ( 0.137 )
        Week 52 (n=75,71)
    0.70 ( 0.182 )
    -0.32 ( 0.184 )
    No statistical analyses for this end point

    Secondary: Growth Velocity at Weeks 26 and 52

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    End point title
    		 Growth Velocity at Weeks 26 and 52
    End point description
    Growth velocity (increase in height per year) at Weeks 26 and 52 were reported. Safety analysis set included all the subjects who were randomised and took at least 1 dose of study agent. Here, 'N' (number of subjects analysed) signifies subjects evaluable for this endpoint and 'n' (number analysed) signifies number of subjects analysed at each specified timepoints.
    End point type
    Secondary
    End point timeframe
    Weeks 26 and 52
    End point values
    		 Placebo Canagliflozin 100 mg Canagliflozin 300 mg
    Number of subjects analysed
    81
    64
    16
    Units: centimetre per year (cm/year)
    arithmetic mean (standard deviation)
        Week 26 (n=81,64,16)
    2.08 ( 3.148 )
    1.94 ( 2.791 )
    1.00 ( 4.294 )
        Week 52 (n=75,59,15)
    1.63 ( 2.624 )
    1.46 ( 1.824 )
    1.76 ( 3.004 )
    No statistical analyses for this end point

    Secondary: Number of Subjects with Changes in Tanner Staging (Females) From Baseline at Weeks 26 and 52

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    End point title
    		 Number of Subjects with Changes in Tanner Staging (Females) From Baseline at Weeks 26 and 52
    End point description
    Tanner Pubertal Staging were assessed in female (F) for pubic hair growth and for breast development in stages (S) 1 to 5. If a subject had reached Tanner S 5, no further Tanner pubertal S assessments were to be completed and reported as ‘not done (ND)’. Pubic hair growth: Tanner S: Pubic hair (1: No hair, 2: Downy hair, 3: More coarse and curly hair, 4: Adult-like hair quality; 5: Hair extends to medial surface of the thighs); Breast development: (1: The nipple is raised a little in this stage. The rest of the breast is still flat, 2: Breast bud forms,3: More elevated, outside areola, 4: Increased breast size, 5: Final adult-size breasts). Categories with at least 1 non-zero data values are reported. Safety analysis: subjects who were randomised and took at least 1 dose of study drug. Baseline=B, Week=W. Here, 'N' (number of subjects analysed) signifies subjects evaluable for this endpoint and 'n' (number analysed) signifies number of subjects analysed at each specified timepoints.
    End point type
    Secondary
    End point timeframe
    Baseline (Day 1), Weeks 26, and 52
    End point values
    		 Placebo Canagliflozin 100 mg Canagliflozin 300 mg
    Number of subjects analysed
    56
    47
    7
    Units: Subjects
        Breast S: F: S2 (at B) to S3 (at W26) (n=56,47,7)
    1
    2
    1
        Breast S: F: S 2 (at B) to ND (at W26) (n=56,47,7)
    1
    0
    0
        Breast S: F: S3 (at B) to S3 (at W26) (n=56,47,7)
    8
    7
    0
        Breast S: F: S3 (at B) to S4 (at W26) (n=56,47,7)
    2
    5
    0
        Breast S: F: S4 (at B) to S4 (at W26) (n=56,47,7)
    15
    7
    2
        Breast S: F: S4 (at B) to S5 (at W26) (n=56,47,7)
    0
    0
    0
        Breast S: F: S5 (at B) to S5 (at W26) (n=56,47,7)
    7
    2
    1
        Breast S: F: S5 (at B) to ND (at W26) (n=56,47,7)
    19
    13
    2
        Breast S: F: S2 (at B) to S2 (at W26) (n=56,47,7)
    0
    3
    0
        Breast S: F: S2 (at B) to S5 (at W26) (n=56,47,7)
    0
    1
    0
        Breast S: F: S2 (at B) to S3 (at W52) (n=53,42,6)
    1
    3
    1
        Breast S: F: S3 (at B) to S3 (at W52) (n=53,42,6)
    3
    2
    0
        Breast S: F: S3 (at B) to S4 (at W52) (n=53,42,6)
    6
    8
    0
        Breast S: F: S3 (at B) to S5 (at W52) (n=53,42,6)
    1
    0
    0
        Breast S: F: S4 (at B) to S4 (at W52) (n=53,42,6)
    11
    5
    1
        Breast S: F: S4 (at B) to S5 (at W52) (n=53,42,6)
    5
    3
    1
        Breast S: F: S4 (at B) to ND (at W52) (n=53,42,6)
    1
    4
    0
        Breast S: F: S5 (at B) to S5 (at W52) (n=53,42,6)
    6
    0
    1
        Breast S: F: S5 (at B) to ND (at W52) (n=53,42,6)
    19
    14
    2
        Breast S: F: S2 (at B) to S2 (at W52) (n=53,42,6)
    0
    1
    0
        Breast S: F: S3 (at B) to S2 (at W 52) (n=53,42,6)
    0
    1
    0
        Pubic Hair:F: S2 (at B) to S3 (at W26) (n=56,47,7)
    1
    0
    0
        Pubic Hair:F: S3 (at B) to S3 (at W26) (n=56,47,7)
    6
    9
    0
        Pubic Hair:F: S3 (at B) to S4 (at W26) (n=56,47,7)
    2
    5
    0
        Pubic Hair:F: S3 (at B) to ND (at W26) (n=56,47,7)
    1
    0
    0
        Pubic Hair:F: S4 (at B) to S4 (at W26) (n=56,47,7)
    18
    7
    3
        Pubic Hair:F: S3 (at B) to S5 (at W26) (n=56,47,7)
    4
    6
    1
        Pubic Hair:F: S5 (at B) to S5 (at W26) (n=56,47,7)
    5
    2
    0
        Pubic Hair:F: S5 (at B) to ND (at W26) (n=56,47,7)
    19
    14
    2
        Pubic Hair:F: S1 (at B) to S1 (at W26) (n=56,47,7)
    0
    1
    1
        Pubic Hair:F: S2 (at B) to S2 (at W26) (n=56,47,7)
    0
    2
    0
        Pubic Hair:F: S2 (at B) to S2 (at W52) (n=53,42,6)
    0
    1
    0
        Pubic Hair:F: S2 (at B) to S3 (at W52) (n=53,42,6)
    1
    0
    0
        Pubic Hair:F: S3 (at B) to S2 (at W52) (n=53,42,6)
    0
    0
    1
        Pubic Hair:F: S3 (at B) to S3 (at W52) (n=53,42,6)
    4
    4
    0
        Pubic Hair:F: S3 (at B) to S4 (at W52) (n=53,42,6)
    3
    8
    0
        Pubic Hair:F: S3 (at B) to S5 (at W52) (n=53,42,6)
    1
    0
    0
        Pubic Hair:F: S4 (at B) to S4 (at W52) (n=53,42,6)
    12
    4
    2
        Pubic Hair:F: S4 (at B) to S5 (at W52) (n=53,42,6)
    6
    8
    2
        Pubic Hair:F: S4 (at B) to ND (at W52) (n=53,42,6)
    4
    0
    1
    No statistical analyses for this end point

    Secondary: Number of Subjects with Changes in Tanner Staging (Males) From Baseline at Weeks 26 and 52

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    End point title
    		 Number of Subjects with Changes in Tanner Staging (Males) From Baseline at Weeks 26 and 52
    End point description
    Tanner Pubertal Staging were assessed in male (M) for pubic hair growth and for genitalia development in S 1 to 5. If a subject had reached Tanner S5, no further Tanner pubertal S assessments were to be completed and reported as ND. Pubic hair growth: Tanner S: Pubic hair (1: No hair, 2: little soft, long, lightly curled hair at penis 3: More coarse and curly hair covered larger area, 4: Adult-like hair quality; 5: Hair extends to medial surface of the thighs); Genitalia development: (1: Testes, scrotum, and penis about same size, 2: Enlargement of scrotum, testes, and penis, 3: Enlargement of penis, 4: The penis and glans became larger, 5: Genitalia size and shape same an adult male). Categories with at least 1 non-zero data values are reported. Safety analysis: subjects who were randomised and took at least 1 dose of study drug. Here, 'N' (number of subjects analysed): subjects evaluable for this endpoint and 'n' (number analysed): subjects analysed at each specified timepoints.
    End point type
    Secondary
    End point timeframe
    Baseline (Day 1), Weeks 26, and 52
    End point values
    		 Placebo Canagliflozin 100 mg Canagliflozin 300 mg
    Number of subjects analysed
    23
    18
    9
    Units: Subjects
        GD: M: S1 (at B) to S2 (at W26) (n=23,18,9)
    0
    0
    1
        GD: M: S1 (at B) to S3 (at W26) (n=23,18,9)
    0
    1
    0
        GD: M: S2 (at B) to S2 (at W26) (n=23,18,9)
    1
    0
    0
        GD: M: S2 (at B) to S3 (at W26) (n=23,18,9)
    1
    1
    0
        GD: M: S3 (at B) to S3 (at W26) (n=23,18,9)
    8
    2
    3
        GD: M: S3 (at B) to S4 (at W26) (n=23,18,9)
    1
    3
    0
        GD: M: S3 (at B) to S5 (at W26) (n=23,18,9)
    1
    0
    0
        GD: M: S4 (at B) to S3 (at W26) (n=23,18,9)
    1
    0
    0
        GD: M: S4 (at B) to S4 (at W26) (n=23,18,9)
    5
    7
    2
        GD: M: S4 (at B) to S5 (at W26) (n=23,18,9)
    1
    0
    0
        GD: M: S5 (at B) to S5 (at W26) (n=23,18,9)
    0
    1
    1
        GD: M: S5 (at B) to ND (at W26) (n=23,18,9)
    4
    3
    2
        GD: M: S1 (at B) to S4 (at W52) (n=23,18,9)
    0
    1
    1
        GD: M: S2 (at B) to S2 (at W52) (n=23,18,9)
    1
    0
    0
        GD: M: S2 (at B) to S3 (at W52) (n=23,18,9)
    1
    0
    0
        GD: M: S3 (at B) to S3 (at W52) (n=23,18,9)
    5
    0
    2
        GD: M: S3 (at B) to S4 (at W52) (n=23,18,9)
    2
    5
    1
        GD: M: S3 (at B) to S5 (at W52) (n=23,18,9)
    3
    0
    0
        GD: M: S4 (at B) to S4 (at W52) (n=23,18,9)
    2
    6
    2
        GD: M: S4 (at B) to S5 (at W52) (n=23,18,9)
    5
    0
    0
        GD: M: S5 (at B) to ND (at W52) (n=23,18,9)
    2
    4
    2
        Pubic Hair:M: S1 (at B) to S2 (at W26) (n=23,18,9)
    1
    1
    1
        Pubic Hair:M: S2 (at B) to S2 (at W26) (n=23,18,9)
    1
    0
    0
        Pubic Hair:M: S2 (at B) to S3 (at W26) (n=23,18,9)
    0
    1
    1
        Pubic Hair:M: S3 (at B) to S2 (at W26) (n=23,18,9)
    1
    0
    0
        Pubic Hair:M: S3 (at B) to S3 (at W26) (n=23,18,9)
    7
    1
    2
        Pubic Hair:M: S3 (at B) to S4 (at W26) (n=23,18,9)
    2
    3
    0
        Pubic Hair:M: S3 (at B) to S5 (at W26) (n=23,18,9)
    1
    0
    0
        Pubic Hair:M: S4 (at B) to S4 (at W26) (n=23,18,9)
    5
    8
    2
        Pubic Hair:M: S4 (at B) to S5 (at W26) (n=23,18,9)
    1
    1
    0
        Pubic Hair:M: S5 (at B) to S5 (at W26) (n=23,18,9)
    0
    0
    1
        Pubic Hair:M: S5 (at B) to ND (at W26) (n=23,18,9)
    4
    3
    2
        Pubic Hair:M: S1 (at B) to S2 (at W52) (n=23,18,9)
    4
    3
    2
        Pubic Hair:M: S2 (at B) to S2 (at W52) (n=23,18,9)
    1
    0
    0
        Pubic Hair:M: S3 (at B) to S3 (at W52) (n=23,18,9)
    4
    0
    0
        Pubic Hair:M: S3 (at B) to S4 (at W52) (n=23,18,9)
    4
    4
    0
        Pubic Hair:M: S3 (at B) to S5 (at W52) (n=23,18,9)
    3
    0
    0
        Pubic Hair:M: S4 (at B) to S4 (at W52) (n=23,18,9)
    2
    7
    2
        Pubic Hair:M: S4 (at B) to S5 (at W52) (n=23,18,9)
    4
    0
    0
        Pubic Hair:M: S5 (at B) to ND (at W52) (n=23,18,9)
    2
    3
    2
    No statistical analyses for this end point

    Secondary: Change From Baseline in Bone Turnover Marker: Serum Osteocalcin and Serum Collagen Type 1 Carboxy-Telopeptide (CTx) at Weeks 26 and 52

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    End point title
    		 Change From Baseline in Bone Turnover Marker: Serum Osteocalcin and Serum Collagen Type 1 Carboxy-Telopeptide (CTx) at Weeks 26 and 52
    End point description
    Change from baseline in bone turnover marker: serum osteocalcin and CTx at Weeks 26 and 52 were reported. Safety analysis set included all the subjects who were randomised and took at least 1 dose of study agent. Here, 'N' (number of subjects analysed) signifies subjects evaluable for this endpoint and 'n' (number analysed) signifies number of subjects analysed at each specified timepoints. Here, 99999 implies standard deviation was not estimable because only one subject was available for the analysis. Here, 9999 implies standard deviation was not estimable as no subject was available for the analysis.
    End point type
    Secondary
    End point timeframe
    Baseline (Day 1), Weeks 26 and 52
    End point values
    		 Placebo Canagliflozin 100 mg Canagliflozin 300 mg
    Number of subjects analysed
    76
    59
    13
    Units: micrograms/liter (mcg/L)
    arithmetic mean (standard deviation)
        Week 26: Serum Osteocalcin (n=78,59,13)
    -3.594 ( 17.0801 )
    -3.328 ( 15.1110 )
    -0.904 ( 10.3083 )
        Week 52: Serum Osteocalcin (n=71,56,14)
    -8.732 ( 19.3027 )
    -5.964 ( 16.8299 )
    -3.475 ( 9.2422 )
        Week 26: CTx (n=3,2,1)
    -0.1530 ( 0.26595 )
    0.3575 ( 0.34295 )
    0.3000 ( 99999 )
        Week 52: CTx (n=1,1,0)
    -0.0240 ( 99999 )
    -0.3710 ( 99999 )
    9999 ( 9999 )
    No statistical analyses for this end point

    Secondary: Urinary Albumin/Creatinine Ratio (ACR) at Weeks 26 and 52

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    End point title
    		 Urinary Albumin/Creatinine Ratio (ACR) at Weeks 26 and 52
    End point description
    Urinary ACR were reported at Weeks 26 and 52. Safety analysis set included all the subjects who were randomised and took at least 1 dose of study agent. Here, 'N' (number of subjects analysed) signifies subjects evaluable for this endpoint and 'n' (number analysed) signifies number of subjects analysed at each specified timepoints.
    End point type
    Secondary
    End point timeframe
    Weeks 26 and 52
    End point values
    		 Placebo Canagliflozin 100 mg Canagliflozin 300 mg
    Number of subjects analysed
    64
    48
    12
    Units: milligrams/gram (mg/gm)
    geometric mean (confidence interval 95%)
        Week 26 (n=64,48,12)
    15.62 (11.24 to 21.71)
    14.41 (9.85 to 21.07)
    24.84 (11.81 to 52.26)
        Week 52 (n=65,47,11)
    14.98 (10.97 to 20.46)
    15.45 (10.75 to 22.22)
    21.27 (10.42 to 43.45)
    No statistical analyses for this end point

    Adverse events

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    Adverse events information
    Timeframe for reporting adverse events
    Baseline (Day 1) up to 30 days post last dose (up to Week 56)
    Adverse event reporting additional description
    Safety was based on the safety analysis set that included all randomised subjects who received at least 1 dose of study drug.
    Assessment type
    		 Non-systematic
    Dictionary used for adverse event reporting
    Dictionary name
    		 MedDRA
    Dictionary version
    26.0
    Reporting groups
    Reporting group title
    Placebo
    Reporting group description
    		 Subjects received orally 1 placebo tablet matching to canagliflozin 100/300 milligrams (mg) once-daily from Day 1 till Week 52. At Week 13, subjects who met re-randomisation criteria (glycated hemoglobin [HbA1c] of >=7.0%, estimated glomerular filtration rate [eGFR] >=60 mL/min/1.73 m^2) at Week 12 were alone re-randomised to receive orally 1 tablet of placebo matching canagliflozin 100 mg and 1 tablet of placebo matching canagliflozin 300 mg once daily till Week 52. Subjects who did not meet the re-randomisation criteria continued to receive orally 1 tablet of placebo matching to canagliflozin 100 mg once daily till Week 52.

    Reporting group title
    Canagliflozin 300 mg
    Reporting group description
    		 Subjects received orally canagliflozin 100 mg tablet once daily from Day 1 till Week 12. At Week 13, subjects who met re-randomisation criteria (HbA1c of >=7.0%, estimated eGFR >=60 mL/min/1.73 m^2) at Week 12 were alone re-randomised at 1:1 ratio to receive orally 1 tablet of canagliflozin 300 mg tablet and 1 tablet of placebo matching canagliflozin 100 mg once daily till Week 52. Subjects who did not meet the re-randomisation criteria continued to receive orally 1 tablet of canagliflozin 100 mg once daily till Week 52.

    Reporting group title
    Canagliflozin 100 mg
    Reporting group description
    		 Subjects received orally canagliflozin 100 mg tablet once daily from Day 1 till Week 12. At Week 13, subjects who met re-randomisation criteria (HbA1c of >=7.0%, estimated eGFR >=60 mL/min/1.73 m^2) at Week 12 were alone re-randomised at 1:1 ratio to receive orally 1 tablet of canagliflozin 100 mg tablet and 1 tablet of placebo matching canagliflozin 300 mg once daily till Week 52. Subjects who did not meet the re-randomisation criteria continued to receive orally 1 tablet of canagliflozin 100 mg once daily till Week 52.

    Serious adverse events
    		 Placebo Canagliflozin 300 mg Canagliflozin 100 mg
    Total subjects affected by serious adverse events
         subjects affected / exposed
    5 / 87 (5.75%)
    1 / 17 (5.88%)
    7 / 67 (10.45%)
         number of deaths (all causes)
    0
    0
    0
         number of deaths resulting from adverse events
    Injury, poisoning and procedural complications
    Ankle Fracture
         subjects affected / exposed
    1 / 87 (1.15%)
    0 / 17 (0.00%)
    0 / 67 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Pregnancy, puerperium and perinatal conditions
    Abortion Spontaneous
         subjects affected / exposed
    1 / 87 (1.15%)
    0 / 17 (0.00%)
    0 / 67 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Immune system disorders
    Anaphylactic Reaction
         subjects affected / exposed
    0 / 87 (0.00%)
    0 / 17 (0.00%)
    1 / 67 (1.49%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Gastrointestinal disorders
    Pancreatitis Acute
         subjects affected / exposed
    0 / 87 (0.00%)
    1 / 17 (5.88%)
    0 / 67 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Hepatobiliary disorders
    Cholelithiasis
         subjects affected / exposed
    0 / 87 (0.00%)
    0 / 17 (0.00%)
    1 / 67 (1.49%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Respiratory, thoracic and mediastinal disorders
    Tonsillar Hypertrophy
         subjects affected / exposed
    1 / 87 (1.15%)
    0 / 17 (0.00%)
    0 / 67 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Psychiatric disorders
    Suicide Attempt
         subjects affected / exposed
    0 / 87 (0.00%)
    0 / 17 (0.00%)
    1 / 67 (1.49%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Infections and infestations
    Pneumonia
         subjects affected / exposed
    0 / 87 (0.00%)
    0 / 17 (0.00%)
    1 / 67 (1.49%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Erysipelas
         subjects affected / exposed
    0 / 87 (0.00%)
    0 / 17 (0.00%)
    1 / 67 (1.49%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Metabolism and nutrition disorders
    Diabetic Ketoacidosis
         subjects affected / exposed
    1 / 87 (1.15%)
    0 / 17 (0.00%)
    1 / 67 (1.49%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Hyperglycaemia
         subjects affected / exposed
    0 / 87 (0.00%)
    0 / 17 (0.00%)
    1 / 67 (1.49%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Diabetes Mellitus Inadequate Control
         subjects affected / exposed
    1 / 87 (1.15%)
    0 / 17 (0.00%)
    0 / 67 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Frequency threshold for reporting non-serious adverse events: 5%
    Non-serious adverse events
    		 Placebo Canagliflozin 300 mg Canagliflozin 100 mg
    Total subjects affected by non serious adverse events
         subjects affected / exposed
    45 / 87 (51.72%)
    14 / 17 (82.35%)
    37 / 67 (55.22%)
    General disorders and administration site conditions
    Pyrexia
         subjects affected / exposed
    3 / 87 (3.45%)
    0 / 17 (0.00%)
    4 / 67 (5.97%)
         occurrences all number
    4
    0
    6
    Fatigue
         subjects affected / exposed
    0 / 87 (0.00%)
    1 / 17 (5.88%)
    0 / 67 (0.00%)
         occurrences all number
    0
    1
    0
    Thirst
         subjects affected / exposed
    0 / 87 (0.00%)
    1 / 17 (5.88%)
    0 / 67 (0.00%)
         occurrences all number
    0
    1
    0
    Immune system disorders
    Seasonal Allergy
         subjects affected / exposed
    0 / 87 (0.00%)
    1 / 17 (5.88%)
    0 / 67 (0.00%)
         occurrences all number
    0
    1
    0
    Reproductive system and breast disorders
    Balanoposthitis
         subjects affected / exposed
    0 / 87 (0.00%)
    1 / 17 (5.88%)
    0 / 67 (0.00%)
         occurrences all number
    0
    1
    0
    Respiratory, thoracic and mediastinal disorders
    Rhinorrhoea
         subjects affected / exposed
    2 / 87 (2.30%)
    1 / 17 (5.88%)
    0 / 67 (0.00%)
         occurrences all number
    2
    2
    0
    Psychiatric disorders
    Autism Spectrum Disorder
         subjects affected / exposed
    0 / 87 (0.00%)
    1 / 17 (5.88%)
    0 / 67 (0.00%)
         occurrences all number
    0
    1
    0
    Investigations
    Blood Glucose Increased
         subjects affected / exposed
    0 / 87 (0.00%)
    1 / 17 (5.88%)
    0 / 67 (0.00%)
         occurrences all number
    0
    1
    0
    Blood Ketone Body Increased
         subjects affected / exposed
    2 / 87 (2.30%)
    1 / 17 (5.88%)
    1 / 67 (1.49%)
         occurrences all number
    2
    1
    1
    High Density Lipoprotein Decreased
         subjects affected / exposed
    0 / 87 (0.00%)
    1 / 17 (5.88%)
    0 / 67 (0.00%)
         occurrences all number
    0
    1
    0
    Injury, poisoning and procedural complications
    Skin Abrasion
         subjects affected / exposed
    1 / 87 (1.15%)
    1 / 17 (5.88%)
    0 / 67 (0.00%)
         occurrences all number
    3
    1
    0
    Skin Laceration
         subjects affected / exposed
    0 / 87 (0.00%)
    1 / 17 (5.88%)
    0 / 67 (0.00%)
         occurrences all number
    0
    2
    0
    Nervous system disorders
    Dizziness
         subjects affected / exposed
    1 / 87 (1.15%)
    1 / 17 (5.88%)
    2 / 67 (2.99%)
         occurrences all number
    1
    1
    4
    Headache
         subjects affected / exposed
    3 / 87 (3.45%)
    1 / 17 (5.88%)
    8 / 67 (11.94%)
         occurrences all number
    3
    2
    11
    Ear and labyrinth disorders
    Vertigo
         subjects affected / exposed
    1 / 87 (1.15%)
    1 / 17 (5.88%)
    0 / 67 (0.00%)
         occurrences all number
    1
    1
    0
    Gastrointestinal disorders
    Nausea
         subjects affected / exposed
    1 / 87 (1.15%)
    2 / 17 (11.76%)
    2 / 67 (2.99%)
         occurrences all number
    1
    2
    2
    Vomiting
         subjects affected / exposed
    2 / 87 (2.30%)
    2 / 17 (11.76%)
    3 / 67 (4.48%)
         occurrences all number
    2
    3
    4
    Diarrhoea
         subjects affected / exposed
    5 / 87 (5.75%)
    1 / 17 (5.88%)
    3 / 67 (4.48%)
         occurrences all number
    7
    1
    3
    Abdominal Pain
         subjects affected / exposed
    0 / 87 (0.00%)
    1 / 17 (5.88%)
    2 / 67 (2.99%)
         occurrences all number
    0
    1
    2
    Skin and subcutaneous tissue disorders
    Skin Lesion
         subjects affected / exposed
    0 / 87 (0.00%)
    1 / 17 (5.88%)
    0 / 67 (0.00%)
         occurrences all number
    0
    1
    0
    Urticaria
         subjects affected / exposed
    0 / 87 (0.00%)
    1 / 17 (5.88%)
    0 / 67 (0.00%)
         occurrences all number
    0
    1
    0
    Renal and urinary disorders
    Ketonuria
         subjects affected / exposed
    0 / 87 (0.00%)
    1 / 17 (5.88%)
    0 / 67 (0.00%)
         occurrences all number
    0
    1
    0
    Musculoskeletal and connective tissue disorders
    Musculoskeletal Pain
         subjects affected / exposed
    0 / 87 (0.00%)
    1 / 17 (5.88%)
    0 / 67 (0.00%)
         occurrences all number
    0
    1
    0
    Myalgia
         subjects affected / exposed
    1 / 87 (1.15%)
    1 / 17 (5.88%)
    1 / 67 (1.49%)
         occurrences all number
    1
    1
    1
    Infections and infestations
    Covid-19
         subjects affected / exposed
    2 / 87 (2.30%)
    1 / 17 (5.88%)
    1 / 67 (1.49%)
         occurrences all number
    2
    1
    1
    Gastroenteritis Viral
         subjects affected / exposed
    0 / 87 (0.00%)
    1 / 17 (5.88%)
    0 / 67 (0.00%)
         occurrences all number
    0
    1
    0
    Genital Herpes
         subjects affected / exposed
    0 / 87 (0.00%)
    1 / 17 (5.88%)
    0 / 67 (0.00%)
         occurrences all number
    0
    2
    0
    Genital Herpes Simplex
         subjects affected / exposed
    0 / 87 (0.00%)
    1 / 17 (5.88%)
    0 / 67 (0.00%)
         occurrences all number
    0
    1
    0
    Genital Infection Fungal
         subjects affected / exposed
    0 / 87 (0.00%)
    1 / 17 (5.88%)
    0 / 67 (0.00%)
         occurrences all number
    0
    1
    0
    External Ear Cellulitis
         subjects affected / exposed
    0 / 87 (0.00%)
    1 / 17 (5.88%)
    0 / 67 (0.00%)
         occurrences all number
    0
    1
    0
    Bacterial Vaginosis
         subjects affected / exposed
    0 / 87 (0.00%)
    1 / 17 (5.88%)
    0 / 67 (0.00%)
         occurrences all number
    0
    1
    0
    Balanitis Candida
         subjects affected / exposed
    0 / 87 (0.00%)
    1 / 17 (5.88%)
    1 / 67 (1.49%)
         occurrences all number
    0
    1
    1
    Rhinitis
         subjects affected / exposed
    2 / 87 (2.30%)
    1 / 17 (5.88%)
    3 / 67 (4.48%)
         occurrences all number
    2
    1
    3
    Influenza
         subjects affected / exposed
    4 / 87 (4.60%)
    1 / 17 (5.88%)
    2 / 67 (2.99%)
         occurrences all number
    6
    1
    2
    Urinary Tract Infection
         subjects affected / exposed
    4 / 87 (4.60%)
    5 / 17 (29.41%)
    1 / 67 (1.49%)
         occurrences all number
    4
    6
    1
    Urinary Tract Infection Bacterial
         subjects affected / exposed
    0 / 87 (0.00%)
    1 / 17 (5.88%)
    0 / 67 (0.00%)
         occurrences all number
    0
    1
    0
    Viral Infection
         subjects affected / exposed
    2 / 87 (2.30%)
    1 / 17 (5.88%)
    0 / 67 (0.00%)
         occurrences all number
    2
    1
    0
    Viral Upper Respiratory Tract Infection
         subjects affected / exposed
    1 / 87 (1.15%)
    1 / 17 (5.88%)
    2 / 67 (2.99%)
         occurrences all number
    1
    1
    2
    Vulvovaginal Candidiasis
         subjects affected / exposed
    0 / 87 (0.00%)
    1 / 17 (5.88%)
    1 / 67 (1.49%)
         occurrences all number
    0
    1
    1
    Upper Respiratory Tract Infection
         subjects affected / exposed
    11 / 87 (12.64%)
    1 / 17 (5.88%)
    3 / 67 (4.48%)
         occurrences all number
    17
    2
    4
    Nasopharyngitis
         subjects affected / exposed
    5 / 87 (5.75%)
    0 / 17 (0.00%)
    8 / 67 (11.94%)
         occurrences all number
    6
    0
    10
    Pharyngitis Streptococcal
         subjects affected / exposed
    0 / 87 (0.00%)
    1 / 17 (5.88%)
    0 / 67 (0.00%)
         occurrences all number
    0
    1
    0
    Pharyngotonsillitis
         subjects affected / exposed
    1 / 87 (1.15%)
    1 / 17 (5.88%)
    1 / 67 (1.49%)
         occurrences all number
    1
    1
    1
    Metabolism and nutrition disorders
    Dehydration
         subjects affected / exposed
    1 / 87 (1.15%)
    1 / 17 (5.88%)
    0 / 67 (0.00%)
         occurrences all number
    1
    1
    0
    Diabetes Mellitus Inadequate Control
         subjects affected / exposed
    0 / 87 (0.00%)
    1 / 17 (5.88%)
    0 / 67 (0.00%)
         occurrences all number
    0
    1
    0
    Hyperglycaemia
         subjects affected / exposed
    5 / 87 (5.75%)
    1 / 17 (5.88%)
    1 / 67 (1.49%)
         occurrences all number
    7
    1
    1
    Vitamin D Deficiency
         subjects affected / exposed
    6 / 87 (6.90%)
    1 / 17 (5.88%)
    3 / 67 (4.48%)
         occurrences all number
    6
    1
    3
    Hypoglycaemia
         subjects affected / exposed
    8 / 87 (9.20%)
    0 / 17 (0.00%)
    3 / 67 (4.48%)
         occurrences all number
    17
    0
    3
    Hypertriglyceridaemia
         subjects affected / exposed
    2 / 87 (2.30%)
    1 / 17 (5.88%)
    0 / 67 (0.00%)
         occurrences all number
    2
    1
    0

    More information

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    Substantial protocol amendments (globally)
    Were there any global substantial amendments to the protocol? Yes
    Date
    Amendment
    27 Mar 2017
    The purpose of the amendment was to modify the study design to allow the assessment of canagliflozin when used with and without titration which is more reflective of how canagliflozin may be used in this pediatric population, and to add ketone monitoring procedures, and some minor editorial changes.
    25 Aug 2017
    The purpose of the amendment was to include changes in the statistical analysis, and minor editorial changes.
    25 Jun 2018
    The purpose of the amendment was to have an independently powered subset of subjects on a background of diet and exercise only where superiority of canagliflozin vs placebo could be assessed.
    14 Aug 2020
    The purpose of the amendment was to include the following changes: Due to slower than expected recruitment in the study and a high rate of screen failures, the power calculation was modified resulting in a reduced sample size. In addition, minor modifications to the inclusion and exclusion criteria had been made.

    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.
    Time to rescue therapy was plotted using the Kaplan Meier method and only graphical representation is available, hence not included in endpoint section based on the requirements.
    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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