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    Clinical Trial Results:
    A Randomized, Double-blind, Placebo Controlled, 2-arm, Parallel-group, 26-week, Multicenter Study to Evaluate the Efficacy, Safety, and Tolerability of Canagliflozin in the Treatment of Subjects with Type 2 Diabetes Mellitus with Inadequate Glycemic Control on Metformin and Sitagliptin Therapy

    Summary
    EudraCT number
    		 2013-004819-40
    Trial protocol
    		 DE  
    Global end of trial date
    11 Sep 2015

    Results information
    Results version number
    		 v1(current)
    This version publication date
    25 Aug 2016
    First version publication date
    25 Aug 2016
    Other versions

    Trial information

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    Trial identification
    Sponsor protocol code
    28431754DIA4004
    Additional study identifiers
    ISRCTN number
    		 -
    US NCT number
    		 NCT02025907
    WHO universal trial number (UTN)
    		 -
    Sponsors
    Sponsor organisation name
    Janssen Research & Development, LLC
    Sponsor organisation address
    Turnhoutseweg 30, BEERSE, Belgium, 2340
    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)
    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
    11 Sep 2015
    Is this the analysis of the primary completion data?
    No
    Global end of trial reached?
    Yes
    Global end of trial date
    11 Sep 2015
    Was the trial ended prematurely?
    No
    General information about the trial
    Main objective of the trial
    The main objectives were to assess the effect of canagliflozin relative to placebo on glycosylated hemoglobin (HbA1c) and to assess the safety and tolerability of canagliflozin.
    Protection of trial subjects
    The safety assessments included the clinical laboratory tests (hematology, serum chemistry, FPG, and urinalysis), fasting lipid, electrocardiogram (ECG), vital signs, hypoglycemic episodes, fasting self-monitored blood glucose (SMBG) and physical examinations. Adverse events (AEs) were assessed throughout the study.
    Background therapy
    		 -
    Evidence for comparator
    		 -
    Actual start date of recruitment
    21 Feb 2014
    Long term follow-up planned
    No
    Independent data monitoring committee (IDMC) involvement?
    No
    Population of trial subjects
    Number of subjects enrolled per country
    Country: Number of subjects enrolled
    Australia: 35
    Country: Number of subjects enrolled
    Canada: 39
    Country: Number of subjects enrolled
    France: 16
    Country: Number of subjects enrolled
    Germany: 29
    Country: Number of subjects enrolled
    United States: 94
    Worldwide total number of subjects
    213
    EEA total number of subjects
    45
    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)
    161
    From 65 to 84 years
    52
    85 years and over
    0

    Subject disposition

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    Recruitment
    Recruitment details
    		 -

    Pre-assignment
    Screening details
    		 Total of 390 subjects screened, out of that 218 subjects were randomly assigned in 1:1 ratio to canagliflozin or placebo treatment. However, One subject was randomized twice (once to placebo and once to canagliflozin) was excluded from the safety analysis set, therefore 216 of the 218 randomized subjects were included in the analyses.

    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 administered with placebo (inactive medication) once daily for 26 weeks.
    Arm type
    		 Placebo

    Investigational medicinal product name
    Placebo
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Capsule
    Routes of administration
    Oral use
    Dosage and administration details
    Subjects administered with matching placebo to canagliflozin orally, once daily for 26 weeks.

    Arm title
    		 Canagliflozin
    Arm description
    		 Subjects administered canagliflozin (JNJ-28431754) 100 milligram (mg) titratable to 300 mg once daily for 26 weeks.
    Arm type
    		 Experimental

    Investigational medicinal product name
    Canagliflozin
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Capsule
    Routes of administration
    Oral use
    Dosage and administration details
    Subjects administered with canagliflozin orally, once daily for 26 weeks.

    Number of subjects in period 1
    		Placebo Canagliflozin
    Started
    106
    107
    Completed
    81
    96
    Not completed
    25
    11
         Physician decision
    2
    -
         Consent withdrawn by subject
    15
    8
         Adverse event, non-fatal
    3
    1
         Lost to follow-up
    2
    2
         Protocol deviation
    2
    -
         Lack of efficacy
    1
    -

    Baseline characteristics

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    Baseline characteristics reporting groups
    Reporting group title
    Placebo
    Reporting group description
    		 Subjects administered with placebo (inactive medication) once daily for 26 weeks.

    Reporting group title
    Canagliflozin
    Reporting group description
    		 Subjects administered canagliflozin (JNJ-28431754) 100 milligram (mg) titratable to 300 mg once daily for 26 weeks.

    Reporting group values
    		 Placebo Canagliflozin Total
    Number of subjects
    		 106 107 213
    Title for AgeCategorical
    Units: subjects
        Adults (18-64 years)
    		 76 85 161
        From 65 to 84 years
    		 30 22 52
        85 years and over
    		 0 0 0
    Title for AgeContinuous
    Units: years
        arithmetic mean (standard deviation)
    		 57.5 ( 10.14 ) 57.4 ( 9.28 ) -
    Title for Gender
    Units: subjects
        Female
    		 51 41 92
        Male
    		 55 66 121

    End points

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    End points reporting groups
    Reporting group title
    Placebo
    Reporting group description
    		 Subjects administered with placebo (inactive medication) once daily for 26 weeks.

    Reporting group title
    Canagliflozin
    Reporting group description
    		 Subjects administered canagliflozin (JNJ-28431754) 100 milligram (mg) titratable to 300 mg once daily for 26 weeks.

    Primary: Change From Baseline in Glycosylated Haemoglobin (HbA1c) at Week 26

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    End point title
    		 Change From Baseline in Glycosylated Haemoglobin (HbA1c) at Week 26
    End point description
    The change in the value of glycosylated hemoglobin (the concentration of glucose bound to hemoglobin as a percent of the absolute maximum that can be bound) from baseline at Week 26 was compared between the different treatment groups. mITT population included all randomized subjects who received at least 1 dose of double blind study drug. A total of 3 subjects were excluded from the mITT population due to potential misconduct and GCP compliance issues. Here, ‘N’ (number of subjects analyzed) signifies those subjects who were evaluable for this outcome measure.
    End point type
    Primary
    End point timeframe
    Baseline and Week 26
    End point values
    		 Placebo Canagliflozin
    Number of subjects analysed
    94
    99
    Units: percentage of glycosylated hemoglobin
        least squares mean (standard error)
    -0.01 ( 0.119 )
    -0.91 ( 0.113 )
    Statistical analysis title
    		 Statistical analysis 1
    Comparison groups
    Placebo v Canagliflozin
    Number of subjects included in analysis
    193
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 < 0.001
    Method
    		 Mixed Model for Repeated Measures (MMRM)
    Parameter type
    		 Least Square (LS) Mean Difference
    Point estimate
    -0.89
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -1.193
         upper limit
    		 -0.592
    Variability estimate
    Standard error of the mean
    Dispersion value
    0.152

    Secondary: Change From Baseline in Fasting Plasma Glucose (FPG) at Week 26

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    End point title
    		 Change From Baseline in Fasting Plasma Glucose (FPG) at Week 26
    End point description
    The change in fasting plasma glucose from baseline at Week 26 was compared between the different treatment groups. mITT population included all randomized subjects who received at least 1 dose of double blind study drug. A total of 3 subjects were excluded from the mITT population due to potential misconduct and GCP compliance issues. Here, ‘N’ (number of subjects analyzed) signifies those subjects who were evaluable for this outcome measure.
    End point type
    Secondary
    End point timeframe
    Baseline and Week 26
    End point values
    		 Placebo Canagliflozin
    Number of subjects analysed
    104
    103
    Units: millimole(s)/litre
        least squares mean (standard error)
    -0.14 ( 0.281 )
    -1.65 ( 0.264 )
    Statistical analysis title
    		 Statistical analysis 1
    Comparison groups
    Placebo v Canagliflozin
    Number of subjects included in analysis
    207
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 < 0.001
    Method
    		 MMRM
    Parameter type
    		 LS Mean difference
    Point estimate
    -1.5
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -2.235
         upper limit
    		 -0.772
    Variability estimate
    Standard error of the mean
    Dispersion value
    0.371

    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 percentage change in body weight from baseline to Week 26 was compared between the different treatment groups. mITT population included all randomized subjects who received at least 1 dose of double blind study drug. A total of 3 subjects were excluded from the mITT population due to potential misconduct and GCP compliance issues. Here, ‘N’ (number of subjects analyzed) signifies those subjects who were evaluable for this outcome measure.
    End point type
    Secondary
    End point timeframe
    Baseline and Week 26
    End point values
    		 Placebo Canagliflozin
    Number of subjects analysed
    104
    103
    Units: percent change
        least squares mean (standard error)
    -1.6 ( 0.337 )
    -3.35 ( 0.324 )
    Statistical analysis title
    		 Statistical analysis 1
    Comparison groups
    Placebo v Canagliflozin
    Number of subjects included in analysis
    207
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 < 0.001
    Method
    		 MMRM
    Parameter type
    		 LS Mean Difference
    Point estimate
    -1.75
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -2.659
         upper limit
    		 -0.851
    Variability estimate
    Standard error of the mean
    Dispersion value
    0.459

    Secondary: Percentage of Subjects With HbA1c Less Than (<) 7.0 Percent at Week 26

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    End point title
    		 Percentage of Subjects With HbA1c Less Than (<) 7.0 Percent at Week 26
    End point description
    The percentage of participants achieved HbA1c less than 7 percent at Week 26 was compared between the different treatment groups. mITT population included all randomized subjects who received at least 1 dose of double blind study drug. A total of 3 subjects were excluded from the mITT population due to potential misconduct and GCP compliance issues. Here, ‘N’ (number of subjects analyzed) signifies those subjects who were evaluable for this outcome measure.
    End point type
    Secondary
    End point timeframe
    Week 26
    End point values
    		 Placebo Canagliflozin
    Number of subjects analysed
    82
    96
    Units: percentage of subjects
        number (not applicable)
    12.2
    32.3
    Statistical analysis title
    		 Statistical analysis 1
    Comparison groups
    Placebo v Canagliflozin
    Number of subjects included in analysis
    178
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.001
    Method
    		 Generalized linear MMRM
    Parameter type
    		 Odds ratio (OR)
    Point estimate
    4.53
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 1.89
         upper limit
    		 10.86

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

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    End point title
    		 Change From Baseline in Systolic Blood Pressure (SBP) at Week 26
    End point description
    The change in systolic blood pressure from baseline at Week 26 was compared between the different treatment groups. mITT population included all randomized subjects who received at least 1 dose of double blind study drug. A total of 3 subjects were excluded from the mITT population due to potential misconduct and GCP compliance issues. Here, ‘N’ (number of subjects analyzed) signifies those subjects who were evaluable for this outcome measure.
    End point type
    Secondary
    End point timeframe
    Baseline and Week 26
    End point values
    		 Placebo Canagliflozin
    Number of subjects analysed
    104
    103
    Units: millimeter of mercury (mmHg)
        least squares mean (standard error)
    0.09 ( 1.123 )
    -5.76 ( 1.078 )
    Statistical analysis title
    		 Statistical analysis 1
    Comparison groups
    Placebo v Canagliflozin
    Number of subjects included in analysis
    207
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 < 0.001
    Method
    		 MMRM
    Parameter type
    		 LS Mean Difference
    Point estimate
    -5.85
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -8.786
         upper limit
    		 -2.914
    Variability estimate
    Standard error of the mean
    Dispersion value
    1.489

    Adverse events

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    Adverse events information
    Timeframe for reporting adverse events
    Baseline to follow up (Approximately 31 Weeks)
    Adverse event reporting additional description
    Safety population included all randomized subjects who received at least 1 dose of double blind study drug.
    Assessment type
    		 Non-systematic
    Dictionary used for adverse event reporting
    Dictionary name
    		 MedDRA
    Dictionary version
    18.0
    Reporting groups
    Reporting group title
    Canagliflozin
    Reporting group description
    		 Subjects administered canagliflozin (JNJ28431754) 100 milligram (mg) titratable to 300 mg once daily for 26 weeks.

    Reporting group title
    Placebo
    Reporting group description
    		 Subjects administered with placebo (inactive medication) once daily for 26 Weeks.

    Serious adverse events
    		 Canagliflozin Placebo
    Total subjects affected by serious adverse events
         subjects affected / exposed
    2 / 108 (1.85%)
    2 / 108 (1.85%)
         number of deaths (all causes)
    0
    0
         number of deaths resulting from adverse events
    Cardiac disorders
    Angina Unstable
    alternative assessment type: Systematic
         subjects affected / exposed
    1 / 108 (0.93%)
    0 / 108 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Nervous system disorders
    Cerebral Infarction
         subjects affected / exposed
    0 / 108 (0.00%)
    1 / 108 (0.93%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Transient Ischaemic Attack
         subjects affected / exposed
    0 / 108 (0.00%)
    1 / 108 (0.93%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Infections and infestations
    Diverticulitis
         subjects affected / exposed
    1 / 108 (0.93%)
    0 / 108 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Frequency threshold for reporting non-serious adverse events: 2%
    Non-serious adverse events
    		 Canagliflozin Placebo
    Total subjects affected by non serious adverse events
         subjects affected / exposed
    18 / 108 (16.67%)
    16 / 108 (14.81%)
    Psychiatric disorders
    Depression
         subjects affected / exposed
    3 / 108 (2.78%)
    0 / 108 (0.00%)
         occurrences all number
    3
    0
    Renal and urinary disorders
    Polyuria
         subjects affected / exposed
    3 / 108 (2.78%)
    3 / 108 (2.78%)
         occurrences all number
    3
    3
    Musculoskeletal and connective tissue disorders
    Back Pain
         subjects affected / exposed
    3 / 108 (2.78%)
    1 / 108 (0.93%)
         occurrences all number
    3
    1
    Pain in Extremity
         subjects affected / exposed
    3 / 108 (2.78%)
    1 / 108 (0.93%)
         occurrences all number
    3
    1
    Infections and infestations
    Nasopharyngitis
    alternative assessment type: Systematic
         subjects affected / exposed
    6 / 108 (5.56%)
    6 / 108 (5.56%)
         occurrences all number
    7
    9
    Upper Respiratory Tract Infection
         subjects affected / exposed
    2 / 108 (1.85%)
    3 / 108 (2.78%)
         occurrences all number
    2
    3
    Metabolism and nutrition disorders
    Hyperglycaemia
         subjects affected / exposed
    0 / 108 (0.00%)
    5 / 108 (4.63%)
         occurrences all number
    0
    5

    More information

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    Substantial protocol amendments (globally)
    Were there any global substantial amendments to the protocol? Yes
    Date
    Amendment
    07 Feb 2014
    The overall reason for the second amendment was to include PRO instruments to assess the subjects satisfaction with their health and their degree of diabetes-related distress.
    18 Sep 2014
    The overall reason for the third amendment was to lower the maximally or near-maximally effective dose of metformin to greater than or equal to (>=) 1,500 milligram per day (mg/day), to remove the prohibition of past use of SGLT2 inhibitors and to clarify the limitations of prior use of other SGLT2 inhibitors.

    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
    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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