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    Clinical Trial Results:
    A dose-ranging, randomized, double-blind, placebo-controlled, parallel-group, multi-center study of the efficacy and safety of 4 doses of imeglimin after 24 weeks of treatment in subjects with type 2 diabetes mellitus

    Summary
    EudraCT number
    		 2012-004045-33
    Trial protocol
    		 LV   HU   EE   CZ   RO  
    Global end of trial date
    10 Jul 2014

    Results information
    Results version number
    		 v1(current)
    This version publication date
    26 Sep 2021
    First version publication date
    26 Sep 2021
    Other versions

    Trial information

    		 Close Top of page
    Trial identification
    Sponsor protocol code
    PXL008-008
    Additional study identifiers
    ISRCTN number
    		 -
    US NCT number
    		 NCT01951235
    WHO universal trial number (UTN)
    		 -
    Sponsors
    Sponsor organisation name
    POXEL SA
    Sponsor organisation address
    259/261 avenue Jean Jaurès, LYON, France, 69007
    Public contact
    Pascale Fouqueray, Poxel SA, 33 437372010,
    Scientific contact
    Pascale Fouqueray, Poxel SA, +33 437372010, pascale.fouqueray@poxelpharma.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
    21 Dec 2017
    Is this the analysis of the primary completion data?
    No
    Global end of trial reached?
    Yes
    Global end of trial date
    10 Jul 2014
    Was the trial ended prematurely?
    No
    General information about the trial
    Main objective of the trial
    To assess the dose-response of imeglimin at 4 doses (500 mg, 1000 mg, 1500 mg and 2000 mg bid) compared to placebo in male and female subjects with type 2 diabetes mellitus after 24 weeks of treatment, using glycosylated hemoglobin (HbA1c) as the primary evaluation criterion.
    Protection of trial subjects
    Subjects, or their legally acceptable representatives, provided their written consent to participate in the study after having been informed about the nature and purpose of the study, participation/termination conditions, and risks and benefits of treatment. The subject information sheet in the local language and prepared in accordance with the ICH GCP guidance was provided by the sponsor for the purpose of obtaining informed consent. Written informed consent was provided at Screening Visit 1 before any study-specific activity and whenever important new information became available that was relevant to the subject’s consent. Subjects were free to discontinue the study at any time without giving their reasons. To overcome the risk to expose subjects with T2DM to an inappropriate glycemic control, some proactive measures were implemented. First, the upper limit of HbA1c inclusion criterion at randomization was limited to 9.5% in order to avoid highly uncontrolled subjects entering the study (see Section 9.3.1). Second, fasting plasma glucose (FPG) was closely monitored throughout the study by the subject (glucometer) and by the investigator at each visit and whenever necessary. Threshold was defined following the Food and Drug Administration (FDA) guidance to withdraw from the study subjects whose glycemic parameters kept deteriorating during the study period in order to initiate rescue therapy.
    Background therapy
    		 No background therapy was allowed during the study.
    Evidence for comparator
    		 The design of this dose-ranging study included a placebo arm in order to compare the efficacy of each dose of imeglimin based on the change in HbA1c values as well as safety and tolerability.
    Actual start date of recruitment
    25 Jan 2013
    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
    Russian Federation: 28
    Country: Number of subjects enrolled
    United States: 45
    Country: Number of subjects enrolled
    Ukraine: 63
    Country: Number of subjects enrolled
    Romania: 68
    Country: Number of subjects enrolled
    Czechia: 15
    Country: Number of subjects enrolled
    Estonia: 31
    Country: Number of subjects enrolled
    Hungary: 60
    Country: Number of subjects enrolled
    Latvia: 72
    Worldwide total number of subjects
    382
    EEA total number of subjects
    246
    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)
    283
    From 65 to 84 years
    99
    85 years and over
    0

    Subject disposition

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    Recruitment
    Recruitment details
    		 Subjects were enrolled at a total of 74 study centers, in the Czech Republic (5 centers), Estonia (6 centers), Hungary (13 centers), Latvia (9 centers), Romania (11 centers), Russia (10 centers), Ukraine (11 centers), and the United States (9 centers). First subject screened: 25Jan2013 - Last subject screened: 02Dec2013

    Pre-assignment
    Screening details
    		 Subjects were screened within 3 weeks, followed by a 3-week placebo run-in period for treatment-naive subjects, or 6-week placebo wash-out/run-in period for subjects previously treated with an oral antidiabetic monotherapy.

    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, Monitor, Data analyst

    Arms
    Are arms mutually exclusive
    Yes

    Arm title
    		 Imeglimin 500 mg twice daily
    Arm description
    		 -
    Arm type
    		 Experimental

    Investigational medicinal product name
    Imeglimin
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Tablet
    Routes of administration
    Oral use
    Dosage and administration details
    1×500 mg tablet of imeglimin twice daily plus 3 tablets of placebo twice daily for 24 weeks

    Arm title
    		 Imeglimin 1000 mg twice daily
    Arm description
    		 -
    Arm type
    		 Experimental

    Investigational medicinal product name
    Imeglimin
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Tablet
    Routes of administration
    Oral use
    Dosage and administration details
    2×500 mg tablets of imeglimin twice daily plus 2 tablets of placebo twice daily for 24 weeks

    Arm title
    		 Imeglimin 1500 mg twice daily
    Arm description
    		 -
    Arm type
    		 Experimental

    Investigational medicinal product name
    Imeglimin
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Tablet
    Routes of administration
    Oral use
    Dosage and administration details
    3×500 mg tablet of imeglimin twice daily plus 1 tablets of placebo twice daily for 24 weeks

    Arm title
    		 Imeglimin 2000 mg twice daily
    Arm description
    		 -
    Arm type
    		 Experimental

    Investigational medicinal product name
    Imeglimin
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Tablet
    Routes of administration
    Oral use
    Dosage and administration details
    4×500 mg tablet of imeglimin twice daily for 24 weeks

    Arm title
    		 Placebo
    Arm description
    		 -
    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
    4 tablets of placebo twice daily for 24 weeks

    Number of subjects in period 1
    		Imeglimin 500 mg twice daily Imeglimin 1000 mg twice daily Imeglimin 1500 mg twice daily Imeglimin 2000 mg twice daily Placebo
    Started
    74
    79
    74
    74
    81
    Completed
    63
    66
    60
    61
    65
    Not completed
    11
    13
    14
    13
    16
         Consent withdrawn by subject
    4
    4
    8
    5
    7
         Intake of non-permitted drug
    -
    -
    1
    -
    1
         Adverse event, non-fatal
    -
    1
    2
    3
    -
         Other reasons
    -
    -
    2
    -
    1
         Not Adequate Treatment Compliance
    1
    -
    -
    -
    -
         Exclusion criteria
    -
    -
    -
    -
    1
         Lack of efficacy
    5
    6
    -
    4
    6
         Protocol deviation
    1
    2
    1
    1
    -

    Baseline characteristics

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    Baseline characteristics reporting groups
    Reporting group title
    Imeglimin 500 mg twice daily
    Reporting group description
    		 -

    Reporting group title
    Imeglimin 1000 mg twice daily
    Reporting group description
    		 -

    Reporting group title
    Imeglimin 1500 mg twice daily
    Reporting group description
    		 -

    Reporting group title
    Imeglimin 2000 mg twice daily
    Reporting group description
    		 -

    Reporting group title
    Placebo
    Reporting group description
    		 -

    Reporting group values
    		 Imeglimin 500 mg twice daily Imeglimin 1000 mg twice daily Imeglimin 1500 mg twice daily Imeglimin 2000 mg twice daily Placebo Total
    Number of subjects
    		 74 79 74 74 81 382
    Age categorical
    Units: Subjects
    Age continuous
    Units: years
        arithmetic mean (standard deviation)
    		 58.1 ± 10.6 58.5 ± 8.9 58.1 ± 8.5 59.0 ± 8.8 58.2 ± 9.3 -
    Gender categorical
    Units: Subjects
        Female
    		 40 54 45 45 44 228
        Male
    		 34 25 29 29 37 154
    BMI
    Units: kg/m²
        arithmetic mean (standard deviation)
    		 31.8 ± 4.5 31.4 ± 4.4 32.0 ± 4.5 31.0 ± 4.5 30.5 ± 4.2 -
    Duration of Diabetes
    Units: Years
        arithmetic mean (standard deviation)
    		 5.2 ± 4.4 5.4 ± 4.1 6.0 ± 5.5 5.7 ± 5.1 5.0 ± 4.1 -
    HbA1c
    Units: percent
        arithmetic mean (standard deviation)
    		 7.95 ± 0.69 8.09 ± 0.77 7.89 ± 0.59 8.04 ± 0.74 7.76 ± 0.62 -
    Fasting Plasma Glucose (FPG)
    Units: mmol/L
        arithmetic mean (standard deviation)
    		 9.92 ± 2.80 10.29 ± 2.14 9.99 ± 2.18 9.76 ± 2.40 9.63 ± 2.12 -
    HOMA-IR
    Units: n/a
        arithmetic mean (standard deviation)
    		 7.3 ± 4.7 8.1 ± 5.9 8.1 ± 6.5 7.6 ± 5.2 12.5 ± 48.9 -

    End points

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    End points reporting groups
    Reporting group title
    Imeglimin 500 mg twice daily
    Reporting group description
    		 -

    Reporting group title
    Imeglimin 1000 mg twice daily
    Reporting group description
    		 -

    Reporting group title
    Imeglimin 1500 mg twice daily
    Reporting group description
    		 -

    Reporting group title
    Imeglimin 2000 mg twice daily
    Reporting group description
    		 -

    Reporting group title
    Placebo
    Reporting group description
    		 -

    Primary: Placebo-adjusted dose-dependent reduction in HbA1c from baseline to Week 24

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    End point title
    		 Placebo-adjusted dose-dependent reduction in HbA1c from baseline to Week 24
    End point description
    End point type
    Primary
    End point timeframe
    Baseline to Week 24
    End point values
    		 Imeglimin 500 mg twice daily Imeglimin 1000 mg twice daily Imeglimin 1500 mg twice daily Imeglimin 2000 mg twice daily Placebo
    Number of subjects analysed
    72
    77
    69
    69
    80
    Units: percent
        least squares mean (standard error)
    0.14 ± 0.114
    -0.09 ± 0.111
    -0.43 ± 0.116
    -0.25 ± 0.117
    0.20 ± 0.109
    Statistical analysis title
    		 Imeglimin 500 mg bid versus Placebo
    Statistical analysis description
    Change in HbA1c from baseline to Week 24 was analyzed using an analysis of covariance (ANCOVA) method where the change in HbA1c from baseline to Week 24 was the outcome variable and country and treatment group were fixed effects. HbA1c values at baseline and subjects naïve of treatment/previously treated were included as covariates. This parameter was assessed by using the last observation carried forward (LOCF) imputation of missing values for the ITT population.
    Comparison groups
    Imeglimin 500 mg twice daily v Placebo
    Number of subjects included in analysis
    152
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.698
    Method
    		 ANCOVA
    Parameter type
    		 Mean difference (final values)
    Point estimate
    -0.061
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -0.37
         upper limit
    		 0.25
    Variability estimate
    Standard error of the mean
    Dispersion value
    0.158
    Statistical analysis title
    		 Imeglimin 1000 mg bid versus Placebo
    Statistical analysis description
    Change in HbA1c from baseline to Week 24 was analyzed using an analysis of covariance (ANCOVA) method where the change in HbA1c from baseline to Week 24 was the outcome variable and country and treatment group were fixed effects. HbA1c values at baseline and subjects naïve of treatment/previously treated were included as covariates. This parameter was assessed by using the last observation carried forward (LOCF) imputation of missing values for the ITT population.
    Comparison groups
    Placebo v Imeglimin 1000 mg twice daily
    Number of subjects included in analysis
    157
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.068
    Method
    		 ANCOVA
    Parameter type
    		 Mean difference (final values)
    Point estimate
    -0.287
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -0.59
         upper limit
    		 0.02
    Variability estimate
    Standard error of the mean
    Dispersion value
    0.156
    Statistical analysis title
    		 Imeglimin 1500 mg bid versus Placebo
    Statistical analysis description
    Change in HbA1c from baseline to Week 24 was analyzed using an analysis of covariance (ANCOVA) method where the change in HbA1c from baseline to Week 24 was the outcome variable and country and treatment group were fixed effects. HbA1c values at baseline and subjects naïve of treatment/previously treated were included as covariates. This parameter was assessed by using the last observation carried forward (LOCF) imputation of missing values for the ITT population.
    Comparison groups
    Placebo v Imeglimin 1500 mg twice daily
    Number of subjects included in analysis
    149
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 < 0.001
    Method
    		 ANCOVA
    Parameter type
    		 Mean difference (final values)
    Point estimate
    -0.625
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -0.94
         upper limit
    		 -0.31
    Variability estimate
    Standard error of the mean
    Dispersion value
    0.159
    Statistical analysis title
    		 Imeglimin 2000 mg bid versus Placebo
    Statistical analysis description
    Change in HbA1c from baseline to Week 24 was analyzed using an analysis of covariance (ANCOVA) method where the change in HbA1c from baseline to Week 24 was the outcome variable and country and treatment group were fixed effects. HbA1c values at baseline and subjects naïve of treatment/previously treated were included as covariates. This parameter was assessed by using the last observation carried forward (LOCF) imputation of missing values for the ITT population.
    Comparison groups
    Imeglimin 2000 mg twice daily v Placebo
    Number of subjects included in analysis
    149
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.006
    Method
    		 ANCOVA
    Parameter type
    		 Mean difference (final values)
    Point estimate
    -0.443
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -0.76
         upper limit
    		 -0.13
    Variability estimate
    Standard error of the mean
    Dispersion value
    0.16

    Secondary: Percentage of subjects achieving an HbA1c response

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    End point title
    		 Percentage of subjects achieving an HbA1c response
    End point description
    The percentage of subjects achieving an HbA1c response at Week 24 (ie, HbA1c ≤ 7.0%) who had an HbA1c value > 7.0% at baseline was compared against placebo using logistic regression analysis. Country, baseline HbA1c value, and subjects naïve of treatment/previously treated were included as covariates.
    End point type
    Secondary
    End point timeframe
    Baseline to Week 24
    End point values
    		 Imeglimin 500 mg twice daily Imeglimin 1000 mg twice daily Imeglimin 1500 mg twice daily Imeglimin 2000 mg twice daily Placebo
    Number of subjects analysed
    64
    72
    68
    63
    71
    Units: percent
        number (not applicable)
    18.1
    15.6
    33.3
    20.3
    12.5
    Statistical analysis title
    		 Imeglimin 500 mg bid versus Placebo
    Statistical analysis description
    Logistic regression
    Comparison groups
    Imeglimin 500 mg twice daily v Placebo
    Number of subjects included in analysis
    135
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.101
    Method
    		 Regression, Logistic
    Confidence interval
    Statistical analysis title
    		 Imeglimin 1000 mg bid versus Placebo
    Statistical analysis description
    Logistic regression
    Comparison groups
    Placebo v Imeglimin 1000 mg twice daily
    Number of subjects included in analysis
    143
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.245
    Method
    		 Regression, Logistic
    Confidence interval
    Statistical analysis title
    		 Imeglimin 1500 mg bid versus Placebo
    Statistical analysis description
    Logistic regression
    Comparison groups
    Placebo v Imeglimin 1500 mg twice daily
    Number of subjects included in analysis
    139
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.005
    Method
    		 Regression, Logistic
    Confidence interval
    Statistical analysis title
    		 Imeglimin 2000 mg bid versus Placebo
    Statistical analysis description
    Logistic regression
    Comparison groups
    Placebo v Imeglimin 2000 mg twice daily
    Number of subjects included in analysis
    134
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.124
    Method
    		 Regression, Logistic
    Confidence interval

    Secondary: Change in FPG from baseline to Week 24

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    End point title
    		 Change in FPG from baseline to Week 24
    End point description
    Change in FPG from baseline to Week 24 was analyzed using an ANCOVA method where the change in FPG from baseline to Week 24 was the outcome variable and country and treatment group were the fixed effects. The corresponding FPG at baseline and subjects naïve of treatment/previously treated were included as covariates. The standard error of the change from baseline was also included. The adjusted mean difference between each dose level against placebo was presented along with the standard error and a 95% CI. Baseline was the last nonmissing observation at Visit 5 or before. Analysis was performed by LOCF.
    End point type
    Secondary
    End point timeframe
    Baseline to Week 24
    End point values
    		 Imeglimin 500 mg twice daily Imeglimin 1000 mg twice daily Imeglimin 1500 mg twice daily Imeglimin 2000 mg twice daily Placebo
    Number of subjects analysed
    72
    77
    69
    69
    80
    Units: mmol/L
        least squares mean (standard error)
    0.368 ± 0.266
    -0.101 ± 0.259
    -0.904 ± 0.272
    -0.269 ± 0.272
    0.347 ± 0.253
    Statistical analysis title
    		 Imeglimin 500 mg bid versus Placebo
    Comparison groups
    Imeglimin 500 mg twice daily v Placebo
    Number of subjects included in analysis
    152
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.956
    Method
    		 ANCOVA
    Parameter type
    		 Mean difference (final values)
    Point estimate
    0.02
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -0.703
         upper limit
    		 0.743
    Variability estimate
    Standard error of the mean
    Dispersion value
    0.368
    Statistical analysis title
    		 Imeglimin 1000 mg bid versus Placebo
    Comparison groups
    Placebo v Imeglimin 1000 mg twice daily
    Number of subjects included in analysis
    157
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.218
    Method
    		 ANCOVA
    Parameter type
    		 Mean difference (final values)
    Point estimate
    -0.448
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -1.162
         upper limit
    		 0.266
    Variability estimate
    Standard error of the mean
    Dispersion value
    0.218
    Statistical analysis title
    		 Imeglimin 1500 mg bid versus Placebo
    Comparison groups
    Placebo v Imeglimin 1500 mg twice daily
    Number of subjects included in analysis
    149
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.001
    Method
    		 ANCOVA
    Parameter type
    		 Mean difference (final values)
    Point estimate
    -1.252
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -1.983
         upper limit
    		 -0.52
    Variability estimate
    Standard error of the mean
    Dispersion value
    0.372
    Statistical analysis title
    		 Imeglimin 2000 mg bid versus Placebo
    Comparison groups
    Placebo v Imeglimin 2000 mg twice daily
    Number of subjects included in analysis
    149
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.098
    Method
    		 ANCOVA
    Parameter type
    		 Mean difference (final values)
    Point estimate
    -0.616
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -1.347
         upper limit
    		 0.115
    Variability estimate
    Standard error of the mean
    Dispersion value
    0.372

    Secondary: Percentage of subjects requiring rescue treatment

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    End point title
    		 Percentage of subjects requiring rescue treatment
    End point description
    The percentage of subjects requiring rescue treatment, due to a high FPG concentration or high HbA1c percentage, any time between the first dose of double-blind study treatment and Week 24 was summarized. The incidence of subjects requiring rescue treatment by Week 24 was compared for each treatment group against placebo using chi-squared analysis.
    End point type
    Secondary
    End point timeframe
    Any time between the first dose of double-blind study treatment and Week 24.
    End point values
    		 Imeglimin 500 mg twice daily Imeglimin 1000 mg twice daily Imeglimin 1500 mg twice daily Imeglimin 2000 mg twice daily Placebo
    Number of subjects analysed
    74
    79
    74
    74
    81
    Units: percent
        number (not applicable)
    6.8
    7.6
    0
    5.4
    7.4
    Statistical analysis title
    		 Imeglimin 500 mg bid versus Placebo
    Comparison groups
    Imeglimin 500 mg twice daily v Placebo
    Number of subjects included in analysis
    155
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.8748
    Method
    		 Chi-squared
    Confidence interval
    Statistical analysis title
    		 Imeglimin 1000 mg bid versus Placebo
    Comparison groups
    Placebo v Imeglimin 1000 mg twice daily
    Number of subjects included in analysis
    160
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.9641
    Method
    		 Chi-squared
    Confidence interval
    Statistical analysis title
    		 Imeglimin 1500 mg bid versus Placebo
    Comparison groups
    Placebo v Imeglimin 1500 mg twice daily
    Number of subjects included in analysis
    155
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.0169
    Method
    		 Chi-squared
    Confidence interval
    Statistical analysis title
    		 Imeglimin 2000 mg bid versus Placebo
    Comparison groups
    Placebo v Imeglimin 2000 mg twice daily
    Number of subjects included in analysis
    155
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.6123
    Method
    		 Chi-squared
    Confidence interval

    Adverse events

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    Adverse events information
    Timeframe for reporting adverse events
    From Informed Consent Form signature up to to the end of the follow-up period
    Adverse event reporting additional description
    Only events that occurred after the first dose intake of the study drug were considered as Treatment Emergent Adverse Events (TEAEs). Only TEAEs are presented in this Section.
    Assessment type
    		 Systematic
    Dictionary used for adverse event reporting
    Dictionary name
    		 MedDRA
    Dictionary version
    17.0
    Reporting groups
    Reporting group title
    Imeglimin 500 mg twice daily
    Reporting group description
    		 -

    Reporting group title
    Imeglimin 1000 mg twice daily
    Reporting group description
    		 -

    Reporting group title
    Imeglimin 1500 mg twice daily
    Reporting group description
    		 -

    Reporting group title
    Imeglimin 2000 mg twice daily
    Reporting group description
    		 -

    Reporting group title
    Placebo
    Reporting group description
    		 -

    Serious adverse events
    		 Imeglimin 500 mg twice daily Imeglimin 1000 mg twice daily Imeglimin 1500 mg twice daily Imeglimin 2000 mg twice daily Placebo
    Total subjects affected by serious adverse events
         subjects affected / exposed
    0 / 74 (0.00%)
    2 / 79 (2.53%)
    1 / 74 (1.35%)
    0 / 74 (0.00%)
    1 / 81 (1.23%)
         number of deaths (all causes)
    0
    0
    0
    0
    0
         number of deaths resulting from adverse events
    0
    0
    0
    0
    0
    Injury, poisoning and procedural complications
    Incisional hernia
         subjects affected / exposed
    0 / 74 (0.00%)
    0 / 79 (0.00%)
    0 / 74 (0.00%)
    0 / 74 (0.00%)
    1 / 81 (1.23%)
         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
    Nervous system disorders
    Sciatica
         subjects affected / exposed
    0 / 74 (0.00%)
    1 / 79 (1.27%)
    0 / 74 (0.00%)
    0 / 74 (0.00%)
    0 / 81 (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
    Respiratory, thoracic and mediastinal disorders
    Lung disorder
         subjects affected / exposed
    0 / 74 (0.00%)
    0 / 79 (0.00%)
    0 / 74 (0.00%)
    0 / 74 (0.00%)
    1 / 81 (1.23%)
         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
    Infections and infestations
    Gangrene
         subjects affected / exposed
    0 / 74 (0.00%)
    0 / 79 (0.00%)
    1 / 74 (1.35%)
    0 / 74 (0.00%)
    0 / 81 (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
    Orchitis
         subjects affected / exposed
    0 / 74 (0.00%)
    1 / 79 (1.27%)
    0 / 74 (0.00%)
    0 / 74 (0.00%)
    0 / 81 (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
    Frequency threshold for reporting non-serious adverse events: 2%
    Non-serious adverse events
    		 Imeglimin 500 mg twice daily Imeglimin 1000 mg twice daily Imeglimin 1500 mg twice daily Imeglimin 2000 mg twice daily Placebo
    Total subjects affected by non serious adverse events
         subjects affected / exposed
    18 / 74 (24.32%)
    28 / 79 (35.44%)
    20 / 74 (27.03%)
    31 / 74 (41.89%)
    25 / 81 (30.86%)
    Investigations
    aPTT prolonged
         subjects affected / exposed
    1 / 74 (1.35%)
    1 / 79 (1.27%)
    1 / 74 (1.35%)
    2 / 74 (2.70%)
    1 / 81 (1.23%)
         occurrences all number
    1
    1
    1
    2
    2
    AST increased
         subjects affected / exposed
    2 / 74 (2.70%)
    0 / 79 (0.00%)
    0 / 74 (0.00%)
    0 / 74 (0.00%)
    0 / 81 (0.00%)
         occurrences all number
    2
    0
    0
    0
    0
    Blood creatine phosphokinase increased
         subjects affected / exposed
    1 / 74 (1.35%)
    0 / 79 (0.00%)
    2 / 74 (2.70%)
    1 / 74 (1.35%)
    1 / 81 (1.23%)
         occurrences all number
    1
    0
    2
    1
    1
    Blood lactic acid increased
         subjects affected / exposed
    1 / 74 (1.35%)
    5 / 79 (6.33%)
    1 / 74 (1.35%)
    2 / 74 (2.70%)
    1 / 81 (1.23%)
         occurrences all number
    1
    5
    1
    2
    1
    ECG ST segment depression
         subjects affected / exposed
    1 / 74 (1.35%)
    0 / 79 (0.00%)
    1 / 74 (1.35%)
    0 / 74 (0.00%)
    2 / 81 (2.47%)
         occurrences all number
    1
    0
    1
    0
    2
    ECG T wave inversion
         subjects affected / exposed
    0 / 74 (0.00%)
    0 / 79 (0.00%)
    1 / 74 (1.35%)
    0 / 74 (0.00%)
    2 / 81 (2.47%)
         occurrences all number
    0
    0
    1
    0
    3
    Nervous system disorders
    Headache
         subjects affected / exposed
    2 / 74 (2.70%)
    2 / 79 (2.53%)
    3 / 74 (4.05%)
    2 / 74 (2.70%)
    2 / 81 (2.47%)
         occurrences all number
    2
    2
    3
    2
    3
    Gastrointestinal disorders
    Abdominal pain
         subjects affected / exposed
    0 / 74 (0.00%)
    0 / 79 (0.00%)
    1 / 74 (1.35%)
    2 / 74 (2.70%)
    0 / 81 (0.00%)
         occurrences all number
    0
    0
    1
    2
    0
    Diarrhoea
         subjects affected / exposed
    2 / 74 (2.70%)
    2 / 79 (2.53%)
    3 / 74 (4.05%)
    6 / 74 (8.11%)
    1 / 81 (1.23%)
         occurrences all number
    2
    2
    3
    10
    1
    Dyspepsia
         subjects affected / exposed
    0 / 74 (0.00%)
    2 / 79 (2.53%)
    0 / 74 (0.00%)
    2 / 74 (2.70%)
    0 / 81 (0.00%)
         occurrences all number
    0
    2
    0
    2
    0
    Nausea
         subjects affected / exposed
    1 / 74 (1.35%)
    1 / 79 (1.27%)
    3 / 74 (4.05%)
    3 / 74 (4.05%)
    1 / 81 (1.23%)
         occurrences all number
    1
    1
    3
    4
    1
    Vomiting
         subjects affected / exposed
    1 / 74 (1.35%)
    0 / 79 (0.00%)
    1 / 74 (1.35%)
    2 / 74 (2.70%)
    2 / 81 (2.47%)
         occurrences all number
    1
    0
    1
    2
    2
    Reproductive system and breast disorders
    Benign prostatic hyperplasia
         subjects affected / exposed
    1 / 74 (1.35%)
    0 / 79 (0.00%)
    0 / 74 (0.00%)
    0 / 74 (0.00%)
    2 / 81 (2.47%)
         occurrences all number
    1
    0
    0
    0
    2
    Musculoskeletal and connective tissue disorders
    Pain in extremity
         subjects affected / exposed
    2 / 74 (2.70%)
    0 / 79 (0.00%)
    1 / 74 (1.35%)
    0 / 74 (0.00%)
    0 / 81 (0.00%)
         occurrences all number
    2
    0
    1
    0
    0
    Infections and infestations
    Bronchitis
         subjects affected / exposed
    1 / 74 (1.35%)
    5 / 79 (6.33%)
    1 / 74 (1.35%)
    0 / 74 (0.00%)
    1 / 81 (1.23%)
         occurrences all number
    1
    6
    1
    0
    1
    Nasopharyngitis
         subjects affected / exposed
    3 / 74 (4.05%)
    2 / 79 (2.53%)
    2 / 74 (2.70%)
    5 / 74 (6.76%)
    2 / 81 (2.47%)
         occurrences all number
    3
    3
    2
    8
    2
    Upper respiratory tract infection
         subjects affected / exposed
    1 / 74 (1.35%)
    1 / 79 (1.27%)
    1 / 74 (1.35%)
    0 / 74 (0.00%)
    2 / 81 (2.47%)
         occurrences all number
    1
    1
    1
    0
    2
    Urinary tract infection
         subjects affected / exposed
    0 / 74 (0.00%)
    0 / 79 (0.00%)
    2 / 74 (2.70%)
    1 / 74 (1.35%)
    0 / 81 (0.00%)
         occurrences all number
    0
    0
    2
    1
    0
    Metabolism and nutrition disorders
    Hyperglycaemia
         subjects affected / exposed
    6 / 74 (8.11%)
    11 / 79 (13.92%)
    2 / 74 (2.70%)
    11 / 74 (14.86%)
    11 / 81 (13.58%)
         occurrences all number
    7
    12
    2
    11
    14

    More information

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    Substantial protocol amendments (globally)
    Were there any global substantial amendments to the protocol? Yes
    Date
    Amendment
    21 Jun 2013
    Firstly, there was a change in the ECG recording schedule for assessment of the exclusion criterion related to the QT/QTc interval from Randomization Visit 5 to Laboratory Visit 4, in order to make the results available for Randomization Visit 5. Additionally, to simplify this criterion, calculation of the QTc interval was changed to use only the Fridericia’s formula. Secondly, a change was made to allow some flexibility in the timeframe for ophthalmology examination. As well as these modifications to the timelines for 2 exclusion criteria, it was also clarified that any overcompliance > 100% of planned study drug intake was required to be reported as a potential overdose in an expedited manner.
    02 Dec 2013
    This amendment was to notify the authorities that the ratio of subjects naïve of treatment versus subjects previously treated that were planned to be recruited changed from 30-40% naïve versus 60-70% previously treated, to approximately 25% naïve and approximately 75% previously treated.

    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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