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    Clinical Trial Results:
    A 26-Week Randomized, Double-Blind, Placebo-Controlled, Dose-Ranging Phase 2 Study to Assess the Safety and Efficacy of SAR425899 in Patients with Type 2 Diabetes Mellitus

    Summary
    EudraCT number
    2016-001328-77
    Trial protocol
    ES   DE   CZ   HU  
    Global end of trial date
    27 Dec 2017

    Results information
    Results version number
    v1(current)
    This version publication date
    06 Jan 2019
    First version publication date
    06 Jan 2019
    Other versions

    Trial information

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    Trial identification
    Sponsor protocol code
    DRI13940
    Additional study identifiers
    ISRCTN number
    -
    US NCT number
    NCT02973321
    WHO universal trial number (UTN)
    U1111-1179-4786
    Sponsors
    Sponsor organisation name
    Sanofi aventis recherche & développement
    Sponsor organisation address
    1 avenue Pierre Brossolette , Chilly-Mazarin, France, 91380
    Public contact
    Trial Transparency Team, Sanofi aventis recherche & développement, Contact-US@sanofi.com
    Scientific contact
    Trial Transparency Team, Sanofi aventis recherche & développement, Contact-US@sanofi.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
    09 Feb 2018
    Is this the analysis of the primary completion data?
    No
    Global end of trial reached?
    Yes
    Global end of trial date
    27 Dec 2017
    Was the trial ended prematurely?
    No
    General information about the trial
    Main objective of the trial
    To assess the dose-response relationship of SAR425899 versus placebo in terms of glycemic control as measured by the change in glycosylated hemoglobin (HbA1c) from baseline to Week 26.
    Protection of trial subjects
    Subjects were fully informed of all pertinent aspects of the clinical trial as well as the possibility to discontinue at any time in language and terms appropriate for the subject and considering the local culture. During the course of the trial, subjects were provided with individual subject cards indicating the nature of the trial the subject is participating, contact details and any information needed in the event of a medical emergency. Collected personal data and human biological samples were processed in compliance with the Sanofi-Aventis Group Personal Data Protection Charter ensuring that the Group abides by the laws governing personal data protection in force in all countries in which it operates.
    Background therapy
    Metformin was orally administered at a stable dose of at least 1500 mg per day or at the maximal tolerated dose depending on the dose regimen which the subject was following prior to screening, unless a safety issue related to this medication occurred. Lifestyle and diet therapy followed before the screening were continued during the study, if applicable.
    Evidence for comparator
    -
    Actual start date of recruitment
    02 Dec 2016
    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
    Spain: 31
    Country: Number of subjects enrolled
    Czech Republic: 14
    Country: Number of subjects enrolled
    Germany: 11
    Country: Number of subjects enrolled
    Hungary: 38
    Country: Number of subjects enrolled
    Canada: 19
    Country: Number of subjects enrolled
    Mexico: 42
    Country: Number of subjects enrolled
    Russian Federation: 33
    Country: Number of subjects enrolled
    United States: 108
    Worldwide total number of subjects
    296
    EEA total number of subjects
    94
    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)
    238
    From 65 to 84 years
    58
    85 years and over
    0

    Subject disposition

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    Recruitment
    Recruitment details
    The study was conducted at 59 centers in 8 countries. A total of 539 subjects were screened between 2 December 2016 and 2 June 2017, of whom, 245 subjects were screen failures. Screen failures were mainly due to exclusion criteria met. The study was double-blind for SAR425899 vs placebo and open-label for active comparator liraglutide.

    Pre-assignment
    Screening details
    A total of 296 subjects were randomized and treated in the study. Randomization was stratified by HbA1c at the screening visit (<8% vs >=8%) and body mass index (BMI) (<35.0 kg/m^2 vs >=35.0 kg/m^2) at Day 1 (start of investigational medicinal product [IMP] administration).

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

    Arms
    Are arms mutually exclusive
    Yes

    Arm title
    Placebo
    Arm description
    Placebo (for SAR425899) subcutaneous (SC) injection once daily (QD) from Week 1 to Week 26, matching 3 SAR425899 dose levels of 0.12 mg, 0.16 mg and 0.20 mg.
    Arm type
    Placebo

    Investigational medicinal product name
    Placebo (for SAR425899)
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Solution for injection in cartridge
    Routes of administration
    Subcutaneous use
    Dosage and administration details
    Placebo self-administered by SC injection.

    Arm title
    SAR425899 0.12 mg
    Arm description
    SAR425899 SC injection QD at maintenance dose of 0.12 mg for 25 weeks (Week 2 to Week 26) following 1 week dose increase step (0.06 mg at Week 1).
    Arm type
    Experimental

    Investigational medicinal product name
    SAR425899
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Solution for injection in cartridge
    Routes of administration
    Subcutaneous use
    Dosage and administration details
    SAR425899 self-administered by SC injection.

    Arm title
    SAR425899 0.16 mg
    Arm description
    SAR425899 SC injection QD at maintenance dose of 0.16 mg for 24 weeks (Week 3 to Week 26) following 2 weeks dose increase step (0.06 mg at Week 1 and 0.12 mg at Week 2).
    Arm type
    Experimental

    Investigational medicinal product name
    SAR425899
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Solution for injection in cartridge
    Routes of administration
    Subcutaneous use
    Dosage and administration details
    SAR425899 self-administered by SC injection.

    Arm title
    SAR425899 0.20 mg
    Arm description
    SAR425899 SC injection QD at maintenance dose of 0.20 mg for 23 weeks (Week 4 to Week 26) following 3 weeks dose increase step (0.06 mg at Week 1, 0.12 mg at Week 2 and 0.16 mg at Week 3).
    Arm type
    Experimental

    Investigational medicinal product name
    SAR425899
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Solution for injection in cartridge
    Routes of administration
    Subcutaneous use
    Dosage and administration details
    SAR425899 self-administered by SC injection.

    Arm title
    Liraglutide
    Arm description
    Liraglutide SC injection QD at maintenance dose of 1.8 mg for 24 weeks (Week 3 to Week 26) following 2 weeks dose increase steps (0.6 mg daily at Week 1 and by 1.2 mg daily at Week 2).
    Arm type
    Active comparator

    Investigational medicinal product name
    Liraglutide
    Investigational medicinal product code
    Other name
    Victoza
    Pharmaceutical forms
    Solution for injection in pre-filled pen
    Routes of administration
    Subcutaneous use
    Dosage and administration details
    Liraglutide self-administered by SC injection using a prefilled multidose pen.

    Number of subjects in period 1
    Placebo SAR425899 0.12 mg SAR425899 0.16 mg SAR425899 0.20 mg Liraglutide
    Started
    33
    66
    66
    64
    67
    Completed
    32
    51
    52
    48
    62
    Not completed
    1
    15
    14
    16
    5
         Other than specified
             -
             5
             3
             3
             1
         Lack of efficacy
             -
             -
             -
             -
             1
         Adverse Event
             1
             10
             11
             13
             3

    Baseline characteristics

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    Baseline characteristics reporting groups
    Reporting group title
    Placebo
    Reporting group description
    Placebo (for SAR425899) subcutaneous (SC) injection once daily (QD) from Week 1 to Week 26, matching 3 SAR425899 dose levels of 0.12 mg, 0.16 mg and 0.20 mg.

    Reporting group title
    SAR425899 0.12 mg
    Reporting group description
    SAR425899 SC injection QD at maintenance dose of 0.12 mg for 25 weeks (Week 2 to Week 26) following 1 week dose increase step (0.06 mg at Week 1).

    Reporting group title
    SAR425899 0.16 mg
    Reporting group description
    SAR425899 SC injection QD at maintenance dose of 0.16 mg for 24 weeks (Week 3 to Week 26) following 2 weeks dose increase step (0.06 mg at Week 1 and 0.12 mg at Week 2).

    Reporting group title
    SAR425899 0.20 mg
    Reporting group description
    SAR425899 SC injection QD at maintenance dose of 0.20 mg for 23 weeks (Week 4 to Week 26) following 3 weeks dose increase step (0.06 mg at Week 1, 0.12 mg at Week 2 and 0.16 mg at Week 3).

    Reporting group title
    Liraglutide
    Reporting group description
    Liraglutide SC injection QD at maintenance dose of 1.8 mg for 24 weeks (Week 3 to Week 26) following 2 weeks dose increase steps (0.6 mg daily at Week 1 and by 1.2 mg daily at Week 2).

    Reporting group values
    Placebo SAR425899 0.12 mg SAR425899 0.16 mg SAR425899 0.20 mg Liraglutide Total
    Number of subjects
    33 66 66 64 67 296
    Age categorical
    Units: Subjects
    Age continuous
    Units: years
        arithmetic mean (standard deviation)
    56.2 ± 9.3 56.8 ± 9.0 54.5 ± 10.1 55.0 ± 10.4 56.1 ± 11.4 -
    Gender categorical
    Units: Subjects
        Female
    15 29 35 28 36 143
        Male
    18 37 31 36 31 153
    BMI
    Units: kg/m^2
        arithmetic mean (standard deviation)
    32.07 ± 4.41 33.67 ± 5.37 34.23 ± 4.68 33.63 ± 4.35 34.23 ± 5.51 -
    Baseline HbA1c
    Units: Percentage of HbA1c
        arithmetic mean (standard deviation)
    8.04 ± 0.86 7.97 ± 0.88 7.99 ± 0.85 8.14 ± 0.94 8.11 ± 0.86 -

    End points

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    End points reporting groups
    Reporting group title
    Placebo
    Reporting group description
    Placebo (for SAR425899) subcutaneous (SC) injection once daily (QD) from Week 1 to Week 26, matching 3 SAR425899 dose levels of 0.12 mg, 0.16 mg and 0.20 mg.

    Reporting group title
    SAR425899 0.12 mg
    Reporting group description
    SAR425899 SC injection QD at maintenance dose of 0.12 mg for 25 weeks (Week 2 to Week 26) following 1 week dose increase step (0.06 mg at Week 1).

    Reporting group title
    SAR425899 0.16 mg
    Reporting group description
    SAR425899 SC injection QD at maintenance dose of 0.16 mg for 24 weeks (Week 3 to Week 26) following 2 weeks dose increase step (0.06 mg at Week 1 and 0.12 mg at Week 2).

    Reporting group title
    SAR425899 0.20 mg
    Reporting group description
    SAR425899 SC injection QD at maintenance dose of 0.20 mg for 23 weeks (Week 4 to Week 26) following 3 weeks dose increase step (0.06 mg at Week 1, 0.12 mg at Week 2 and 0.16 mg at Week 3).

    Reporting group title
    Liraglutide
    Reporting group description
    Liraglutide SC injection QD at maintenance dose of 1.8 mg for 24 weeks (Week 3 to Week 26) following 2 weeks dose increase steps (0.6 mg daily at Week 1 and by 1.2 mg daily at Week 2).

    Subject analysis set title
    SAR425899 0.06 mg
    Subject analysis set type
    Safety analysis
    Subject analysis set description
    Subjects received SAR425899 SC injection QD at dose of 0.06 for 26 weeks: 0.06 mg from Week 1 to Week 26 (for 26 weeks).

    Primary: Change From Baseline in HbA1c to Week 26

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    End point title
    Change From Baseline in HbA1c to Week 26
    End point description
    Change in HbA1c was calculated by subtracting baseline value from Week 26 value. Missing post-baseline values were imputed by placebo control-based multiple imputation (MI) method under the missing not at random framework. Analysis was performed on Intent-to-treat (ITT) population which included all randomized subjects, irrespective of compliance with the study protocol and procedures.
    End point type
    Primary
    End point timeframe
    Baseline, Week 26
    End point values
    Placebo SAR425899 0.12 mg SAR425899 0.16 mg SAR425899 0.20 mg Liraglutide
    Number of subjects analysed
    33
    66
    66
    64
    67
    Units: percentage of HbA1c
        least squares mean (standard error)
    -0.663 ± 0.169
    -1.517 ± 0.137
    -1.618 ± 0.133
    -1.562 ± 0.131
    -1.312 ± 0.118
    Statistical analysis title
    1st trend test:SAR425899 0.20,0.16,0.12 mg,placebo
    Statistical analysis description
    Analysis was performed using analysis of covariance (ANCOVA) model with treatment groups, randomization strata of screening HbA1c value (<8, >=8 %), randomization strata of Visit 4 (Day 1) BMI (<35.0 kg/m^2, >=35.0 kg/m^2), and country as fixed effects and baseline HbA1c as a covariate. Overall 1st trend test based on a contrast with coefficients of +3, +1, -1, -3 and 0 for SAR425899 0.20 mg, 0.16 mg, 0.12 mg, placebo and liraglutide. Here it is test 1 of testing order.
    Comparison groups
    SAR425899 0.12 mg v SAR425899 0.16 mg v SAR425899 0.20 mg v Placebo
    Number of subjects included in analysis
    229
    Analysis specification
    Pre-specified
    Analysis type
    other [1]
    P-value
    < 0.0001 [2]
    Method
    ANCOVA
    Confidence interval
    Notes
    [1] - The overall Type 1 error for multiple comparisons of the HbA1c and body weight was controlled by a Hierarchical testing procedure. Testing was performed in following sequence: 1. 1st trend test for HbA1c, 2. 1st trend test for body weight, 3. 2nd trend test for HbA1c, 4. 2nd trend test for body weight, 5. 3rd trend test for HbA1c, 6. 3rd trend test for body weight.
    [2] - Hierarchical testing procedure continued only, if the previous comparison was statistically significant. Threshold for significance at 0.05 level.
    Statistical analysis title
    2nd Trend Test: SAR425899 0.16 mg vs Placebo
    Statistical analysis description
    Analysis was performed using ANCOVA model with treatment groups, randomization strata of screening HbA1c value (<8, >=8 %), randomization strata of Visit 4 (Day 1) BMI (<35.0 kg/m^2, >=35.0 kg/m^2), and country as fixed effects and baseline HbA1c as a covariate. Second Trend test based on a contrast with coefficients of 0, +1, 0, -1 and 0 for SAR425899 0.20 mg, 0.16 mg, 0.12 mg, placebo and liraglutide, respectively. Here, it is test no. 3 of hierarchical testing sequence.
    Comparison groups
    SAR425899 0.16 mg v Placebo
    Number of subjects included in analysis
    99
    Analysis specification
    Pre-specified
    Analysis type
    other [3]
    P-value
    < 0.0001 [4]
    Method
    ANCOVA
    Parameter type
    LS Mean difference
    Point estimate
    -0.956
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    -1.359
         upper limit
    -0.552
    Variability estimate
    Standard error of the mean
    Dispersion value
    0.206
    Notes
    [3] - Hierarchical testing procedure continued only, if the previous comparison was statistically significant.
    [4] - Threshold for significance at 0.05 level.
    Statistical analysis title
    3rd Trend Test: SAR425899 0.12 mg vs Placebo
    Statistical analysis description
    Analysis was performed using ANCOVA model with treatment groups, randomization strata of screening HbA1c value (<8, >=8 %), randomization strata of Visit 4 (Day 1) BMI (<35.0 kg/m^2, >=35.0 kg/m^2), and country as fixed effects and baseline HbA1c as a covariate. Third Trend test based on a contrast with coefficients of 0, 0, +1, -1 and 0 for SAR425899 0.20 mg, 0.16 mg, 0.12 mg, placebo and liraglutide, respectively. Here, it is test no. 5 of hierarchical testing sequence.
    Comparison groups
    SAR425899 0.12 mg v Placebo
    Number of subjects included in analysis
    99
    Analysis specification
    Pre-specified
    Analysis type
    other [5]
    P-value
    < 0.0001 [6]
    Method
    ANCOVA
    Parameter type
    LS Mean difference
    Point estimate
    -0.854
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    -1.264
         upper limit
    -0.444
    Variability estimate
    Standard error of the mean
    Dispersion value
    0.209
    Notes
    [5] - Hierarchical testing procedure continued only, if the previous comparison was statistically significant.
    [6] - Threshold for significance at 0.05 level.

    Secondary: Mean Change From Baseline in Body Weight to Week 26

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    End point title
    Mean Change From Baseline in Body Weight to Week 26
    End point description
    Change in body weight was calculated by subtracting baseline value from Week 26 value. Missing post-baseline values were imputed by placebo control-based MI method under the missing not at random framework. Analysis was performed on ITT population.
    End point type
    Secondary
    End point timeframe
    Baseline, Week 26
    End point values
    Placebo SAR425899 0.12 mg SAR425899 0.16 mg SAR425899 0.20 mg Liraglutide
    Number of subjects analysed
    33
    66
    66
    64
    67
    Units: kg
        least squares mean (standard error)
    -1.759 ± 0.734
    -4.276 ± 0.564
    -5.330 ± 0.549
    -4.407 ± 0.559
    -4.590 ± 0.521
    Statistical analysis title
    1st trend test:SAR425899 0.20,0.16,0.12 mg,placebo
    Statistical analysis description
    Analysis was performed using ANCOVA model with treatment groups, randomization strata of screening HbA1c value (<8, >=8 %), randomization strata of Day 1 BMI (<35.0 kg/m^2, >=35.0 kg/m^2), and country as fixed effects and baseline body weight as a covariate. Here, it is test no. 2 of hierarchical testing sequence.
    Comparison groups
    SAR425899 0.12 mg v SAR425899 0.16 mg v SAR425899 0.20 mg v Placebo
    Number of subjects included in analysis
    229
    Analysis specification
    Pre-specified
    Analysis type
    other [7]
    P-value
    = 0.0012 [8]
    Method
    ANCOVA
    Confidence interval
    Notes
    [7] - Hierarchical testing procedure continued only, if the previous comparison was statistically significant.
    [8] - Threshold for significance at 0.05 level.
    Statistical analysis title
    2nd Trend Test: SAR425899 0.16 mg vs Placebo
    Statistical analysis description
    Analysis was performed using ANCOVA model with treatment groups, randomization strata of screening HbA1c value (<8, >=8 %), randomization strata of Day 1 BMI (<35.0 kg/m^2, >=35.0 kg/m^2), and country as fixed effects and baseline body weight as a covariate. Here, it is test no. 4 of hierarchical testing sequence.
    Comparison groups
    SAR425899 0.16 mg v Placebo
    Number of subjects included in analysis
    99
    Analysis specification
    Pre-specified
    Analysis type
    other [9]
    P-value
    < 0.0001 [10]
    Method
    ANCOVA
    Parameter type
    LS Mean difference
    Point estimate
    -3.57
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    -5.309
         upper limit
    -1.832
    Variability estimate
    Standard error of the mean
    Dispersion value
    0.887
    Notes
    [9] - Hierarchical testing procedure continued only, if the previous comparison was statistically significant
    [10] - Threshold for significance at 0.05 level.
    Statistical analysis title
    3rd Trend Test: SAR425899 0.12 mg vs Placebo
    Statistical analysis description
    Analysis was performed using ANCOVA model with treatment groups, randomization strata of screening HbA1c value (<8, >=8 %), randomization strata of Day 1 BMI (<35.0 kg/m^2, >=35.0 kg/m^2), and country as fixed effects and baseline body weight as a covariate. Here, it is test no. 6 of hierarchical testing sequence.
    Comparison groups
    SAR425899 0.12 mg v Placebo
    Number of subjects included in analysis
    99
    Analysis specification
    Pre-specified
    Analysis type
    other [11]
    P-value
    = 0.0047 [12]
    Method
    ANCOVA
    Parameter type
    LS Mean difference
    Point estimate
    -2.517
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    -4.264
         upper limit
    -0.77
    Variability estimate
    Standard error of the mean
    Dispersion value
    0.891
    Notes
    [11] - Hierarchical testing procedure continued only, if the previous comparison was statistically significant.
    [12] - Threshold for significance at 0.05 level.

    Secondary: Percentage of Subjects reached HbA1c Target of <6.5% or <7% at Week 26

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    End point title
    Percentage of Subjects reached HbA1c Target of <6.5% or <7% at Week 26
    End point description
    The analysis included assessment collected during the study, including those obtained after IMP discontinuation or introduction of rescue therapy. Subjects with no measurement at Week 26 were treated as non-responders. Analysis was performed on ITT population.
    End point type
    Secondary
    End point timeframe
    Week 26
    End point values
    Placebo SAR425899 0.12 mg SAR425899 0.16 mg SAR425899 0.20 mg Liraglutide
    Number of subjects analysed
    33
    66
    66
    64
    67
    Units: percentage of subjects
    number (not applicable)
        Subjects with HbA1c Target of <6.5%
    12.1
    47.0
    51.5
    48.4
    44.8
        Subjects with HbA1c Target of <7%
    36.4
    66.7
    68.2
    65.6
    67.2
    No statistical analyses for this end point

    Secondary: Percentage of Subjects Achieving >=5% or >=10% Body Weight Loss at Week 26

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    End point title
    Percentage of Subjects Achieving >=5% or >=10% Body Weight Loss at Week 26
    End point description
    The analysis included assessment collected during the study, including those obtained after IMP discontinuation or introduction of rescue therapy. Subjects with no measurement at Week 26 were treated as non-responders. Analysis was performed on ITT population.
    End point type
    Secondary
    End point timeframe
    Week 26
    End point values
    Placebo SAR425899 0.12 mg SAR425899 0.16 mg SAR425899 0.20 mg Liraglutide
    Number of subjects analysed
    33
    66
    66
    64
    67
    Units: percentage of subjects
    number (not applicable)
        Subjects Achieving >=5% Body Weight Loss
    3.0
    33.3
    45.5
    35.9
    40.3
        Subjects Achieving >=10% Body Weight Loss
    0.0
    12.1
    13.6
    15.6
    9.0
    No statistical analyses for this end point

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

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    End point title
    Change From Baseline in Fasting Plasma Glucose (FPG) to Week 26
    End point description
    Change in FPG was calculated by subtracting baseline value from Week 26 value. Missing post-baseline values were imputed by placebo control-based MI method under the missing not at random framework. Analysis was performed on ITT population.
    End point type
    Secondary
    End point timeframe
    Baseline, Week 26
    End point values
    Placebo SAR425899 0.12 mg SAR425899 0.16 mg SAR425899 0.20 mg Liraglutide
    Number of subjects analysed
    33
    66
    66
    64
    67
    Units: mmol/L
        least squares mean (standard error)
    -0.931 ± 0.394
    -2.408 ± 0.308
    -2.548 ± 0.301
    -2.318 ± 0.312
    -2.124 ± 0.280
    No statistical analyses for this end point

    Secondary: Change From Baseline in Average 7 Point Self-Monitoring Plasma Glucose (SMPG) to Week 26

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    End point title
    Change From Baseline in Average 7 Point Self-Monitoring Plasma Glucose (SMPG) to Week 26
    End point description
    Change in 7-point SMPG profile from baseline to Week 26 was assessed by summary statistics. Analysis was performed on ITT population. Analysis was performed on ITT population. Overall number of subjects analysed= subjects with at least 1 baseline & 1 post-baseline SMPG assessment during 26 week treatment period.
    End point type
    Secondary
    End point timeframe
    Baseline, Week 26
    End point values
    Placebo SAR425899 0.12 mg SAR425899 0.16 mg SAR425899 0.20 mg Liraglutide
    Number of subjects analysed
    21
    40
    43
    44
    49
    Units: mmol/L
        arithmetic mean (standard deviation)
    -1.82 ± 3.11
    -2.86 ± 2.62
    -2.63 ± 2.70
    -2.49 ± 3.18
    -2.21 ± 2.33
    No statistical analyses for this end point

    Secondary: Percentage of Subjects Requiring Rescue Therapy

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    End point title
    Percentage of Subjects Requiring Rescue Therapy
    End point description
    Rescue medication was introduced in case FPG or HbA1c values were above pre-defined thresholds, and if no reasons were found for insufficient glucose control, and appropriate action failed to decrease FPG / HbA1c under the threshold values (from baseline to Week 8: FPG >270 mg/dL 15.0 mmol/L, from Week 8 to Week 14: FPG >13.3 mmol/L, and from Week 14 to Week 26: FPG >11.1 mmol/L or HbA1c>8%). The choice of rescue therapy was at the Investigator’s discretion with the exception of using glucagon-like peptide-1 receptor (GLP-1R) agonists or dipeptidyl peptidase 4 (DPP4) inhibitors. Analysis was performed on ITT population.
    End point type
    Secondary
    End point timeframe
    Baseline up to 26 weeks
    End point values
    Placebo SAR425899 0.12 mg SAR425899 0.16 mg SAR425899 0.20 mg Liraglutide
    Number of subjects analysed
    33
    66
    66
    64
    67
    Units: percentage of subjects
        number (not applicable)
    18.2
    0.0
    1.5
    3.1
    6.0
    No statistical analyses for this end point

    Secondary: Change From Baseline in β-Cell Function to Week 26

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    End point title
    Change From Baseline in β-Cell Function to Week 26
    End point description
    Beta-cell function was assessed by homeostatic model assessment (HOMA)-beta, derived from FPG and fasting plasma insulin (FPI). Analysis was performed on ITT population.
    End point type
    Secondary
    End point timeframe
    Baseline, Week 26
    End point values
    Placebo SAR425899 0.12 mg SAR425899 0.16 mg SAR425899 0.20 mg Liraglutide
    Number of subjects analysed
    33
    66
    66
    64
    67
    Units: HOMA-β
        least squares mean (standard error)
    15.025 ± 19.785
    26.768 ± 15.833
    31.122 ± 16.467
    17.932 ± 14.397
    27.263 ± 13.234
    No statistical analyses for this end point

    Secondary: Change From Baseline in Insulin Resistance to Week 26

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    End point title
    Change From Baseline in Insulin Resistance to Week 26
    End point description
    Insulin Resistance was assessed by homeostasis model assessment for insulin resistance (HOMA-IR), derived from FPG and FPI. Analysis was performed on ITT population.
    End point type
    Secondary
    End point timeframe
    Baseline, Week 26
    End point values
    Placebo SAR425899 0.12 mg SAR425899 0.16 mg SAR425899 0.20 mg Liraglutide
    Number of subjects analysed
    33
    66
    66
    64
    67
    Units: HOMA-IR
        least squares mean (standard error)
    -1.315 ± 0.865
    -1.244 ± 0.670
    -2.233 ± 0.664
    -2.324 ± 0.649
    -1.405 ± 0.613
    No statistical analyses for this end point

    Secondary: Change From Baseline in Pharmacodynamic Biomarkers to Week 26 - Waist and Hip Circumferences

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    End point title
    Change From Baseline in Pharmacodynamic Biomarkers to Week 26 - Waist and Hip Circumferences
    End point description
    Waist circumference was measured at the midpoint between the lower margin of the least palpable rib and the top of the iliac crest, using a stretch-resistant tape providing a constant 100 g tension. Hip circumference was measured around the widest portion of the buttocks, with the tape parallel to the floor. Each measurement was repeated twice; if the measurements were within 1 cm of one another, the average was calculated, and if the difference exceeded 1 cm, the measurements were repeated. Analysis was performed on ITT population.
    End point type
    Secondary
    End point timeframe
    Baseline, Week 26
    End point values
    Placebo SAR425899 0.12 mg SAR425899 0.16 mg SAR425899 0.20 mg Liraglutide
    Number of subjects analysed
    33
    66
    66
    64
    67
    Units: cm
    arithmetic mean (standard error)
        Waist Circumference
    -2.0 ± 0.75
    -5.3 ± 1.34
    -2.3 ± 1.61
    -3.2 ± 0.66
    -4.0 ± 2.03
        Hip Circumference
    -1.42 ± 0.781
    -4.46 ± 1.378
    -1.97 ± 1.572
    -4.09 ± 0.945
    -2.56 ± 1.513
    No statistical analyses for this end point

    Adverse events

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    Adverse events information
    Timeframe for reporting adverse events
    All Adverse Events (AEs) were collected from signature of the informed consent form until 3 days after last treatment administration (Day 185).
    Adverse event reporting additional description
    Reported AEs were treatment-emergent AEs that is AEs that developed/worsened or became serious during the 26-week 'treatment period' (Treatment period was defined as time from the first injection of IMP up to last injection of IMP + 3 days). Safety Analysis set.
    Assessment type
    Systematic
    Dictionary used for adverse event reporting
    Dictionary name
    MedDRA
    Dictionary version
    20.1
    Reporting groups
    Reporting group title
    Placebo
    Reporting group description
    Placebo (for SAR425899) subcutaneous (SC) injection once daily (QD) from Week 1 to Week 26, matching 3 SAR425899 dose levels of 0.12 mg, 0.16 mg and 0.20 mg.

    Reporting group title
    SAR425899 0.06 mg
    Reporting group description
    Subjects received SAR425899 SC injection QD at dose of 0.06 for 26 weeks: 0.06 mg from Week 1 to Week 26 (for 26 weeks).

    Reporting group title
    SAR425899 0.12 mg
    Reporting group description
    SAR425899 SC injection QD at maintenance dose of 0.12 mg for 25 weeks (Week 2 to Week 26) following 1 week dose increase step (0.06 mg at Week 1).

    Reporting group title
    SAR425899 0.16 mg
    Reporting group description
    SAR425899 SC injection QD at maintenance dose of 0.16 mg for 24 weeks (Week 3 to Week 26) following 2 weeks dose increase step (0.06 mg at Week 1 and 0.12 mg at Week 2).

    Reporting group title
    SAR425899 0.20 mg
    Reporting group description
    SAR425899 SC injection QD at maintenance dose of 0.20 mg for 23 weeks (Week 4 to Week 26) following 3 weeks dose increase step (0.06 mg at Week 1, 0.12 mg at Week 2 and 0.16 mg at Week 3).

    Reporting group title
    Liraglutide
    Reporting group description
    Liraglutide SC injection QD at maintenance dose of 1.8 mg for 24 weeks (Week 3 to Week 26) following 2 weeks dose increase steps (0.6 mg daily at Week 1 and by 1.2 mg daily at Week 2).

    Serious adverse events
    Placebo SAR425899 0.06 mg SAR425899 0.12 mg SAR425899 0.16 mg SAR425899 0.20 mg Liraglutide
    Total subjects affected by serious adverse events
         subjects affected / exposed
    0 / 33 (0.00%)
    2 / 18 (11.11%)
    3 / 72 (4.17%)
    1 / 59 (1.69%)
    2 / 47 (4.26%)
    2 / 67 (2.99%)
         number of deaths (all causes)
    0
    0
    0
    0
    0
    0
         number of deaths resulting from adverse events
    0
    0
    0
    0
    0
    0
    Vascular disorders
    Hypertensive Crisis
         subjects affected / exposed
    0 / 33 (0.00%)
    0 / 18 (0.00%)
    1 / 72 (1.39%)
    0 / 59 (0.00%)
    0 / 47 (0.00%)
    0 / 67 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    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
    0 / 0
    Neoplasms benign, malignant and unspecified (incl cysts and polyps)
    Metastases To Adrenals
         subjects affected / exposed
    0 / 33 (0.00%)
    0 / 18 (0.00%)
    0 / 72 (0.00%)
    0 / 59 (0.00%)
    0 / 47 (0.00%)
    1 / 67 (1.49%)
         occurrences causally related to treatment / all
    0 / 0
    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
    0 / 0
    Pancreatic Carcinoma
         subjects affected / exposed
    0 / 33 (0.00%)
    0 / 18 (0.00%)
    1 / 72 (1.39%)
    0 / 59 (0.00%)
    0 / 47 (0.00%)
    0 / 67 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    Rectal Adenocarcinoma
         subjects affected / exposed
    0 / 33 (0.00%)
    0 / 18 (0.00%)
    0 / 72 (0.00%)
    0 / 59 (0.00%)
    0 / 47 (0.00%)
    1 / 67 (1.49%)
         occurrences causally related to treatment / all
    0 / 0
    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
    0 / 0
    Cardiac disorders
    Sinus Tachycardia
         subjects affected / exposed
    0 / 33 (0.00%)
    0 / 18 (0.00%)
    0 / 72 (0.00%)
    0 / 59 (0.00%)
    0 / 47 (0.00%)
    1 / 67 (1.49%)
         occurrences causally related to treatment / all
    0 / 0
    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
    0 / 0
    Nervous system disorders
    Hypoglycaemic Unconsciousness
         subjects affected / exposed
    0 / 33 (0.00%)
    0 / 18 (0.00%)
    0 / 72 (0.00%)
    1 / 59 (1.69%)
    0 / 47 (0.00%)
    0 / 67 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    1 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Loss Of Consciousness
         subjects affected / exposed
    0 / 33 (0.00%)
    0 / 18 (0.00%)
    0 / 72 (0.00%)
    1 / 59 (1.69%)
    0 / 47 (0.00%)
    0 / 67 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    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
    0 / 0
    Gastrointestinal disorders
    Pancreatic Cyst
         subjects affected / exposed
    0 / 33 (0.00%)
    1 / 18 (5.56%)
    0 / 72 (0.00%)
    0 / 59 (0.00%)
    0 / 47 (0.00%)
    0 / 67 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Pancreatitis Chronic
         subjects affected / exposed
    0 / 33 (0.00%)
    1 / 18 (5.56%)
    0 / 72 (0.00%)
    0 / 59 (0.00%)
    0 / 47 (0.00%)
    0 / 67 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Hepatobiliary disorders
    Cholecystitis Acute
         subjects affected / exposed
    0 / 33 (0.00%)
    1 / 18 (5.56%)
    0 / 72 (0.00%)
    0 / 59 (0.00%)
    0 / 47 (0.00%)
    0 / 67 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Infections and infestations
    Cellulitis Staphylococcal
         subjects affected / exposed
    0 / 33 (0.00%)
    0 / 18 (0.00%)
    1 / 72 (1.39%)
    0 / 59 (0.00%)
    0 / 47 (0.00%)
    0 / 67 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    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
    0 / 0
    Pneumonia
         subjects affected / exposed
    0 / 33 (0.00%)
    0 / 18 (0.00%)
    0 / 72 (0.00%)
    0 / 59 (0.00%)
    1 / 47 (2.13%)
    0 / 67 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Urinary Tract Infection
         subjects affected / exposed
    0 / 33 (0.00%)
    0 / 18 (0.00%)
    0 / 72 (0.00%)
    0 / 59 (0.00%)
    1 / 47 (2.13%)
    0 / 67 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Frequency threshold for reporting non-serious adverse events: 5%
    Non-serious adverse events
    Placebo SAR425899 0.06 mg SAR425899 0.12 mg SAR425899 0.16 mg SAR425899 0.20 mg Liraglutide
    Total subjects affected by non serious adverse events
         subjects affected / exposed
    10 / 33 (30.30%)
    18 / 18 (100.00%)
    49 / 72 (68.06%)
    45 / 59 (76.27%)
    34 / 47 (72.34%)
    34 / 67 (50.75%)
    Vascular disorders
    Aortic Arteriosclerosis
         subjects affected / exposed
    0 / 33 (0.00%)
    1 / 18 (5.56%)
    0 / 72 (0.00%)
    0 / 59 (0.00%)
    0 / 47 (0.00%)
    0 / 67 (0.00%)
         occurrences all number
    0
    1
    0
    0
    0
    0
    Hot Flush
         subjects affected / exposed
    0 / 33 (0.00%)
    1 / 18 (5.56%)
    0 / 72 (0.00%)
    0 / 59 (0.00%)
    0 / 47 (0.00%)
    0 / 67 (0.00%)
         occurrences all number
    0
    1
    0
    0
    0
    0
    Immune system disorders
    Hypersensitivity
         subjects affected / exposed
    0 / 33 (0.00%)
    1 / 18 (5.56%)
    0 / 72 (0.00%)
    0 / 59 (0.00%)
    0 / 47 (0.00%)
    0 / 67 (0.00%)
         occurrences all number
    0
    1
    0
    0
    0
    0
    General disorders and administration site conditions
    Asthenia
         subjects affected / exposed
    0 / 33 (0.00%)
    1 / 18 (5.56%)
    1 / 72 (1.39%)
    1 / 59 (1.69%)
    1 / 47 (2.13%)
    1 / 67 (1.49%)
         occurrences all number
    0
    1
    1
    1
    1
    1
    Fatigue
         subjects affected / exposed
    1 / 33 (3.03%)
    1 / 18 (5.56%)
    1 / 72 (1.39%)
    2 / 59 (3.39%)
    5 / 47 (10.64%)
    3 / 67 (4.48%)
         occurrences all number
    1
    1
    1
    2
    6
    3
    Injection Site Pain
         subjects affected / exposed
    0 / 33 (0.00%)
    1 / 18 (5.56%)
    0 / 72 (0.00%)
    0 / 59 (0.00%)
    0 / 47 (0.00%)
    0 / 67 (0.00%)
         occurrences all number
    0
    1
    0
    0
    0
    0
    Injection Site Reaction
         subjects affected / exposed
    0 / 33 (0.00%)
    1 / 18 (5.56%)
    1 / 72 (1.39%)
    0 / 59 (0.00%)
    0 / 47 (0.00%)
    1 / 67 (1.49%)
         occurrences all number
    0
    1
    1
    0
    0
    1
    Pyrexia
         subjects affected / exposed
    0 / 33 (0.00%)
    1 / 18 (5.56%)
    0 / 72 (0.00%)
    0 / 59 (0.00%)
    1 / 47 (2.13%)
    1 / 67 (1.49%)
         occurrences all number
    0
    1
    0
    0
    1
    1
    Injury, poisoning and procedural complications
    Ligament Sprain
         subjects affected / exposed
    0 / 33 (0.00%)
    1 / 18 (5.56%)
    0 / 72 (0.00%)
    0 / 59 (0.00%)
    0 / 47 (0.00%)
    1 / 67 (1.49%)
         occurrences all number
    0
    1
    0
    0
    0
    1
    Investigations
    Alanine Aminotransferase Increased
         subjects affected / exposed
    0 / 33 (0.00%)
    1 / 18 (5.56%)
    0 / 72 (0.00%)
    0 / 59 (0.00%)
    0 / 47 (0.00%)
    0 / 67 (0.00%)
         occurrences all number
    0
    1
    0
    0
    0
    0
    Blood Creatinine Increased
         subjects affected / exposed
    0 / 33 (0.00%)
    1 / 18 (5.56%)
    0 / 72 (0.00%)
    1 / 59 (1.69%)
    0 / 47 (0.00%)
    0 / 67 (0.00%)
         occurrences all number
    0
    1
    0
    1
    0
    0
    Lipase Increased
         subjects affected / exposed
    0 / 33 (0.00%)
    1 / 18 (5.56%)
    1 / 72 (1.39%)
    0 / 59 (0.00%)
    3 / 47 (6.38%)
    1 / 67 (1.49%)
         occurrences all number
    0
    1
    2
    0
    4
    1
    Weight Decreased
         subjects affected / exposed
    0 / 33 (0.00%)
    1 / 18 (5.56%)
    0 / 72 (0.00%)
    0 / 59 (0.00%)
    0 / 47 (0.00%)
    0 / 67 (0.00%)
         occurrences all number
    0
    2
    0
    0
    0
    0
    Cardiac disorders
    Arteriosclerosis Coronary Artery
         subjects affected / exposed
    0 / 33 (0.00%)
    1 / 18 (5.56%)
    0 / 72 (0.00%)
    0 / 59 (0.00%)
    0 / 47 (0.00%)
    0 / 67 (0.00%)
         occurrences all number
    0
    1
    0
    0
    0
    0
    Cardiac Failure Chronic
         subjects affected / exposed
    0 / 33 (0.00%)
    1 / 18 (5.56%)
    0 / 72 (0.00%)
    0 / 59 (0.00%)
    0 / 47 (0.00%)
    0 / 67 (0.00%)
         occurrences all number
    0
    1
    0
    0
    0
    0
    Blood and lymphatic system disorders
    Splenomegaly
         subjects affected / exposed
    0 / 33 (0.00%)
    1 / 18 (5.56%)
    0 / 72 (0.00%)
    0 / 59 (0.00%)
    0 / 47 (0.00%)
    0 / 67 (0.00%)
         occurrences all number
    0
    1
    0
    0
    0
    0
    Nervous system disorders
    Dizziness
         subjects affected / exposed
    2 / 33 (6.06%)
    0 / 18 (0.00%)
    4 / 72 (5.56%)
    3 / 59 (5.08%)
    1 / 47 (2.13%)
    2 / 67 (2.99%)
         occurrences all number
    2
    0
    4
    3
    1
    2
    Headache
         subjects affected / exposed
    1 / 33 (3.03%)
    3 / 18 (16.67%)
    5 / 72 (6.94%)
    1 / 59 (1.69%)
    1 / 47 (2.13%)
    3 / 67 (4.48%)
         occurrences all number
    1
    4
    5
    1
    2
    3
    Gastrointestinal disorders
    Abdominal Discomfort
         subjects affected / exposed
    0 / 33 (0.00%)
    1 / 18 (5.56%)
    1 / 72 (1.39%)
    2 / 59 (3.39%)
    0 / 47 (0.00%)
    1 / 67 (1.49%)
         occurrences all number
    0
    1
    1
    2
    0
    1
    Abdominal Distension
         subjects affected / exposed
    0 / 33 (0.00%)
    2 / 18 (11.11%)
    0 / 72 (0.00%)
    5 / 59 (8.47%)
    1 / 47 (2.13%)
    1 / 67 (1.49%)
         occurrences all number
    0
    2
    0
    7
    1
    2
    Abdominal Pain
         subjects affected / exposed
    1 / 33 (3.03%)
    1 / 18 (5.56%)
    1 / 72 (1.39%)
    3 / 59 (5.08%)
    5 / 47 (10.64%)
    2 / 67 (2.99%)
         occurrences all number
    2
    1
    1
    3
    6
    2
    Abdominal Pain Upper
         subjects affected / exposed
    0 / 33 (0.00%)
    1 / 18 (5.56%)
    3 / 72 (4.17%)
    4 / 59 (6.78%)
    2 / 47 (4.26%)
    1 / 67 (1.49%)
         occurrences all number
    0
    1
    3
    5
    2
    1
    Chronic Gastritis
         subjects affected / exposed
    0 / 33 (0.00%)
    1 / 18 (5.56%)
    0 / 72 (0.00%)
    0 / 59 (0.00%)
    0 / 47 (0.00%)
    0 / 67 (0.00%)
         occurrences all number
    0
    1
    0
    0
    0
    0
    Constipation
         subjects affected / exposed
    1 / 33 (3.03%)
    0 / 18 (0.00%)
    5 / 72 (6.94%)
    6 / 59 (10.17%)
    3 / 47 (6.38%)
    2 / 67 (2.99%)
         occurrences all number
    1
    0
    5
    6
    3
    2
    Diarrhoea
         subjects affected / exposed
    2 / 33 (6.06%)
    7 / 18 (38.89%)
    15 / 72 (20.83%)
    11 / 59 (18.64%)
    9 / 47 (19.15%)
    8 / 67 (11.94%)
         occurrences all number
    2
    10
    23
    16
    14
    10
    Duodenitis
         subjects affected / exposed
    0 / 33 (0.00%)
    1 / 18 (5.56%)
    0 / 72 (0.00%)
    0 / 59 (0.00%)
    0 / 47 (0.00%)
    0 / 67 (0.00%)
         occurrences all number
    0
    1
    0
    0
    0
    0
    Dyspepsia
         subjects affected / exposed
    0 / 33 (0.00%)
    6 / 18 (33.33%)
    13 / 72 (18.06%)
    4 / 59 (6.78%)
    3 / 47 (6.38%)
    5 / 67 (7.46%)
         occurrences all number
    0
    8
    14
    4
    4
    5
    Eructation
         subjects affected / exposed
    0 / 33 (0.00%)
    2 / 18 (11.11%)
    1 / 72 (1.39%)
    2 / 59 (3.39%)
    1 / 47 (2.13%)
    0 / 67 (0.00%)
         occurrences all number
    0
    3
    1
    2
    1
    0
    Flatulence
         subjects affected / exposed
    0 / 33 (0.00%)
    1 / 18 (5.56%)
    4 / 72 (5.56%)
    2 / 59 (3.39%)
    1 / 47 (2.13%)
    3 / 67 (4.48%)
         occurrences all number
    0
    1
    4
    2
    1
    3
    Gastrooesophageal Reflux Disease
         subjects affected / exposed
    0 / 33 (0.00%)
    3 / 18 (16.67%)
    2 / 72 (2.78%)
    0 / 59 (0.00%)
    2 / 47 (4.26%)
    1 / 67 (1.49%)
         occurrences all number
    0
    3
    2
    0
    2
    1
    Gingival Pain
         subjects affected / exposed
    0 / 33 (0.00%)
    1 / 18 (5.56%)
    0 / 72 (0.00%)
    0 / 59 (0.00%)
    0 / 47 (0.00%)
    0 / 67 (0.00%)
         occurrences all number
    0
    1
    0
    0
    0
    0
    Irritable Bowel Syndrome
         subjects affected / exposed
    0 / 33 (0.00%)
    1 / 18 (5.56%)
    0 / 72 (0.00%)
    0 / 59 (0.00%)
    0 / 47 (0.00%)
    0 / 67 (0.00%)
         occurrences all number
    0
    1
    0
    0
    0
    0
    Nausea
         subjects affected / exposed
    5 / 33 (15.15%)
    13 / 18 (72.22%)
    33 / 72 (45.83%)
    33 / 59 (55.93%)
    26 / 47 (55.32%)
    21 / 67 (31.34%)
         occurrences all number
    8
    22
    45
    41
    36
    25
    Pyloric Sphincter Insufficiency
         subjects affected / exposed
    0 / 33 (0.00%)
    1 / 18 (5.56%)
    0 / 72 (0.00%)
    0 / 59 (0.00%)
    0 / 47 (0.00%)
    0 / 67 (0.00%)
         occurrences all number
    0
    1
    0
    0
    0
    0
    Vomiting
         subjects affected / exposed
    2 / 33 (6.06%)
    10 / 18 (55.56%)
    21 / 72 (29.17%)
    14 / 59 (23.73%)
    17 / 47 (36.17%)
    1 / 67 (1.49%)
         occurrences all number
    2
    17
    32
    23
    24
    1
    Hepatobiliary disorders
    Hepatic Steatosis
         subjects affected / exposed
    0 / 33 (0.00%)
    1 / 18 (5.56%)
    0 / 72 (0.00%)
    0 / 59 (0.00%)
    1 / 47 (2.13%)
    0 / 67 (0.00%)
         occurrences all number
    0
    1
    0
    0
    1
    0
    Musculoskeletal and connective tissue disorders
    Neck Pain
         subjects affected / exposed
    0 / 33 (0.00%)
    1 / 18 (5.56%)
    0 / 72 (0.00%)
    0 / 59 (0.00%)
    0 / 47 (0.00%)
    0 / 67 (0.00%)
         occurrences all number
    0
    1
    0
    0
    0
    0
    Metabolism and nutrition disorders
    Decreased Appetite
         subjects affected / exposed
    1 / 33 (3.03%)
    2 / 18 (11.11%)
    4 / 72 (5.56%)
    5 / 59 (8.47%)
    4 / 47 (8.51%)
    3 / 67 (4.48%)
         occurrences all number
    1
    3
    4
    5
    4
    3
    Hypokalaemia
         subjects affected / exposed
    0 / 33 (0.00%)
    1 / 18 (5.56%)
    0 / 72 (0.00%)
    0 / 59 (0.00%)
    0 / 47 (0.00%)
    0 / 67 (0.00%)
         occurrences all number
    0
    1
    0
    0
    0
    0
    Infections and infestations
    Herpes Zoster
         subjects affected / exposed
    0 / 33 (0.00%)
    1 / 18 (5.56%)
    0 / 72 (0.00%)
    0 / 59 (0.00%)
    0 / 47 (0.00%)
    0 / 67 (0.00%)
         occurrences all number
    0
    1
    0
    0
    0
    0
    Upper Respiratory Tract Infection
         subjects affected / exposed
    2 / 33 (6.06%)
    1 / 18 (5.56%)
    0 / 72 (0.00%)
    2 / 59 (3.39%)
    0 / 47 (0.00%)
    0 / 67 (0.00%)
         occurrences all number
    2
    1
    0
    2
    0
    0

    More information

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    Substantial protocol amendments (globally)

    Were there any global substantial amendments to the protocol? Yes
    Date
    Amendment
    23 Jan 2017
    - To add urinary free-cortisol and creatinine measured in 24 hours urines at baseline and in Visit 12 (Week 26, End of treatment). - To make a change to the exclusion criteria (add a clarification on methods of contraception). - To add metabolic acidosis as a new adverse event of special interest. - To add amylase/lipase assessment in Visits 9 and 11.

    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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