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    Clinical Trial Results:
    A Twenty-Six Week, Randomized, Open-Label, 2-Arm Parallel Group Real World Pragmatic Trial to Assess the Clinical and Health Outcomes Benefit of Transition to Toujeo® Compared to Standard of Care Insulin, in Basal Insulin Treated Patients With Uncontrolled Type 2 Diabetes Mellitus, With Six Month Extension

    Summary
    EudraCT number
    2015-001832-39
    Trial protocol
    IE   FI   ES  
    Global end of trial date
    20 Oct 2017

    Results information
    Results version number
    v1(current)
    This version publication date
    04 Nov 2018
    First version publication date
    04 Nov 2018
    Other versions

    Trial information

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    Trial identification
    Sponsor protocol code
    LPS14060
    Additional study identifiers
    ISRCTN number
    -
    US NCT number
    NCT02967211
    WHO universal trial number (UTN)
    U1111-1170-8132
    Other trial identifiers
    Study Name: Regain Control
    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
    20 Dec 2017
    Is this the analysis of the primary completion data?
    No
    Global end of trial reached?
    Yes
    Global end of trial date
    20 Oct 2017
    Was the trial ended prematurely?
    No
    General information about the trial
    Main objective of the trial
    To demonstrate non-inferiority of Toujeo versus “standard of care” basal insulin therapy as measured by glycated hemoglobin (HbA1c) change from baseline to Month 6.
    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
    Subjects received oral anti diabetic drugs (OADs), glucagon-like peptide 1 receptor agonist (GLP1-RA) as background therapy at the discretion of the investigator and consistent with local labeling guidelines for use with insulin.
    Evidence for comparator
    Standard of care basal insulin i.e., any commercially available long-acting or intermediate insulins, or any basal insulins (except Toujeo) including biosimilars was used as comparator.
    Actual start date of recruitment
    21 Dec 2015
    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
    Romania: 82
    Country: Number of subjects enrolled
    Spain: 165
    Country: Number of subjects enrolled
    United Kingdom: 68
    Country: Number of subjects enrolled
    Finland: 42
    Country: Number of subjects enrolled
    France: 37
    Country: Number of subjects enrolled
    Brazil: 102
    Country: Number of subjects enrolled
    Italy: 111
    Country: Number of subjects enrolled
    Switzerland: 2
    Worldwide total number of subjects
    609
    EEA total number of subjects
    505
    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)
    356
    From 65 to 84 years
    253
    85 years and over
    0

    Subject disposition

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    Recruitment
    Recruitment details
    The study was conducted at 98 active sites in 8 countries. A total of 795 subjects were screened between 21 December 2015 and 7 October 2016, of which 186 were screen failures. Screen failures were mainly due to HbA1c <=7.0% at screening visit.

    Pre-assignment
    Screening details
    A total of 609 subjects were randomized, stratified by GLP1-RA use in 6 months prior to randomization (yes, no), sulfonylurea (SU) use at the time of randomization (yes, no), and screening HbA1c category (<9.0%, >=9.0%). Assignment to arms was done centrally using interactive response technology (IRT) in 1:1 ratio (Toujeo: Standard of care).

    Period 1
    Period 1 title
    Overall Study (overall period)
    Is this the baseline period?
    Yes
    Allocation method
    Randomised - controlled
    Blinding used
    Not blinded

    Arms
    Are arms mutually exclusive
    Yes

    Arm title
    Toujeo
    Arm description
    Toujeo® (Insulin glargine, 300 Units [U]/mL) subcutaneous (SC) injection once daily up to Month 12 on top of non-insulin anti-diabetic treatment.
    Arm type
    Experimental

    Investigational medicinal product name
    Insulin glargine
    Investigational medicinal product code
    HOE901-U300
    Other name
    Toujeo®
    Pharmaceutical forms
    Solution for injection in pre-filled pen
    Routes of administration
    Subcutaneous use
    Dosage and administration details
    Insulin glargine, 300 U/mL (dose range of 1 Unit to 80 Units) was self-administered by deep SC injection at any time of the day according to the local label and titration was performed according to local guidelines and/or the investigator’s discretion.

    Arm title
    Standard of Care
    Arm description
    "Standard of care" commercially available basal insulin SC injection administered according to local label up to Month 12 on top of non-insulin anti-diabetic treatment.
    Arm type
    Active comparator

    Investigational medicinal product name
    Basal insulin
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Solution for injection in pre-filled pen
    Routes of administration
    Subcutaneous use
    Dosage and administration details
    Long acting or intermediate insulins, or any basal insulins (except Toujeo) including biosimilars with an appropriate pen device was self-administered by deep SC injection according to local label and titration was performed according to local guidelines and/or the investigator’s discretion.

    Number of subjects in period 1
    Toujeo Standard of Care
    Started
    305
    304
    Treated
    304
    304
    Completed
    289
    291
    Not completed
    16
    13
         Randomized but not treated
             1
             -
         Protocol deviation
             2
             -
         Other than specified
             5
             4
         Adverse event
             -
             2
         Consent withdrawn by subject
             7
             7
         Lost to follow-up
             1
             -

    Baseline characteristics

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    Baseline characteristics reporting groups
    Reporting group title
    Toujeo
    Reporting group description
    Toujeo® (Insulin glargine, 300 Units [U]/mL) subcutaneous (SC) injection once daily up to Month 12 on top of non-insulin anti-diabetic treatment.

    Reporting group title
    Standard of Care
    Reporting group description
    "Standard of care" commercially available basal insulin SC injection administered according to local label up to Month 12 on top of non-insulin anti-diabetic treatment.

    Reporting group values
    Toujeo Standard of Care Total
    Number of subjects
    305 304 609
    Age categorical
    Units: Subjects
    Age continuous
    Units: years
        arithmetic mean (standard deviation)
    62.1 ± 10.1 62.0 ± 9.6 -
    Gender categorical
    Units: Subjects
        Female
    142 136 278
        Male
    163 168 331
    Body Mass Index (BMI)
    Units: kg/m^2
        arithmetic mean (standard deviation)
    32.03 ± 6.06 32.02 ± 6.05 -
    Duration of Type 2 Diabetes Mellitus
    Units: years
        arithmetic mean (standard deviation)
    13.78 ± 7.38 13.61 ± 7.82 -
    Baseline HbA1c
    Units: percentage of HbA1c
        arithmetic mean (standard deviation)
    8.58 ± 1.10 8.51 ± 1.18 -
    Basal Insulin Daily Dose
    Data for daily basal insulin dose (U/kg) was reported for a total of 608 subjects (Toujeo: 304 and Standard of Care: 304).
    Units: U/kg
        arithmetic mean (standard deviation)
    0.406 ± 0.209 0.406 ± 0.226 -

    End points

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    End points reporting groups
    Reporting group title
    Toujeo
    Reporting group description
    Toujeo® (Insulin glargine, 300 Units [U]/mL) subcutaneous (SC) injection once daily up to Month 12 on top of non-insulin anti-diabetic treatment.

    Reporting group title
    Standard of Care
    Reporting group description
    "Standard of care" commercially available basal insulin SC injection administered according to local label up to Month 12 on top of non-insulin anti-diabetic treatment.

    Primary: Change From Baseline in HbA1c to Month 6

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    End point title
    Change From Baseline in HbA1c to Month 6
    End point description
    Change in HbA1c was calculated by subtracting baseline value from Month 6 value. Adjusted least square means and standard errors were obtained from a mixed-effect model with repeated measures (MMRM) to account for missing data, using all post-baseline HbA1c data available during the 6 month randomized period (defined as the time from randomization up to Day 180) regardless of study drug discontinuation or intensification. Analysis was performed on Intent-to-treat (ITT) population which included all randomized subjects, who received at least 1 dose of IMP, regardless of whether treatment was actually being received & analysed as per allocated treatment group. Number of subjects analysed=subjects with at least 1 baseline & 1 post-baseline HbA1c assessment during the 6 month randomized period.
    End point type
    Primary
    End point timeframe
    Baseline, Month 6
    End point values
    Toujeo Standard of Care
    Number of subjects analysed
    291
    296
    Units: percentage of HbA1c
        least squares mean (standard error)
    -0.23 ± 0.056
    -0.41 ± 0.056
    Statistical analysis title
    Toujeo vs. Standard of Care
    Statistical analysis description
    A hierarchical step-down testing procedure was used to control type 1 error. Analysis was performed using a MMRM approach with fixed categorical effects of treatment arm, visit, treatment-by-visit interaction, multicountry organization (MCO), randomization strata of SU use (yes/no), randomization strata of GLP-1 receptor agonist use (yes/no), as well as continuous fixed covariates of baseline HbA1c and baseline HbA1c value-by-visit interaction.
    Comparison groups
    Toujeo v Standard of Care
    Number of subjects included in analysis
    587
    Analysis specification
    Pre-specified
    Analysis type
    non-inferiority [1]
    P-value
    = 0.0554 [2]
    Method
    Mixed models analysis
    Parameter type
    Least Square (LS) Mean difference
    Point estimate
    0.17
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    0.015
         upper limit
    0.329
    Variability estimate
    Standard error of the mean
    Dispersion value
    0.08
    Notes
    [1] - Non-inferiority of Toujeo vs. Standard of Care was demonstrated if the upper bound of the two-sided 95% confidence interval (CI) for the difference between groups was <0.3%.
    [2] - Threshold for significance at 0.025 level.

    Secondary: Change From Baseline in HbA1c to Month 12

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    End point title
    Change From Baseline in HbA1c to Month 12
    End point description
    Change in HbA1c was calculated by subtracting baseline value from Month 12 value. Adjusted least square means and standard errors were obtained from a mixed-effect model with repeated measurements. Analysis was performed on ITT population. Here, number of subjects analysed = subjects with at least one baseline and one postbaseline HbA1c assessment during the 12 month randomized period (defined as the time from randomization up to Day 360).
    End point type
    Secondary
    End point timeframe
    Baseline, Month 12
    End point values
    Toujeo Standard of Care
    Number of subjects analysed
    281
    287
    Units: percentage of HbA1c
        least squares mean (standard error)
    -0.37 ± 0.062
    -0.35 ± 0.062
    No statistical analyses for this end point

    Secondary: Percentage of Subjects Who Achieved a Target HbA1c of < 7% at Month 6 and Month 12

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    End point title
    Percentage of Subjects Who Achieved a Target HbA1c of < 7% at Month 6 and Month 12
    End point description
    Measurements at Month 6 and Month 12 were considered in the analysis. Analysis was performed on ITT population.
    End point type
    Secondary
    End point timeframe
    Month 6 and Month 12
    End point values
    Toujeo Standard of Care
    Number of subjects analysed
    305
    304
    Units: percentage of subjects
    number (not applicable)
        At Month 6
    8.5
    14.5
        At Month 12
    11.1
    10.2
    No statistical analyses for this end point

    Secondary: Percentage of Subjects Who Achieved a Target HbA1c of <7% Without Severe and/or Symptomatic Documented Hypoglycaemia (Blood Glucose <=70 mg/dL [<=3.9 mmol/L]) and <54 mg/dL [<3.0 mmol/L]) at Month 6 and Month 12

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    End point title
    Percentage of Subjects Who Achieved a Target HbA1c of <7% Without Severe and/or Symptomatic Documented Hypoglycaemia (Blood Glucose <=70 mg/dL [<=3.9 mmol/L]) and <54 mg/dL [<3.0 mmol/L]) at Month 6 and Month 12
    End point description
    Severe hypoglycaemia was an event in which the subject required the assistance of another person to actively administer carbohydrate, glucagon, or other resuscitative actions. Documented symptomatic hypoglycaemia was an event during which typical symptoms of hypoglycaemia were accompanied by a measured plasma glucose concentration of <=70 mg/dL (3.9 mmol/L) or <54 mg/dL (3.0 mmol/L). Analysis was performed on ITT population.
    End point type
    Secondary
    End point timeframe
    Month 6 and Month 12
    End point values
    Toujeo Standard of Care
    Number of subjects analysed
    305
    304
    Units: percentage of subjects
    number (not applicable)
        At (<=70 mg/dL [3.9 mmol/L]): Month 6
    5.6
    11.2
        At (<54 mg/dL [3.0 mmol/L]): Month 6
    7.2
    12.5
        At (<=70 mg/dL [3.9 mmol/L]): Month 12
    6.6
    6.3
        At (<54 mg/dL [3.0 mmol/L]): Month 12
    9.2
    7.9
    No statistical analyses for this end point

    Secondary: Percentage of Subjects Who Remained on Assigned Basal Insulin Therapy Without Intensification at Month 6 and Month 12

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    End point title
    Percentage of Subjects Who Remained on Assigned Basal Insulin Therapy Without Intensification at Month 6 and Month 12
    End point description
    Intensification was defined by: addition of an OAD or GLP-1 RA, addition of a rapid acting insulin, increase in dose of any of their background anti-diabetes medications. Remaining on assigned therapy was defined by - subjects who neither permanently withdraw nor switch from Toujeo to “standard of care” basal insulin or from “standard of care” basal insulin to Toujeo. Analysis was performed on ITT population.
    End point type
    Secondary
    End point timeframe
    Month 6 and Month 12
    End point values
    Toujeo Standard of Care
    Number of subjects analysed
    305
    304
    Units: percentage of subjects
    number (not applicable)
        At Month 6
    79.7
    79.9
        At Month 12
    66.6
    71.4
    No statistical analyses for this end point

    Secondary: Change From Baseline in Fasting Plasma Glucose (FPG) to Month 6 and Month 12

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    End point title
    Change From Baseline in Fasting Plasma Glucose (FPG) to Month 6 and Month 12
    End point description
    Change in FPG was calculated by subtracting baseline value from Month 6 and Month 12 value. Adjusted least squares means and standard errors were obtained from a MMRM approach including all post-baseline FPG data available during the 12 month randomized period. Analysis was run on subjects of ITT population with at least one baseline and one post-baseline FPG assessment during the 12 month randomized period (defined as the time from randomization up to Day 360). Here 'n' signifies subjects with at least one baseline and one post baseline FPG values at specified time points.
    End point type
    Secondary
    End point timeframe
    Baseline, Month 6 and Month 12
    End point values
    Toujeo Standard of Care
    Number of subjects analysed
    293
    295
    Units: mmol/L
    least squares mean (standard error)
        Change At Month 6 (n = 289, 290)
    -0.72 ± 0.156
    -1.21 ± 0.155
        Change At Month 12 (n = 281, 286)
    -1.30 ± 0.177
    -1.26 ± 0.176
    No statistical analyses for this end point

    Secondary: Percentage of Subjects With At Least One Hypoglycaemic Event (Severe and/or Confirmed Hypoglycaemia [<=70 mg/dL and < 54 mg/dL]) During 12 Month On–Treatment Period

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    End point title
    Percentage of Subjects With At Least One Hypoglycaemic Event (Severe and/or Confirmed Hypoglycaemia [<=70 mg/dL and < 54 mg/dL]) During 12 Month On–Treatment Period
    End point description
    Severe hypoglycaemia was an event in which the subject required the assistance of another person to actively administer carbohydrate, glucagon, or other resuscitative actions. Severe and/or confirmed hypoglycaemia event was a severe event or an event confirmed with plasma glucose =<70 mg/dL (=<3.9 mmol/L), or < 54 mg/dL (<3.0 mmol/L). Assessment was done during 12-month on-treatment period i.e. time from the first study drug intake up to 1 day after last injection of study drug. Analysis was performed on safety population defined as all randomized subjects who received at least one dose of Toujeo or “standard of care” basal insulin, regardless of the study drug administered.
    End point type
    Secondary
    End point timeframe
    Baseline up to Month 12
    End point values
    Toujeo Standard of Care
    Number of subjects analysed
    304
    304
    Units: percentage of subjects
    number (not applicable)
        At <=70 mg/dL
    33.9
    33.9
        At <54 mg/dL
    15.1
    13.2
    No statistical analyses for this end point

    Adverse events

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    Adverse events information
    Timeframe for reporting adverse events
    All Adverse Events (AE) were collected from signature of the informed consent form up to the final visit (Week 52) regardless of seriousness or relationship to investigational product.
    Adverse event reporting additional description
    Treatment-emergent AEs were AEs that developed or worsened or became serious during the 12-month on-treatment period i.e. time from the first study drug intake up to 1 day after last injection of study drug. Treatment-emergent AEs leading to death were analysed. Analysis was performed on safety population.
    Assessment type
    Systematic
    Dictionary used for adverse event reporting
    Dictionary name
    MedDRA
    Dictionary version
    20.1
    Reporting groups
    Reporting group title
    Toujeo
    Reporting group description
    Toujeo® (Insulin glargine, 300 Units U/mL) SC injection once daily up to Month 12 on top of non-insulin anti-diabetic treatment.

    Reporting group title
    Standard of Care
    Reporting group description
    "Standard of care" commercially available basal insulin SC injection administered according to local label up to Month 12 on top of non-insulin anti-diabetic treatment.

    Serious adverse events
    Toujeo Standard of Care
    Total subjects affected by serious adverse events
         subjects affected / exposed
    41 / 304 (13.49%)
    36 / 304 (11.84%)
         number of deaths (all causes)
    2
    1
         number of deaths resulting from adverse events
    Vascular disorders
    Hypertension
         subjects affected / exposed
    1 / 304 (0.33%)
    0 / 304 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Neoplasms benign, malignant and unspecified (incl cysts and polyps)
    Basal Cell Carcinoma
         subjects affected / exposed
    0 / 304 (0.00%)
    1 / 304 (0.33%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Breast Neoplasm
         subjects affected / exposed
    1 / 304 (0.33%)
    0 / 304 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Endometrial Cancer Stage Iii
         subjects affected / exposed
    0 / 304 (0.00%)
    1 / 304 (0.33%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Gastrointestinal Carcinoma
         subjects affected / exposed
    1 / 304 (0.33%)
    0 / 304 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    Metastases To Lung
         subjects affected / exposed
    1 / 304 (0.33%)
    0 / 304 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    Oesophageal Carcinoma
         subjects affected / exposed
    0 / 304 (0.00%)
    1 / 304 (0.33%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pancreatic Carcinoma Metastatic
         subjects affected / exposed
    0 / 304 (0.00%)
    1 / 304 (0.33%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pancreatic Neoplasm
         subjects affected / exposed
    1 / 304 (0.33%)
    0 / 304 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Rectal Adenocarcinoma
         subjects affected / exposed
    1 / 304 (0.33%)
    0 / 304 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    General disorders and administration site conditions
    Non-Cardiac Chest Pain
         subjects affected / exposed
    1 / 304 (0.33%)
    0 / 304 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Psychiatric disorders
    Depression
         subjects affected / exposed
    0 / 304 (0.00%)
    1 / 304 (0.33%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Schizophrenia
         subjects affected / exposed
    0 / 304 (0.00%)
    1 / 304 (0.33%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Suicide Attempt
         subjects affected / exposed
    0 / 304 (0.00%)
    1 / 304 (0.33%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Reproductive system and breast disorders
    Ovarian Cyst
         subjects affected / exposed
    0 / 304 (0.00%)
    1 / 304 (0.33%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Prostatitis
         subjects affected / exposed
    1 / 304 (0.33%)
    0 / 304 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pelvic Pain
         subjects affected / exposed
    0 / 304 (0.00%)
    1 / 304 (0.33%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Injury, poisoning and procedural complications
    Brain Contusion
         subjects affected / exposed
    1 / 304 (0.33%)
    0 / 304 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Fall
         subjects affected / exposed
    1 / 304 (0.33%)
    0 / 304 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Femoral Neck Fracture
         subjects affected / exposed
    1 / 304 (0.33%)
    0 / 304 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Hand Fracture
         subjects affected / exposed
    1 / 304 (0.33%)
    0 / 304 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Hip Fracture
         subjects affected / exposed
    1 / 304 (0.33%)
    0 / 304 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Meniscus Injury
         subjects affected / exposed
    1 / 304 (0.33%)
    0 / 304 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Perineal Injury
         subjects affected / exposed
    0 / 304 (0.00%)
    1 / 304 (0.33%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Spinal Fracture
         subjects affected / exposed
    1 / 304 (0.33%)
    0 / 304 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Toxicity To Various Agents
         subjects affected / exposed
    0 / 304 (0.00%)
    1 / 304 (0.33%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Investigations
    Alanine Aminotransferase Increased
         subjects affected / exposed
    1 / 304 (0.33%)
    1 / 304 (0.33%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Cardiac disorders
    Acute Myocardial Infarction
         subjects affected / exposed
    1 / 304 (0.33%)
    1 / 304 (0.33%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 1
    0 / 1
    Angina Pectoris
         subjects affected / exposed
    1 / 304 (0.33%)
    3 / 304 (0.99%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 3
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    Atrial Fibrillation
         subjects affected / exposed
    0 / 304 (0.00%)
    2 / 304 (0.66%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Atrial Flutter
         subjects affected / exposed
    0 / 304 (0.00%)
    1 / 304 (0.33%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Atrioventricular Block
         subjects affected / exposed
    1 / 304 (0.33%)
    0 / 304 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Atrioventricular Block Complete
         subjects affected / exposed
    1 / 304 (0.33%)
    0 / 304 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Bradyarrhythmia
         subjects affected / exposed
    1 / 304 (0.33%)
    0 / 304 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Cardiac Failure
         subjects affected / exposed
    1 / 304 (0.33%)
    1 / 304 (0.33%)
         occurrences causally related to treatment / all
    0 / 3
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Cardiac Failure Chronic
         subjects affected / exposed
    1 / 304 (0.33%)
    0 / 304 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Cardiac Failure Congestive
         subjects affected / exposed
    2 / 304 (0.66%)
    2 / 304 (0.66%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 3
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Cardiorenal Syndrome
         subjects affected / exposed
    0 / 304 (0.00%)
    1 / 304 (0.33%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Coronary Artery Disease
         subjects affected / exposed
    1 / 304 (0.33%)
    1 / 304 (0.33%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Left Ventricular Dysfunction
         subjects affected / exposed
    0 / 304 (0.00%)
    1 / 304 (0.33%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Mitral Valve Stenosis
         subjects affected / exposed
    0 / 304 (0.00%)
    1 / 304 (0.33%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Thyrotoxic Cardiomyopathy
         subjects affected / exposed
    0 / 304 (0.00%)
    1 / 304 (0.33%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Respiratory, thoracic and mediastinal disorders
    Chronic Obstructive Pulmonary Disease
         subjects affected / exposed
    1 / 304 (0.33%)
    0 / 304 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Dyspnoea
         subjects affected / exposed
    1 / 304 (0.33%)
    0 / 304 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Interstitial Lung Disease
         subjects affected / exposed
    1 / 304 (0.33%)
    0 / 304 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pleural Effusion
         subjects affected / exposed
    1 / 304 (0.33%)
    0 / 304 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pulmonary Oedema
         subjects affected / exposed
    0 / 304 (0.00%)
    1 / 304 (0.33%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Respiratory Failure
         subjects affected / exposed
    3 / 304 (0.99%)
    0 / 304 (0.00%)
         occurrences causally related to treatment / all
    0 / 3
    0 / 0
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    Blood and lymphatic system disorders
    Haemorrhagic Anaemia
         subjects affected / exposed
    1 / 304 (0.33%)
    0 / 304 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Hypochromic Anaemia
         subjects affected / exposed
    1 / 304 (0.33%)
    0 / 304 (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
    Dementia Alzheimer's Type
         subjects affected / exposed
    0 / 304 (0.00%)
    1 / 304 (0.33%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Hypoglycaemic Unconsciousness
         subjects affected / exposed
    2 / 304 (0.66%)
    0 / 304 (0.00%)
         occurrences causally related to treatment / all
    2 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Hypoxic-Ischaemic Encephalopathy
         subjects affected / exposed
    0 / 304 (0.00%)
    1 / 304 (0.33%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Ischaemic Stroke
         subjects affected / exposed
    1 / 304 (0.33%)
    1 / 304 (0.33%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Lacunar Infarction
         subjects affected / exposed
    0 / 304 (0.00%)
    1 / 304 (0.33%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Lacunar Stroke
         subjects affected / exposed
    1 / 304 (0.33%)
    0 / 304 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Polyneuropathy
         subjects affected / exposed
    1 / 304 (0.33%)
    0 / 304 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Presyncope
         subjects affected / exposed
    1 / 304 (0.33%)
    0 / 304 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Syncope
         subjects affected / exposed
    0 / 304 (0.00%)
    2 / 304 (0.66%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Eye disorders
    Retinal Artery Thrombosis
         subjects affected / exposed
    0 / 304 (0.00%)
    1 / 304 (0.33%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Ear and labyrinth disorders
    Vertigo Positional
         subjects affected / exposed
    1 / 304 (0.33%)
    0 / 304 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Gastrointestinal disorders
    Diarrhoea
         subjects affected / exposed
    0 / 304 (0.00%)
    1 / 304 (0.33%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Intestinal Obstruction
         subjects affected / exposed
    0 / 304 (0.00%)
    1 / 304 (0.33%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Hepatobiliary disorders
    Cholangitis
         subjects affected / exposed
    0 / 304 (0.00%)
    1 / 304 (0.33%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Hepatic Steato-Fibrosis
         subjects affected / exposed
    0 / 304 (0.00%)
    1 / 304 (0.33%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Cholecystitis Chronic
         subjects affected / exposed
    0 / 304 (0.00%)
    1 / 304 (0.33%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Hepatic Steatosis
         subjects affected / exposed
    1 / 304 (0.33%)
    0 / 304 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Jaundice Cholestatic
         subjects affected / exposed
    1 / 304 (0.33%)
    0 / 304 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Renal and urinary disorders
    Acute Kidney Injury
         subjects affected / exposed
    1 / 304 (0.33%)
    2 / 304 (0.66%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 3
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Chronic Kidney Disease
         subjects affected / exposed
    2 / 304 (0.66%)
    0 / 304 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Detrusor Sphincter Dyssynergia
         subjects affected / exposed
    1 / 304 (0.33%)
    0 / 304 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Nephrotic Syndrome
         subjects affected / exposed
    1 / 304 (0.33%)
    0 / 304 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Renal Impairment
         subjects affected / exposed
    0 / 304 (0.00%)
    1 / 304 (0.33%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Urinary Retention
         subjects affected / exposed
    0 / 304 (0.00%)
    1 / 304 (0.33%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Skin and subcutaneous tissue disorders
    Skin Ulcer
         subjects affected / exposed
    1 / 304 (0.33%)
    0 / 304 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Musculoskeletal and connective tissue disorders
    Gouty Tophus
         subjects affected / exposed
    1 / 304 (0.33%)
    0 / 304 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Intervertebral Disc Protrusion
         subjects affected / exposed
    2 / 304 (0.66%)
    0 / 304 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Metabolism and nutrition disorders
    Dehydration
         subjects affected / exposed
    1 / 304 (0.33%)
    0 / 304 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Diabetes Mellitus Inadequate Control
         subjects affected / exposed
    0 / 304 (0.00%)
    1 / 304 (0.33%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Diabetic Ketoacidosis
         subjects affected / exposed
    1 / 304 (0.33%)
    0 / 304 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Hyperglycaemia
         subjects affected / exposed
    1 / 304 (0.33%)
    0 / 304 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Hyponatraemia
         subjects affected / exposed
    1 / 304 (0.33%)
    0 / 304 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Infections and infestations
    Bacterial Prostatitis
         subjects affected / exposed
    0 / 304 (0.00%)
    1 / 304 (0.33%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Campylobacter Gastroenteritis
         subjects affected / exposed
    2 / 304 (0.66%)
    0 / 304 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Cellulitis
         subjects affected / exposed
    1 / 304 (0.33%)
    1 / 304 (0.33%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Erysipelas
         subjects affected / exposed
    1 / 304 (0.33%)
    0 / 304 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Escherichia Sepsis
         subjects affected / exposed
    1 / 304 (0.33%)
    0 / 304 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Gastroenteritis
         subjects affected / exposed
    1 / 304 (0.33%)
    0 / 304 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Gingivitis
         subjects affected / exposed
    1 / 304 (0.33%)
    0 / 304 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Lower Respiratory Tract Infection
         subjects affected / exposed
    0 / 304 (0.00%)
    1 / 304 (0.33%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Osteomyelitis
         subjects affected / exposed
    1 / 304 (0.33%)
    0 / 304 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pneumonia
         subjects affected / exposed
    2 / 304 (0.66%)
    2 / 304 (0.66%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pneumonia Pneumococcal
         subjects affected / exposed
    0 / 304 (0.00%)
    1 / 304 (0.33%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pneumonia Viral
         subjects affected / exposed
    1 / 304 (0.33%)
    0 / 304 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pyelonephritis Chronic
         subjects affected / exposed
    0 / 304 (0.00%)
    1 / 304 (0.33%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Urinary Tract Infection
         subjects affected / exposed
    0 / 304 (0.00%)
    1 / 304 (0.33%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Urosepsis
         subjects affected / exposed
    1 / 304 (0.33%)
    0 / 304 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Viral Infection
         subjects affected / exposed
    1 / 304 (0.33%)
    0 / 304 (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: 5%
    Non-serious adverse events
    Toujeo Standard of Care
    Total subjects affected by non serious adverse events
         subjects affected / exposed
    16 / 304 (5.26%)
    18 / 304 (5.92%)
    Infections and infestations
    Nasopharyngitis
         subjects affected / exposed
    16 / 304 (5.26%)
    18 / 304 (5.92%)
         occurrences all number
    16
    20

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    Substantial protocol amendments (globally)

    Were there any global substantial amendments to the protocol? Yes
    Date
    Amendment
    18 Dec 2015
    Following changes were made: - Added exclusion criterion for subjects with hypersensitivity to Toujeo or excipients, - added a sensitivity analysis for the primary endpoint on the per-protocol population instead of the 6-month completer population, - clarified the definition of the per-protocol population and the 6-month completer population, - added the alpha-glucosidase inhibitor class to the list of oral agents, - removed the value “self-monitored plasma glucose (SMPG) <=70 mg/dL” in order to collect probable symptomatic and relative hypoglycaemia, - clarified the responsibilities of reporting AEs by the Investigators or third party, - extended the period between last subject last visit and database lock, - clarified the origin of the hypoglycemic control subscale, - clarified that the standard of care basal insulin could be provided by the site or dispensing pharmacy, -removed the term “country” as an effect in statistical models in order to prevent convergence issues, - clarified that laboratory testing could be performed during the entire screening period, - clarified contraceptive methods for subjects in the United Kingdom, clarified AE reporting instructions for alanine aminotransferase (ALT) increase, - clarified the definition of procedure and consequence for subjects who withdrew from the study.

    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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