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    Clinical Trial Results:
    A 24-Week, Multicenter, Randomized, Open-Label, 2-Arm Parallel-Group Study Evaluating the Efficacy and Safety of Patient- Versus Physician-Managed Titration of Insulin Glargine U300 in Type 2 Diabetes Mellitus

    Summary
    EudraCT number
    2015-001626-42
    Trial protocol
    CZ   GB   ES   SK   DK   GR   SI   PL   HR  
    Global end of trial date
    08 Jun 2017

    Results information
    Results version number
    v1(current)
    This version publication date
    17 Jun 2018
    First version publication date
    17 Jun 2018
    Other versions

    Trial information

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    Trial identification
    Sponsor protocol code
    LPS14409
    Additional study identifiers
    ISRCTN number
    -
    US NCT number
    -
    WHO universal trial number (UTN)
    -
    Other trial identifiers
    Study Name: TAKE 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
    09 Aug 2017
    Is this the analysis of the primary completion data?
    No
    Global end of trial reached?
    Yes
    Global end of trial date
    08 Jun 2017
    Was the trial ended prematurely?
    No
    General information about the trial
    Main objective of the trial
    To demonstrate non-inferiority in terms of glycemic control, measured as change from baseline to Week 24 in glycated hemoglobin (HbA1c), of a subject - versus a physician-managed titration algorithm, for the treatment with HOE901-U300 (insulin glargine U300), in subjects with inadequately controlled type-2 diabetes mellitus (T2DM).
    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
    Non-insulin antihyperglycemic background therapy administered at a stable dose for at least 12 weeks prior to the screening and was continued throughout the study. Doses were to be kept stable throughout the study unless there was a specific safety issue related to these treatments. Basal insulin taken prior to the study (if any) was discontinued and switched to study IMP at randomization.
    Evidence for comparator
    -
    Actual start date of recruitment
    19 Feb 2016
    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
    Switzerland: 16
    Country: Number of subjects enrolled
    Poland: 200
    Country: Number of subjects enrolled
    Slovakia: 30
    Country: Number of subjects enrolled
    Slovenia: 6
    Country: Number of subjects enrolled
    Spain: 89
    Country: Number of subjects enrolled
    United Kingdom: 49
    Country: Number of subjects enrolled
    Croatia: 28
    Country: Number of subjects enrolled
    Czech Republic: 78
    Country: Number of subjects enrolled
    Denmark: 18
    Country: Number of subjects enrolled
    Greece: 117
    Worldwide total number of subjects
    631
    EEA total number of subjects
    615
    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)
    329
    From 65 to 84 years
    301
    85 years and over
    1

    Subject disposition

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    Recruitment
    Recruitment details
    The study was conducted at 79 centres in 10 countries. A total of 771 subjects were screened between 19 February 2016 & 30 November 2016, of which 140 subjects were screen failures. Screen failures were mainly due to HbA1c <7.0% or >10% for subjects taking basal insulin & ˂7.5% or >11.0% for insulin-naïve subjects at the screening visit.

    Pre-assignment
    Screening details
    A total of 631 subjects were randomized in 1:1 ratio to either of the 2 titration modality arms. Randomization was stratified by HbA1c at screening (<8.5% vs >=8.5%), by previous use of insulin (yes vs no) & by use of sulfonylurea at screening (yes vs no).

    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
    Subject-Managed Titration
    Arm description
    Subjects received HOE901-U300 once daily for 24 weeks. The dose was self-titrated every 3-4 days to achieve fasting self-measured plasma glucose (SMPG) in the target range of 4.4 to 7.2 mmol/L (80-130 mg/dL).
    Arm type
    Experimental

    Investigational medicinal product name
    Insulin glargine
    Investigational medicinal product code
    HOE901
    Other name
    Toujeo®
    Pharmaceutical forms
    Solution for injection in pre-filled pen
    Routes of administration
    Subcutaneous use
    Dosage and administration details
    HOE901-U300 (Insulin glargine, 300 U/mL) self-administered by deep subcutaneous (SC) injection at approximately the same time every day. Insulin-naïve subjects were started with an initial dose of 0.2 U/kg HOE901-U300. In insulin-pretreated subjects, switching from once-daily basal insulin products to once-daily HOE901-U300 was done unit-to-unit based on the previous basal insulin dose; in case of switching from twice daily basal insulin products to once-daily HOE901-U300, the recommended initial HOE901-U300 dose had to be 80% of the total daily dose of basal insulin that was discontinued.

    Arm title
    Physician-Managed Titration
    Arm description
    Subjects received HOE901-U300 once daily for 24 weeks. The dose was titrated by physician at each study visit according to study design (weekly for the first 8 weeks, bi-weekly until Week 12 and then monthly until end of treatment) to achieve fasting SMPG in the target range of 4.4 to 7.2 mmol/L (80-130 mg/dL).
    Arm type
    Active comparator

    Investigational medicinal product name
    Insulin glargine
    Investigational medicinal product code
    HOE901
    Other name
    Toujeo®
    Pharmaceutical forms
    Solution for injection in pre-filled pen
    Routes of administration
    Subcutaneous use
    Dosage and administration details
    HOE901-U300 (Insulin glargine, 300 U/mL) was self-administered by deep SC injection at approximately the same time every day. Insulin-naïve subjects were started with an initial dose of 0.2 U/kg HOE901-U300. In insulin-pretreated subjects, switching from once-daily basal insulin products to once-daily HOE901-U300 was done unit-to-unit based on the previous basal insulin dose; in case of switching from twice daily basal insulin products to once-daily HOE901-U300, the recommended initial HOE901-U300 dose had to be 80% of the total daily dose of basal insulin that was discontinued.

    Number of subjects in period 1
    Subject-Managed Titration Physician-Managed Titration
    Started
    314
    317
    Completed
    307
    311
    Not completed
    7
    6
         Randomized but not treated
             2
             1
         Other than specified
             5
             4
         Adverse event
             -
             1

    Baseline characteristics

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    Baseline characteristics reporting groups
    Reporting group title
    Subject-Managed Titration
    Reporting group description
    Subjects received HOE901-U300 once daily for 24 weeks. The dose was self-titrated every 3-4 days to achieve fasting self-measured plasma glucose (SMPG) in the target range of 4.4 to 7.2 mmol/L (80-130 mg/dL).

    Reporting group title
    Physician-Managed Titration
    Reporting group description
    Subjects received HOE901-U300 once daily for 24 weeks. The dose was titrated by physician at each study visit according to study design (weekly for the first 8 weeks, bi-weekly until Week 12 and then monthly until end of treatment) to achieve fasting SMPG in the target range of 4.4 to 7.2 mmol/L (80-130 mg/dL).

    Reporting group values
    Subject-Managed Titration Physician-Managed Titration Total
    Number of subjects
    314 317 631
    Age categorical
    Units: Subjects
    Age continuous
    Units: years
        arithmetic mean (standard deviation)
    63.69 ± 8.84 62.97 ± 9.00 -
    Gender categorical
    Units: Subjects
        Female
    156 158 314
        Male
    158 159 317
    Body mass index (BMI)
    Units: kg/m^2
        arithmetic mean (standard deviation)
    31.68 ± 5.53 31.75 ± 5.43 -
    Duration of type 2 diabetes mellitus (T2DM)
    Units: years
        arithmetic mean (standard deviation)
    12.9 ± 7.2 12.8 ± 6.9 -
    Glycated Haemoglobin (HbA1c %)
    Units: percentage (%)
        arithmetic mean (standard deviation)
    8.40 ± 0.89 8.42 ± 0.92 -
    Fasting Plasma Glucose
    Units: mg/dL
        arithmetic mean (standard deviation)
    172.92 ± 48.13 167.17 ± 47.18 -
    Median fasting pre-breakfast Self Monitored Plasma Glucose (SMPG)
    Baseline median fasting pre-breakfast SMPG refers to the median of all available fasting pre-breakfast SMPG collected during the 7 day preceding Day 1 (Day 1 included).
    Units: mg/dL
        arithmetic mean (standard deviation)
    150.94 ± 37.85 148.84 ± 37.37 -

    End points

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    End points reporting groups
    Reporting group title
    Subject-Managed Titration
    Reporting group description
    Subjects received HOE901-U300 once daily for 24 weeks. The dose was self-titrated every 3-4 days to achieve fasting self-measured plasma glucose (SMPG) in the target range of 4.4 to 7.2 mmol/L (80-130 mg/dL).

    Reporting group title
    Physician-Managed Titration
    Reporting group description
    Subjects received HOE901-U300 once daily for 24 weeks. The dose was titrated by physician at each study visit according to study design (weekly for the first 8 weeks, bi-weekly until Week 12 and then monthly until end of treatment) to achieve fasting SMPG in the target range of 4.4 to 7.2 mmol/L (80-130 mg/dL).

    Primary: Change in HbA1c From Baseline to Week 24

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    End point title
    Change in HbA1c From Baseline to Week 24
    End point description
    Analysis was performed on intent-to-treat (ITT) population that included all randomized subjects, irrespective of the titration arm actually being used at the time of the analysis. Change in HbA1c was calculated by subtracting baseline value from Week 24 value. Adjusted least square (LS) means and standard errors (SE) were obtained from a mixed-effect model with repeated measures (MMRM), using all post-baseline HbA1c data available on the 24-week on-treatment period (defined as the time from the first dose of investigational medicinal product [IMP] up to 7 days after the last dose of IMP or up to the introduction of rescue therapy, whichever was earlier). Here, number of subjects analyzed = subjects with both baseline and at least one post-baseline HbA1c assessment during the 24-week on-treatment period.
    End point type
    Primary
    End point timeframe
    Baseline, Week 24
    End point values
    Subject-Managed Titration Physician-Managed Titration
    Number of subjects analysed
    308
    311
    Units: percentage of HbA1c
        least squares mean (standard error)
    -0.97 ± 0.05
    -0.84 ± 0.05
    Statistical analysis title
    Subject-managed vs Physician-managed Titration
    Statistical analysis description
    Analysis was performed using a MMRM approach with fixed categorical effects of titration modality arm, visit, titration modality arm-by-visit interaction, randomization strata (sulfonylurea use [Yes/No], previous use of insulin[Yes/No]), as well as continuous fixed covariates of baseline HbA1c & baseline HbA1c value-by-visit interaction.
    Comparison groups
    Physician-Managed Titration v Subject-Managed Titration
    Number of subjects included in analysis
    619
    Analysis specification
    Pre-specified
    Analysis type
    non-inferiority [1]
    Method
    Parameter type
    LS mean difference
    Point estimate
    -0.13
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    -0.2619
         upper limit
    -0.0004
    Variability estimate
    Standard error of the mean
    Dispersion value
    0.07
    Notes
    [1] - Non-inferiority comparison was demonstrated if upper bound of 2-sided 95% confidence interval(CI) was <0.3%.
    Statistical analysis title
    Subject-managed vs Physician-managed Titration
    Statistical analysis description
    Analysis was performed using a MMRM approach. A hierarchical step-down testing procedure was applied to control the Type I error. If non inferiority was established then step 2 was to test superiority of subject managed titration over physician managed titration.
    Comparison groups
    Subject-Managed Titration v Physician-Managed Titration
    Number of subjects included in analysis
    619
    Analysis specification
    Pre-specified
    Analysis type
    superiority [2]
    Method
    Parameter type
    LS Mean Difference
    Point estimate
    -0.13
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    -0.2619
         upper limit
    -0.0004
    Variability estimate
    Standard error of the mean
    Dispersion value
    0.07
    Notes
    [2] - Superiority was demonstrated if the upper bound of the 2-sided 95% CI was <0 (zero).

    Secondary: Percentage of Subjects Reaching Targeted Fasting SMPG (80-130 mg/dL [4.4 -7.2 mmol/L)] at Week 12 and Week 24

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    End point title
    Percentage of Subjects Reaching Targeted Fasting SMPG (80-130 mg/dL [4.4 -7.2 mmol/L)] at Week 12 and Week 24
    End point description
    Median pre-breakfast SMPG at Week 12 and week 24 were derived using the median value of fasting pre-breakfast SMPGs collected between days [79, 85] and days [163,169] respectively. The 24-week on-treatment period occurred from the first dose of IMP up to 1 day after the last dose of IMP or up to the introduction of rescue therapy, whichever was earlier. Analysis was performed on ITT population.
    End point type
    Secondary
    End point timeframe
    Week 12 and Week 24
    End point values
    Subject-Managed Titration Physician-Managed Titration
    Number of subjects analysed
    314
    317
    Units: percentage of subjects
    number (not applicable)
        Week 12
    74.8
    68.8
        Week 24
    72.9
    65.3
    No statistical analyses for this end point

    Secondary: Percentage of Subjects Achieving Targeted Fasting SMPG (80-130 mg/dL [4.4 -7.2 mmol/L]) Without Experiencing Severe and/or Confirmed Hypoglycemia <54 mg/dL (3.0 mmol/L) at Week 12 and Week 24

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    End point title
    Percentage of Subjects Achieving Targeted Fasting SMPG (80-130 mg/dL [4.4 -7.2 mmol/L]) Without Experiencing Severe and/or Confirmed Hypoglycemia <54 mg/dL (3.0 mmol/L) at Week 12 and Week 24
    End point description
    Severe and/or Confirmed hypoglycemia event was an event requiring assistance from another person for corrective measurements or an event with measured plasma glucose =<70 mg/dL (3.9 mmol/L). For hypoglycaemia, the 24-week on-treatment period occurred from the first dose of IMP up to 2 days after the last dose of IMP or up to the introduction of rescue therapy, whichever was earlier. Analysis was performed on ITT population.
    End point type
    Secondary
    End point timeframe
    Week 12 and Week 24
    End point values
    Subject-Managed Titration Physician-Managed Titration
    Number of subjects analysed
    314
    317
    Units: percentage of subjects
    number (not applicable)
        Week 12
    71.7
    65.6
        Week 24
    67.5
    58.4
    No statistical analyses for this end point

    Secondary: Change in HbA1c From Baseline to Week 12

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    End point title
    Change in HbA1c From Baseline to Week 12
    End point description
    Change in HbA1c was calculated by subtracting baseline value from Week 12 value. Adjusted least square (LS) means and standard errors (SE) were obtained from MMRM using all post-baseline values recorded from first dose of IMP up to 7 days after last IMP dose or up to the introduction of rescue therapy, whichever was earlier. Analysis was performed on ITT population. Here, Number of subjects analyzed=subjects with available data for this endpoint.
    End point type
    Secondary
    End point timeframe
    Baseline, Week 12
    End point values
    Subject-Managed Titration Physician-Managed Titration
    Number of subjects analysed
    304
    310
    Units: percentage of HbA1c
        least squares mean (standard error)
    -0.88 ± 0.04
    -0.78 ± 0.04
    No statistical analyses for this end point

    Secondary: Change From Baseline in Fasting Plasma Glucose to Week 12 and Week 24

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    End point title
    Change From Baseline in Fasting Plasma Glucose to Week 12 and Week 24
    End point description
    Change in fasting plasma glucose was calculated by subtracting baseline value from Week 12 and Week 24 values. Adjusted LS means and SE were obtained from MMRM using all post-baseline values recorded from first dose of IMP up to 1 day after last IMP dose or up to the introduction of rescue therapy, whichever was earlier. Analysis was performed on ITT population. Here, “n”= subjects with both baseline and at least one post-baseline fasting plasma glucose assessment at specified timepoints.
    End point type
    Secondary
    End point timeframe
    Baseline, Week 12 and Week 24
    End point values
    Subject-Managed Titration Physician-Managed Titration
    Number of subjects analysed
    314
    317
    Units: mg/dL
    least squares mean (standard deviation)
        Change at Week 12 (n= 296, 296)
    -34.15 ± 1.98
    -32.80 ± 1.98
        Change at Week 24 (n= 287, 288)
    -30.98 ± 2.03
    -29.59 ± 2.03
    No statistical analyses for this end point

    Secondary: Time from Baseline to Reach Targeted Fasting SMPG (80-130 mg/dL [4.4 –7.2 mmol/L]) During the 24 Week on Treatment Period

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    End point title
    Time from Baseline to Reach Targeted Fasting SMPG (80-130 mg/dL [4.4 –7.2 mmol/L]) During the 24 Week on Treatment Period
    End point description
    Cumulative incidence of subjects reaching SMPG target range was estimated using the Kaplan-Meier method (curve over time). Data below was expressed as the percentage of subjects reaching SMPG at least once during the 24 week treatment period. The censoring time is the number of weeks composing the 24-week on-treatment period for SMPG. Analysis was performed on ITT population.
    End point type
    Secondary
    End point timeframe
    Baseline to Week 24
    End point values
    Subject-Managed Titration Physician-Managed Titration
    Number of subjects analysed
    314
    317
    Units: percentage of subjects
        number (not applicable)
    97.5
    95.7
    No statistical analyses for this end point

    Secondary: Change From Baseline in Body Weight to Week 12 and Week 24

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    End point title
    Change From Baseline in Body Weight to Week 12 and Week 24
    End point description
    Change in body weight was calculated by subtracting baseline value from Week 12 and Week 24 values. Adjusted LS means and SE were obtained from MMRM using all post-baseline values recorded from first dose of IMP up to 2 days after last IMP dose or up to the introduction of rescue therapy, whichever was earlier. Analysis was performed on safety population which included all randomized subjects treated with at least one dose of IMP. Here, "n"= subjects with both baseline and at least one post-baseline body weight assessment at specified timepoints.
    End point type
    Secondary
    End point timeframe
    Baseline, Week 12 and Week 24
    End point values
    Subject-Managed Titration Physician-Managed Titration
    Number of subjects analysed
    312
    316
    Units: kg
    least squares mean (standard error)
        Change at Week 12 (n= 307, 312)
    0.36 ± 0.13
    0.12 ± 0.12
        Change at Week 24 (n= 308, 309)
    0.84 ± 0.17
    0.50 ± 0.17
    No statistical analyses for this end point

    Secondary: Percentage of Subjects With At Least One Hypoglycemia Event (Any Hypoglycemia, Severe and/or Confirmed Hypoglycemia) During On-treatment Period

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    End point title
    Percentage of Subjects With At Least One Hypoglycemia Event (Any Hypoglycemia, Severe and/or Confirmed Hypoglycemia) During On-treatment Period
    End point description
    Severe hypoglycemia was an event that required assistance of another person to actively administer carbohydrate, glucagon, or other resuscitative actions. Severe and/or confirmed hypoglycemia event was a severe event or an event associated with plasma glucose =<70 mg/dL (=<3.9 mmol/L). Hypoglycemic episodes with plasma glucose of <54 mg/dL (<3.0 mmol/L) were also analyzed. On-treatment period was defined as the time from first dose of IMP to 2 days after the last dose of IMP or up to the introduction of rescue therapy, whichever was earlier. Analysis was performed on safety population.
    End point type
    Secondary
    End point timeframe
    First dose of study drug up to 24 weeks (or 2 days after the last dose administration)
    End point values
    Subject-Managed Titration Physician-Managed Titration
    Number of subjects analysed
    312
    316
    Units: percentage of subjects
    number (not applicable)
        Any hypoglycemia
    36.2
    37.0
        Severe and/or confirmed hypoglycemia(=<70 mg/dL)
    33.3
    34.2
        Severe and/or confirmed hypoglycemia(<54 mg/dL)
    7.4
    7.9
    No statistical analyses for this end point

    Secondary: Percentage of Subjects With At Least One Nocturnal Hypoglycemia Event (Any Hypoglycemia, Severe and/or Confirmed Hypoglycemia) During On-treatment Period

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    End point title
    Percentage of Subjects With At Least One Nocturnal Hypoglycemia Event (Any Hypoglycemia, Severe and/or Confirmed Hypoglycemia) During On-treatment Period
    End point description
    Nocturnal hypoglycemia was hypoglycemia that occurred between 00:00 and 05:59 hours (clock time), regardless the subject was awake or woke up because of the event. Severe hypoglycemia was an event that required assistance of another person to actively administer carbohydrate, glucagon, or other resuscitative actions. Severe and/or confirmed hypoglycemia event was a severe event or an event associated with plasma glucose =<70 mg/dL (=<3.9 mmol/L). Hypoglycemic episodes with plasma glucose of <54 mg/dL (<3.0 mmol/L) were also analyzed. On-treatment period was defined as the time from first dose of IMP to 2 days after the last dose of IMP or up to the introduction of rescue therapy, whichever was earlier. Analysis was performed on safety population.
    End point type
    Secondary
    End point timeframe
    First dose of study drug up to 24 weeks (or 2 days after the last dose administration)
    End point values
    Subject-Managed Titration Physician-Managed Titration
    Number of subjects analysed
    312
    316
    Units: percentage of subjects
    number (not applicable)
        Any hypoglycemia
    8
    11.4
        Severe and/or confirmed hypoglycemia (=<70 mg/dL)
    6.7
    10.1
        Severe and/or confirmed hypoglycemia(<54 mg/dL)
    1.3
    2.2
    No statistical analyses for this end point

    Secondary: Change From Baseline in Total Diabetes Distress Scale at Week 12 and Week 24

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    End point title
    Change From Baseline in Total Diabetes Distress Scale at Week 12 and Week 24
    End point description
    The Diabetes distress scale (DDS) is a validated questionnaire that evaluates subject’s emotional distress related to diabetes disease burden. It consists of 17 questions, each rated on a 6-point Likert scale (from 1 to 6). Total DDS score (mean of the 17 questions) ranged from 1 (no problem) to 6 (a serious problem). Higher score indicated greater emotional distress. Analysis was performed on ITT population. Here, "n"= subjects with both baseline and at least one post baseline DDS assessment at specified time-points.
    End point type
    Secondary
    End point timeframe
    Baseline, Week 12 and Week 24
    End point values
    Subject-Managed Titration Physician-Managed Titration
    Number of subjects analysed
    314
    317
    Units: units on a scale
    least squares mean (standard error)
        Change at Week 12 (n= 298, 295)
    -0.24 ± 0.04
    -0.22 ± 0.04
        Change at Week 24 (n= 292, 293)
    -0.24 ± 0.04
    -0.16 ± 0.04
    No statistical analyses for this end point

    Secondary: Change From Baseline in Total Diabetes Empowerment Scale at Week 12 and Week 24

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    End point title
    Change From Baseline in Total Diabetes Empowerment Scale at Week 12 and Week 24
    End point description
    The Diabetes Empowerment scale (DES) is a validated measure with 28 items which evaluates diabetes-related psychosocial self-efficacy. The scale includes three subscales: managing the psychosocial aspect of diabetes, assessing dissatisfaction and readiness to change, setting and achieving diabetes goals. The total DES score was the mean of the 28 items ranging from 1 (strongly disagree) to 5 (strongly agree) on a Likert scale, higher score indicated better quality of life. Analysis was performed on ITT population. Here, "n"= subjects with both baseline and at least one post baseline DES assessment at specified time-points.
    End point type
    Secondary
    End point timeframe
    Baseline, Week 12, Week 24
    End point values
    Subject-Managed Titration Physician-Managed Titration
    Number of subjects analysed
    314
    317
    Units: units on a scale
    arithmetic mean (standard deviation)
        Change at Week 12 (n= 301, 303)
    0.14 ± 0.43
    0.06 ± 0.47
        Change at Week 24 (n= 298, 298)
    0.19 ± 0.45
    0.12 ± 0.49
    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 up to the final visit (Week 25) regardless of seriousness or relationship to investigational product.
    Adverse event reporting additional description
    Reported AEs are TEAEs that is AEs that developed/worsened during ‘on treatment period’ (time from first dose of IMP up to 2 days after last dose of IMP, regardless of introduction of rescue therapy).
    Assessment type
    Systematic
    Dictionary used for adverse event reporting
    Dictionary name
    MedDRA
    Dictionary version
    20.0
    Reporting groups
    Reporting group title
    Physician-Managed Titration
    Reporting group description
    Subjects received HOE901-U300 once daily for 24 weeks. The dose was titrated by physician at each study visit (weekly for the first 8 weeks, bi-weekly until Week 12 and then monthly until end of treatment to achieve fasting SMPG in the target range of 4.4 to 7.2 mmol/L (80-130 mg/dL).

    Reporting group title
    Subject-Managed Titration
    Reporting group description
    Subjects received HOE901-U300 once daily for 24 weeks. The dose was self-titrated every 3-4 days to achieve fasting self-measured plasma glucose (SMPG) in the target range of 4.4 to 7.2 mmol/L (80-130 mg/dL).

    Serious adverse events
    Physician-Managed Titration Subject-Managed Titration
    Total subjects affected by serious adverse events
         subjects affected / exposed
    12 / 316 (3.80%)
    10 / 312 (3.21%)
         number of deaths (all causes)
    0
    0
         number of deaths resulting from adverse events
    Injury, poisoning and procedural complications
    Lumbar Vertebral Fracture
         subjects affected / exposed
    1 / 316 (0.32%)
    0 / 312 (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)
    Invasive Breast Carcinoma
         subjects affected / exposed
    1 / 316 (0.32%)
    0 / 312 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Cardiac disorders
    Acute Coronary Syndrome
         subjects affected / exposed
    0 / 316 (0.00%)
    1 / 312 (0.32%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Cardiac Failure
         subjects affected / exposed
    1 / 316 (0.32%)
    0 / 312 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Atrial Fibrillation
         subjects affected / exposed
    1 / 316 (0.32%)
    1 / 312 (0.32%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Cardiac Failure Acute
         subjects affected / exposed
    1 / 316 (0.32%)
    0 / 312 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Respiratory, thoracic and mediastinal disorders
    Pulmonary Embolism
         subjects affected / exposed
    1 / 316 (0.32%)
    0 / 312 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pneumonitis
         subjects affected / exposed
    0 / 316 (0.00%)
    1 / 312 (0.32%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pulmonary Hypertension
         subjects affected / exposed
    1 / 316 (0.32%)
    0 / 312 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Nervous system disorders
    Cerebral Circulatory Failure
         subjects affected / exposed
    1 / 316 (0.32%)
    0 / 312 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Cerebral Infarction
         subjects affected / exposed
    1 / 316 (0.32%)
    0 / 312 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Hypoglycaemic Unconsciousness
         subjects affected / exposed
    0 / 316 (0.00%)
    1 / 312 (0.32%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Partial Seizures
         subjects affected / exposed
    1 / 316 (0.32%)
    0 / 312 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Ischaemic Stroke
         subjects affected / exposed
    1 / 316 (0.32%)
    1 / 312 (0.32%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Vertebrobasilar Insufficiency
         subjects affected / exposed
    0 / 316 (0.00%)
    1 / 312 (0.32%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Eye disorders
    Age-Related Macular Degeneration
         subjects affected / exposed
    0 / 316 (0.00%)
    1 / 312 (0.32%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Gastrointestinal disorders
    Abdominal Strangulated Hernia
         subjects affected / exposed
    0 / 316 (0.00%)
    1 / 312 (0.32%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Colitis Ischaemic
         subjects affected / exposed
    1 / 316 (0.32%)
    0 / 312 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Intestinal Obstruction
         subjects affected / exposed
    0 / 316 (0.00%)
    1 / 312 (0.32%)
         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
    Cervical Polyp
         subjects affected / exposed
    1 / 316 (0.32%)
    0 / 312 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Vulval Leukoplakia
         subjects affected / exposed
    0 / 316 (0.00%)
    1 / 312 (0.32%)
         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
    Lichen Sclerosus
         subjects affected / exposed
    0 / 316 (0.00%)
    1 / 312 (0.32%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Musculoskeletal and connective tissue disorders
    Psoriatic Arthropathy
         subjects affected / exposed
    1 / 316 (0.32%)
    0 / 312 (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
    Infective Exacerbation Of Chronic Obstructive Airways Disease
         subjects affected / exposed
    0 / 316 (0.00%)
    1 / 312 (0.32%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pneumonia
         subjects affected / exposed
    2 / 316 (0.63%)
    0 / 312 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    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
    Physician-Managed Titration Subject-Managed Titration
    Total subjects affected by non serious adverse events
         subjects affected / exposed
    21 / 316 (6.65%)
    22 / 312 (7.05%)
    Infections and infestations
    Viral Upper Respiratory Tract Infection
         subjects affected / exposed
    21 / 316 (6.65%)
    22 / 312 (7.05%)
         occurrences all number
    24
    24

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    Substantial protocol amendments (globally)

    Were there any global substantial amendments to the protocol? No

    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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