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    Clinical Trial Results:
    National, Randomized, Controlled, Open-label, Parallel-Group Study Comparing the Efficacy and Safety of Two Different Titration Algorithm Approaches (Physician Managed Versus Patient Managed) for New Insulin Glargine U300 Therapy in Type 2 Diabetes Patients

    Summary
    EudraCT number
    2015-001167-39
    Trial protocol
    IT  
    Global end of trial date
    05 Oct 2017

    Results information
    Results version number
    v1(current)
    This version publication date
    19 Oct 2018
    First version publication date
    19 Oct 2018
    Other versions

    Trial information

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    Trial identification
    Sponsor protocol code
    GLARGL07537
    Additional study identifiers
    ISRCTN number
    -
    US NCT number
    -
    WHO universal trial number (UTN)
    -
    Other trial identifiers
    Study Name: Italian Titration Approach Study
    Sponsors
    Sponsor organisation name
    Sanofi S.p.A
    Sponsor organisation address
    Viale L. Bodio 37/b, Milano, Italy, 20158
    Public contact
    Sanofi aventis recherche & développement, Trial Transparency Team, contact-US@sanofi.com
    Scientific contact
    Sanofi aventis recherche & développement, Trial Transparency Team, 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
    06 Feb 2018
    Is this the analysis of the primary completion data?
    No
    Global end of trial reached?
    Yes
    Global end of trial date
    05 Oct 2017
    Was the trial ended prematurely?
    No
    General information about the trial
    Main objective of the trial
    To demonstrate the non-inferiority, in terms of glycemic control, of a subject-managed (nurse assisted) versus a physician-managed algorithm for titrating Insulin glargine 300 U/ml (HOE901-U300) in insulin naïve type 2 diabetes mellitus (T2DM) subjects inadequately controlled with oral antidiabetic agents.
    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) at a stable dose in accordance to the authorized local labelling for use with insulin.
    Evidence for comparator
    -
    Actual start date of recruitment
    28 Aug 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
    Italy: 359
    Worldwide total number of subjects
    359
    EEA total number of subjects
    359
    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)
    163
    From 65 to 84 years
    196
    85 years and over
    0

    Subject disposition

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    Recruitment
    Recruitment details
    The study was conducted in 46 centres in Italy. A total of 458 subjects were screened between 28 August 2015 and 23 March 2017, of which 99 subjects were screen failures. Screen failures were mainly due to inclusion criteria not met.

    Pre-assignment
    Screening details
    A total of 359 subjects were randomized in 1:1 ratio to either of the 2 titration modality arms.

    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
    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 12 weeks, bi-weekly until Week 24) to achieve fasting Self-Measured Plasma Glucose (SMPG) in the target range of 80-110 mg/dL.
    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 subcutaneous (SC) injection once in the evening, at approximately the same time every day (i.e., without exceeding +/- 3 hours compared to the usual time) in the abdominal wall, the deltoid or the thigh. Within a given area, location should be changed (rotated) each time to prevent injection-site skin reactions.

    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 SMPG in the target range of 80-110 mg/dL.
    Arm type
    Active comparator

    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 SC injection once in the evening, at approximately the same time every day (i.e., without exceeding +/- 3 hours compared to the usual time) in the abdominal wall, the deltoid or the thigh. Within a given area, location should be changed (rotated) each time to prevent injection-site skin reactions.

    Number of subjects in period 1
    Physician-Managed Titration Subject-Managed Titration
    Started
    181
    178
    Treated
    180
    175
    Completed
    169
    170
    Not completed
    12
    8
         Other than specified
             3
             2
         Adverse event
             1
             1
         Consent withdrawn by subject
             5
             4
         Lost to follow-up
             3
             1

    Baseline characteristics

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    Baseline characteristics 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 according to study design (weekly for the first 12 weeks, bi-weekly until Week 24) to achieve fasting Self-Measured Plasma Glucose (SMPG) in the target range of 80-110 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 SMPG in the target range of 80-110 mg/dL.

    Reporting group values
    Physician-Managed Titration Subject-Managed Titration Total
    Number of subjects
    181 178 359
    Age categorical
    Units: Subjects
    Age continuous
    Units: years
        arithmetic mean (standard deviation)
    63.71 ± 9.87 64.04 ± 9.76 -
    Gender categorical
    Units: Subjects
        Female
    71 66 137
        Male
    110 112 222
    Body mass index (BMI)
    Data for BMI was reported for a total of 355 subjects (Physician-Managed: 180 and Subject-Managed of Care: 175).
    Units: Kg/m^2
        arithmetic mean (standard deviation)
    30.11 ± 5.02 30.54 ± 6.18 -
    Duration of T2DM
    Units: Years
        arithmetic mean (standard deviation)
    11.57 ± 7.82 11.59 ± 7.40 -
    Glycated Haemoglobin (HbA1c %)
    Data for Glycated Haemoglobin was reported for a total of 355 subjects (Physician-Managed: 180 and Subject-Managed: 175).
    Units: percentage of HbA1c
        arithmetic mean (standard deviation)
    8.82 ± 0.64 8.77 ± 0.67 -

    End points

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    End points 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 according to study design (weekly for the first 12 weeks, bi-weekly until Week 24) to achieve fasting Self-Measured Plasma Glucose (SMPG) in the target range of 80-110 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 SMPG in the target range of 80-110 mg/dL.

    Primary: Change From Baseline in HbA1c to Week 24

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    End point title
    Change From Baseline in HbA1c to Week 24
    End point description
    Change in HbA1c was calculated by subtracting baseline value from Week 24 value. Adjusted least square means and standard errors were obtained from a mixed-effect model. Analysis was performed on ITT population that included all randomized subjects who received at least one dose of study drug and had a baseline assessment of primary efficacy variable. Subjects were analysed as per allocated treatment group.
    End point type
    Primary
    End point timeframe
    Baseline, Week 24
    End point values
    Physician-Managed Titration Subject-Managed Titration
    Number of subjects analysed
    180
    175
    Units: percentage of HbA1c
        least squares mean (standard error)
    -1.49 ± 0.06
    -1.60 ± 0.06
    Statistical analysis title
    Subject-Managed Titration vs Physician-Managed
    Statistical analysis description
    Analysis was performed using a linear mixed-effect model approach with titration approach and center as fixed effects and the HbA1c baseline value as covariate.
    Comparison groups
    Subject-Managed Titration v Physician-Managed Titration
    Number of subjects included in analysis
    355
    Analysis specification
    Pre-specified
    Analysis type
    non-inferiority [1]
    Method
    Parameter type
    Least Square (LS) Mean Difference
    Point estimate
    -0.11
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    -0.26
         upper limit
    0.04
    Variability estimate
    Standard error of the mean
    Dispersion value
    0.08
    Notes
    [1] - Non-inferiority of subject-managed titration versus physician-managed titration was demonstrated if the upper bound of the two-sided 95% confidence interval (CI) for the difference between groups was <0.3%.

    Secondary: Percentage of Subjects With At Least One Confirmed and/or Severe Nocturnal Hypoglycemic Events (Hypoglycemia <=70 mg/dL [3.9 mmol/L]) From Baseline to Week 24

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    End point title
    Percentage of Subjects With At Least One Confirmed and/or Severe Nocturnal Hypoglycemic Events (Hypoglycemia <=70 mg/dL [3.9 mmol/L]) From Baseline to Week 24
    End point description
    Severe hypoglycemia is an event requiring assistance of another person to actively administer carbohydrate, glucagon, or perform 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). Nocturnal hypoglycemia was hypoglycemia that occurred between 00:00 and 05:59 hours (clock time). Analysis was performed on ITT population.
    End point type
    Secondary
    End point timeframe
    Baseline to Week 24
    End point values
    Physician-Managed Titration Subject-Managed Titration
    Number of subjects analysed
    180
    175
    Units: percentage of subjects
        number (not applicable)
    4.44
    3.43
    No statistical analyses for this end point

    Secondary: Change From Baseline in Fasting Plasma Glucose (FPG) to Week 24

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    End point title
    Change From Baseline in Fasting Plasma Glucose (FPG) to Week 24
    End point description
    Change in FPG was calculated by subtracting baseline value from Week 24 value. Analysis was performed on ITT population.
    End point type
    Secondary
    End point timeframe
    Baseline, Week 24
    End point values
    Physician-Managed Titration Subject-Managed Titration
    Number of subjects analysed
    180
    175
    Units: mg/dL
        least squares mean (standard error)
    -60.93 ± 2.49
    -60.89 ± 2.34
    No statistical analyses for this end point

    Secondary: Change From Baseline in Insulin Dose (U/kg Body Weight) to Week 24

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    End point title
    Change From Baseline in Insulin Dose (U/kg Body Weight) to Week 24
    End point description
    Changes in insulin dose were based on the median of the fasting SMPG values measured on 3 consecutive days, the last being the day of titration. Change in daily insulin dose was calculated by subtracting baseline value from Week 24 value. Analysis was performed on ITT population. Here, number of subjects analysed=subjects with available data for this endpoint.
    End point type
    Secondary
    End point timeframe
    Baseline, Week 24
    End point values
    Physician-Managed Titration Subject-Managed Titration
    Number of subjects analysed
    170
    165
    Units: U/kg
        arithmetic mean (standard deviation)
    0.16 ± 0.14
    0.19 ± 0.17
    No statistical analyses for this end point

    Adverse events

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    Adverse events information [1]
    Timeframe for reporting adverse events
    All adverse events (AEs) were collected from signature of the informed consent form up to the final visit (Week 24) regardless of seriousness or relationship to investigational product.
    Adverse event reporting additional description
    Reported AEs are treatment-emergent AEs that developed/worsened or became serious during on-treatment period from first dose of the study drug up to two days after the last dose of study drug for both titration groups. Analysis was performed on safety population that included all randomized subjects who have taken at least one dose of study drug.
    Assessment type
    Systematic
    Dictionary used for adverse event reporting
    Dictionary name
    MedDRA
    Dictionary version
    20.1
    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 according to study design (weekly for the first 12 weeks, bi-weekly until Week 24 to achieve fasting SMPG in the target range of 80-110 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 80-110 mg/dL.

    Notes
    [1] - There are no non-serious adverse events recorded for these results. It is expected that there will be at least one non-serious adverse event reported.
    Justification: There were no non-serious adverse events at 5% frequency threshold.
    Serious adverse events
    Physician managed titration Subject managed titration
    Total subjects affected by serious adverse events
         subjects affected / exposed
    11 / 180 (6.11%)
    3 / 175 (1.71%)
         number of deaths (all causes)
    0
    0
         number of deaths resulting from adverse events
    0
    0
    Injury, poisoning and procedural complications
    Rib Fracture
         subjects affected / exposed
    1 / 180 (0.56%)
    0 / 175 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Cardiac disorders
    Angina Pectoris
         subjects affected / exposed
    1 / 180 (0.56%)
    0 / 175 (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 / 180 (0.56%)
    0 / 175 (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
    0 / 180 (0.00%)
    1 / 175 (0.57%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Atrial Fibrillation
         subjects affected / exposed
    1 / 180 (0.56%)
    0 / 175 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Coronary Artery Disease
         subjects affected / exposed
    2 / 180 (1.11%)
    0 / 175 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Myocardial Ischaemia
         subjects affected / exposed
    1 / 180 (0.56%)
    0 / 175 (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
    Acute Pulmonary Oedema
         subjects affected / exposed
    1 / 180 (0.56%)
    0 / 175 (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 / 180 (0.56%)
    0 / 175 (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
    Carotid Artery Disease
         subjects affected / exposed
    0 / 180 (0.00%)
    1 / 175 (0.57%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Gastrointestinal disorders
    Constipation
         subjects affected / exposed
    1 / 180 (0.56%)
    0 / 175 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Skin and subcutaneous tissue disorders
    Skin Ulcer
         subjects affected / exposed
    0 / 180 (0.00%)
    1 / 175 (0.57%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Metabolism and nutrition disorders
    Hypoglycaemia
         subjects affected / exposed
    1 / 180 (0.56%)
    0 / 175 (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
    Osteomyelitis
         subjects affected / exposed
    0 / 180 (0.00%)
    1 / 175 (0.57%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Tonsillitis
         subjects affected / exposed
    1 / 180 (0.56%)
    0 / 175 (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
    Physician managed titration Subject managed titration
    Total subjects affected by non serious adverse events
         subjects affected / exposed
    0 / 180 (0.00%)
    0 / 175 (0.00%)

    More information

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    Substantial protocol amendments (globally)

    Were there any global substantial amendments to the protocol? Yes
    Date
    Amendment
    21 Dec 2016
    Following amendment changes were made: The sample size was changed to 354 randomized subjects. Per protocol population was added to the analysis populations in order to provide supportive information for the analysis of the primary variable.

    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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