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    Clinical Trial Results:
    A Randomized, Open-label, 2-arm Parallel-group, Multicenter, 26-week Study Assessing the Safety and Efficacy of H0E901-U300 Versus Lantus in Older Patients with Type 2 Diabetes Inadequately Controlled on Antidiabetic Regimens Either Including no Insulin, or with Basal Insulin as Their Only Insulin

    Summary
    EudraCT number
    		 2014-002399-10
    Trial protocol
    		 SE   HU   DE   ES   IT   GB   PL  
    Global end of trial date
    20 May 2016

    Results information
    Results version number
    		 v1(current)
    This version publication date
    03 Jun 2017
    First version publication date
    03 Jun 2017
    Other versions

    Trial information

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    Trial identification
    Sponsor protocol code
    EFC13799
    Additional study identifiers
    ISRCTN number
    		 -
    US NCT number
    		 NCT02320721
    WHO universal trial number (UTN)
    		 U1111-1159-3018
    Other trial identifiers
    		 Study Name: SENIOR
    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
    12 Sep 2016
    Is this the analysis of the primary completion data?
    No
    Global end of trial reached?
    Yes
    Global end of trial date
    20 May 2016
    Was the trial ended prematurely?
    No
    General information about the trial
    Main objective of the trial
    To demonstrate the non-inferiority of H0E901-U300 to Lantus, in change of glycated hemoglobin A1c (HbA1c) from baseline to Week 26.
    Protection of trial subjects
    Subjects were fully informed of all pertinent aspects of the clinical trial as well as the possibility to discontinue at any time in language and terms appropriate for the subject and considering the local culture. During the course of the trial, subjects were provided with individual subject cards indicating the nature of the trial the subject was 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 antidiabetic drugs, except thiazolidinediones taken at a stable dose for at least 8 weeks prior to the screening visit might be continued. Doses were to be kept stable throughout the study unless there were safety concerns.
    Evidence for comparator
    		 -
    Actual start date of recruitment
    16 Jan 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
    Argentina: 35
    Country: Number of subjects enrolled
    Australia: 35
    Country: Number of subjects enrolled
    Canada: 92
    Country: Number of subjects enrolled
    Colombia: 16
    Country: Number of subjects enrolled
    Japan: 19
    Country: Number of subjects enrolled
    Korea, Republic of: 25
    Country: Number of subjects enrolled
    Mexico: 37
    Country: Number of subjects enrolled
    Peru: 71
    Country: Number of subjects enrolled
    United States: 367
    Country: Number of subjects enrolled
    Poland: 51
    Country: Number of subjects enrolled
    Romania: 39
    Country: Number of subjects enrolled
    Spain: 80
    Country: Number of subjects enrolled
    Sweden: 33
    Country: Number of subjects enrolled
    United Kingdom: 16
    Country: Number of subjects enrolled
    France: 8
    Country: Number of subjects enrolled
    Germany: 14
    Country: Number of subjects enrolled
    Hungary: 50
    Country: Number of subjects enrolled
    Italy: 26
    Worldwide total number of subjects
    1014
    EEA total number of subjects
    317
    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)
    0
    From 65 to 84 years
    1005
    85 years and over
    9

    Subject disposition

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    Recruitment
    Recruitment details
    		 The study was conducted at 162 study centers across 18 countries. A total of 1515 subjects were screened between 16 January 2015 and 14 October 2015, of whom 501 were screen failures.

    Pre-assignment
    Screening details
    		 A total of 1014 subjects were randomized in 1:1 ratio to either HOE901-U300 or Lantus, stratified by screening hemoglobin A1c (HbA1c) values (<8% or ≥8%); previous use of insulin (insulin-naïve versus pre-treated); and use of sulfonylurea or meglitinides at screening (’yes’ versus ‘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
    		 HOE901-U300
    Arm description
    		 HOE901-U300 (Insulin glargine, 300 U/mL) subcutaneous (SC) injection once daily up to Week 26 on top of stable non-insulin antihyperglycemic therapy.
    Arm type
    		 Experimental

    Investigational medicinal product name
    Insulin glargine
    Investigational medicinal product code
    Other name
    Toujeo®
    Pharmaceutical forms
    Solution for injection in pre-filled pen
    Routes of administration
    Subcutaneous use
    Dosage and administration details
    Self-administered by SC injection in the evening using a pre-filled pen. Dose titration to achieve fasting self-monitored plasma glucose (SMPG) from 90 to 130 mg/dL (5.0 to 7.2 mmol/L).

    Arm title
    		 Lantus
    Arm description
    		 Lantus (Insulin glargine, 100 U/mL) SC injection once daily up to Week 26 on top of stable non-insulin antihyperglycemic therapy.
    Arm type
    		 Active comparator

    Investigational medicinal product name
    Insulin glargine
    Investigational medicinal product code
    Other name
    Lantus
    Pharmaceutical forms
    Solution for injection in pre-filled pen
    Routes of administration
    Subcutaneous use
    Dosage and administration details
    Self-administered by SC injection in the evening using a pre-filled pen. Dose titration to achieve fasting SMPG from 90 to 130 mg/dL (5.0 to 7.2 mmol/L).

    Number of subjects in period 1
    		HOE901-U300 Lantus
    Started
    508
    506
    Treated (Safety Population)
    508
    505
    Completed
    481
    472
    Not completed
    27
    34
         Randomized but not treated
    -
    1
         Poor Compliance to protocol
    3
    7
         Adverse event
    6
    6
         Other than specified
    15
    20
         Hypoglycemia
    1
    -
         Lack of efficacy
    2
    -

    Baseline characteristics

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    Baseline characteristics reporting groups
    Reporting group title
    HOE901-U300
    Reporting group description
    		 HOE901-U300 (Insulin glargine, 300 U/mL) subcutaneous (SC) injection once daily up to Week 26 on top of stable non-insulin antihyperglycemic therapy.

    Reporting group title
    Lantus
    Reporting group description
    		 Lantus (Insulin glargine, 100 U/mL) SC injection once daily up to Week 26 on top of stable non-insulin antihyperglycemic therapy.

    Reporting group values
    		 HOE901-U300 Lantus Total
    Number of subjects
    		 508 506 1014
    Age categorical
    Units: Subjects
        <75 years of age
    		 373 400 773
        ≥75 years of age
    		 135 106 241
    Age continuous
    Units: years
        arithmetic mean (standard deviation)
    		 71.1 ( 4.9 ) 70.8 ( 4.8 ) -
    Gender categorical
    Units: Subjects
        Female
    		 258 229 487
        Male
    		 250 277 527
    Randomization strata of insulin
    Units: Subjects
        Insulin-naive
    		 166 165 331
        Insulin pre-treated
    		 342 341 683
    Body Mass Index (BMI)
    Measure Analysis Population Description: Number of subjects analyzed = subjects with available data for this baseline measure.
    Units: kg/m^2
        arithmetic mean (standard deviation)
    		 30.9 ( 5.5 ) 31.2 ( 5.7 ) -
    Duration of Type 2 Diabetes
    Units: years
        arithmetic mean (standard deviation)
    		 15.29 ( 8.17 ) 15.35 ( 7.7 ) -
    Baseline Glycated Hemoglobin A1c (HbA1c)
    Units: percentage of HbA1c
        arithmetic mean (standard deviation)
    		 8.2 ( 0.91 ) 8.22 ( 0.92 ) -

    End points

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    End points reporting groups
    Reporting group title
    HOE901-U300
    Reporting group description
    		 HOE901-U300 (Insulin glargine, 300 U/mL) subcutaneous (SC) injection once daily up to Week 26 on top of stable non-insulin antihyperglycemic therapy.

    Reporting group title
    Lantus
    Reporting group description
    		 Lantus (Insulin glargine, 100 U/mL) SC injection once daily up to Week 26 on top of stable non-insulin antihyperglycemic therapy.

    Primary: Change in HbA1c From Baseline to Week 26

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    End point title
    		 Change in HbA1c From Baseline to Week 26
    End point description
    Adjusted least square (LS) means were obtained from analysis of covariance (ANCOVA) after multiple imputation of missing data including post baseline HbA1c data during the 26-week randomized period. Intent-to-treat (ITT) population included all randomized subjects regardless of whether the treatment kit was used, and analyzed according to the treatment group allocated by randomization.
    End point type
    Primary
    End point timeframe
    Baseline, Week 26
    End point values
    		 HOE901-U300 Lantus
    Number of subjects analysed
    508
    506
    Units: percentage of hemoglobin
        least squares mean (standard error)
    -0.89 ( 0.038 )
    -0.91 ( 0.042 )
    Statistical analysis title
    		 HOE901-U300, Lantus
    Statistical analysis description
    Analysis was performed using ANCOVA model including the fixed categorical effects of treatment group, randomization strata, as well as the continuous fixed covariates of baseline value and following multiple imputation procedure for missing data.
    Comparison groups
    HOE901-U300 v Lantus
    Number of subjects included in analysis
    1014
    Analysis specification
    Pre-specified
    Analysis type
    		 non-inferiority [1]
    Method
    Parameter type
    		 LS Mean Difference
    Point estimate
    0.02
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -0.092
         upper limit
    		 0.129
    Variability estimate
    Standard error of the mean
    Dispersion value
    0.056
    Notes
    [1] - Non-inferiority of HOE901-U300 vs Lantus 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 Severe and/ or Confirmed (≤3.9 mmol/L [70 mg/dL]) Nocturnal Hypoglycemia (22:00 to 08:59 Hours Next Morning) During 26-Week Randomized Period

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    End point title
    		 Percentage of Subjects With At Least One Severe and/ or Confirmed (≤3.9 mmol/L [70 mg/dL]) Nocturnal Hypoglycemia (22:00 to 08:59 Hours Next Morning) During 26-Week Randomized Period
    End point description
    Estimated percentages from multiple imputation approach including data from the 26-week randomized period. Severe hypoglycemia was an event that required assistance of another person to actively administer carbohydrate, glucagon, or other resuscitative actions. Confirmed hypoglycemia was an event associated with plasma glucose ≤3.9 mmol/L (70 mg/dL). ITT population.
    End point type
    Secondary
    End point timeframe
    Baseline up to Week 26
    End point values
    		 HOE901-U300 Lantus
    Number of subjects analysed
    508
    506
    Units: percentage of subjects
        number (not applicable)
    48.3
    47.7
    Statistical analysis title
    		 HOE901-U300, Lantus
    Statistical analysis description
    Analysis was done by Cochran-Mantel-Haenszel method with randomization strata (screening HbA1c [<8.0%; ≥8.0%], previous use of insulin [naive, pre-treated], use of sulfonylurea or meglitinides at screening [yes, no]), following multiple imputation procedure for missing data.
    Comparison groups
    HOE901-U300 v Lantus
    Number of subjects included in analysis
    1014
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority [2]
    P-value
    		 = 0.8415 [3]
    Method
    		 Cochran-Mantel-Haenszel
    Parameter type
    		 Relative risk
    Point estimate
    1.01
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.89
         upper limit
    		 1.153
    Notes
    [2] - A hierarchical testing procedure was used to control type I error and handle multiple endpoint analyses. Testing was then performed sequentially in the order the endpoints are reported. The hierarchical testing sequence continued only if previous endpoint was statistically significant at 0.05 level.
    [3] - Threshold for significance at 0.05 level.

    Secondary: Percentage of Subjects With At Least One Severe and/ or Confirmed (≤3.9 mmol/L [70 mg/dL]) Nocturnal Hypoglycemia (00:00 to 05:59 Hours) During 26-Week Randomized Period

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    End point title
    		 Percentage of Subjects With At Least One Severe and/ or Confirmed (≤3.9 mmol/L [70 mg/dL]) Nocturnal Hypoglycemia (00:00 to 05:59 Hours) During 26-Week Randomized Period
    End point description
    Estimated percentages from multiple imputation approach including data from the 26-week randomized period. Severe hypoglycemia was an event that required assistance of another person to actively administer carbohydrate, glucagon, or other resuscitative actions. Confirmed hypoglycemia was an event associated with plasma glucose ≤3.9 mmol/L (70 mg/dL). ITT population.
    End point type
    Secondary
    End point timeframe
    Baseline up to Week 26
    End point values
    		 HOE901-U300 Lantus
    Number of subjects analysed
    508
    506
    Units: percentage of subjects
        number (not applicable)
    20.2
    22.5
    No statistical analyses for this end point

    Secondary: Percentage of Subjects With At Least One Severe and/ or Confirmed (≤3.9 mmol/L [70 mg/dL]) Hypoglycemia Occurring at Any Time of the Day During 26-Week Randomized Period

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    End point title
    		 Percentage of Subjects With At Least One Severe and/ or Confirmed (≤3.9 mmol/L [70 mg/dL]) Hypoglycemia Occurring at Any Time of the Day During 26-Week Randomized Period
    End point description
    Estimated percentages from multiple imputation approach including data from the 26-week randomized period. Severe hypoglycemia was an event that required assistance of another person to actively administer carbohydrate, glucagon, or other resuscitative actions. Confirmed hypoglycemia was an event associated with plasma glucose ≤3.9 mmol/L (70 mg/dL). ITT population.
    End point type
    Secondary
    End point timeframe
    Baseline up to Week 26
    End point values
    		 HOE901-U300 Lantus
    Number of subjects analysed
    508
    506
    Units: percentage of subjects
        number (not applicable)
    59.4
    62.7
    No statistical analyses for this end point

    Secondary: Percentage of Subjects With HbA1c <7.5% or HbA1c <7% During 26-Week Randomized Period

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    End point title
    		 Percentage of Subjects With HbA1c <7.5% or HbA1c <7% During 26-Week Randomized Period
    End point description
    Subjects without any available HbA1c assessment at Week 26 were considered as non-responders in the analyses. ITT population.
    End point type
    Secondary
    End point timeframe
    Baseline up to Week 26
    End point values
    		 HOE901-U300 Lantus
    Number of subjects analysed
    508
    506
    Units: percentage of subjects
    number (not applicable)
        HbA1c <7.5%
    60.6
    58.9
        HbA1c <7.0%
    33.3
    35.2
    No statistical analyses for this end point

    Secondary: Percentage of Subjects With HbA1c <7.5% or <7.0% at Week 26 and No Severe and/or Confirmed (≤3.9 mmol/L [70 mg/dL]) Hypoglycemia During 26-Week Randomized Period

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    End point title
    		 Percentage of Subjects With HbA1c <7.5% or <7.0% at Week 26 and No Severe and/or Confirmed (≤3.9 mmol/L [70 mg/dL]) Hypoglycemia During 26-Week Randomized Period
    End point description
    Severe hypoglycemia was an event that required assistance of another person to actively administer carbohydrate, glucagon, or other resuscitative actions. Confirmed hypoglycemia was an event associated with plasma glucose ≤3.9 mmol/L (70 mg/dL). ITT population.
    End point type
    Secondary
    End point timeframe
    Baseline up to Week 26
    End point values
    		 HOE901-U300 Lantus
    Number of subjects analysed
    508
    506
    Units: percentage of subjects
    number (not applicable)
        HbA1c <7.5%
    26.4
    21.5
        HbA1c <7.0%
    14
    12.3
    No statistical analyses for this end point

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

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    End point title
    		 Change in Fasting Plasma Glucose (FPG) From Baseline to Week 26
    End point description
    Adjusted LS means from multiple imputation approach including post baseline values during the 26-week randomized period. ITT population. Here 'number of subjects analysed' signifies subjects with available data for this end point.
    End point type
    Secondary
    End point timeframe
    Baseline, Week 26
    End point values
    		 HOE901-U300 Lantus
    Number of subjects analysed
    484
    482
    Units: mmol/L
        least squares mean (standard error)
    -1.68 ( 0.122 )
    -1.77 ( 0.135 )
    No statistical analyses for this end point

    Secondary: Change in World Health Organization-5 (WHO-5) Well-Being Questionnaire Percentage Score From Baseline to Week 26

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    End point title
    		 Change in World Health Organization-5 (WHO-5) Well-Being Questionnaire Percentage Score From Baseline to Week 26
    End point description
    WHO-5 well-being index evaluates positive psychological well-being during the past 2 weeks and consists of 5 questions, each rated on a 6-point Likert scale from 0 (not present) to 5 (constantly present). Total raw score was transformed into a percentage score ranging from 0 (worst possible quality of life) to 100 (best possible quality of life). ITT population. Here ‘number of subjects analysed’ signifies subjects with available data for this end point.
    End point type
    Secondary
    End point timeframe
    Baseline, Week 26
    End point values
    		 HOE901-U300 Lantus
    Number of subjects analysed
    484
    476
    Units: scores on a scale
        least squares mean (standard error)
    -1.16 ( 0.751 )
    0.22 ( 0.758 )
    No statistical analyses for this end point

    Secondary: Percentage of Subjects Requiring Rescue Therapy Over the 26 Weeks of Treatment

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    End point title
    		 Percentage of Subjects Requiring Rescue Therapy Over the 26 Weeks of Treatment
    End point description
    Routine fasting self-monitored plasma glucose (SMPG) and central laboratory FPG (and HbA1c after Week 14) values were used to determine the requirement of rescue medication. Threshold values at Week 14: FPG >200 mg/dL (11 mmol/L), or HbA1c >8.5%. ITT population.
    End point type
    Secondary
    End point timeframe
    Baseline up to Week 26
    End point values
    		 HOE901-U300 Lantus
    Number of subjects analysed
    508
    506
    Units: percentage of subjects
        number (not applicable)
    3.7
    2.6
    No statistical analyses for this end point

    Other pre-specified: Percentage of Subjects With Hypoglycemia (Any Hypoglycemia, Documented Symptomatic Hypoglycemia, Severe and/or Confirmed Hypoglycemia) During the 26 Weeks of Treatment

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    End point title
    		 Percentage of Subjects With Hypoglycemia (Any Hypoglycemia, Documented Symptomatic Hypoglycemia, Severe and/or Confirmed Hypoglycemia) During the 26 Weeks of Treatment
    End point description
    Hypoglycemia events were hypoglycemia of any category, severe hypoglycemia (an event that required assistance of another person to actively administer carbohydrate, glucagon, or other resuscitative actions); documented symptomatic hypoglycemia (symptoms of hypoglycemia with plasma glucose ≤3.9 mmol/L [70 mg/dL]); confirmed hypoglycemia (with or without symptoms of hypoglycemia and plasma glucose ≤3.9 mmol/L). Safety population included all randomized subjects who actually received at least 1 dose or part of a dose of investigational medicinal product (IMP) and analyzed according to the treatment actually received. Here 'n' signifies number of subjects evaluable for this end point in the specified categories.
    End point type
    Other pre-specified
    End point timeframe
    Baseline up to Week 26
    End point values
    		 HOE901-U300 Lantus
    Number of subjects analysed
    508
    505
    Units: percentage of subjects
    number (not applicable)
        Any hypoglycemia (n= 508, 505)
    62.6
    66.5
        Documented symptomatic hypoglycemia (n=508, 505)
    32.9
    34.7
        Severe and/or confirmed hypoglycemia (n= 508, 505)
    58.1
    60.6
        Severe and/or confirmed:<75years (n=373, 399)
    59.2
    60.9
        Severe and/or confirmed:≥75 years age (n=135, 106)
    54.8
    59.4
    No statistical analyses for this end point

    Other pre-specified: Hypoglycemia (Any Hypoglycemia, Documented Symptomatic Hypoglycemia, Severe and/or Confirmed Hypoglycemia) Event Rate Per Subject Year During the 26 Weeks of Treatment

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    End point title
    		 Hypoglycemia (Any Hypoglycemia, Documented Symptomatic Hypoglycemia, Severe and/or Confirmed Hypoglycemia) Event Rate Per Subject Year During the 26 Weeks of Treatment
    End point description
    Hypoglycemia events were hypoglycemia of any category, severe hypoglycemia (an event that required assistance of another person to actively administer carbohydrate, glucagon, or other resuscitative actions); documented symptomatic hypoglycemia (symptoms of hypoglycemia with plasma glucose ≤3.9 mmol/L [70 mg/dL]); confirmed hypoglycemia (with or without symptoms of hypoglycemia and plasma glucose ≤3.9 mmol/L). Safety population.
    End point type
    Other pre-specified
    End point timeframe
    Baseline up to Week 26
    End point values
    		 HOE901-U300 Lantus
    Number of subjects analysed
    508
    505
    Units: rate per subject year
    number (not applicable)
        Any hypoglycemia
    6.06
    7.74
        Documented symptomatic hypoglycemia
    1.85
    2.56
        Severe and/or confirmed hypoglycemia
    5.17
    6.36
    No statistical analyses for this end point

    Post-hoc: Hypoglycemia (Any Hypoglycemia, Documented Symptomatic Hypoglycemia, Severe and/or Confirmed Hypoglycemia) Event Rate Per Subject Year: By Age Categorical Data During the 26 Weeks of Treatment

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    End point title
    		 Hypoglycemia (Any Hypoglycemia, Documented Symptomatic Hypoglycemia, Severe and/or Confirmed Hypoglycemia) Event Rate Per Subject Year: By Age Categorical Data During the 26 Weeks of Treatment
    End point description
    Hypoglycemia events were hypoglycemia of any category, severe hypoglycemia (an event that required assistance of another person to actively administer carbohydrate, glucagon, or other resuscitative actions); documented symptomatic hypoglycemia (symptoms of hypoglycemia with plasma glucose ≤3.9 mmol/L [70 mg/dL]); confirmed hypoglycemia (with or without symptoms of hypoglycemia and plasma glucose ≤3.9 mmol/L). Safety population. Here 'n' signifies number of subjects evaluable for this end point in the specified categories.
    End point type
    Post-hoc
    End point timeframe
    Baseline up to Week 26
    End point values
    		 HOE901-U300 Lantus
    Number of subjects analysed
    508
    505
    Units: event rate per subject year
    number (not applicable)
        Any hypoglycemia:<75 years age (n= 373, 399)
    6.44
    7.85
        Any hypoglycemia:≥75 years age (n= 135,106)
    5.01
    7.32
        Documented symptomatic:<75 years (n=373, 399)
    2.11
    2.52
        Documented symptomatic:≥75 years (n=135, 106)
    1.12
    2.71
        Severe and/or confirmed:<75 years (n= 373, 399)
    5.43
    6.37
        Severe and/or confirmed:≥75 years(n= 135, 106)
    4.46
    6.28
    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 (Day 184) regardless of seriousness or relationship to IMP.
    Adverse event reporting additional description
    Reported AEs and deaths were treatment emergent that is AEs that developed/worsened and deaths that occurred during 'on treatment period' (from first dose of IMP injection up to 2 days after the last injection of IMP, regardless of introduction of rescue therapy). Analysis was performed using safety population which included all treated subjects.
    Assessment type
    		 Systematic
    Dictionary used for adverse event reporting
    Dictionary name
    		 MedDRA
    Dictionary version
    19.0
    Reporting groups
    Reporting group title
    HOE901-U300
    Reporting group description
    		 HOE901-U300 (Insulin glargine, 300 U/mL) SC injection once daily up to Week 26 on top of stable non-insulin antihyperglycemic therapy.

    Reporting group title
    Lantus
    Reporting group description
    		 Lantus (Insulin glargine, 100 U/mL) SC injection once daily up to Week 26 on top of stable non-insulin antihyperglycemic therapy.

    Serious adverse events
    		 HOE901-U300 Lantus
    Total subjects affected by serious adverse events
         subjects affected / exposed
    41 / 508 (8.07%)
    34 / 505 (6.73%)
         number of deaths (all causes)
    1
    0
         number of deaths resulting from adverse events
    Neoplasms benign, malignant and unspecified (incl cysts and polyps)
    Adenocarcinoma Of Colon
         subjects affected / exposed
    1 / 508 (0.20%)
    0 / 505 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Basal Cell Carcinoma
         subjects affected / exposed
    1 / 508 (0.20%)
    1 / 505 (0.20%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Bladder Cancer
         subjects affected / exposed
    0 / 508 (0.00%)
    1 / 505 (0.20%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Bowen's Disease
         subjects affected / exposed
    1 / 508 (0.20%)
    0 / 505 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Breast Cancer
         subjects affected / exposed
    0 / 508 (0.00%)
    1 / 505 (0.20%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Chronic Lymphocytic Leukaemia
         subjects affected / exposed
    1 / 508 (0.20%)
    0 / 505 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Endometrial Cancer Metastatic
         subjects affected / exposed
    1 / 508 (0.20%)
    0 / 505 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    Glioblastoma
         subjects affected / exposed
    0 / 508 (0.00%)
    1 / 505 (0.20%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Hepatic Neoplasm
         subjects affected / exposed
    0 / 508 (0.00%)
    1 / 505 (0.20%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    Lung Adenocarcinoma
         subjects affected / exposed
    1 / 508 (0.20%)
    0 / 505 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Lung Neoplasm
         subjects affected / exposed
    0 / 508 (0.00%)
    1 / 505 (0.20%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Oesophageal Adenocarcinoma
         subjects affected / exposed
    0 / 508 (0.00%)
    1 / 505 (0.20%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pancreatic Carcinoma
         subjects affected / exposed
    2 / 508 (0.39%)
    0 / 505 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Prostate Cancer
         subjects affected / exposed
    3 / 508 (0.59%)
    1 / 505 (0.20%)
         occurrences causally related to treatment / all
    0 / 3
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Rectal Cancer
         subjects affected / exposed
    0 / 508 (0.00%)
    1 / 505 (0.20%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Squamous Cell Carcinoma Of Skin
         subjects affected / exposed
    1 / 508 (0.20%)
    0 / 505 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Transitional Cell Carcinoma
         subjects affected / exposed
    0 / 508 (0.00%)
    1 / 505 (0.20%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Vascular disorders
    Hypertensive Crisis
         subjects affected / exposed
    1 / 508 (0.20%)
    2 / 505 (0.40%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Peripheral Venous Disease
         subjects affected / exposed
    1 / 508 (0.20%)
    0 / 505 (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
    Death
         subjects affected / exposed
    1 / 508 (0.20%)
    0 / 505 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    Reproductive system and breast disorders
    Benign Prostatic Hyperplasia
         subjects affected / exposed
    1 / 508 (0.20%)
    0 / 505 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Breast Mass
         subjects affected / exposed
    0 / 508 (0.00%)
    1 / 505 (0.20%)
         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
    Pleural Effusion
         subjects affected / exposed
    1 / 508 (0.20%)
    0 / 505 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Investigations
    Hepatic Enzyme Increased
         subjects affected / exposed
    1 / 508 (0.20%)
    0 / 505 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Injury, poisoning and procedural complications
    Ankle Fracture
         subjects affected / exposed
    0 / 508 (0.00%)
    1 / 505 (0.20%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Fall
         subjects affected / exposed
    1 / 508 (0.20%)
    0 / 505 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Femur Fracture
         subjects affected / exposed
    0 / 508 (0.00%)
    1 / 505 (0.20%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Heart Injury
         subjects affected / exposed
    0 / 508 (0.00%)
    1 / 505 (0.20%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Cardiac disorders
    Acute Left Ventricular Failure
         subjects affected / exposed
    0 / 508 (0.00%)
    1 / 505 (0.20%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Acute Myocardial Infarction
         subjects affected / exposed
    2 / 508 (0.39%)
    1 / 505 (0.20%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Angina Unstable
         subjects affected / exposed
    2 / 508 (0.39%)
    0 / 505 (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
    0 / 508 (0.00%)
    2 / 505 (0.40%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Atrioventricular Block
         subjects affected / exposed
    1 / 508 (0.20%)
    0 / 505 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Cardiac Failure Chronic
         subjects affected / exposed
    0 / 508 (0.00%)
    1 / 505 (0.20%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    Cardiac Failure Congestive
         subjects affected / exposed
    1 / 508 (0.20%)
    0 / 505 (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 / 508 (0.39%)
    2 / 505 (0.40%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Myocardial Ischaemia
         subjects affected / exposed
    0 / 508 (0.00%)
    1 / 505 (0.20%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Sinus Node Dysfunction
         subjects affected / exposed
    1 / 508 (0.20%)
    0 / 505 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Tachycardia
         subjects affected / exposed
    1 / 508 (0.20%)
    0 / 505 (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
    Embolic Stroke
         subjects affected / exposed
    1 / 508 (0.20%)
    0 / 505 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Hypoglycaemic Coma
         subjects affected / exposed
    1 / 508 (0.20%)
    0 / 505 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Hypoglycaemic Unconsciousness
         subjects affected / exposed
    1 / 508 (0.20%)
    0 / 505 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Iiird Nerve Paresis
         subjects affected / exposed
    1 / 508 (0.20%)
    0 / 505 (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
    2 / 508 (0.39%)
    0 / 505 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    Loss Of Consciousness
         subjects affected / exposed
    1 / 508 (0.20%)
    0 / 505 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Neuromyopathy
         subjects affected / exposed
    1 / 508 (0.20%)
    0 / 505 (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
    1 / 508 (0.20%)
    1 / 505 (0.20%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Transient Ischaemic Attack
         subjects affected / exposed
    0 / 508 (0.00%)
    1 / 505 (0.20%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Blood and lymphatic system disorders
    Anaemia
         subjects affected / exposed
    0 / 508 (0.00%)
    1 / 505 (0.20%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Gastrointestinal disorders
    Gastric Ulcer Haemorrhage
         subjects affected / exposed
    1 / 508 (0.20%)
    0 / 505 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Ileus
         subjects affected / exposed
    0 / 508 (0.00%)
    1 / 505 (0.20%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Rectal Haemorrhage
         subjects affected / exposed
    1 / 508 (0.20%)
    0 / 505 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Hepatobiliary disorders
    Bile Duct Stone
         subjects affected / exposed
    1 / 508 (0.20%)
    0 / 505 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Cholecystitis
         subjects affected / exposed
    1 / 508 (0.20%)
    0 / 505 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Cholecystitis Acute
         subjects affected / exposed
    1 / 508 (0.20%)
    0 / 505 (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
    Angioedema
         subjects affected / exposed
    1 / 508 (0.20%)
    0 / 505 (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 / 508 (0.20%)
    1 / 505 (0.20%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Chronic Kidney Disease
         subjects affected / exposed
    1 / 508 (0.20%)
    0 / 505 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Renal Colic
         subjects affected / exposed
    0 / 508 (0.00%)
    1 / 505 (0.20%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Endocrine disorders
    Adrenal Mass
         subjects affected / exposed
    1 / 508 (0.20%)
    0 / 505 (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
    Back Pain
         subjects affected / exposed
    1 / 508 (0.20%)
    0 / 505 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Chondrocalcinosis Pyrophosphate
         subjects affected / exposed
    1 / 508 (0.20%)
    0 / 505 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Osteoarthritis
         subjects affected / exposed
    0 / 508 (0.00%)
    1 / 505 (0.20%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Infections and infestations
    Arthritis Infective
         subjects affected / exposed
    1 / 508 (0.20%)
    0 / 505 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Bacterial Pyelonephritis
         subjects affected / exposed
    0 / 508 (0.00%)
    1 / 505 (0.20%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Diverticulitis
         subjects affected / exposed
    0 / 508 (0.00%)
    1 / 505 (0.20%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Empyema
         subjects affected / exposed
    0 / 508 (0.00%)
    1 / 505 (0.20%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Endocarditis Bacterial
         subjects affected / exposed
    1 / 508 (0.20%)
    0 / 505 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Lung Infection
         subjects affected / exposed
    0 / 508 (0.00%)
    1 / 505 (0.20%)
         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 / 508 (0.20%)
    0 / 505 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Perirectal Abscess
         subjects affected / exposed
    1 / 508 (0.20%)
    0 / 505 (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
    1 / 508 (0.20%)
    3 / 505 (0.59%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 3
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pyelonephritis
         subjects affected / exposed
    0 / 508 (0.00%)
    2 / 505 (0.40%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Urosepsis
         subjects affected / exposed
    1 / 508 (0.20%)
    0 / 505 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Metabolism and nutrition disorders
    Hyperkalaemia
         subjects affected / exposed
    1 / 508 (0.20%)
    0 / 505 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Hypoglycaemia
         subjects affected / exposed
    1 / 508 (0.20%)
    1 / 505 (0.20%)
         occurrences causally related to treatment / all
    0 / 1
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Hyponatraemia
         subjects affected / exposed
    1 / 508 (0.20%)
    0 / 505 (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
    		 HOE901-U300 Lantus
    Total subjects affected by non serious adverse events
         subjects affected / exposed
    62 / 508 (12.20%)
    64 / 505 (12.67%)
    Infections and infestations
    Nasopharyngitis
         subjects affected / exposed
    37 / 508 (7.28%)
    38 / 505 (7.52%)
         occurrences all number
    45
    44
    Upper Respiratory Tract Infection
         subjects affected / exposed
    27 / 508 (5.31%)
    28 / 505 (5.54%)
         occurrences all number
    30
    30

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    Substantial protocol amendments (globally)
    Were there any global substantial amendments to the protocol? Yes
    Date
    Amendment
    04 Mar 2016
    Following amendments were made: Modified Statistical approach to efficacy analyses based on health authority recommendations. Specifically, an ITT approach was used for the primary analysis of primary and secondary efficacy endpoints. A sensitivity analysis using only on-treatment data was performed on the primary and main secondary efficacy endpoints. The definition of the efficacy analysis population was updated accordingly.

    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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    The status and protocol content of GB trials is no longer updated since 1 January 2021. For the UK, as of 31 January 2021, EU Law applies only to the territory of Northern Ireland (NI) to the extent foreseen in the Protocol on Ireland/NI. Legal notice
    As of 31 January 2023, all EU/EEA initial clinical trial applications must be submitted through CTIS . Updated EudraCT trials information and information on PIP/Art 46 trials conducted exclusively in third countries continues to be submitted through EudraCT and published on this website.

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