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    Clinical Trial Results:
    6-Month, Multicenter, Randomized, Open-label, 2-Arm, Parallel-group Study Comparing the Efficacy and Safety of a New Formulation of Insulin Glargine and Lantus® Injected Once Daily in Children and Adolescents age 6 - 17 Years with Type 1 Diabetes Mellitus with a 6-month Safety Extension Period

    Summary
    EudraCT number
    		 2015-002084-42
    Trial protocol
    		 GB   HU   LV   IT   DE   CZ   FR   ES   PL   SE   DK   BG   Outside EU/EEA  
    Global end of trial date
    20 Dec 2018

    Results information
    Results version number
    		 v1(current)
    This version publication date
    04 Jul 2019
    First version publication date
    04 Jul 2019
    Other versions

    Trial information

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    Trial identification
    Sponsor protocol code
    EFC13957
    Additional study identifiers
    ISRCTN number
    		 -
    US NCT number
    		 NCT02735044
    WHO universal trial number (UTN)
    		 U1111-1168-4546
    Sponsors
    Sponsor organisation name
    Sanofi aventis recherche & développement
    Sponsor organisation address
    1 avenue Pierre Brossolette, Chilly, 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?
    Yes
    Results analysis stage
    Analysis stage
    Final
    Date of interim/final analysis
    23 Jan 2019
    Is this the analysis of the primary completion data?
    No
    Global end of trial reached?
    Yes
    Global end of trial date
    20 Dec 2018
    Was the trial ended prematurely?
    No
    General information about the trial
    Main objective of the trial
    To compare the efficacy of a new formulation of insulin glargine (HOE901-U300) to Lantus in terms of change of HbA1c from baseline to endpoint (month 6) in children and adolescents with type 1 diabetes mellitus.
    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
    		 Fast acting mealtime insulin analogs were required to be used 6 months prior screening visit. The type of insulin were to remain unchanged during the study.
    Evidence for comparator
    		 -
    Actual start date of recruitment
    14 Apr 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
    Argentina: 31
    Country: Number of subjects enrolled
    Brazil: 27
    Country: Number of subjects enrolled
    Canada: 21
    Country: Number of subjects enrolled
    Chile: 22
    Country: Number of subjects enrolled
    Israel: 15
    Country: Number of subjects enrolled
    Japan: 14
    Country: Number of subjects enrolled
    Macedonia, the former Yugoslav Republic of: 10
    Country: Number of subjects enrolled
    Mexico: 50
    Country: Number of subjects enrolled
    Russian Federation: 35
    Country: Number of subjects enrolled
    Serbia: 11
    Country: Number of subjects enrolled
    United States: 35
    Country: Number of subjects enrolled
    Poland: 20
    Country: Number of subjects enrolled
    Romania: 28
    Country: Number of subjects enrolled
    Spain: 15
    Country: Number of subjects enrolled
    Sweden: 1
    Country: Number of subjects enrolled
    United Kingdom: 10
    Country: Number of subjects enrolled
    Bulgaria: 20
    Country: Number of subjects enrolled
    Czech Republic: 9
    Country: Number of subjects enrolled
    Denmark: 1
    Country: Number of subjects enrolled
    France: 4
    Country: Number of subjects enrolled
    Germany: 4
    Country: Number of subjects enrolled
    Hungary: 39
    Country: Number of subjects enrolled
    Italy: 26
    Country: Number of subjects enrolled
    Latvia: 15
    Worldwide total number of subjects
    463
    EEA total number of subjects
    192
    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)
    143
    Adolescents (12-17 years)
    320
    Adults (18-64 years)
    0
    From 65 to 84 years
    0
    85 years and over
    0

    Subject disposition

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    Recruitment
    Recruitment details
    		 The study was conducted at 105 centers in 24 countries. A total of 616 subjects were screened between 14 April 2016 and 31 October 2017, of which 153 were screen failures. Screen failures were mainly due to glycated hemoglobin (HbA1c) level outside of defined ranges per eligibility criteria.

    Pre-assignment
    Screening details
    		 A total of 463 subjects were randomized in the study. Randomization was stratified by age group (<12 years and >=12 years) and by HbA1c (<8.5% and >=8.5%). Assignment to arms was done centrally using interactive voice system in 1:1 ratio.

    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
    		 Insulin glargine 300 Units/milliliter (U/mL) Subcutaneous (SC) injection once daily in the morning or evening for 12 months.
    Arm type
    		 Experimental

    Investigational medicinal product name
    Insulin glargine
    Investigational medicinal product code
    Other name
    Toujeo
    Pharmaceutical forms
    Injection
    Routes of administration
    Subcutaneous use
    Dosage and administration details
    Insulin glargine 300 U/mL SC injection using a prefilled pen. Dose titration to achieve fasting self-monitored plasma glucose (SMPG) from 90 to 130 milligram/deciliter (mg/dL) (5.0 to 7.2 millimol per liter [mmol/L]).

    Arm title
    		 Lantus
    Arm description
    		 Insulin glargine 100 U/mL SC injection once daily in the morning or evening for 12 months.
    Arm type
    		 Experimental

    Investigational medicinal product name
    Insulin glargine
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Injection
    Routes of administration
    Subcutaneous use
    Dosage and administration details
    Insulin glargine 100 U/mL SC injection using a prefilled 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
    233
    230
    Completed
    217
    207
    Not completed
    16
    23
         Adverse Event
    3
    3
         Randomized and not treated
    -
    2
         Other than specified
    5
    11
         Poor compliance to protocol
    7
    7
         Lack of efficacy
    1
    -

    Baseline characteristics

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    Baseline characteristics reporting groups
    Reporting group title
    HOE901-U300
    Reporting group description
    		 Insulin glargine 300 Units/milliliter (U/mL) Subcutaneous (SC) injection once daily in the morning or evening for 12 months.

    Reporting group title
    Lantus
    Reporting group description
    		 Insulin glargine 100 U/mL SC injection once daily in the morning or evening for 12 months.

    Reporting group values
    		 HOE901-U300 Lantus Total
    Number of subjects
    		 233 230 463
    Age categorical
    Units: Subjects
    Age continuous
    Units: years
        arithmetic mean (standard deviation)
    		 12.9 ( 2.9 ) 12.9 ( 2.9 ) -
    Gender categorical
    Units: Subjects
        Female
    		 105 121 226
        Male
    		 128 109 237
    Race
    Units: Subjects
        American Indian or Alaska Native
    		 0 0 0
        Asian
    		 11 6 17
        Native Hawaiian or Other Pacific Islander
    		 0 0 0
        Black or African American
    		 8 6 14
        White
    		 211 211 422
        More than one race
    		 2 2 4
        Unknown or Not Reported
    		 0 1 1
        Not recorded
    		 1 4 5
    Body Mass Index (BMI)
    Units: BMI percentile
        arithmetic mean (standard deviation)
    		 67.52 ( 26.62 ) 69.13 ( 26.64 ) -
    Hemoglobin A1C (HbA1C)
    Units: percentage of A1C
        arithmetic mean (standard deviation)
    		 8.65 ( 0.88 ) 8.61 ( 0.87 ) -

    End points

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    End points reporting groups
    Reporting group title
    HOE901-U300
    Reporting group description
    		 Insulin glargine 300 Units/milliliter (U/mL) Subcutaneous (SC) injection once daily in the morning or evening for 12 months.

    Reporting group title
    Lantus
    Reporting group description
    		 Insulin glargine 100 U/mL SC injection once daily in the morning or evening for 12 months.

    Primary: Change From Baseline in HbA1c to Month 6

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    End point title
    		 Change From Baseline in HbA1c to Month 6
    End point description
    Change in HbA1c was calculated by subtracting baseline value from Month 6 value. Adjusted least-square (LS) means and standard errors (SE) were obtained using analysis of covariance (ANCOVA) after multiple imputations of missing data using post-baseline HbA1c data available on the main 6-month randomized period. Analysis was performed on intent-to-treat (ITT) population that included all randomized subjects, regardless of whether the treatment kit was used, and was analysed according to the allocated treatment group. Here, number of subjects analysed signified number of subjects with available data for the endpoint.
    End point type
    Primary
    End point timeframe
    Baseline to Month 6
    End point values
    		 HOE901-U300 Lantus
    Number of subjects analysed
    232
    230
    Units: Percentage of HbA1c
        arithmetic mean (standard deviation)
    -0.399 ( 0.063 )
    -0.402 ( 0.064 )
    Statistical analysis title
    		 HOE901-U300, Lantus
    Statistical analysis description
    Analysis was performed using ANCOVA models which included the treatment group, the randomization stratum of age group at screening visit (<12 years and >=12 years), and the continuous fixed covariates of the baseline HbA1c value.
    Comparison groups
    HOE901-U300 v Lantus
    Number of subjects included in analysis
    462
    Analysis specification
    Pre-specified
    Analysis type
    		 non-inferiority [1]
    Method
    Parameter type
    		 LS Mean difference
    Point estimate
    0.004
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -0.172
         upper limit
    		 0.179
    Variability estimate
    Standard error of the mean
    Dispersion value
    0.09
    Notes
    [1] - Non-inferiority of HOE901-U300 versus Lantus was demonstrated if the upper bound of the two-sided 95% confidence interval (CI) for the difference in the mean change in HbA1c from baseline to month 6 was <0.3%.
    Statistical analysis title
    		 HOE901-U300, Lantus
    Statistical analysis description
    A step-wise closed testing approach was used to control the type I error. Analysis was performed using ANCOVA models which included the treatment group, the randomization stratum of age group at screening visit (<12 years and >=12 years), and the continuous fixed covariates of the baseline HbA1c value.
    Comparison groups
    HOE901-U300 v Lantus
    Number of subjects included in analysis
    462
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority [2]
    P-value
    		 = 0.965 [3]
    Method
    		 ANCOVA
    Confidence interval
    Notes
    [2] - Superiority of HOE901-U300 versus Lantus was demonstrated if the upper bound of the two-sided 95% CI for the difference between treatment groups was <0 (zero).
    [3] - Threshold for significance at 0.025 level.

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

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    End point title
    		 Change From Baseline in Fasting Plasma Glucose (FPG) to Month 6
    End point description
    Change in FPG was calculated by subtracting baseline value from Month 6 value. Adjusted LS means and SE were obtained using ANCOVA after multiple imputation to address missing data in the main 6 month randomized period. Analysis was performed on ITT population. Here, number of subjects analysed signified number of subjects with available data for the endpoint.
    End point type
    Secondary
    End point timeframe
    Baseline to Month 6
    End point values
    		 HOE901-U300 Lantus
    Number of subjects analysed
    232
    230
    Units: millimole per liter (mmol/L)
        least squares mean (standard deviation)
    -0.563 ( 0.372 )
    -0.549 ( 0.372 )
    No statistical analyses for this end point

    Secondary: Percentage of Subjects With HbA1c Values of <7.5% at Month 6

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    End point title
    		 Percentage of Subjects With HbA1c Values of <7.5% at Month 6
    End point description
    Subjects without any available HbA1c assessment at month 6 and/or with a premature study discontinuation during the main 6-month randomized period were considered as a failure (non-responders) in the analysis. Analysis was performed using Cochran-Mantel-Haenszel (CMH) method with randomization strata of screening HbA1c (<8.5%; >=8.5%) and randomization strata of age at screening (<12 years, >=12 years). Analysis was performed on ITT population.
    End point type
    Secondary
    End point timeframe
    Month 6
    End point values
    		 HOE901-U300 Lantus
    Number of subjects analysed
    233
    230
    Units: percentage of subjects
        number (not applicable)
    26.18
    23.48
    No statistical analyses for this end point

    Secondary: Percentage of Subjects With HbA1c Values of <7.5% Without Any Episode of Severe and/or Documented Self- Monitored Plasma Glucose ([SMPG] <54 mg/dL [3.0 mmol/L]) Symptomatic Hypoglycemia During the Last 3 Months of the Main 6-month Randomized Period

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    End point title
    		 Percentage of Subjects With HbA1c Values of <7.5% Without Any Episode of Severe and/or Documented Self- Monitored Plasma Glucose ([SMPG] <54 mg/dL [3.0 mmol/L]) Symptomatic Hypoglycemia During the Last 3 Months of the Main 6-month Randomized Period
    End point description
    Subjects without any available HbA1c assessment at month 6 and/or with a premature study discontinuation during the main 6-month randomized period were considered as a failure (non-responders) in the analysis. Analysis was performed using Cochran-Mantel-Haenszel (CMH) method with randomization strata of screening HbA1c (<8.5%; >=8.5%) and randomization strata of age at screening (<12 years, >=12 years). Analysis was performed on ITT population.
    End point type
    Secondary
    End point timeframe
    upto Month 6
    End point values
    		 HOE901-U300 Lantus
    Number of subjects analysed
    233
    230
    Units: percentage of subjects
        number (not applicable)
    4.29
    4.78
    No statistical analyses for this end point

    Secondary: Percentage of Subjects With FPG of <=130 mg/dL (7.2 mmol/L) at Month 6

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    End point title
    		 Percentage of Subjects With FPG of <=130 mg/dL (7.2 mmol/L) at Month 6
    End point description
    Subjects without any available FPG assessment at month 6 and/or with a premature study discontinuation during the main 6-month randomized period were considered as a failure (non-responders) in the analysis. Analysis was performed using CMH method with randomization strata of screening HbA1c (<8.5%; >=8.5%) and randomization strata of age at screening (<12 years, >=12 years). Analysis was performed on ITT population.
    End point type
    Secondary
    End point timeframe
    Month 6
    End point values
    		 HOE901-U300 Lantus
    Number of subjects analysed
    233
    230
    Units: percentage of subjects
        number (not applicable)
    27.47
    26.52
    No statistical analyses for this end point

    Secondary: Percentage of Subjects With FPG of <=130 mg/dL (7.2 mmol/L) Without Any Episode of Severe and/or Documented (SMPG <54 mg/dL [3.0 mmol/L]) Symptomatic Hypoglycemia During the Last 3 Months of the Main 6-month Randomized Period

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    End point title
    		 Percentage of Subjects With FPG of <=130 mg/dL (7.2 mmol/L) Without Any Episode of Severe and/or Documented (SMPG <54 mg/dL [3.0 mmol/L]) Symptomatic Hypoglycemia During the Last 3 Months of the Main 6-month Randomized Period
    End point description
    Subjects without any available HbA1c assessment at month 6 and/or with a premature study discontinuation during the main 6-month randomized period were considered as a failure (non-responders) in the analysis. Analysis was performed using CMH method with randomization strata of screening HbA1c (<8.5%; >=8.5%) and randomization strata of age at screening (<12 years, >=12 years). Analysis was performed on ITT population.
    End point type
    Secondary
    End point timeframe
    upto Month 6
    End point values
    		 HOE901-U300 Lantus
    Number of subjects analysed
    233
    230
    Units: percentage of subjects
        number (not applicable)
    9.44
    7.39
    No statistical analyses for this end point

    Secondary: Change From Baseline in 24-Hour Mean Plasma Glucose Based on 8-point SMPG Profiles to Month 6

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    End point title
    		 Change From Baseline in 24-Hour Mean Plasma Glucose Based on 8-point SMPG Profiles to Month 6
    End point description
    8-point SMPG profiles were measured at the following 8 points: between 01:00 and 04:00 AM at night, pre-breakfast, 2 hours after breakfast, pre-lunch, 2 hours after lunch, pre-dinner, 2 hours after dinner, and bedtime. Analysis was performed using a ANCOVA model including the fixed categorical effects of treatment group, randomization strata of screening HbA1c (<8.5%; >=8.5%), randomization strata of age at screening (<12 years, >=12 years) and the baseline 24-hour average 8-point profile SMPG. Analysis was performed on ITT population. Here, number of subjects analysed signified number of subjects with available data for the endpoint.
    End point type
    Secondary
    End point timeframe
    Baseline to Month 6
    End point values
    		 HOE901-U300 Lantus
    Number of subjects analysed
    147
    146
    Units: mmol/L
        least squares mean (standard error)
    0.139 ( 0.249 )
    -0.266 ( 0.250 )
    No statistical analyses for this end point

    Secondary: Change From Baseline in Variability of 24-Hour Mean Plasma Glucose Based on 8-point SMPG Profiles at Month 6

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    End point title
    		 Change From Baseline in Variability of 24-Hour Mean Plasma Glucose Based on 8-point SMPG Profiles at Month 6
    End point description
    8-point SMPG profiles were measured at the following 8 points: between 01:00 and 04:00 (clock time) at night, pre-breakfast, 2 hours after breakfast, pre-lunch, 2 hours after lunch, pre-dinner, 2 hours after dinner, and bedtime. Variability was the mean of coefficient of variation calculated over the 8-point SMPG. Analysis was performed using a ANCOVA model including the fixed categorical effects of treatment group, randomization strata of screening HbA1c (<8.5%; >=8.5%) and randomization strata of age at screening (<12 years, >=12 years). Analysis was performed on ITT population. Here, number of subjects analysed signified number of subjects with available data for the endpoint.
    End point type
    Secondary
    End point timeframe
    Baseline, Month 6
    End point values
    		 HOE901-U300 Lantus
    Number of subjects analysed
    147
    146
    Units: percentage of mean variability
        least squares mean (standard error)
    1.469 ( 1.409 )
    0.789 ( 1.415 )
    No statistical analyses for this end point

    Secondary: Change From Baseline to Month 6 in 8-Point SMPG Profile Per Time Point

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    End point title
    		 Change From Baseline to Month 6 in 8-Point SMPG Profile Per Time Point
    End point description
    8-point SMPG profiles were measured for following 8 time points at Baseline and Month 6: between 01:00 and 04:00 (clock time) at night, pre-breakfast, 2 hours after breakfast, pre-lunch, 2 hours after lunch, pre-dinner, 2 hours after dinner, and bedtime. Analysis was performed on ITT population. Here, ‘n’ = subjects with available data for each specified category.
    End point type
    Secondary
    End point timeframe
    Baseline to Month 6
    End point values
    		 HOE901-U300 Lantus
    Number of subjects analysed
    233
    230
    Units: mmol/L
    arithmetic mean (standard deviation)
        Between 01:00 and 04:00 at night (n=109,116)
    0.84 ( 6.94 )
    -0.60 ( 7.08 )
        Pre-breakfast (n=141,142)
    -0.41 ( 5.48 )
    -1.71 ( 6.56 )
        2 hours after breakfast (n=135,128)
    -0.26 ( 7.18 )
    -0.62 ( 6.78 )
        Pre-lunch (n=144,140)
    0.43 ( 6.99 )
    1.11 ( 6.85 )
        2 hours after lunch (n=131, 129)
    0.49 ( 7.64 )
    -0.55 ( 7.20 )
        Pre-dinner (n=141, 126)
    0.29 ( 8.05 )
    -0.02 ( 6.78 )
        2 hours after dinner (n= 125, 124)
    0.51 ( 8.53 )
    0.60 ( 6.86 )
        Bedtime (n=114,117)
    0.86 ( 7.60 )
    -0.60 ( 7.00 )
    No statistical analyses for this end point

    Secondary: Percentage of Subjects With at Least One Hypoglycemic Events (Any Hypoglycemia, Severe Hypoglycemia, Documented Symptomatic, Probable Symptomatic, Asymptomatic Hypoglycemia, Pseudo-hypoglycemia and Severe and/or Confirmed Hypoglycemia) at Month 12

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    End point title
    		 Percentage of Subjects With at Least One Hypoglycemic Events (Any Hypoglycemia, Severe Hypoglycemia, Documented Symptomatic, Probable Symptomatic, Asymptomatic Hypoglycemia, Pseudo-hypoglycemia and Severe and/or Confirmed Hypoglycemia) at Month 12
    End point description
    Severe hypoglycemia: an event in which the child/adolescent having altered mental status and cannot assist in their care, is semiconscious or unconscious, or in coma ± convulsions and may require parenteral therapy (glucagon or glucose). Documented symptomatic hypoglycemia: an event during which typical symptoms of hypoglycemia were accompanied by a measured plasma glucose concentration of <=70 mg/dL (3.9 mmol/L). Asymptomatic hypoglycemia: an event not accompanied by typical symptoms of hypoglycemia but with a measured plasma glucose concentration <=70 mg/dL. Probable symptomatic hypoglycemia: an event during which symptoms of hypoglycemia were not accompanied by plasma glucose determination but was presumably caused by a plasma glucose concentration <=70 mg/dL. Pseudo-hypoglycemia:an event with any of the typical symptoms of hypoglycaemia with plasma glucose concentration >70 mg/dL. Analysis was performed on safety population.
    End point type
    Secondary
    End point timeframe
    Month 12
    End point values
    		 HOE901-U300 Lantus
    Number of subjects analysed
    233
    228
    Units: percentage of subjects
    number (not applicable)
        Any hypoglycemia
    99.1
    98.7
        Severe Hypoglycemia
    8.6
    11.0
        Documented Symptomatic Hypoglycemia
    94.8
    93.9
        Probable Symptomatic Hypoglycemia
    10.3
    13.6
        Asymptomatic Hypoglycemia
    88.4
    89.5
        Pseudo-hypoglycemia
    15.9
    14.5
        Severe and/or documented hypoglycemia
    99.1
    98.2
    No statistical analyses for this end point

    Secondary: Percentage of Subjects With Any Hyperglycemia With Ketosis at Month 12

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    End point title
    		 Percentage of Subjects With Any Hyperglycemia With Ketosis at Month 12
    End point description
    Hyperglycemia with ketosis was defined as SMPG >=252 mg/dL (14 mmol/L) with accompanying self-measured blood ketones >=1.5 mmol/L. Analysis was performed on the safety population which included all randomized subjects who actually received at least 1 dose or part of a dose of investigational medicinal product (IMP) and was analysed according to treatment received.
    End point type
    Secondary
    End point timeframe
    Month 12
    End point values
    		 HOE901-U300 Lantus
    Number of subjects analysed
    233
    228
    Units: percentage of subjects
        number (not applicable)
    9.9
    13.6
    No statistical analyses for this end point

    Adverse events

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    Adverse events information
    Timeframe for reporting adverse events
    All Adverse Events (AEs) were collected from signature of the informed consent form until the end of the study (Week 58) regardless of seriousness or relationship to investigational product.
    Adverse event reporting additional description
    Reported AEs and deaths are treatment-emergent adverse events that is AEs that developed, worsened or became serious during the ‘on treatment period’ (time from first dose of IMP up to 2 days after last injection of IMP). Analysis was performed on safety population.
    Assessment type
    		 Systematic
    Dictionary used for adverse event reporting
    Dictionary name
    		 MedDRA
    Dictionary version
    21.1
    Reporting groups
    Reporting group title
    HOE901-U300
    Reporting group description
    		 Insulin glargine 300 U/mL SC injection once daily in the morning or evening for 12 months.

    Reporting group title
    Lantus
    Reporting group description
    		 Insulin glargine 100 U/mL SC injection once daily in the morning or evening for 12 months.

    Serious adverse events
    		 HOE901-U300 Lantus
    Total subjects affected by serious adverse events
         subjects affected / exposed
    35 / 233 (15.02%)
    31 / 228 (13.60%)
         number of deaths (all causes)
    1
    0
         number of deaths resulting from adverse events
    0
    0
    Investigations
    Alanine Aminotransferase Increased
         subjects affected / exposed
    3 / 233 (1.29%)
    1 / 228 (0.44%)
         occurrences causally related to treatment / all
    0 / 3
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Injury, poisoning and procedural complications
    Accidental Overdose
         subjects affected / exposed
    1 / 233 (0.43%)
    1 / 228 (0.44%)
         occurrences causally related to treatment / all
    1 / 1
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Electric Shock
         subjects affected / exposed
    0 / 233 (0.00%)
    1 / 228 (0.44%)
         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 / 233 (0.43%)
    0 / 228 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    Radius Fracture
         subjects affected / exposed
    1 / 233 (0.43%)
    0 / 228 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Rib Fracture
         subjects affected / exposed
    1 / 233 (0.43%)
    0 / 228 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Upper Limb Fracture
         subjects affected / exposed
    1 / 233 (0.43%)
    0 / 228 (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
    Autonomic Nervous System Imbalance
         subjects affected / exposed
    1 / 233 (0.43%)
    0 / 228 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Epilepsy
         subjects affected / exposed
    0 / 233 (0.00%)
    1 / 228 (0.44%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Hypoglycaemic Coma
         subjects affected / exposed
    1 / 233 (0.43%)
    0 / 228 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Hypoglycaemic Seizure
         subjects affected / exposed
    8 / 233 (3.43%)
    10 / 228 (4.39%)
         occurrences causally related to treatment / all
    3 / 11
    4 / 10
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Hypoglycaemic Unconsciousness
         subjects affected / exposed
    6 / 233 (2.58%)
    10 / 228 (4.39%)
         occurrences causally related to treatment / all
    4 / 10
    4 / 11
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Seizure
         subjects affected / exposed
    1 / 233 (0.43%)
    0 / 228 (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 / 233 (0.43%)
    0 / 228 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pregnancy, puerperium and perinatal conditions
    Anembryonic Gestation
         subjects affected / exposed
    1 / 233 (0.43%)
    0 / 228 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Reproductive system and breast disorders
    Testicular Torsion
         subjects affected / exposed
    0 / 233 (0.00%)
    1 / 228 (0.44%)
         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
    Dermal Cyst
         subjects affected / exposed
    1 / 233 (0.43%)
    0 / 228 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Psychiatric disorders
    Completed Suicide
         subjects affected / exposed
    1 / 233 (0.43%)
    0 / 228 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    Confusional State
         subjects affected / exposed
    0 / 233 (0.00%)
    1 / 228 (0.44%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Endocrine disorders
    Adrenal Insufficiency
         subjects affected / exposed
    0 / 233 (0.00%)
    1 / 228 (0.44%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Infections and infestations
    Appendicitis
         subjects affected / exposed
    1 / 233 (0.43%)
    2 / 228 (0.88%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Gastroenteritis
         subjects affected / exposed
    1 / 233 (0.43%)
    1 / 228 (0.44%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Gastroenteritis Viral
         subjects affected / exposed
    1 / 233 (0.43%)
    0 / 228 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Meningococcal Infection
         subjects affected / exposed
    0 / 233 (0.00%)
    1 / 228 (0.44%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Septic Shock
         subjects affected / exposed
    0 / 233 (0.00%)
    1 / 228 (0.44%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Tonsillitis
         subjects affected / exposed
    0 / 233 (0.00%)
    1 / 228 (0.44%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Urinary Tract Infection
         subjects affected / exposed
    1 / 233 (0.43%)
    1 / 228 (0.44%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Vulvitis
         subjects affected / exposed
    0 / 233 (0.00%)
    1 / 228 (0.44%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Metabolism and nutrition disorders
    Diabetes Mellitus Inadequate Control
         subjects affected / exposed
    2 / 233 (0.86%)
    2 / 228 (0.88%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Diabetic Ketoacidosis
         subjects affected / exposed
    5 / 233 (2.15%)
    6 / 228 (2.63%)
         occurrences causally related to treatment / all
    1 / 5
    0 / 6
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Diabetic Metabolic Decompensation
         subjects affected / exposed
    1 / 233 (0.43%)
    0 / 228 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Hyperglycaemia
         subjects affected / exposed
    1 / 233 (0.43%)
    0 / 228 (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
    2 / 233 (0.86%)
    0 / 228 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Ketosis
         subjects affected / exposed
    1 / 233 (0.43%)
    0 / 228 (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
    105 / 233 (45.06%)
    118 / 228 (51.75%)
    Nervous system disorders
    Headache
         subjects affected / exposed
    19 / 233 (8.15%)
    15 / 228 (6.58%)
         occurrences all number
    38
    23
    Gastrointestinal disorders
    Vomiting
         subjects affected / exposed
    14 / 233 (6.01%)
    9 / 228 (3.95%)
         occurrences all number
    20
    10
    Respiratory, thoracic and mediastinal disorders
    Oropharyngeal Pain
         subjects affected / exposed
    15 / 233 (6.44%)
    7 / 228 (3.07%)
         occurrences all number
    17
    7
    Infections and infestations
    Gastroenteritis
         subjects affected / exposed
    12 / 233 (5.15%)
    10 / 228 (4.39%)
         occurrences all number
    14
    14
    Influenza
         subjects affected / exposed
    14 / 233 (6.01%)
    19 / 228 (8.33%)
         occurrences all number
    17
    25
    Nasopharyngitis
         subjects affected / exposed
    37 / 233 (15.88%)
    39 / 228 (17.11%)
         occurrences all number
    57
    60
    Pharyngitis
         subjects affected / exposed
    14 / 233 (6.01%)
    22 / 228 (9.65%)
         occurrences all number
    18
    29
    Upper Respiratory Tract Infection
         subjects affected / exposed
    20 / 233 (8.58%)
    18 / 228 (7.89%)
         occurrences all number
    28
    21
    Metabolism and nutrition disorders
    Ketosis
         subjects affected / exposed
    19 / 233 (8.15%)
    30 / 228 (13.16%)
         occurrences all number
    50
    52
    Overweight
         subjects affected / exposed
    2 / 233 (0.86%)
    13 / 228 (5.70%)
         occurrences all number
    2
    13

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    Substantial protocol amendments (globally)
    Were there any global substantial amendments to the protocol? Yes
    Date
    Amendment
    29 Jan 2016
    Following protocol changes were implemented before the study was initiated. - Primary and secondary efficacy analyses were modified to include all post-baseline data regardless of treatment discontinuation. - Change to the minimum rate of subjects to be randomized from the age range < 12 years. - Standard deviation assumption for sample size determination was modified. - Removal of sampling for hematology and clinical chemistry at baseline visit. - Change to the dose adjustment rules of the IMP to provide more structured guidance for adjustment of the IMP dose. - Change to the prohibited concomitant therapy by clarifying that short-term use of non-study antihyperglycemic agents other than the IMP or non-investigational medicinal product (NIMP) was not considered as a prohibited therapy and that use of prohibited therapy would result in the subject’s withdrawal from the study treatment rather than from the study. - Change specifying the descriptive purpose of secondary efficacy analyses.
    23 Aug 2016
    Following protocol changes were made: - Change to statistical methodology in primary and secondary endpoint analyses was made to replace the the mixed-effect model with repeated measures (MMRM) by a multiple imputation approach. - Change in eligibility criteria to lift the upper limit of the HbA1c range from 10% to 11%. - Change to instructions for hyperglycemia with ketosis. - Change to instructions for glucose meter by providing recommendations for tests with the control solution. - Change to instructions for handling of subjects after permanent treatment discontinuation by highlighting importance of collecting key parameters at scheduled study endpoint. - Change to utilization of Pharmacokinetic data by removing objective of comparison with historical data in adults.

    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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