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    Clinical Trial Results:
    A 24-week, randomized, open-label, parallel group multinational comparison of Lantus® (insulin glargine) given in the morning as once-a-day basal insulin versus Neutral Protamine Hagedorn (NPH) insulin, in children with type 1 diabetes mellitus aged at least 1 year to less than 6 years

    Summary
    EudraCT number
    		 2009-011231-12
    Trial protocol
    		 HU   CZ   ES   DE   AT   Outside EU/EEA  
    Global end of trial date
    30 Mar 2011

    Results information
    Results version number
    		 v1
    This version publication date
    01 Apr 2016
    First version publication date
    21 Jan 2015
    Other versions
    		 v2

    Trial information

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    Trial identification
    Sponsor protocol code
    EFC11202
    Additional study identifiers
    ISRCTN number
    		 -
    US NCT number
    		 NCT00993473
    WHO universal trial number (UTN)
    		 -
    Sponsors
    Sponsor organisation name
    Sanofi aventis recherche & développement
    Sponsor organisation address
    1 avenue Pierre Brossolette, Chilly-Mazarin , France, 91380
    Public contact
    Trial Tranparency Team, sanofi-aventis recherche & développement, Contact-Us@sanofi.com
    Scientific contact
    Trial Tranparency Team, sanofi-aventis recherche & développement, Contact-Us@sanofi.com
    Paediatric regulatory details
    Is trial part of an agreed paediatric investigation plan (PIP)
    Yes
    EMA paediatric investigation plan number(s)
    		 EMEA-000387-PIP01-08
    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
    19 May 2011
    Is this the analysis of the primary completion data?
    No
    Global end of trial reached?
    Yes
    Global end of trial date
    30 Mar 2011
    Was the trial ended prematurely?
    No
    General information about the trial
    Main objective of the trial
    The primary study objective was to compare the rate of "all hypoglycemia" (composite outcome of the following hypoglycemia events: symptomatic hypoglycemia episodes, low continuous glucose monitoring system [CGMS] excursions confirmed by fingerstick blood glucose [FSBG], low FSBG readings performed at other times) between children treated with Lantus (insulin glargine) and Neutral Protamine Hagedorn (NPH) insulin.
    Protection of trial subjects
    The study was conducted by investigators experienced in the treatment of paediatric subjects. The parent(s) or guardian(s) as well as the children were fully informed of all pertinent aspects of the clinical trial as well as the possibility to discontinue at any time. In addition to the consent form for the parent(s)/guardian(s), an assent form in child-appropriate language was provided and explained to the child. Repeated invasive procedures were minimized. The number of blood samples as well as the amount of blood drawn were adjusted according to age and weight. A topical anaesthesia may have been used to minimize distress and discomfort.
    Background therapy
    		 Insulin lispro (Humalog®) was provided as principal bolus insulin for subcutaneous injection in the form of either pen device doseable in 0.5 units increments or vials of lispro 100 units per millilitre (U/mL). Multiple injections were given before meals and/or at bedtime at the discretion of the Investigator. Regular human insulin could be used as bolus insulin as well.
    Evidence for comparator
    		 -
    Actual start date of recruitment
    15 Oct 2009
    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
    Germany: 2
    Country: Number of subjects enrolled
    Austria: 1
    Country: Number of subjects enrolled
    Spain: 4
    Country: Number of subjects enrolled
    Czech Republic: 7
    Country: Number of subjects enrolled
    Poland: 2
    Country: Number of subjects enrolled
    Hungary: 11
    Country: Number of subjects enrolled
    Brazil: 13
    Country: Number of subjects enrolled
    Chile: 6
    Country: Number of subjects enrolled
    India: 13
    Country: Number of subjects enrolled
    Mexico: 12
    Country: Number of subjects enrolled
    Peru: 5
    Country: Number of subjects enrolled
    Russian Federation: 18
    Country: Number of subjects enrolled
    South Africa: 13
    Country: Number of subjects enrolled
    Turkey: 2
    Country: Number of subjects enrolled
    United States: 9
    Country: Number of subjects enrolled
    Romania: 7
    Worldwide total number of subjects
    125
    EEA total number of subjects
    34
    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)
    1
    Children (2-11 years)
    124
    Adolescents (12-17 years)
    0
    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 in 61 centres (72 were initiated) in 16 countries between October 15, 2009 and March 30, 2011.

    Pre-assignment
    Screening details
    		 A total of 165 subjects were screened and 125 were randomized. Forty subjects (24.2%) failed the screening selection process, mainly due to noncompliance with the study required Continuous Glucose Monitoring (CGM) performance and other procedures.

    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
    		 Lantus (Insulin Glargine)
    Arm description
    		 Lantus (insulin glargine) given as basal insulin once a day in the morning.
    Arm type
    		 Experimental

    Investigational medicinal product name
    Insulin Glargine
    Investigational medicinal product code
    HOE901
    Other name
    Lantus®
    Pharmaceutical forms
    Solution for injection
    Routes of administration
    Subcutaneous use
    Dosage and administration details
    Dose: titrated to achieve the following glycemic targets without hypoglycemia: - Fasting blood glucose (BG) between 90 and 145 milligram per decilitre (mg/dL) (5.0 to 8.0 millimole per litre [mmol/L]), inclusive, - Bedtime BG between 120 and 180 mg/dL (6.7 to10.0 mmol/L), inclusive, - Nocturnal BG between 80 and 162 mg/dL (4.4 to 9.0 mmol/L), inclusive; and - HbA1c less than (<) 7.5%.

    Arm title
    		 NPH Insulin
    Arm description
    		 NPH human insulin given as basal insulin either once or twice per day generally in the morning and/or at bedtime.
    Arm type
    		 Active comparator

    Investigational medicinal product name
    Neutral Protamine Hagedorn (NPH) insulin
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Solution for injection in pre-filled pen, Solution for injection
    Routes of administration
    Subcutaneous use
    Dosage and administration details
    Titrated to achieve the following glycemic targets without hypoglycemia: - Fasting blood glucose (BG) between 90 and 145 mg/dL (5.0 to 8.0 mmol/L), inclusive, - Bedtime BG between 120 and 180 mg/dL (6.7 to10.0 mmol/L), inclusive, - Nocturnal BG between 80 and 162 mg/dL (4.4 to 9.0 mmol/L), inclusive; and - HbA1c <7.5%.

    Number of subjects in period 1
    		Lantus (Insulin Glargine) NPH Insulin
    Started
    61
    64
    Completed
    57
    54
    Not completed
    4
    10
         Consent withdrawn by subject
    1
    5
         Family event
    1
    -
         Adverse event
    -
    2
         Technical problem with CGM device
    -
    1
         Lost to follow-up
    1
    -
         Protocol deviation
    1
    2

    Baseline characteristics

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    Baseline characteristics reporting groups
    Reporting group title
    Lantus (Insulin Glargine)
    Reporting group description
    		 Lantus (insulin glargine) given as basal insulin once a day in the morning.

    Reporting group title
    NPH Insulin
    Reporting group description
    		 NPH human insulin given as basal insulin either once or twice per day generally in the morning and/or at bedtime.

    Reporting group values
    		 Lantus (Insulin Glargine) NPH Insulin Total
    Number of subjects
    		 61 64 125
    Age categorical
    Units: Subjects
        Less than or equal to 3 Years
    		 10 17 27
        Greater than 3 years
    		 51 47 98
    Age continuous
    Units: years
        arithmetic mean (standard deviation)
    		 4.3 ± 0.9 4.1 ± 1 -
    Gender categorical
    Units: Subjects
        Female
    		 29 34 63
        Male
    		 32 30 62
    Race
    Units: Subjects
        Caucasian/White
    		 53 48 101
        Black
    		 2 2 4
        Asian/Oriental
    		 4 11 15
        Other
    		 2 3 5
    Ethnicity
    Units: Subjects
        Hispanic
    		 17 13 30
        Non Hispanic
    		 44 51 95
    Treated by bolus insulin at baseline
    Units: Subjects
        Yes
    		 54 58 112
        No
    		 7 6 13
    Treated by basal insulin at baseline
    Units: Subjects
        Yes
    		 58 57 115
        No
    		 3 7 10
    Treated by mixed (bolus & basal) insulin at baseline
    Units: Subjects
        Yes
    		 5 8 13
        No
    		 56 56 112
    Number of daily basal insulin injections at baseline
    Units: Subjects
        One (1)
    		 32 41 73
        Two (2)
    		 21 15 36
        Greater than or equal to three (3)
    		 5 1 6
        Not treated with basal insulin at baseline
    		 3 7 10
    Total daily dose of basal insulin injection at baseline
    Units: Subjects
        Analyzed
    		 57 57 114
        Not treated by basal insulin or missing
    		 4 7 11
    Total daily dose of bolus insulin injection at baseline
    Units: Subjects
        Analyzed
    		 52 57 109
        Not treated by bolus insulin or missing
    		 9 7 16
    Duration of Diabetes (Median)
    Units: years
        median (full range (min-max))
    		 1.63 (1 to 5.3) 2.05 (1 to 4.9) -
    Duration of Diabetes (Mean)
    Units: years
        arithmetic mean (standard deviation)
    		 2.12 ± 1.16 2.12 ± 1.01 -
    Total daily dose of basal insulin injection at baseline (Mean)
    Units: International Units
        arithmetic mean (standard deviation)
    		 7.29 ± 4.11 7.61 ± 4.77 -
    Total daily dose of basal insulin injection at baseline (Median)
    Units: International Units
        median (full range (min-max))
    		 6 (2 to 24) 6 (1.5 to 24) -
    Total daily dose of bolus insulin injection at baseline (Mean)
    Units: International Units
        arithmetic mean (standard deviation)
    		 7.14 ± 3.64 7.98 ± 7.2 -
    Total daily dose of bolus insulin injection at baseline (Median)
    Units: International Units
        median (full range (min-max))
    		 7.75 (1.3 to 16) 7 (0.8 to 45) -

    End points

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    End points reporting groups
    Reporting group title
    Lantus (Insulin Glargine)
    Reporting group description
    		 Lantus (insulin glargine) given as basal insulin once a day in the morning.

    Reporting group title
    NPH Insulin
    Reporting group description
    		 NPH human insulin given as basal insulin either once or twice per day generally in the morning and/or at bedtime.

    Primary: Event Rate of "All Hypoglycemia"

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    End point title
    		 Event Rate of "All Hypoglycemia"
    End point description
    Defined as the Total Number of Episodes Divided by the Total Duration of the On-treatment Period in Years (Events Per Patient-year). The rate of "all hypoglycemia" was calculated from "all hypoglycemia" episodes which occurred during the 24-week on-treatment period and consisted of: - symptomatic hypoglycemia episodes validated by the study investigator based on entries in subjects' diaries, - low continuous glucose monitoring system (CGMS) excursions (interstitial glucose <70 mg/dL [3.9 mmol/L]) confirmed by fingerstick blood glucose (FSBG) <70 mg/dL, - low FSBG readings (values <70 mg/dL) performed at other times. The efficacy population consisted of all randomized subjects who received at least one dose of the study medication (modified intent-to-treat [mITT] population). For efficacy analyses, subjects were analyzed in the treatment group allocated by the Interactive Voice Response System (IVRS) at randomization (as randomized).
    End point type
    Primary
    End point timeframe
    6 months
    End point values
    		 Lantus (Insulin Glargine) NPH Insulin
    Number of subjects analysed
    61
    64
    Units: number of events per patient-year
        arithmetic mean (standard deviation)
    192.75 ± 119.28
    168.91 ± 101.04
    Statistical analysis title
    		 Event Rate of "All Hypoglycemia"
    Statistical analysis description
    The sample size was calculated to ensure sufficient power so that the upper bound of the 2-sided 95% confidence interval (CI) for the Lantus/NPH ratio would not exceed 1.15 based on an expected overall rate of "all hypoglycemia“ of 80 events per patient-year of exposure to NPH insulin and to Lantus. It was planned to randomize at least 45 and up to approximately 60 subjects in each of the 2 treatment groups so that at least 70 subjects would complete the 24 weeks of treatment.
    Comparison groups
    NPH Insulin v Lantus (Insulin Glargine)
    Number of subjects included in analysis
    125
    Analysis specification
    Pre-specified
    Analysis type
    		 non-inferiority [1]
    Method
    		 Generalized Linear Model
    Parameter type
    		 Risk ratio (RR)
    Point estimate
    1.18
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.97
         upper limit
    		 1.44
    Variability estimate
    Standard error of the mean
    Dispersion value
    0.12
    Notes
    [1] - Noninferiority would be demonstrated if the upper bound of the 95% CI for the ratio of the rate of “all hypoglycemia” in the Lantus group to the rate in the NPH group was <1.15. Superiority would be demonstrated if the upper bound of the 95% CI was <1. The margin for noninferiority corresponded to one-half of the 30% difference in hypoglycemia event rate considered as a clinically significant difference by American Diabetes Association 2005 Working Group on Hypoglycemia.

    Secondary: Event Rate of Symptomatic Hypoglycemia (Individual Component of Primary Endpoint)

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    End point title
    		 Event Rate of Symptomatic Hypoglycemia (Individual Component of Primary Endpoint)
    End point description
    Event rate is defined as total number of episodes divided by the total duration of the on-treatment period in years (Events Per Patient-year). Symptomatic hypoglycemia: any event with clinical symptoms considered to result from hypoglycemia, validated by the study investigator based on data from patient diaries. Analysis was performed in mITT population.
    End point type
    Secondary
    End point timeframe
    6 months
    End point values
    		 Lantus (Insulin Glargine) NPH Insulin
    Number of subjects analysed
    61
    64
    Units: Events per patient-year
        arithmetic mean (standard deviation)
    25.54 ± 37.25
    33.02 ± 47.95
    No statistical analyses for this end point

    Secondary: Severe Symptomatic Hypoglycemia Episodes

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    End point title
    		 Severe Symptomatic Hypoglycemia Episodes
    End point description
    Severe symptomatic hypoglycemia: any event with clinical symptoms considered to result from a hypoglycemic episode for which the subjects required the assistance of a third party (that is, other than the subjects, or a parent/usual caregiver; for example, from emergency personnel), because the subjects/parents could not treat the event with acute neurological impairment directly resulting from the hypoglycemic event. The occurrence of seizure, coma, unconsciousness, or the use of glucagon, were also to qualify a hypoglycemic episode as severe. Analysis was performed on mITT population.
    End point type
    Secondary
    End point timeframe
    6 months
    End point values
    		 Lantus (Insulin Glargine) NPH Insulin
    Number of subjects analysed
    61
    64
    Units: Episodes
    4
    2
    No statistical analyses for this end point

    Secondary: Event Rate of Severe Symptomatic Hypoglycemia

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    End point title
    		 Event Rate of Severe Symptomatic Hypoglycemia
    End point description
    Defined as the Total Number of Episodes Divided by the Total Duration of the On-treatment Period in Years. Severe symptomatic hypoglycemia: any event with clinical symptoms considered to result from a hypoglycemic episode for which the subjects required the assistance of a third party (that is other than the subject, or a parent/usual caregiver; example, from emergency personnel), because the subjects/parents could not treat the event with acute neurological impairment directly resulting from the hypoglycemic event. The occurrence of seizure, coma, unconsciousness, or the use of glucagon, were also to qualify a hypoglycemic episode as severe. Analysis was performed on mITT population.
    End point type
    Secondary
    End point timeframe
    6 months
    End point values
    		 Lantus (Insulin Glargine) NPH Insulin
    Number of subjects analysed
    61
    64
    Units: Number of events per patient-year
        arithmetic mean (standard deviation)
    0.14 ± 0.55
    0.07 ± 0.38
    No statistical analyses for this end point

    Secondary: Event Rate of Nocturnal Hypoglycemia

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    End point title
    		 Event Rate of Nocturnal Hypoglycemia
    End point description
    Defined as the Total Number of "All Hypoglycemia" Episodes Divided by the Total Duration of the On-treatment Period in Years. Nocturnal hypoglycemia: any event from the “all hypoglycemia” total that occurred between 23:00 and 07:00 hours. Analysis was performed on mITT population.
    End point type
    Secondary
    End point timeframe
    6 months
    End point values
    		 Lantus (Insulin Glargine) NPH Insulin
    Number of subjects analysed
    61
    64
    Units: Number of events per patient-year
        arithmetic mean (standard deviation)
    33.5 ± 25.62
    30.92 ± 24.97
    No statistical analyses for this end point

    Secondary: Event Rate of Nocturnal Symptomatic Hypoglycemia

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    End point title
    		 Event Rate of Nocturnal Symptomatic Hypoglycemia
    End point description
    Defined as the Total Number of Episodes Divided by the Total Duration of the On-treatment Period in Years. Nocturnal symptomatic hypoglycemia: any symptomatic hypoglycemic event that occurred between 23:00 and 07:00 hours. Analysis was performed on mITT population.
    End point type
    Secondary
    End point timeframe
    6 months
    End point values
    		 Lantus (Insulin Glargine) NPH Insulin
    Number of subjects analysed
    61
    64
    Units: number of events per patient-year
        arithmetic mean (standard deviation)
    2.38 ± 5.42
    3.65 ± 6.75
    No statistical analyses for this end point

    Secondary: Severe Nocturnal Hypoglycemia Episodes

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    End point title
    		 Severe Nocturnal Hypoglycemia Episodes
    End point description
    Severe nocturnal symptomatic hypoglycemia: any severe symptomatic hypoglycemic event that occurred between 23:00 and 07:00 hours. Analysis was performed on mITT population.
    End point type
    Secondary
    End point timeframe
    6 months
    End point values
    		 Lantus (Insulin Glargine) NPH Insulin
    Number of subjects analysed
    61
    64
    Units: Episodes
    1
    0
    No statistical analyses for this end point

    Secondary: Event Rate of Severe Nocturnal Hypoglycemia

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    End point title
    		 Event Rate of Severe Nocturnal Hypoglycemia
    End point description
    Defined as the Total Number of Episodes Divided by the Total Duration of the On-treatment Period in Years. Severe nocturnal symptomatic hypoglycemia: any severe symptomatic hypoglycemic event that occurred between 23:00 and 07:00 hours. Analysis was performed on mITT population.
    End point type
    Secondary
    End point timeframe
    6 months
    End point values
    		 Lantus (Insulin Glargine) NPH Insulin
    Number of subjects analysed
    61
    64
    Units: number of events per patient-year
        arithmetic mean (standard deviation)
    0.04 ± 0.29
    0 ± 0
    No statistical analyses for this end point

    Secondary: HbA1c: End of Treatment and Change From Baseline to End of Treatment

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    End point title
    		 HbA1c: End of Treatment and Change From Baseline to End of Treatment
    End point description
    Analysis was performed on mITT population. However post-baseline HbA1c values were missing for 9 subjects: 2 subjects in the Lantus group and 7 in the NPH group.
    End point type
    Secondary
    End point timeframe
    baseline, 6 months
    End point values
    		 Lantus (Insulin Glargine) NPH Insulin
    Number of subjects analysed
    61
    64
    Units: percentage of hemoglobin
    arithmetic mean (standard deviation)
        Baseline HbA1c (n = 61, 64)
    8.023 ± 1.049
    8.248 ± 1.429
        End of treatment HbA1c (n = 59, 57)
    8.071 ± 0.884
    8.344 ± 1.161
        Absolute change from baseline (n = 59, 57)
    0.036 ± 0.979
    0 ± 1.035
    No statistical analyses for this end point

    Secondary: HbA1c: End of Treatment and Change From Baseline to End of Treatment (ANCOVA Estimates)

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    End point title
    		 HbA1c: End of Treatment and Change From Baseline to End of Treatment (ANCOVA Estimates)
    End point description
    Assessed using an analysis of covariance (ANCOVA) model with treatment, and randomization strata (baseline number of CGM hypoglycemic excursions <0.5 events/24hours or ≥0.5 events/24 hours, and baseline HbA1c <8.5% or ≥8.5%) as fixed effects, and using the baseline value as covariate. Analysis was performed on mITT population.
    End point type
    Secondary
    End point timeframe
    baseline, 6 months
    End point values
    		 Lantus (Insulin Glargine) NPH Insulin
    Number of subjects analysed
    61
    64
    Units: percentage of hemoglobin
    arithmetic mean (standard deviation)
        End of treatment HbA1c (ANCOVA)
    8.139 ± 0.1065
    8.232 ± 0.1134
        Absolute change from baseline HbA1c (ANCOVA)
    -0.048 ± 0.1065
    0.045 ± 0.1134
    No statistical analyses for this end point

    Secondary: Percentage of Subjects Reaching HbA1c Target of Less Than 7.5% at the End of Treatment Visit

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    End point title
    		 Percentage of Subjects Reaching HbA1c Target of Less Than 7.5% at the End of Treatment Visit
    End point description
    Percentage of subjects reaching International Society for Pediatric and Adolescent Diabetes (ISPAD)-recommended goals of Glycosylated Hemoglobin A1c <7.5% at the end of treatment visit. The population analyzed consisted of subjects from the mITT population (as defined for primary outcome measure) with post-baseline HbA1c values. 2 subjects from the Lantus group and 7 from the NPH group had no post-baseline HbA1c value.
    End point type
    Secondary
    End point timeframe
    6 months
    End point values
    		 Lantus (Insulin Glargine) NPH Insulin
    Number of subjects analysed
    59
    57
    Units: percentage of subjects
        number (not applicable)
    22
    22.8
    No statistical analyses for this end point

    Secondary: Average Daily Blood Glucose (BG) Based on CGMS Values

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    End point title
    		 Average Daily Blood Glucose (BG) Based on CGMS Values
    End point description
    Analysis was performed on mITT population. However 1 patient in the NPH group did not have baseline CGM value and 2 other patients (1 in the Lantus group and 1 in the NPH group) did not have on-treatment CGM values.
    End point type
    Secondary
    End point timeframe
    baseline, 6 months
    End point values
    		 Lantus (Insulin Glargine) NPH Insulin
    Number of subjects analysed
    61
    64
    Units: mmol/L
    arithmetic mean (standard deviation)
        Baseline daily BG (n= 61, 63)
    11.263 ± 1.887
    11.17 ± 1.986
        End of treatment daily BG (n= 60, 63)
    11.085 ± 2.077
    11.712 ± 2.166
        Absolute change from baseline (n= 60, 62)
    -0.218 ± 2.399
    0.501 ± 1.906
    No statistical analyses for this end point

    Other pre-specified: Number of Subjects With Different Types of Hypoglycemia Events

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    End point title
    		 Number of Subjects With Different Types of Hypoglycemia Events
    End point description
    Definitions of the different types of hypoglycemia events provided in the outcome measure description of the corresponding event rates. Analysis was performed on mITT population.
    End point type
    Other pre-specified
    End point timeframe
    6 months
    End point values
    		 Lantus (Insulin Glargine) NPH Insulin
    Number of subjects analysed
    61
    64
    Units: subjects
        Subjects with "All hypoglycemia"
    61
    63
        Subjects with symptomatic hypoglycemia
    40
    44
        Subjects with severe symptomatic hypoglycemia
    4
    2
        Subjects with nocturnal hypoglycemia
    59
    60
        Subjects with nocturnal symptomatic hypoglycemia
    17
    28
        Subjects with severe noct. sympto. hypoglycemia
    1
    0
        Subjects with "All confirmed low CGMS excursions"
    60
    61
        Subjects with "All confirmed low FSBG"
    61
    63
    No statistical analyses for this end point

    Other pre-specified: Percent of Blood Glucose (BG) Within the Range of 70 – 180 mg/dL (3.9-10 mmol/L)

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    End point title
    		 Percent of Blood Glucose (BG) Within the Range of 70 – 180 mg/dL (3.9-10 mmol/L)
    End point description
    Calculated for each subject as the percent of all on-treatment CGMS values falling within the range of 70 – 180 mg/dL (3.9 – 10 mmol/L) inclusive. The population analyzed consisted of subjects from the mITT population (as defined for primary outcome measure) with on-treatment CGM values (1 subject from the Lantus group and 1 from the NPH group did not have on-treatment CGM).
    End point type
    Other pre-specified
    End point timeframe
    6 months
    End point values
    		 Lantus (Insulin Glargine) NPH Insulin
    Number of subjects analysed
    60
    63
    Units: percent of CGMS values within the range
        arithmetic mean (standard deviation)
    41.667 ± 12.048
    38.158 ± 10.908
    No statistical analyses for this end point

    Other pre-specified: Blood Glucose Variability Based on All On-treatment CGMS Values

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    End point title
    		 Blood Glucose Variability Based on All On-treatment CGMS Values
    End point description
    Calculated for any given subject as the standard deviation (SD) of all CGMS interstitial glucose values recorded over all CGMS placements. The population analyzed consisted of subjects from the mITT population (as defined for primary outcome measure) with on-treatment CGM values (1 subject from the Lantus group and 1 from the NPH group did not have on-treatment CGM).
    End point type
    Other pre-specified
    End point timeframe
    6 months
    End point values
    		 Lantus (Insulin Glargine) NPH Insulin
    Number of subjects analysed
    60
    63
    Units: mmol/L
        arithmetic mean (standard deviation)
    4.954 ± 0.826
    5.089 ± 0.731
    No statistical analyses for this end point

    Other pre-specified: Nocturnal Blood Glucose Variability Based on All On-treatment CGMS Values

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    End point title
    		 Nocturnal Blood Glucose Variability Based on All On-treatment CGMS Values
    End point description
    Calculated for any given subject as the standard deviation (SD) of all CGMS interstitial glucose values recorded during the nocturnal time period (between 23:00 and 07:00 hours). The population analyzed consisted of subjects from the mITT population (as defined for primary outcome measure) with on-treatment CGM values (1 subject from the Lantus group and 1 from the NPH group did not have on-treatment CGM).
    End point type
    Other pre-specified
    End point timeframe
    6 months
    End point values
    		 Lantus (Insulin Glargine) NPH Insulin
    Number of subjects analysed
    60
    63
    Units: mmol/L
        arithmetic mean (standard deviation)
    4.747 ± 0.973
    4.837 ± 0.825
    No statistical analyses for this end point

    Post-hoc: Event Rate of "All Confirmed Low CGMS Excursions" (Individual Component of Primary Endpoint)

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    End point title
    		 Event Rate of "All Confirmed Low CGMS Excursions" (Individual Component of Primary Endpoint)
    End point description
    Defined as the Total Number of Episodes Divided by the Total Duration of the On-treatment Period in Years (Events Per Patient-year) "All confirmed low CGMS excursions" consisted of all low CGMS excursions (interstitial glucose <70 mg/dL [3.9 mmol/L]) confirmed by fingerstick blood glucose (FSBG) <70 mg/dL. Analysis was performed on mITT population.
    End point type
    Post-hoc
    End point timeframe
    6 months
    End point values
    		 Lantus (Insulin Glargine) NPH Insulin
    Number of subjects analysed
    61
    64
    Units: events per patient year
        arithmetic mean (standard deviation)
    74.61 ± 74.09
    71.6 ± 53.2
    No statistical analyses for this end point

    Post-hoc: Event Rate of "All Confirmed Low FSBG" (Individual Component of the Primary Endpoint)

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    End point title
    		 Event Rate of "All Confirmed Low FSBG" (Individual Component of the Primary Endpoint)
    End point description
    Defined as the Total Number of Episodes Divided by the Total Duration of the On-treatment Period in Years (Events Per Patient-year). "All confirmed low FSBG" consisted of all low FSBG readings (values <70 mg/dL) performed at other times. Analysis was performed on mITT population.
    End point type
    Post-hoc
    End point timeframe
    6 months
    End point values
    		 Lantus (Insulin Glargine) NPH Insulin
    Number of subjects analysed
    61
    64
    Units: events per patient year
        arithmetic mean (standard deviation)
    192.69 ± 121.78
    168.24 ± 101.21
    No statistical analyses for this end point

    Adverse events

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    Adverse events information
    Timeframe for reporting adverse events
    Adverse events were monitored from baseline to 7 days after last treatment visit.
    Adverse event reporting additional description
    The safety analyses were conducted according to the treatment received rather than according to the randomization groups.
    Assessment type
    		 Non-systematic
    Dictionary used for adverse event reporting
    Dictionary name
    		 MedDRA
    Dictionary version
    14.0
    Reporting groups
    Reporting group title
    Lantus (insulin glargine)
    Reporting group description
    		 Lantus (insulin glargine) given as basal insulin once a day in the morning by subcutaneous injection.

    Reporting group title
    NPH insulin
    Reporting group description
    		 Neutral Protamine Hagedorn (NPH) human insulin given as basal insulin either once or twice per day generally in the morning and /or at bedtime by subcutaneous injection.

    Serious adverse events
    		 Lantus (insulin glargine) NPH insulin
    Total subjects affected by serious adverse events
         subjects affected / exposed
    8 / 62 (12.90%)
    2 / 63 (3.17%)
         number of deaths (all causes)
    0
    0
         number of deaths resulting from adverse events
    0
    0
    Gastrointestinal disorders
    Abdominal Pain
    alternative assessment type: Systematic
         subjects affected / exposed
    1 / 62 (1.61%)
    0 / 63 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Gastritis
    alternative assessment type: Systematic
         subjects affected / exposed
    2 / 62 (3.23%)
    0 / 63 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Infections and infestations
    Lower Respiratory Tract Infection
    alternative assessment type: Systematic
         subjects affected / exposed
    0 / 62 (0.00%)
    1 / 63 (1.59%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Viral Infection
    alternative assessment type: Systematic
         subjects affected / exposed
    1 / 62 (1.61%)
    0 / 63 (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
    Dehydration
    alternative assessment type: Systematic
         subjects affected / exposed
    1 / 62 (1.61%)
    0 / 63 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Diabetic Ketoacidosis
    alternative assessment type: Systematic
         subjects affected / exposed
    1 / 62 (1.61%)
    1 / 63 (1.59%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Hypoglycaemic Seizure
    alternative assessment type: Systematic
         subjects affected / exposed
    2 / 62 (3.23%)
    0 / 63 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Frequency threshold for reporting non-serious adverse events: 5%
    Non-serious adverse events
    		 Lantus (insulin glargine) NPH insulin
    Total subjects affected by non serious adverse events
         subjects affected / exposed
    30 / 62 (48.39%)
    33 / 63 (52.38%)
    General disorders and administration site conditions
    Device Lead Damage
    alternative assessment type: Systematic
         subjects affected / exposed
    5 / 62 (8.06%)
    2 / 63 (3.17%)
         occurrences all number
    5
    2
    Pyrexia
    alternative assessment type: Systematic
         subjects affected / exposed
    3 / 62 (4.84%)
    7 / 63 (11.11%)
         occurrences all number
    3
    7
    Gastrointestinal disorders
    Vomiting
    alternative assessment type: Systematic
         subjects affected / exposed
    5 / 62 (8.06%)
    4 / 63 (6.35%)
         occurrences all number
    5
    4
    Respiratory, thoracic and mediastinal disorders
    Cough
    alternative assessment type: Systematic
         subjects affected / exposed
    2 / 62 (3.23%)
    4 / 63 (6.35%)
         occurrences all number
    2
    4
    Infections and infestations
    Bronchitis
    alternative assessment type: Systematic
         subjects affected / exposed
    3 / 62 (4.84%)
    5 / 63 (7.94%)
         occurrences all number
    3
    5
    Gastroenteritis
    alternative assessment type: Systematic
         subjects affected / exposed
    6 / 62 (9.68%)
    6 / 63 (9.52%)
         occurrences all number
    6
    6
    Nasopharyngitis
    alternative assessment type: Systematic
         subjects affected / exposed
    6 / 62 (9.68%)
    5 / 63 (7.94%)
         occurrences all number
    6
    5
    Otitis Media
    alternative assessment type: Systematic
         subjects affected / exposed
    1 / 62 (1.61%)
    4 / 63 (6.35%)
         occurrences all number
    1
    4
    Pharyngitis
    alternative assessment type: Systematic
         subjects affected / exposed
    6 / 62 (9.68%)
    2 / 63 (3.17%)
         occurrences all number
    6
    2
    Tonsillitis
    alternative assessment type: Systematic
         subjects affected / exposed
    1 / 62 (1.61%)
    4 / 63 (6.35%)
         occurrences all number
    1
    4
    Upper Respiratory Tract Infection
    alternative assessment type: Systematic
         subjects affected / exposed
    4 / 62 (6.45%)
    6 / 63 (9.52%)
         occurrences all number
    4
    6

    More information

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    Substantial protocol amendments (globally)
    Were there any global substantial amendments to the protocol? Yes
    Date
    Amendment
    14 Oct 2009
    Modifications of several aspects of the original protocol to in order to define procedures for screening, PK, and adverse event reporting.
    28 Mar 2011
    Modification of the PK analysis study objective, insulin glargine antibody assessment, and methodology section.

    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.
    There are numerous potential biases that could affect the timing and frequency of performance of sporadic FSBG, such as mealtime dosing and choice of bolus insulin dose, stability and familiarity with insulin regimens, and parental anxiety levels.
    For support, Contact us.
    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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