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    Clinical Trial Results:
    Six-month, Randomized, Open-label, Parallel-group Comparison of SAR341402 to NovoLog®/NovoRapid® in Adult Patients With Diabetes Mellitus Also Using Insulin Glargine, with a 6-month Safety Extension Period

    Summary
    EudraCT number
    		 2017-000091-28
    Trial protocol
    		 HU   FI   DE   PL  
    Global end of trial date
    12 Jan 2019

    Results information
    Results version number
    		 v2(current)
    This version publication date
    14 Nov 2020
    First version publication date
    22 Jan 2020
    Other versions
    		 v1
    Version creation reason
    • New data added to full data set
    Subgroup analysis data were added to full data set

    Trial information

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    Trial identification
    Sponsor protocol code
    EFC15081
    Additional study identifiers
    ISRCTN number
    		 -
    US NCT number
    		 NCT03211858
    WHO universal trial number (UTN)
    		 U1111-1191-5775
    Other trial identifiers
    		 Study name: Gemelli 1
    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
    24 May 2019
    Is this the analysis of the primary completion data?
    No
    Global end of trial reached?
    Yes
    Global end of trial date
    12 Jan 2019
    Was the trial ended prematurely?
    No
    General information about the trial
    Main objective of the trial
    To demonstrate non-inferiority of SAR341402 versus NovoLog/NovoRapid in glycated hemoglobin A1c (HbA1c) change from baseline to Week 26 in subjects with type 1 or type 2 diabetes mellitus (T1DM or T2DM) also using Lantus®.
    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
    		 Insulin glargine 100 units per millilitre (U/mL) (Lantus) was given as the mandatory background basal insulin therapy and was injected once daily (QD) subcutaneously consistent with the local label. Doses of Lantus were adjusted to achieve glycemic target for fasting, pre-prandial plasma glucose between 4.4 to 7.2 millimoles per litre (mmol/L) (80 to 130 milligram/deciLitre [mg/dL]) without hypoglycemia.
    Evidence for comparator
    		 -
    Actual start date of recruitment
    02 Aug 2017
    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
    Poland: 56
    Country: Number of subjects enrolled
    Finland: 23
    Country: Number of subjects enrolled
    Germany: 26
    Country: Number of subjects enrolled
    Hungary: 73
    Country: Number of subjects enrolled
    Japan: 65
    Country: Number of subjects enrolled
    Russian Federation: 19
    Country: Number of subjects enrolled
    United States: 335
    Worldwide total number of subjects
    597
    EEA total number of subjects
    178
    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)
    498
    From 65 to 84 years
    98
    85 years and over
    1

    Subject disposition

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    Recruitment
    Recruitment details
    		 The study was conducted at 82 centres in 7 countries. A total of 846 subjects were screened between 02 August 2017 and 29 December 2017, of which 249 subjects were screen failures. Screen failures were mainly due to HbA1c level less than (<) 7.0 percent (%) or greater than (>) 10% at the screening visit.

    Pre-assignment
    Screening details
    		 Randomisation was stratified by HbA1c at screening visit (<8%, greater than or equal to [>=] 8%), prior use of NovoLog/NovoRapid (Yes, No), geographical region (Europe, United States [US], Japan) and type 1 or 2 of diabetes mellitus (T1DM/T2DM [US only]). Assigned to arms in 1:1 ratio (SAR341402: NovoLog/NovoRapid).

    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
    		 SAR341402
    Arm description
    		 SAR341402 100 U/mL subcutaneous (SC) injection, before meals intake on top of QD Insulin Glargine, up to Week 52.
    Arm type
    		 Experimental

    Investigational medicinal product name
    Insulin aspart
    Investigational medicinal product code
    SAR341402
    Other name
    Pharmaceutical forms
    Solution for injection
    Routes of administration
    Subcutaneous use
    Dosage and administration details
    SAR341402 100 U/mL (dose range of 1 unit to 80 units), once daily self-administered SC injection in 3 mL pre-filled disposable SoloSTAR® pens. Dose adjusted to achieve a 2-hour postprandial plasma glucose of <10mmol/L (<180mg/dL).

    Arm title
    		 NovoLog/NovoRapid
    Arm description
    		 NovoLog/NovoRapid 100 U/mL SC injection, before meals intake on top of QD Insulin Glargine, up to Week 52.
    Arm type
    		 Active comparator

    Investigational medicinal product name
    Insulin aspart
    Investigational medicinal product code
    Other name
    Novolog/Novorapid
    Pharmaceutical forms
    Solution for injection
    Routes of administration
    Subcutaneous use
    Dosage and administration details
    NovoLog/NovoRapid 100 U/mL (dose range of 1 unit to 60 units), once daily self-administered SC injection in 3 mL pre-filled disposable FlexPens. Dose adjusted to achieve a 2-hour postprandial plasma glucose of <10mmol/L (<180mg/dL) while avoiding hypoglycemia.

    Number of subjects in period 1
    		SAR341402 NovoLog/NovoRapid
    Started
    301
    296
    Treated
    301
    296
    Completed
    264
    263
    Not completed
    37
    33
         Adverse Event
    8
    6
         Non-serious Hypoglycemia
    1
    -
         Other than specified
    22
    21
         Poor compliance to protocol
    6
    2
         Lack of efficacy
    -
    4

    Baseline characteristics

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    Baseline characteristics reporting groups
    Reporting group title
    SAR341402
    Reporting group description
    		 SAR341402 100 U/mL subcutaneous (SC) injection, before meals intake on top of QD Insulin Glargine, up to Week 52.

    Reporting group title
    NovoLog/NovoRapid
    Reporting group description
    		 NovoLog/NovoRapid 100 U/mL SC injection, before meals intake on top of QD Insulin Glargine, up to Week 52.

    Reporting group values
    		 SAR341402 NovoLog/NovoRapid Total
    Number of subjects
    		 301 296 597
    Age categorical
    Units: Subjects
    Age continuous
    Units: years
        arithmetic mean (standard deviation)
    		 48.4 ( 14.8 ) 47.8 ( 15.4 ) -
    Gender categorical
    Units: Subjects
        Female
    		 122 119 241
        Male
    		 179 177 356
    Race
    Units: Subjects
        American Indian or Alaska Native
    		 0 2 2
        Asian
    		 37 37 74
        Native Hawaiian or Other Pacific Islander
    		 3 0 3
        Black or African American
    		 11 8 19
        White
    		 248 242 490
        More than one race
    		 0 3 3
        Unknown or Not Reported
    		 2 4 6
    Randomization Strata of Types of Diabetes
    Units: Subjects
        Type 1 Diabetes Mellitus
    		 250 247 497
        Type 2 Diabetes Mellitus
    		 51 49 100
    Randomisation Strata of Screening HbA1c Categories
    Units: Subjects
        HbA1c <8%
    		 143 138 281
        HbA1c >=8%
    		 158 158 316
    Randomisation Strata of Prior Use of NovoLog/ NovoRapid
    Here, "No" signifies subject who had prior use of Humalog/Liprolog; "Yes" signifies prior use of NovoLog/NovoRapid.
    Units: Subjects
        No (Humalog/ Liprolog)
    		 109 108 217
        Yes (NovoLog/ NovoRapid)
    		 192 188 380
    Randomisation strata of geographical region
    Units: Subjects
        Europe
    		 98 99 197
        Japan
    		 33 32 65
        US
    		 170 165 335
    Baseline Body Mass Index (BMI)
    Units: kilogram/metre square^2 (kg/m^2)
        arithmetic mean (standard deviation)
    		 27.45 ( 4.58 ) 27.46 ( 4.99 ) -
    Duration of Diabetes
    Units: years
        arithmetic mean (standard deviation)
    		 19.5 ( 11.9 ) 19.4 ( 11.8 ) -
    Glycated Haemoglobin
    Units: percentage of hemoglobin
        arithmetic mean (standard deviation)
    		 8.00 ( 0.77 ) 7.94 ( 0.70 ) -

    End points

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    End points reporting groups
    Reporting group title
    SAR341402
    Reporting group description
    		 SAR341402 100 U/mL subcutaneous (SC) injection, before meals intake on top of QD Insulin Glargine, up to Week 52.

    Reporting group title
    NovoLog/NovoRapid
    Reporting group description
    		 NovoLog/NovoRapid 100 U/mL SC injection, before meals intake on top of QD Insulin Glargine, up to Week 52.

    Subject analysis set title
    Prior NovoLog/NovoRapid Use: SAR341402
    Subject analysis set type
    		 Sub-group analysis
    Subject analysis set description
    Subjects with prior use of NovoLog/NovoRapid (as per randomisation stratum), receiving SAR341402 100 U/mL SC injection, before meals intake on top of QD Insulin Glargine, up to Week 52.

    Subject analysis set title
    Prior NovoLog/NovoRapid Use: NovoLog/NovoRapid
    Subject analysis set type
    		 Sub-group analysis
    Subject analysis set description
    Subjects with prior use of NovoLog/NovoRapid (as per randomisation stratum), receiving NovoLog/NovoRapid 100 U/mL SC injection, before meals intake on top of QD Insulin Glargine, up to Week 52.

    Subject analysis set title
    Prior Humalog/Liprolog Use: SAR341402
    Subject analysis set type
    		 Sub-group analysis
    Subject analysis set description
    Subjects with prior use of Humalog/Liprolog (as per randomisation stratum), receiving SAR341402 100 U/mL SC injection, before meals intake on top of QD Insulin Glargine, up to Week 52.

    Subject analysis set title
    Prior Humalog/Liprolog Use: NovoLog/NovoRapid
    Subject analysis set type
    		 Sub-group analysis
    Subject analysis set description
    Subjects with prior use of Humalog/Liprolog (as per randomisation stratum), receiving NovoLog/NovoRapid 100 U/mL SC injection, before meals intake on top of QD Insulin Glargine, up to Week 52.

    Primary: Change in Glycated Hemoglobin A1c (HbA1c) From Baseline to Week 26

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    End point title
    		 Change in Glycated Hemoglobin A1c (HbA1c) From Baseline to Week 26
    End point description
    All values up to Week 26 were taken into account in the analysis, regardless of adherence to treatment. Change in HbA1c was calculated by subtracting baseline value from Week 26 value. Missing changes at Week 26 were imputed using a retrieved dropout multiple imputation method (separately for subjects who prematurely discontinued or completed treatment). Adjusted least square (LS) means and standard errors (SE) were obtained using an analysis of covariance (ANCOVA) model on data obtained from the multiple imputations (results were combined using Rubin’s formulae). Analysis was performed on intent-to-treat (ITT) population, which included all randomised subjects, irrespective of compliance with the study protocol and procedures.
    End point type
    Primary
    End point timeframe
    Baseline, Week 26
    End point values
    		 SAR341402 NovoLog/NovoRapid
    Number of subjects analysed
    301
    296
    Units: percentage of HbA1c
        least squares mean (standard error)
    -0.38 ( 0.042 )
    -0.30 ( 0.041 )
    Statistical analysis title
    		 SAR341402 Versus NovoLog/NovoRapid
    Statistical analysis description
    Analysis was performed using ANCOVA with treatment group (SAR341402, NovoLog/NovoRapid), the randomisation strata of geographical region, type of diabetes and prior use of NovoLog/NovoRapid as fixed categorical effects, as well as the continuous fixed covariate of baseline HbA1c value.
    Comparison groups
    SAR341402 v NovoLog/NovoRapid
    Number of subjects included in analysis
    597
    Analysis specification
    Pre-specified
    Analysis type
    		 non-inferiority [1]
    Method
    Parameter type
    		 LS Mean difference
    Point estimate
    -0.08
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -0.192
         upper limit
    		 0.039
    Variability estimate
    Standard error of the mean
    Dispersion value
    0.059
    Notes
    [1] - Non-inferiority of SAR341402 over NovoLog/NovoRapid was demonstrated if upper bound of the 2-sided 95% confidence interval (CI) of the difference between SAR341402 and NovoLog/NovoRapid was <0.3%. If non-inferiority was demonstrated, using a hierarchical step down testing procedure, the inverse non-inferiority of NovoLog/NovoRapid over SAR341402 was tested and was demonstrated if lower bound of the 2-sided 95% CI of the difference between SAR341402 and NovoLog/NovoRapid was > -0.3%.

    Secondary: Change in HbA1c From Baseline to Week 52

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    End point title
    		 Change in HbA1c From Baseline to Week 52
    End point description
    All values up to Week 52 were taken into account in the analysis, regardless of adherence to treatment. Change in HbA1c was calculated by subtracting baseline value from Week 52 value. Missing changes at Week 52 were imputed using a retrieved dropout multiple imputation method (separately for subjects who prematurely discontinued or completed treatment). Adjusted LS means and SE were obtained using ANCOVA model on data obtained from the multiple imputations (results were combined using Rubin’s formulae). Analysis was performed on ITT population.
    End point type
    Secondary
    End point timeframe
    Baseline, Week 52
    End point values
    		 SAR341402 NovoLog/NovoRapid
    Number of subjects analysed
    301
    296
    Units: percentage of HbA1c
        least squares mean (standard error)
    -0.25 ( 0.057 )
    -0.26 ( 0.059 )
    No statistical analyses for this end point

    Secondary: Percentage of Subjects With HbA1c <7% at Week 26 and Week 52

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    End point title
    		 Percentage of Subjects With HbA1c <7% at Week 26 and Week 52
    End point description
    Subjects who had no available assessment at Week 26 and Week 52 were considered as non-responders. Analysis was performed on ITT population.
    End point type
    Secondary
    End point timeframe
    Week 26 and Week 52
    End point values
    		 SAR341402 NovoLog/NovoRapid
    Number of subjects analysed
    301
    296
    Units: percentage of subjects
    number (not applicable)
        At Week 26
    16.6
    14.5
        At Week 52
    19.6
    18.2
    No statistical analyses for this end point

    Secondary: Change in Fasting Plasma Glucose (FPG) From Baseline to Week 26 and Week 52

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    End point title
    		 Change in Fasting Plasma Glucose (FPG) From Baseline to Week 26 and Week 52
    End point description
    All values up to Week 26 and Week 52 were taken into account in the analysis, regardless of adherence to treatment. Change in FPG at Weeks 26 and 52 was calculated by subtracting baseline value from Week 26 and Week 52 values, respectively. Missing changes at Week 26 and Week 52 were imputed using a retrieved dropout multiple imputation method (separately for subjects who prematurely discontinued or completed treatment). Adjusted LS means and SE were obtained using ANCOVA analysis on data obtained from the multiple imputations (results were combined using Rubin’s formulae). Analysis was performed on ITT population.
    End point type
    Secondary
    End point timeframe
    Baseline, Week 26 and Week 52
    End point values
    		 SAR341402 NovoLog/NovoRapid
    Number of subjects analysed
    301
    296
    Units: millimoles per liter (mmol/L)
    least squares mean (standard error)
        At Week 26
    -0.49 ( 0.249 )
    -0.17 ( 0.245 )
        At Week 52
    -0.10 ( 0.366 )
    -0.34 ( 0.359 )
    No statistical analyses for this end point

    Secondary: Change in the Mean 24-hour Plasma Glucose (PG) Concentration From Baseline to Week 26 and Week 52

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    End point title
    		 Change in the Mean 24-hour Plasma Glucose (PG) Concentration From Baseline to Week 26 and Week 52
    End point description
    Mean 24-hour PG concentration was calculated by 7-point self-measured plasma glucose (SMPG) profiles with PG measurements before and 2-hours after each main meal and at bedtime. Mean 24-hour PG concentration was calculated for each profile and then averaged across profiles performed in week before a visit. All calculated values up to Week 26 and Week 52 were taken for analysis, regardless of adherence to treatment. Change in mean 24-hour PG concentration was calculated by subtracting baseline value from Week 26 and Week 52 values. Missing changes at Week 26 and Week 52 were imputed using return-to-baseline multiple imputation method (values imputed as subject baseline plus an error). Adjusted LS means and SE were obtained using ANCOVA analysis on data obtained from multiple imputations (results were combined using Rubin’s formulae). Analysis was performed on ITT population. Here, ‘number of subjects analysed’ = subjects with a baseline for this end point.
    End point type
    Secondary
    End point timeframe
    Baseline, Week 26 and Week 52
    End point values
    		 SAR341402 NovoLog/NovoRapid
    Number of subjects analysed
    301
    295
    Units: mmol/L
    least squares mean (standard error)
        At Week 26
    -0.34 ( 0.120 )
    -0.53 ( 0.121 )
        At Week 52
    0.12 ( 0.144 )
    -0.18 ( 0.147 )
    No statistical analyses for this end point

    Secondary: Change in Postprandial Plasma Glucose (PPG) Excursion From Baseline to Week 26 and Week 52

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    End point title
    		 Change in Postprandial Plasma Glucose (PPG) Excursion From Baseline to Week 26 and Week 52
    End point description
    Plasmsa glucose excursions were calculated at breakfast, lunch and dinner for each 7-point SMPG profile,as 2-hour PPG minus plasma glucose value obtained 30 minutes prior to start of meal. Values of PG excursions at each visit were then calculated as average across profiles performed in week before visit. All calculated values up to Week 26 and Week 52 were taken into account in the analysis, regardless of adherence to treatment. Change in PPG excursions at Weeks 26 and 52 was calculated by subtracting baseline value from Week 26 and Week 52 values, respectively. Missing changes at Week 26 and Week 52 were imputed using a return-to-baseline multiple imputation method (values imputed as subject baseline plus an error).Adjusted LS means and SE were obtained using ANCOVA analysis on data obtained from the multiple imputations (results were combined using Rubin’s formulae). Analysis was performed on ITT population. Here, ‘n’= number of subjects with a baseline for each specified category.
    End point type
    Secondary
    End point timeframe
    Baseline, Week 26, and Week 52
    End point values
    		 SAR341402 NovoLog/NovoRapid
    Number of subjects analysed
    301
    296
    Units: mmol/L
    least squares mean (standard error)
        Week 26: At Breakfast (n = 288, 288)
    0.50 ( 0.232 )
    0.65 ( 0.233 )
        Week 26: At Lunch (n = 290, 291)
    0.18 ( 0.230 )
    0.12 ( 0.228 )
        Week 26: At Dinner (n = 290, 292)
    0.36 ( 0.243 )
    0.66 ( 0.243 )
        Week 52: At Breakfast (n = 288, 288)
    0.73 ( 0.253 )
    0.91 ( 0.255 )
        Week 52: At Lunch (n = 290, 291)
    0.43 ( 0.252 )
    0.34 ( 0.251 )
        Week 52: At Dinner (n = 290, 292)
    0.26 ( 0.255 )
    0.51 ( 0.254 )
    No statistical analyses for this end point

    Secondary: Change in 7-Point SMPG Profiles From Baseline to Week 26 and Week 52 Per Time Point

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    End point title
    		 Change in 7-Point SMPG Profiles From Baseline to Week 26 and Week 52 Per Time Point
    End point description
    7-point SMPG profiles were measured at the following 7 points at each visit (Baseline, Week 26, and Week 52): before breakfast, 2 hours after breakfast, before lunch, 2 hours after lunch, before dinner, 2 hours after dinner, and bedtime. For each time point, the value at each visit was calculated as the average of values obtained for the same time point across profiles performed in the week before the visit. Analysis was performed on ITT population. Here, ‘n’ = number of subjects with available data for at baseline, Week 26/Week 52 for the specified 7-point SMPG time point.
    End point type
    Secondary
    End point timeframe
    Baseline, Week 26 and Week 52
    End point values
    		 SAR341402 NovoLog/NovoRapid
    Number of subjects analysed
    301
    296
    Units: mmol/L
    arithmetic mean (standard deviation)
        Week 26: Before Breakfast (n = 254, 253)
    -0.62 ( 4.48 )
    -0.50 ( 3.98 )
        Week 26: 2 Hours After Breakfast (n = 236, 229)
    -0.39 ( 4.97 )
    -0.30 ( 4.12 )
        Week 26: Before Lunch (n = 250, 253)
    -0.60 ( 4.14 )
    -0.60 ( 4.25 )
        Week 26: 2 Hours After Lunch (n = 246, 251)
    -0.61 ( 4.54 )
    -0.62 ( 4.65 )
        Week 26: Before Dinner (n = 256, 251)
    -0.04 ( 4.87 )
    -0.78 ( 4.12 )
        Week 26: 2 Hours After Dinner (n = 240, 245)
    -0.36 ( 4.71 )
    -0.25 ( 4.14 )
        Week 26: Bedtime (n = 239, 238)
    -0.71 ( 5.13 )
    -0.54 ( 4.03 )
        Week 52: Before Breakfast (n = 240, 229)
    -0.54 ( 4.80 )
    -0.31 ( 4.37 )
        Week 52: 2 Hours After Breakfast (n = 226, 214)
    -0.21 ( 4.30 )
    0.05 ( 4.31 )
        Week 52: Before Lunch (n = 233, 230)
    0.24 ( 4.64 )
    -0.13 ( 4.24 )
        Week 52: 2 Hours After Lunch (n = 231, 227)
    0.05 ( 5.01 )
    -0.37 ( 4.64 )
        Week 52: Before Dinner (n = 238, 231)
    0.75 ( 5.59 )
    -0.06 ( 4.26 )
        Week 52: 2 Hours After Dinner (n = 227, 227)
    0.16 ( 4.60 )
    -0.17 ( 4.63 )
        Week 52: Bedtime (n = 220, 215)
    -0.11 ( 4.98 )
    0.10 ( 4.30 )
    No statistical analyses for this end point

    Secondary: Number of Subjects With at Least One Hypoglycemic Event

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    End point title
    		 Number of Subjects With at Least One Hypoglycemic Event
    End point description
    Severe hypoglycemia was an event in which the subject required the assistance of another person to actively administer carbohydrate, glucagon, or other resuscitative actions, because the subject was not capable of helping self. Documented symptomatic hypoglycemia was an event during which typical symptoms of hypoglycemia were accompanied by a measured plasma glucose concentration of less than or equal to (<=) 3.9 mmol/L (<=70 mg/dL) or plasma glucose level of <3.0 mmol/L (54 mg/dL). Percentage of subjects with at least one hypoglycemia event (any, severe and documented [both thresholds]) were reported. Analysis was performed on safety population that included all randomised subjects who received at least one dose of IMP, analysed according to the treatment actually received.
    End point type
    Secondary
    End point timeframe
    From first injection of investigational medicinal product (IMP) up to Week 26 or up to 1 day after last injection of IMP, whichever comes earlier, for Week 26 analysis, and from first injection of IMP up to 1 day after last injection of IMP for Week 52
    End point values
    		 SAR341402 NovoLog/NovoRapid
    Number of subjects analysed
    301
    296
    Units: subjects
    number (not applicable)
        Week 26: Any hypoglycemia
    291
    285
        Week 26: Severe hypoglycemia
    12
    10
        Week 26: Documented symptomatic <=3.9 mmol/L
    264
    251
        Week 26: Documented symptomatic < 3.0 mmol/L
    207
    193
        Week 52: Any hypoglycemia
    295
    290
        Week 52: Severe hypoglycemia
    18
    14
        Week 52: Documented symptomatic <=3.9 mmol/L
    274
    267
        Week 52:Documented symptomatic < 3.0 mmol/L
    223
    220
    No statistical analyses for this end point

    Secondary: Number of Hypoglycemia Events Per Subject-Year

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    End point title
    		 Number of Hypoglycemia Events Per Subject-Year
    End point description
    Number of hypoglycemia events (any, severe and documented [both thresholds]) per subject-year of exposure were reported. Severe hypoglycemia was an event in which the subject required the assistance of another person to actively administer carbohydrate, glucagon, or other resuscitative actions, because the subject was not capable of helping self. Documented symptomatic hypoglycemia was an event during which typical symptoms of hypoglycemia were accompanied by a measured plasma glucose concentration of <=3.9 mmol/L (<=70 mg/dL) or plasma glucose level of <3.0 mmol/L (54 mg/dL). Analysis was performed on safety population.
    End point type
    Secondary
    End point timeframe
    From first injection of IMP up to Week 26 or up to 1 day after last injection of IMP, whichever comes earlier, for Week 26 analysis, and from first injection of IMP up to 1 day after last injection of IMP for Week 52
    End point values
    		 SAR341402 NovoLog/NovoRapid
    Number of subjects analysed
    301
    296
    Units: events per subject-year
    number (not applicable)
        Week 26: Any hypoglycemia
    73.33
    69.71
        Week 26: Severe hypoglycemia
    0.14
    0.10
        Week 26: Documented symptomatic <=3.9 mmol/L
    40.36
    36.37
        Week 26: Documented symptomatic <3.0 mmol/L
    11.18
    9.81
        Week 52: Any hypoglycemia
    66.00
    64.46
        Week 52: Severe hypoglycemia
    0.12
    0.08
        Week 52: Documented symptomatic <=3.9 mmol/L
    35.68
    33.73
        Week 52: Documented symptomatic <3.0 mmol/L
    9.37
    8.91
    No statistical analyses for this end point

    Secondary: Percentage of Subjects With Hypersensitivity Reactions and Injection Site Reactions

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    End point title
    		 Percentage of Subjects With Hypersensitivity Reactions and Injection Site Reactions
    End point description
    Subjects with at least one treatment-emergent adverse event linked to hypersensitivity reaction and injection site reaction regardless of relationship to IMP during the main 6-month and the 12-month on-treatment periods was assessed and reported. Analysis was performed on safety population.
    End point type
    Secondary
    End point timeframe
    From first injection of IMP up to Week 26 or up to 1 day after last injection of IMP, whichever comes earlier, for Week 26 analysis, and from first injection of IMP up to 1 day after last injection of IMP for Week 52
    End point values
    		 SAR341402 NovoLog/NovoRapid
    Number of subjects analysed
    301
    296
    Units: percentage of subjects
    number (not applicable)
        Week 26: Hypersensitivity Reactions
    3.7
    3.7
        Week 26: Injection site reactions
    0.7
    1.4
        Week 52: Hypersensitivity Reactions
    5.6
    7.1
        Week 52: Injection site reactions
    0.7
    1.4
    No statistical analyses for this end point

    Secondary: Percentage of Subjects With at Least One Positive Anti-Insulin Aspart Antibodies (AIAs) Sample

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    End point title
    		 Percentage of Subjects With at Least One Positive Anti-Insulin Aspart Antibodies (AIAs) Sample
    End point description
    Subjects with at least one positive AIA sample at baseline or at any time during the on-treatment period (Prevalence). Analysis was performed on AIA population, which included all subjects who received at least one dose of IMP and had at least one AIA sample available for analysis during the on-treatment period, analysed according to the treatment actually received. Here, ‘n’ = number of subjects included in the AIA population at Week 26 and Week 52.
    End point type
    Secondary
    End point timeframe
    From first injection of IMP up to Week 26 or up to 1 day after last injection of IMP, whichever comes earlier, for Week 26 analysis, and from first injection of IMP up to 1 day after last injection of IMP for Week 52
    End point values
    		 SAR341402 NovoLog/NovoRapid
    Number of subjects analysed
    298
    292
    Units: percentage of subjects
    number (not applicable)
        At Week 26 (n = 296, 292)
    48.0
    52.4
        At Week 52 (n = 298, 292)
    54.7
    58.2
    No statistical analyses for this end point

    Secondary: Percentage of Subjects With Treatment Induced, Treatment-Boosted and Treatment-Emergent Anti-insulin Aspart Antibodies

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    End point title
    		 Percentage of Subjects With Treatment Induced, Treatment-Boosted and Treatment-Emergent Anti-insulin Aspart Antibodies
    End point description
    AIA incidence were categorised as follows 1) Subjects with treatment-induced AIAs were those who developed AIA following IMP administration (subjects with at least one positive AIA sample at any time during on-treatment period, in those subjects without pre-existing AIA or with missing baseline sample). 2) Subjects with treatment-boosted AIAs were those with pre-existing AIAs that were boosted to a significant higher titer following IMP administration (subjects with at least one AIA sample with at least a 4-fold increase in titers compared to baseline value at any time during on-treatment period). 3) Subjects with treatment-emergent AIA were defined as subjects with treatment-induced, or treatment-boosted AIAs. Analysis was performed on AIA population. Here, ‘n’ = number of subjects included in the AIA population at Week 26 and Week 52 and with negative or missing AIA status at baseline (for treatment-induced AIA) or with positive AIA status at baseline (for treatment-boosted AIA).
    End point type
    Secondary
    End point timeframe
    From first injection of IMP up to Week 26 or up to 1 day after last injection of IMP, whichever comes earlier, for Week 26 analysis, and from first injection of IMP up to 1 day after last injection of IMP for Week 52
    End point values
    		 SAR341402 NovoLog/NovoRapid
    Number of subjects analysed
    298
    292
    Units: percentage of subjects
    number (not applicable)
        Week 26: Treatment-Induced AIA (n = 200, 194)
    23.0
    28.4
        Week 26: Treatment-Boosted AIA (n = 96, 98)
    4.2
    5.1
        Week 26: Treatment-Emergent AIA (n = 296, 292)
    16.9
    20.5
        Week 52: Treatment-Induced AIA (n = 202, 194)
    33.2
    37.1
        Week 52: Treatment-Boosted AIA (n = 96, 98)
    9.4
    13.3
        Week 52: Treatment-Emergent AIA (n = 298, 292)
    25.5
    29.1
    No statistical analyses for this end point

    Other pre-specified: Change in Glycated Hemoglobin A1c From Baseline to Week 26 and Week 52: Subgroup Analysis by Prior Use of NovoLog/NovoRapid or Humalog/Liprolog

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    End point title
    		 Change in Glycated Hemoglobin A1c From Baseline to Week 26 and Week 52: Subgroup Analysis by Prior Use of NovoLog/NovoRapid or Humalog/Liprolog
    End point description
    All values up to Week 26 and Week 52 were taken into account in the analysis, regardless of adherence to treatment. Change in HbA1c at Week 26 and Week 52 was calculated by subtracting baseline value from Week 26 and Week 52 value, respectively. Missing changes at Week 26 and Week 52 were imputed using a retrieved dropout multiple imputation method (separately for subjects who prematurely discontinued or completed treatment). Adjusted LS means and SE were obtained using ANCOVA model on data obtained from the multiple imputations (results were combined using Rubin’s formulae). Analysis was performed on ITT population and data was summarised separately for each treatment arm in each subgroup (based on the prior use of NovoLog/NovoRapid or Humalog/Liprolog).
    End point type
    Other pre-specified
    End point timeframe
    Baseline, Week 26 and Week 52
    End point values
    		 Prior NovoLog/NovoRapid Use: SAR341402 Prior NovoLog/NovoRapid Use: NovoLog/NovoRapid Prior Humalog/Liprolog Use: SAR341402 Prior Humalog/Liprolog Use: NovoLog/NovoRapid
    Number of subjects analysed
    192
    188
    109
    108
    Units: percentage of HbA1c
    least squares mean (standard error)
        At Week 26
    -0.37 ( 0.052 )
    -0.33 ( 0.052 )
    -0.39 ( 0.070 )
    -0.24 ( 0.067 )
        At Week 52
    -0.28 ( 0.065 )
    -0.26 ( 0.069 )
    -0.19 ( 0.091 )
    -0.26 ( 0.087 )
    No statistical analyses for this end point

    Other pre-specified: Number of Subjects With at Least One Hypoglycemic Event: Subgroup Analysis by Prior Use of NovoLog/ NovoRapid or Humalog/Liprolog

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    End point title
    		 Number of Subjects With at Least One Hypoglycemic Event: Subgroup Analysis by Prior Use of NovoLog/ NovoRapid or Humalog/Liprolog
    End point description
    Severe hypoglycemia was an event in which the subject required the assistance of another person to actively administer carbohydrate, glucagon, or other resuscitative actions, because the subject was not capable of helping self. Documented symptomatic hypoglycemia was an event during which typical symptoms of hypoglycemia were accompanied by a measured plasma glucose concentration of <=3.9 mmol/L (<=70 mg/dL) or plasma glucose level of <3.0 mmol/L (<54 mg/dL). Analysis was performed on safety population and data was summarised separately for each treatment arm in each subgroup (based on the prior use of NovoLog/NovoRapid or Humalog/Liprolog).
    End point type
    Other pre-specified
    End point timeframe
    From first injection of IMP up to Week 26 or up to 1 day after last injection of IMP, whichever comes earlier, for Week 26 analysis, and from first injection of IMP up to 1 day after last injection of IMP for Week 52
    End point values
    		 Prior NovoLog/NovoRapid Use: SAR341402 Prior NovoLog/NovoRapid Use: NovoLog/NovoRapid Prior Humalog/Liprolog Use: SAR341402 Prior Humalog/Liprolog Use: NovoLog/NovoRapid
    Number of subjects analysed
    192
    188
    109
    108
    Units: subjects
        Week 26: Any hypoglycemia
    187
    179
    104
    106
        Week 26: Severe hypoglycemia
    6
    7
    6
    3
        Week 26: Documented symptomatic <=3.9 mmol/L
    170
    162
    94
    89
        Week 26: Documented symptomatic < 3.0 mmol/L
    139
    123
    67
    70
        Week 52: Any hypoglycemia
    190
    184
    105
    106
        Week 52: Severe hypoglycemia
    10
    9
    8
    5
        Week 52: Documented symptomatic <=3.9 mmol/L
    175
    171
    99
    96
        Week 52: Documented symptomatic < 3.0 mmol/L
    149
    138
    74
    82
    No statistical analyses for this end point

    Other pre-specified: Number of Subjects With Adverse Events: Subgroup Analysis by Prior Use of NovoLog/NovoRapid or Humalog/ Liprolog

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    End point title
    		 Number of Subjects With Adverse Events: Subgroup Analysis by Prior Use of NovoLog/NovoRapid or Humalog/ Liprolog
    End point description
    Any untoward medical occurrence in a subject who received IMP was considered an AE without regard to possibility of causal relationship with this treatment. Treatment-emergent adverse events (TEAEs) were defined as AEs that developed or worsened or became serious during the main 6-month or 12-month on-treatment periods. Analysis was performed on safety population and data was summarised separately for each treatment arm in each subgroup (based on the prior use of NovoLog/NovoRapid or Humalog/Liprolog).
    End point type
    Other pre-specified
    End point timeframe
    From first injection of IMP up to Week 26 or up to 1 day after last injection of IMP, whichever comes earlier for Week 26 analysis, and from first injection of IMP up to 1 day after last injection of IMP for Week 52
    End point values
    		 Prior NovoLog/NovoRapid Use: SAR341402 Prior NovoLog/NovoRapid Use: NovoLog/NovoRapid Prior Humalog/Liprolog Use: SAR341402 Prior Humalog/Liprolog Use: NovoLog/NovoRapid
    Number of subjects analysed
    192
    188
    109
    108
    Units: subjects
        Week 26: Any TEAE
    92
    94
    64
    52
        Week 52: Any TEAE
    115
    109
    69
    59
    No statistical analyses for this end point

    Other pre-specified: Percentage of Subjects With Treatment-Induced, Treatment-Boosted and Treatment-Emergent Anti-insulin Aspart Antibodies (AIAs): Subgroup Analysis by Prior Use of NovoLog/NovoRapid or Humalog/Liprolog

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    End point title
    		 Percentage of Subjects With Treatment-Induced, Treatment-Boosted and Treatment-Emergent Anti-insulin Aspart Antibodies (AIAs): Subgroup Analysis by Prior Use of NovoLog/NovoRapid or Humalog/Liprolog
    End point description
    Subjects with treatment-induced AIAs were those who developed AIA following IMP (subjects with at least 1 positive AIA sample at any time during on-treatment period, in those subjects without pre-existing AIA or with missing baseline sample). Subjects with treatment-boosted AIAs were those with pre-existing AIAs that were boosted to a significant higher titer following IMP (subjects with at least 1 AIA sample with at least a 4-fold increase in titers compared to baseline value at any time during on-treatment period). Subjects with treatment-emergent AIA were defined as subjects with treatment-induced, or treatment-boosted AIAs. Data was summarised separately for each treatment arm in each subgroup (based on prior use of NovoLog/NovoRapid or Humalog/Liprolog). AIA population. Here, ‘n’= subjects included in AIA population at Week 26 and 52 and with negativeor missing AIA status at baseline (for treatment-induced AIA) or with positive AIA status at baseline (for treatment-boosted AIA).
    End point type
    Other pre-specified
    End point timeframe
    From first injection of IMP up to Week 26 or up to 1 day after last injection of IMP, whichever comes earlier, for Week 26 analysis, and from first injection of IMP up to 1 day after last injection of IMP for Week 52
    End point values
    		 Prior NovoLog/NovoRapid Use: SAR341402 Prior NovoLog/NovoRapid Use: NovoLog/NovoRapid Prior Humalog/Liprolog Use: SAR341402 Prior Humalog/Liprolog Use: NovoLog/NovoRapid
    Number of subjects analysed
    191
    185
    107
    107
    Units: percentage of subjects
    number (not applicable)
        Week 26:Treatment-Induced AIA (n=123, 120, 77, 74)
    18.7
    28.3
    29.9
    28.4
        Week 26:Treatment-Boosted AIA (n= 68, 65, 28, 33)
    1.5
    4.6
    10.7
    6.1
        Week 26:Treatment-Emergent AIA(n=191,185,105,107)
    12.6
    20.0
    24.8
    21.5
        Week 52:Treatment-Induced AIA (n=123, 120, 79, 74)
    30.1
    34.2
    38.0
    41.9
        Week 52:Treatment-Boosted AIA (n=68, 65, 28, 33)
    5.9
    15.4
    17.9
    9.1
        Week 52:Treatment-Emergent AIA(n=191,185,107,107)
    21.5
    27.6
    32.7
    31.8
    No statistical analyses for this end point

    Other pre-specified: Change in Daily Insulin Dose From Baseline to Day 1, Week 26 and Week 52

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    End point title
    		 Change in Daily Insulin Dose From Baseline to Day 1, Week 26 and Week 52
    End point description
    Change in daily insulin dose (basal, mealtime and total) was calculated by subtracting baseline value from Day 1, Week 26 and Week 52 values respectively. Baseline was defined as the median of daily doses available in the week prior to the first injection of IMP (corresponding to doses of the pre-study insulin), value at Day 1 as the median of daily doses available in the week after the first injection of IMP (first doses of IMP), and value at Week 26 and Week 52 as the median of daily doses available in the week prior to each visit. Analysis was performed on safety population. Here, ‘n’ = subjects with available data for each specified category.
    End point type
    Other pre-specified
    End point timeframe
    Baseline, Day 1, Week 26 and Week 52
    End point values
    		 SAR341402 NovoLog/NovoRapid
    Number of subjects analysed
    301
    296
    Units: Units/kilogram (U/kg)
    arithmetic mean (standard deviation)
        Basal insulin dose at Day 1 (n= 290, 283)
    -0.004 ( 0.036 )
    -0.000 ( 0.023 )
        Mealtime insulin dose at Day 1 (n= 287, 279)
    0.003 ( 0.074 )
    0.003 ( 0.091 )
        Total insulin dose at Day 1 (n= 284, 276)
    -0.001 ( 0.076 )
    0.002 ( 0.090 )
        Basal insulin dose at Week 26 (n= 271, 270)
    0.005 ( 0.081 )
    0.003 ( 0.088 )
        Mealtime insulin dose at Week 26 (n= 268, 265)
    -0.011 ( 0.133 )
    0.011 ( 0.116 )
        Total insulin dose at Week 26 (n= 263, 262)
    -0.007 ( 0.167 )
    0.015 ( 0.170 )
        Basal insulin dose at Week 52 (n= 253, 253)
    0.006 ( 0.085 )
    0.005 ( 0.095 )
        Mealtime insulin dose at Week 52 (n= 251, 255)
    -0.001 ( 0.152 )
    0.009 ( 0.123 )
        Total insulin dose at Week 52 (n= 248, 251)
    0.005 ( 0.175 )
    0.013 ( 0.165 )
    No statistical analyses for this end point

    Post-hoc: Change in Daily Insulin Dose From Baseline to Day 1, Week 26 and Week 52: Subgroup Analysis by Prior Use of NovoLog/NovoRapid or Humalog/Liprolog

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    End point title
    		 Change in Daily Insulin Dose From Baseline to Day 1, Week 26 and Week 52: Subgroup Analysis by Prior Use of NovoLog/NovoRapid or Humalog/Liprolog
    End point description
    Change in daily insulin dose (basal, mealtime and total) was calculated by subtracting baseline value from Day 1, Week 26 and Week 52 values respectively. Baseline was defined as the median of daily doses available in the week prior to the first injection of IMP (corresponding to doses of the pre-study insulin), value at Day 1 as the median of daily doses available in the week after the first injection of IMP (first doses of IMP), and value at Week 26 and Week 52 as the median of daily doses available in the week prior to each visit. Analysis was performed on safety population and data was summarised separately for each treatment arm in each subgroup (based on the prior use of NovoLog/NovoRapid or Humalog/Liprolog). Here, ‘n’ = subjects with available data for each specified category.
    End point type
    Post-hoc
    End point timeframe
    Baseline, Day 1, Week 26, Week 52
    End point values
    		 Prior NovoLog/NovoRapid Use: SAR341402 Prior NovoLog/NovoRapid Use: NovoLog/NovoRapid Prior Humalog/Liprolog Use: SAR341402 Prior Humalog/Liprolog Use: NovoLog/NovoRapid
    Number of subjects analysed
    192
    188
    109
    108
    Units: U/kg
    arithmetic mean (standard deviation)
        Basal insulin dose at Day 1 (n= 182,182,108,101)
    -0.005 ( 0.037 )
    0.0000 ( 0.021 )
    -0.002 ( 0.033 )
    -0.002 ( 0.026 )
        Mealtime insulin dose at Day 1(n=183,179,104, 100)
    -0.000 ( 0.073 )
    -0.003 ( 0.071 )
    0.008 ( 0.075 )
    0.013 ( 0.118 )
        Total insulin dose at Day 1 (n= 180,178, 104, 98)
    -0.006 ( 0.075 )
    -0.003 ( 0.077 )
    0.006 ( 0.079 )
    0.011 ( 0.111 )
        Basal insulin dose at Week 26 (n= 174,173,97, 97)
    0.003 ( 0.087 )
    0.009 ( 0.065 )
    0.008 ( 0.070 )
    -0.006 ( 0.118 )
        Mealtime insulin dose at Week 26 (n=175,170,93,95)
    -0.009 ( 0.133 )
    0.019 ( 0.114 )
    -0.015 ( 0.133 )
    -0.003 ( 0.121 )
        Total insulin dose at Week 26 (n= 171,168, 92, 94)
    -0.007 ( 0.171 )
    0.027 ( 0.142 )
    -0.008 ( 0.159 )
    -0.006 ( 0.210 )
        Basal insulin dose at Week 52 (n= 163,158, 90, 95)
    0.004 ( 0.094 )
    0.013 ( 0.088 )
    0.010 ( 0.067 )
    -0.009 ( 0.105 )
        Mealtime insulin dose at Week 52 (n=164,160,87,95)
    -0.000 ( 0.156 )
    0.015 ( 0.132 )
    -0.001 ( 0.147 )
    -0.001 ( 0.105 )
        Total insulin dose at Week 52 (n= 161,157,87,94)
    0.003 ( 0.177 )
    0.025 ( 0.169 )
    0.009 ( 0.171 )
    -0.009 ( 0.156 )
    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) weeks were collected from signature of the informed consent form up to the study completion (up to 52 Weeks) regardless of seriousness or relationship to investigational product.
    Adverse event reporting additional description
    Reported AEs and deaths are treatment-emergent AEs, that is AEs that developed/worsened or became serious and deaths that occurred during the ‘12-month on-treatment period’ (time from the first injection of IMP to 1 day after the 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
    SAR341402
    Reporting group description
    		 SAR341402 100 U/mL subcutaneous (SC) injection, before meals intake on top of QD Insulin Glargine, up to Week 52.

    Reporting group title
    NovoLog/NovoRapid
    Reporting group description
    		 NovoLog/NovoRapid 100 U/mL SC injection, before meals intake on top of QD Insulin Glargine, up to Week 52.

    Serious adverse events
    		 SAR341402 NovoLog/NovoRapid
    Total subjects affected by serious adverse events
         subjects affected / exposed
    36 / 301 (11.96%)
    29 / 296 (9.80%)
         number of deaths (all causes)
    1
    2
         number of deaths resulting from adverse events
    Neoplasms benign, malignant and unspecified (incl cysts and polyps)
    Colon Adenoma
         subjects affected / exposed
    0 / 301 (0.00%)
    1 / 296 (0.34%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pancreatic Carcinoma Metastatic
         subjects affected / exposed
    0 / 301 (0.00%)
    1 / 296 (0.34%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Prolymphocytic Leukaemia
         subjects affected / exposed
    0 / 301 (0.00%)
    1 / 296 (0.34%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    Squamous Cell Carcinoma Of Skin
         subjects affected / exposed
    1 / 301 (0.33%)
    0 / 296 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Vascular disorders
    Deep Vein Thrombosis
         subjects affected / exposed
    0 / 301 (0.00%)
    1 / 296 (0.34%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    General disorders and administration site conditions
    Asthenia
         subjects affected / exposed
    0 / 301 (0.00%)
    1 / 296 (0.34%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Chest Pain
         subjects affected / exposed
    1 / 301 (0.33%)
    0 / 296 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Sudden Death
         subjects affected / exposed
    0 / 301 (0.00%)
    1 / 296 (0.34%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    Respiratory, thoracic and mediastinal disorders
    Acute Respiratory Failure
         subjects affected / exposed
    0 / 301 (0.00%)
    1 / 296 (0.34%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Atelectasis
         subjects affected / exposed
    1 / 301 (0.33%)
    0 / 296 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pleural Effusion
         subjects affected / exposed
    0 / 301 (0.00%)
    1 / 296 (0.34%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pneumonia Aspiration
         subjects affected / exposed
    1 / 301 (0.33%)
    0 / 296 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pneumonitis
         subjects affected / exposed
    1 / 301 (0.33%)
    0 / 296 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pneumothorax Spontaneous
         subjects affected / exposed
    0 / 301 (0.00%)
    1 / 296 (0.34%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pulmonary Embolism
         subjects affected / exposed
    0 / 301 (0.00%)
    1 / 296 (0.34%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Injury, poisoning and procedural complications
    Accidental Overdose
         subjects affected / exposed
    4 / 301 (1.33%)
    2 / 296 (0.68%)
         occurrences causally related to treatment / all
    9 / 9
    1 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Device Use Error
         subjects affected / exposed
    2 / 301 (0.66%)
    0 / 296 (0.00%)
         occurrences causally related to treatment / all
    2 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Procedural Pain
         subjects affected / exposed
    0 / 301 (0.00%)
    1 / 296 (0.34%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Road Traffic Accident
         subjects affected / exposed
    0 / 301 (0.00%)
    1 / 296 (0.34%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Ulna Fracture
         subjects affected / exposed
    1 / 301 (0.33%)
    0 / 296 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Vascular Pseudoaneurysm
         subjects affected / exposed
    0 / 301 (0.00%)
    1 / 296 (0.34%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Cardiac disorders
    Acute Myocardial Infarction
         subjects affected / exposed
    1 / 301 (0.33%)
    0 / 296 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Angina Pectoris
         subjects affected / exposed
    0 / 301 (0.00%)
    1 / 296 (0.34%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Cardiac Arrest
         subjects affected / exposed
    0 / 301 (0.00%)
    1 / 296 (0.34%)
         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
    0 / 301 (0.00%)
    1 / 296 (0.34%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Chronic Left Ventricular Failure
         subjects affected / exposed
    0 / 301 (0.00%)
    1 / 296 (0.34%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Myocardial Infarction
         subjects affected / exposed
    0 / 301 (0.00%)
    1 / 296 (0.34%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Nervous system disorders
    Carpal Tunnel Syndrome
         subjects affected / exposed
    1 / 301 (0.33%)
    0 / 296 (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
    1 / 301 (0.33%)
    0 / 296 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Hyperglycaemic Unconsciousness
         subjects affected / exposed
    0 / 301 (0.00%)
    1 / 296 (0.34%)
         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 / 301 (0.33%)
    1 / 296 (0.34%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Hypoglycaemic Seizure
         subjects affected / exposed
    3 / 301 (1.00%)
    2 / 296 (0.68%)
         occurrences causally related to treatment / all
    2 / 3
    0 / 4
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Hypoglycaemic Unconsciousness
         subjects affected / exposed
    10 / 301 (3.32%)
    4 / 296 (1.35%)
         occurrences causally related to treatment / all
    8 / 13
    1 / 5
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Loss Of Consciousness
         subjects affected / exposed
    0 / 301 (0.00%)
    1 / 296 (0.34%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Polyneuropathy
         subjects affected / exposed
    0 / 301 (0.00%)
    1 / 296 (0.34%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Syncope
         subjects affected / exposed
    1 / 301 (0.33%)
    0 / 296 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Transient Ischaemic Attack
         subjects affected / exposed
    1 / 301 (0.33%)
    1 / 296 (0.34%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Gastrointestinal disorders
    Colitis Ischaemic
         subjects affected / exposed
    1 / 301 (0.33%)
    0 / 296 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Gastric Ulcer
         subjects affected / exposed
    1 / 301 (0.33%)
    0 / 296 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Peptic Ulcer Haemorrhage
         subjects affected / exposed
    0 / 301 (0.00%)
    1 / 296 (0.34%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Small Intestinal Haemorrhage
         subjects affected / exposed
    1 / 301 (0.33%)
    0 / 296 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Hepatobiliary disorders
    Biliary Dyskinesia
         subjects affected / exposed
    1 / 301 (0.33%)
    0 / 296 (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
    Diabetic Foot
         subjects affected / exposed
    2 / 301 (0.66%)
    0 / 296 (0.00%)
         occurrences causally related to treatment / all
    0 / 5
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Renal and urinary disorders
    Intercapillary Glomerulosclerosis
         subjects affected / exposed
    0 / 301 (0.00%)
    1 / 296 (0.34%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Nephrolithiasis
         subjects affected / exposed
    1 / 301 (0.33%)
    0 / 296 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Tubulointerstitial Nephritis
         subjects affected / exposed
    1 / 301 (0.33%)
    0 / 296 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Endocrine disorders
    Inappropriate Antidiuretic Hormone Secretion
         subjects affected / exposed
    0 / 301 (0.00%)
    1 / 296 (0.34%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Musculoskeletal and connective tissue disorders
    Intervertebral Disc Protrusion
         subjects affected / exposed
    1 / 301 (0.33%)
    0 / 296 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Rotator Cuff Syndrome
         subjects affected / exposed
    2 / 301 (0.66%)
    0 / 296 (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
    Bronchitis
         subjects affected / exposed
    1 / 301 (0.33%)
    0 / 296 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Bronchitis Bacterial
         subjects affected / exposed
    1 / 301 (0.33%)
    0 / 296 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Cellulitis
         subjects affected / exposed
    0 / 301 (0.00%)
    2 / 296 (0.68%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Clostridium Difficile Colitis
         subjects affected / exposed
    1 / 301 (0.33%)
    0 / 296 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Diabetic Foot Infection
         subjects affected / exposed
    0 / 301 (0.00%)
    1 / 296 (0.34%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Endophthalmitis
         subjects affected / exposed
    0 / 301 (0.00%)
    1 / 296 (0.34%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Herpes Zoster
         subjects affected / exposed
    1 / 301 (0.33%)
    0 / 296 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Osteomyelitis Chronic
         subjects affected / exposed
    0 / 301 (0.00%)
    1 / 296 (0.34%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pneumonia
         subjects affected / exposed
    0 / 301 (0.00%)
    1 / 296 (0.34%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pyelonephritis Acute
         subjects affected / exposed
    1 / 301 (0.33%)
    0 / 296 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Sepsis
         subjects affected / exposed
    0 / 301 (0.00%)
    2 / 296 (0.68%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Wound Infection
         subjects affected / exposed
    0 / 301 (0.00%)
    1 / 296 (0.34%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Metabolism and nutrition disorders
    Diabetic Ketoacidosis
         subjects affected / exposed
    4 / 301 (1.33%)
    1 / 296 (0.34%)
         occurrences causally related to treatment / all
    0 / 4
    0 / 1
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    Hypoglycaemia
         subjects affected / exposed
    3 / 301 (1.00%)
    2 / 296 (0.68%)
         occurrences causally related to treatment / all
    7 / 9
    1 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Frequency threshold for reporting non-serious adverse events: 5%
    Non-serious adverse events
    		 SAR341402 NovoLog/NovoRapid
    Total subjects affected by non serious adverse events
         subjects affected / exposed
    70 / 301 (23.26%)
    66 / 296 (22.30%)
    Infections and infestations
    Influenza
         subjects affected / exposed
    15 / 301 (4.98%)
    12 / 296 (4.05%)
         occurrences all number
    15
    13
    Nasopharyngitis
         subjects affected / exposed
    34 / 301 (11.30%)
    29 / 296 (9.80%)
         occurrences all number
    45
    39
    Upper Respiratory Tract Infection
         subjects affected / exposed
    22 / 301 (7.31%)
    28 / 296 (9.46%)
         occurrences all number
    28
    31

    More information

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    Substantial protocol amendments (globally)
    Were there any global substantial amendments to the protocol? Yes
    Date
    Amendment
    31 Oct 2017
    Following changes were made: Change to the inclusion/exclusion criteria; Clarified criteria for permanent treatment discontinuation; Clarified frequency of SMPG to assist insulin titration after reaching target ranges for plasma glucose; Simplified hypoglycemia events analysis by the time of the day; Changes in planned presentation of subject disposition and in time periods of interest for extent of investigational medicinal product exposure; Removal of analysis of hypoglycemia events by treatment period. Inserted “approximately” throughout the document for number of subjects.
    13 Dec 2017
    Following changes were made: Inclusion of additional exploratory statistical analyses of AIAs; Increase of the number of subjects.

    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

    Online references
    http://www.ncbi.nlm.nih.gov/pubmed/31804851
    http://www.ncbi.nlm.nih.gov/pubmed/32068436
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