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    Clinical Trial Results:
    Efficacy and Safety of FIAsp compared to insulin aspart both in Combination with insulin detemir in Adults with Type 1 Diabetes

    Summary
    EudraCT number
    		 2010-024049-53
    Trial protocol
    		 BE   HU   CZ   GB   DE   PL   FI  
    Global end of trial date
    11 Jun 2015

    Results information
    Results version number
    		 v1(current)
    This version publication date
    26 Jun 2016
    First version publication date
    26 Jun 2016
    Other versions

    Trial information

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    Trial identification
    Sponsor protocol code
    NN1218-3852
    Additional study identifiers
    ISRCTN number
    		 -
    US NCT number
    		 NCT01831765
    WHO universal trial number (UTN)
    		 U1111-1118-2442
    Sponsors
    Sponsor organisation name
    Novo Nordisk A/S
    Sponsor organisation address
    Novo Allé, Bagsvaerd, Denmark, 2880
    Public contact
    Global Clinical Registry (GCR,1452), Novo Nordisk A/S, clinicaltrials@novonordisk.com
    Scientific contact
    Global Clinical Registry (GCR,1452), Novo Nordisk A/S, clinicaltrials@novonordisk.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
    25 Jan 2016
    Is this the analysis of the primary completion data?
    Yes
    Primary completion date
    11 Jun 2015
    Global end of trial reached?
    Yes
    Global end of trial date
    11 Jun 2015
    Was the trial ended prematurely?
    No
    General information about the trial
    Main objective of the trial
    To confirm efficacy of treatment with meal time faster-acting insulin aspart (FIAsp) in terms of glycaemic control measured by change from baseline in glycosylated haemoglobin (HbA1c) after 26 weeks of randomised treatment by comparing it to meal time insulin aspart both in combination with insulin detemir, using a non-inferiority approach.
    Protection of trial subjects
    The trial was conducted in accordance with the Declaration of Helsinki, ICH Good Clinical Practice and FDA 21 CFR 312.120.
    Background therapy
    		 Insulin detemir, a long-acting insulin analogue was used as part of a basal−bolus insulin regimen. During run-in, insulin detemir was titrated in a treat-to-target fashion on a weekly basis to the prebreakfast glycaemic target of 4.0−5.0 mmol/L (71−90 mg/dL) and the predinner glycaemic target of 4.0−6.0 mmol/L (71−108 mg/dL) if the subject was on a twice daily regimen, in accordance with the titration guideline. When needed, dose adjustments of basal insulin were allowed after the run-in period at the discretion of the investigator. However, changing the dose frequency after randomisation was not allowed.
    Evidence for comparator
    		 Not applicable
    Actual start date of recruitment
    26 Aug 2013
    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: 66
    Country: Number of subjects enrolled
    United Kingdom: 60
    Country: Number of subjects enrolled
    Belgium: 27
    Country: Number of subjects enrolled
    Czech Republic: 48
    Country: Number of subjects enrolled
    Finland: 28
    Country: Number of subjects enrolled
    Germany: 193
    Country: Number of subjects enrolled
    Hungary: 46
    Country: Number of subjects enrolled
    United States: 603
    Country: Number of subjects enrolled
    Canada: 72
    Worldwide total number of subjects
    1143
    EEA total number of subjects
    468
    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)
    1057
    From 65 to 84 years
    86
    85 years and over
    0

    Subject disposition

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    Recruitment
    Recruitment details
    		 The trial was conducted at 165 sites in 9 countries, as follows: Belgium: 5 sites, Canada: 12 sites, Czech Republic: 5 sites; Finland: 6 sites; Germany: 25 sites; Hungary: 5 sites; Poland: 6 sites; United Kingdom: 9 sites; United States: 92 sites.

    Pre-assignment
    Screening details
    		 Screening visit was within 2 weeks prior to run-in visit to assess subject’s eligibility.Visit 2(week -8),subjects confirmed eligible enrolled in 8-week run-in period during which basal insulin treatment was optimised using treat-to-target approach.All subjects received once/twice daily insulin detemir and NovoRapid®/NovoLog® during run-in period.

    Period 1
    Period 1 title
    Overall Study (overall period)
    Is this the baseline period?
    		 Yes
    Allocation method
    Randomised - controlled
    Blinding used
    		 Double blind
    Roles blinded
    		 Subject, Investigator
    Blinding implementation details
    The treatment was double-blinded for the mealtime faster aspart and NovoRapid®/NovoLog® arms and open-labelled for the postmeal faster aspart arm all in combination with open label insulin detemir. In case safety committee recommended unblinding of any data, an independent adhoc group was established to maintain the blinding.

    Arms
    Are arms mutually exclusive
    Yes

    Arm title
    		 Faster aspart (meal)
    Arm description
    		 The subjects in this arm were administered mealtime faster aspart in combination with once or twice daily insulin detemir in a basal−bolus regimen. Mealtime faster aspart was administered subcutaneously 0−2 minutes before each main meal. Subjects who, prior to screening, had used the principles of flexible dosing based on the meal carbohydrate content, and who were assessed by the investigator to be adequately trained in this method, were to continue using this method for bolus adjustment during the treatment period. All other subjects were to use a predefined bolus-dosing algorithm to adjust the bolus dose during the treatment period. Additional bolus dosing was allowed at the investigator’s recommendation.
    Arm type
    		 Experimental

    Investigational medicinal product name
    Faster-acting insulin aspart
    Investigational medicinal product code
    Other name
    Insulin aspart
    Pharmaceutical forms
    Suspension for injection in pre-filled pen
    Routes of administration
    Subcutaneous use
    Dosage and administration details
    Faster aspart, 100 U/mL solution for subcutaneous injection was provided in a prefilled 3 mL PDS290 peninjector (blinded for the mealtime arm). Insulin detemir (Levemir®), 100 U/mL solution for subcutaneous injection was provided in a 3 mL FlexPen®. The dose of faster aspart was titrated to the premeal or bedtime glycaemic target of 4.0−6.0 mmol/L (71−108 mg/dL) using either predefined bolus-dosing algorithm or using principles of flexible dosing based on the meal carbohydrate content. Bolus titration took place twice weekly for subjects who followed the pre-defined bolus dosing algorithms. At the scheduled visit, the investigator titrated based on the previous 3 or 4 days and the subject titrated based on the remaining data as appropriate between scheduled visit as instructed by the investigator. Subjects using the principles of flexible dosing based on the meal carbohydrate content continued to do so, and adjusted the dose several times daily.

    Arm title
    		 Faster aspart (post)
    Arm description
    		 The subjects in this arm were administered postmeal faster aspart in combination with once or twice daily insulin detemir in a basal−bolus regimen.Postmeal faster aspart was administered subcutaneously 20 minutes after the start of the meal. Subjects who, prior to screening, had used the principles of flexible dosing based on the meal carbohydrate content, and who were assessed by the investigator to be adequately trained in this method, were to continue using this method for bolus adjustment during the treatment period. All other subjects were to use a predefined bolus-dosing algorithm to adjust the bolus dose during the treatment period. Additional bolus dosing was allowed at the investigator’s recommendation.
    Arm type
    		 Experimental

    Investigational medicinal product name
    Faster-acting insulin aspart
    Investigational medicinal product code
    Other name
    Insulin aspart
    Pharmaceutical forms
    Suspension for injection in pre-filled pen
    Routes of administration
    Subcutaneous use
    Dosage and administration details
    Faster aspart, 100 U/mL solution for subcutaneous injection was provided in a prefilled 3 mL PDS290 peninjector (open-label for the postmeal arm). Insulin detemir (Levemir®), 100 U/mL solution for subcutaneous injection was provided in a 3 mL FlexPen®. The dose of faster aspart was titrated to the premeal or bedtime glycaemic target of 4.0−6.0 mmol/L (71−108 mg/dL) using either using a predefined bolus-dosing algorithm or using the principles of flexible dosing based on the meal carbohydrate content. Bolus titration took place twice weekly for subjects who followed the pre-defined bolus dosing algorithms. At the scheduled visit, the investigator titrated based on the last 3 or 4 previous days and the subject titrated based on the remaining data as appropriate between scheduled visit as instructed by the investigator. Subjects using the principles of flexible dosing based on the meal carbohydrate content continued to do so, and adjusted the dose several times daily.

    Arm title
    		 NovoRapid (meal)
    Arm description
    		 The subjects in this arm were administered mealtime NovoRapid®/NovoLog® in combination with once or twice daily insulin detemir in a basal-bolus regimen. Mealtime NovoRapid®/NovoLog® was administered subcutaneously 0−2 minutes before each main meal. Subjects who, prior to screening, had used the principles of flexible dosing based on the meal carbohydrate content, and who were assessed by the investigator to be adequately trained in this method, were to continue using this method for bolus adjustment during the treatment period. All other subjects were to use a predefined bolus-dosing algorithm to adjust the bolus dose during the treatment period. Additional bolus dosing was allowed at the investigator’s recommendation.
    Arm type
    		 Active comparator

    Investigational medicinal product name
    Insulin aspart
    Investigational medicinal product code
    Other name
    NovoRapid®, NovoLog®
    Pharmaceutical forms
    Suspension for injection in pre-filled pen
    Routes of administration
    Subcutaneous use
    Dosage and administration details
    NovoRapid®/NovoLog®, 100 U/mL solution for subcutaneous injection was provided in a prefilled 3 mL PDS290 pen-injector. Insulin detemir (Levemir®), 100 U/mL solution for subcutaneous injection was provided in a 3 mL FlexPen®. The dose of NovoRapid®/NovoLog® was titrated to the premeal or bedtime glycaemic target of 4.0−6.0 mmol/L (71−108 mg/dL) using either using a predefined bolus-dosing algorithm or using the principles of flexible dosing based on the meal carbohydrate content. Bolus titration took place twice weekly for subjects who followed the pre-defined bolus dosing algorithms. At the scheduled visit, the investigator titrated based on the previous 3 or 4 days and the subject titrated based on the remaining data as appropriate between scheduled visit as instructed by the investigator. Subjects using the principles of flexible dosing based on the meal carbohydrate content continued to do so, and adjusted the dose several times daily.

    Number of subjects in period 1
    		Faster aspart (meal) Faster aspart (post) NovoRapid (meal)
    Started
    381
    382
    380
    Completed 26 weeks
    351
    355
    356
    Completed 52 weeks
    337
    0 [1]
    338
    Completed
    337
    355
    338
    Not completed
    44
    27
    42
         Adverse event, serious fatal
    -
    1
    1
         Consent withdrawn by subject
    22
    7
    17
         Other, sponsor and PI decided to close site
    1
    1
    -
         Adverse event, non-fatal
    5
    3
    3
         Withdrawal criteria
    12
    10
    16
         Pregnancy
    1
    1
    2
         Lost to follow-up
    2
    3
    3
         Other, sponsor withdrew subject
    -
    1
    -
         Lack of efficacy
    1
    -
    -
    Notes
    [1] - The number of subjects at this milestone seems inconsistent with the number of subjects in the arm. It is expected that the number of subjects will be greater than, or equal to the number that completed, minus those who left.
    Justification: This group did not continue in the study after 26 weeks. The completed subjects for this group represents the treatment period till 26 weeks, while completed for other groups represents treatment period till 52 weeks.

    Baseline characteristics

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    Baseline characteristics reporting groups
    Reporting group title
    Faster aspart (meal)
    Reporting group description
    		 The subjects in this arm were administered mealtime faster aspart in combination with once or twice daily insulin detemir in a basal−bolus regimen. Mealtime faster aspart was administered subcutaneously 0−2 minutes before each main meal. Subjects who, prior to screening, had used the principles of flexible dosing based on the meal carbohydrate content, and who were assessed by the investigator to be adequately trained in this method, were to continue using this method for bolus adjustment during the treatment period. All other subjects were to use a predefined bolus-dosing algorithm to adjust the bolus dose during the treatment period. Additional bolus dosing was allowed at the investigator’s recommendation.

    Reporting group title
    Faster aspart (post)
    Reporting group description
    		 The subjects in this arm were administered postmeal faster aspart in combination with once or twice daily insulin detemir in a basal−bolus regimen.Postmeal faster aspart was administered subcutaneously 20 minutes after the start of the meal. Subjects who, prior to screening, had used the principles of flexible dosing based on the meal carbohydrate content, and who were assessed by the investigator to be adequately trained in this method, were to continue using this method for bolus adjustment during the treatment period. All other subjects were to use a predefined bolus-dosing algorithm to adjust the bolus dose during the treatment period. Additional bolus dosing was allowed at the investigator’s recommendation.

    Reporting group title
    NovoRapid (meal)
    Reporting group description
    		 The subjects in this arm were administered mealtime NovoRapid®/NovoLog® in combination with once or twice daily insulin detemir in a basal-bolus regimen. Mealtime NovoRapid®/NovoLog® was administered subcutaneously 0−2 minutes before each main meal. Subjects who, prior to screening, had used the principles of flexible dosing based on the meal carbohydrate content, and who were assessed by the investigator to be adequately trained in this method, were to continue using this method for bolus adjustment during the treatment period. All other subjects were to use a predefined bolus-dosing algorithm to adjust the bolus dose during the treatment period. Additional bolus dosing was allowed at the investigator’s recommendation.

    Reporting group values
    		 Faster aspart (meal) Faster aspart (post) NovoRapid (meal) Total
    Number of subjects
    		 381 382 380 1143
    Age categorical
    Units: Subjects
        Adults (18-64 years)
    		 346 359 352 1057
        From 65-84 years
    		 35 23 28 86
    Age continuous
    Units: years
        arithmetic mean (standard deviation)
    		 46.1 ( 13.8 ) 43.5 ( 13.7 ) 43.7 ( 14 ) -
    Gender categorical
    Units: Subjects
        Female
    		 166 163 142 471
        Male
    		 215 219 238 672
    Body weight
    Units: kg
        arithmetic mean (standard deviation)
    		 78.56 ( 14.89 ) 80.49 ( 15.93 ) 80.15 ( 15.21 ) -
    HbA1c
    Units: % of haemoglobin
        arithmetic mean (standard deviation)
    		 7.62 ( 0.71 ) 7.63 ( 0.72 ) 7.58 ( 0.68 ) -

    End points

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    End points reporting groups
    Reporting group title
    Faster aspart (meal)
    Reporting group description
    		 The subjects in this arm were administered mealtime faster aspart in combination with once or twice daily insulin detemir in a basal−bolus regimen. Mealtime faster aspart was administered subcutaneously 0−2 minutes before each main meal. Subjects who, prior to screening, had used the principles of flexible dosing based on the meal carbohydrate content, and who were assessed by the investigator to be adequately trained in this method, were to continue using this method for bolus adjustment during the treatment period. All other subjects were to use a predefined bolus-dosing algorithm to adjust the bolus dose during the treatment period. Additional bolus dosing was allowed at the investigator’s recommendation.

    Reporting group title
    Faster aspart (post)
    Reporting group description
    		 The subjects in this arm were administered postmeal faster aspart in combination with once or twice daily insulin detemir in a basal−bolus regimen.Postmeal faster aspart was administered subcutaneously 20 minutes after the start of the meal. Subjects who, prior to screening, had used the principles of flexible dosing based on the meal carbohydrate content, and who were assessed by the investigator to be adequately trained in this method, were to continue using this method for bolus adjustment during the treatment period. All other subjects were to use a predefined bolus-dosing algorithm to adjust the bolus dose during the treatment period. Additional bolus dosing was allowed at the investigator’s recommendation.

    Reporting group title
    NovoRapid (meal)
    Reporting group description
    		 The subjects in this arm were administered mealtime NovoRapid®/NovoLog® in combination with once or twice daily insulin detemir in a basal-bolus regimen. Mealtime NovoRapid®/NovoLog® was administered subcutaneously 0−2 minutes before each main meal. Subjects who, prior to screening, had used the principles of flexible dosing based on the meal carbohydrate content, and who were assessed by the investigator to be adequately trained in this method, were to continue using this method for bolus adjustment during the treatment period. All other subjects were to use a predefined bolus-dosing algorithm to adjust the bolus dose during the treatment period. Additional bolus dosing was allowed at the investigator’s recommendation.

    Subject analysis set title
    Faster aspart (meal)-as treated
    Subject analysis set type
    		 Safety analysis
    Subject analysis set description
    The subjects in this arm were administered mealtime faster aspart in combination with once or twice daily insulin detemir in basal−bolus regimen. Mealtime faster aspart was administered subcutaneously 0−2 minutes before each main meal. Subjects who prior to screening had used principles of flexible dosing based on meal carbohydrate content, and who were assessed by investigator to be adequately trained in this method, were to continue using this method for bolus adjustment during treatment period. All other subjects were to use predefined bolus-dosing algorithm to adjust bolus dose during treatment period. Additional bolus dosing was allowed at investigator’s recommendation. A total of 5 subjects were randomised to the postmeal faster aspart arm but had consistently throughout the trial taken their bolus insulin before the meal, hence were included as treated in the safety analysis set for this arm (number of subjects: 386).

    Subject analysis set title
    Faster aspart (post)-as treated
    Subject analysis set type
    		 Safety analysis
    Subject analysis set description
    The subjects in this arm were administered postmeal faster aspart in combination with once or twice daily insulin detemir in basal−bolus regimen. Postmeal faster aspart was administered subcutaneously 20 minutes after start of meal. Subjects who prior to screening had used principles of flexible dosing based on meal carbohydrate content, and who were assessed by investigator to be adequately trained in this method, were to continue using this method for bolus adjustment during treatment period. All other subjects were to use predefined bolus-dosing algorithm to adjust bolus dose during treatment period. Additional bolus dosing was allowed at investigator’s recommendation. A total of 5 subjects were randomised to the postmeal faster aspart arm but had consistently throughout the trial taken their bolus insulin before the meal, hence were included as treated and included in the mealtime faster aspart arm instead (number of subjects: 377).

    Subject analysis set title
    NovoRapid (meal)-as treated
    Subject analysis set type
    		 Safety analysis
    Subject analysis set description
    The subjects in this arm were administered mealtime NovoRapid®/NovoLog® in combination with once or twice daily insulin detemir in a basal-bolus regimen. Mealtime NovoRapid®/NovoLog® was administered subcutaneously 0−2 minutes before each main meal. Subjects who, prior to screening, had used the principles of flexible dosing based on the meal carbohydrate content, and who were assessed by the investigator to be adequately trained in this method, were to continue using this method for bolus adjustment during the treatment period. All other subjects were to use a predefined bolus-dosing algorithm to adjust the bolus dose during the treatment period. Additional bolus dosing was allowed at the investigator’s recommendation. Number of subjects in this arm: 380.

    Primary: Change from baseline in HbA1c

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    End point title
    		 Change from baseline in HbA1c
    End point description
    Change from baseline in HbA1c after 26 weeks of randomised treatment. The analysis of this efficacy endpoint was based on the full analysis set (FAS). FAS included all randomised subjects. The statistical evaluation of the FAS was to follow the intention-to-treat (ITT) principle and subjects contributed to the evaluation ‘as randomised’. For this endpoint, baseline and week 26 have been presented, where week 26 data is end of trial containing last available measurement.
    End point type
    Primary
    End point timeframe
    After 26 weeks of randomised treatment
    End point values
    		 Faster aspart (meal) Faster aspart (post) NovoRapid (meal)
    Number of subjects analysed
    381
    382
    380
    Units: percentage
    arithmetic mean (standard deviation)
        Baseline
    7.62 ( 0.71 )
    7.63 ( 0.72 )
    7.58 ( 0.68 )
        Week 26
    7.31 ( 0.77 )
    7.51 ( 0.77 )
    7.42 ( 0.78 )
    Statistical analysis title
    		 Primary statistical analysis
    Statistical analysis description
    Change from baseline in HbA1c analysed using a mixed-effect model for repeated measurements including visit 14, 18, 22, 26, 30, 34 and 36. The model included treatment, region and strata (combination of bolus adjusting method, basal treatment regimen and continuous glucose monitoring (CGM) and frequently sampled meal test subgroup) as fixed effects, subject as random effect, baseline HbA1c as covariate and interaction between all fixed effects and visit, and between the covariate and visit.
    Comparison groups
    Faster aspart (meal) v NovoRapid (meal)
    Number of subjects included in analysis
    761
    Analysis specification
    Pre-specified
    Analysis type
    		 non-inferiority [1]
    Method
    Parameter type
    		 Mean difference (final values)
    Point estimate
    -0.15
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -0.23
         upper limit
    		 -0.07
    Notes
    [1] - Noninferiority was considered confirmed if the upper boundary of the two-sided 95% CI was below or equal to 0.4% or equivalent if the p-value for noninferiority for the one-sided test of null hypothesis (H0): D >0.4% against the alternative hypothesis (HA): D ≤0.4%, was less than or equal to 2.5%, where D is the mean treatment difference (mealtime faster aspart minus NovoRapid®/NovoLog®).
    Statistical analysis title
    		 Primary statistical analysis
    Statistical analysis description
    Change from baseline in HbA1c analysed using a mixed-effect model for repeated measurements including visit 14, 18, 22, 26, 30, 34 and 36. The model included treatment, region and strata (combination of bolus adjusting method, basal treatment regimen and continuous glucose monitoring (CGM) and frequently sampled meal test subgroup) as fixed effects, subject as random effect, baseline HbA1c as covariate and interaction between all fixed effects and visit, and between the covariate and visit.
    Comparison groups
    Faster aspart (post) v NovoRapid (meal)
    Number of subjects included in analysis
    762
    Analysis specification
    Pre-specified
    Analysis type
    		 non-inferiority [2]
    Method
    Parameter type
    		 Mean difference (final values)
    Point estimate
    0.04
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -0.04
         upper limit
    		 0.12
    Notes
    [2] - Noninferiority was considered confirmed if the upper boundary of the two-sided 95% CI was below or equal to 0.4% or equivalent if the p-value for noninferiority for the one-sided test of null hypothesis (H0): D >0.4% against the alternative hypothesis (HA): D ≤0.4%, was less than or equal to 2.5%, where D is the mean treatment difference (postmeal faster aspart minus NovoRapid®/NovoLog®).

    Secondary: Change from baseline in 2-hour PPG increment (meal test)

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    End point title
    		 Change from baseline in 2-hour PPG increment (meal test)
    End point description
    Change from baseline in 2-hour PPG increments after 26 weeks of randomised treatment (meal test). The analysis of this efficacy endpoint was based on FAS. FAS included all randomised subjects. For this endpoint, baseline and week 26 have been presented, where week 26 data is end of trial containing last available measurement. Here, 'n' specifies the number of subjects with data available for 2-hour PPG increment at baseline (Faster aspart (meal) = 379, Faster aspart (post) = 377 and NovoRapid (meal) = 375) and at week 26 ( Faster aspart (meal) = 381, Faster aspart (post) = 382 and NovoRapid (meal) = 380).
    End point type
    Secondary
    End point timeframe
    After 26 weeks of randomised treatment
    End point values
    		 Faster aspart (meal) Faster aspart (post) NovoRapid (meal)
    Number of subjects analysed
    381
    382
    380
    Units: mmol/L
    arithmetic mean (standard deviation)
        Baseline (n = 379, 377, 375)
    6.06 ( 5.16 )
    6.06 ( 4.9 )
    6.24 ( 4.81 )
        Week 26 (n = 381, 382, 380)
    5.88 ( 4.67 )
    6.73 ( 4.67 )
    6.55 ( 4.78 )
    No statistical analyses for this end point

    Secondary: Change from baseline in HbA1c (post meal arm)

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    End point title
    		 Change from baseline in HbA1c (post meal arm) [3]
    End point description
    Change from baseline in HbA1c (post meal arm) after 26 weeks of randomised treatment. This endpoint was summarised using the FAS. FAS included all randomised subjects. For this endpoint, baseline and week 26 have been presented, where week 26 data is end of trial containing last available measurement.
    End point type
    Secondary
    End point timeframe
    After 26 weeks of randomised treatment
    Notes
    [3] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
    Justification: The change from baseline in HbA1c was analysed here for the postmeal faster aspart versus NovoRapid®/NovoLog® and hence the data is provided for the faster aspart (post) and the NovoRapid (meal) arm.
    End point values
    		 Faster aspart (post) NovoRapid (meal)
    Number of subjects analysed
    382
    380
    Units: Percentage
    arithmetic mean (standard deviation)
        Baseline
    7.63 ( 0.72 )
    7.58 ( 0.68 )
        Week 26
    7.51 ( 0.77 )
    7.42 ( 0.78 )
    No statistical analyses for this end point

    Secondary: Number of treatment emergent confirmed hypoglycaemic episodes

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    End point title
    		 Number of treatment emergent confirmed hypoglycaemic episodes
    End point description
    Number of treatment-emergent severe or BG confirmed hypoglycaemic episodes from baseline until week 26. A hypoglycaemic episode was defined as treatment-emergent if the onset of the episode was on or after the first day of exposure to randomised treatment and no later than 1 day after the last day of randomised treatment. Severe or BG confirmed is an episode that is severe according to the American Diabetes Association (ADA) classification (an episode requiring assistance of another person to actively administer carbohydrate, glucagon, or take other corrective actions) or BG confirmed by a PG value <3.1 mmol/L (56 mg/dL) with or without symptoms consistent with hypoglycaemia. This endpoint was summarized using the safety analysis set.
    End point type
    Secondary
    End point timeframe
    From baseline until 26 weeks of randomised treatment
    End point values
    		 Faster aspart (meal)-as treated Faster aspart (post)-as treated NovoRapid (meal)-as treated
    Number of subjects analysed
    386
    377
    380
    Units: Number of episodes
        Severe or BG confirmed
    5899
    5443
    5865
    No statistical analyses for this end point

    Secondary: Change from baseline in body weight

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    End point title
    		 Change from baseline in body weight
    End point description
    Change from baseline in body weight after 26 weeks of randomised treatment. This endpoint was summarised using the FAS. FAS included all randomised subjects. For this endpoint baseline, and week 26 have been presented, where week 26 data is end of trial containing last available measurement. Here, 'n' specifies the number of subjects with data available for body weight at baseline (Faster aspart (meal) = 381, Faster aspart (post) = 382 and NovoRapid (meal) = 378) and at week 26 (Faster aspart (meal) = 381, Faster aspart (post) = 382 and NovoRapid (meal) = 380).
    End point type
    Secondary
    End point timeframe
    After 26 weeks of randomised treatment
    End point values
    		 Faster aspart (meal) Faster aspart (post) NovoRapid (meal)
    Number of subjects analysed
    381
    382
    380
    Units: kg
    arithmetic mean (standard deviation)
        Baseline (n=381, 382, 378)
    78.56 ( 14.89 )
    80.49 ( 15.93 )
    80.21 ( 15.21 )
        Week 26 (n=381, 382, 380)
    79.21 ( 15.25 )
    81.17 ( 16.45 )
    80.69 ( 15.44 )
    No statistical analyses for this end point

    Secondary: Adverse events

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    End point title
    		 Adverse events
    End point description
    All treatment emergent adverse events (TEAEs) from baseline until 52 weeks of randomised treatment. A TEAE was defined as an event that had an onset date on or after the first day of exposure to randomised treatment, and no later than 7 days after the last day of randomised treatment.
    End point type
    Secondary
    End point timeframe
    From the first day of exposure to randomised treatment and until 26 +1 weeks [faster aspart (post)] or until 26+26+1 weeks [faster aspart (meal) and NovoRapid®/NovoLog® (meal)].
    End point values
    		 Faster aspart (meal)-as treated Faster aspart (post)-as treated NovoRapid (meal)-as treated
    Number of subjects analysed
    386
    377
    380
    Units: event rate/100 patient yrs of exposure
        number (not applicable)
    445.8
    441
    411
    No statistical analyses for this end point

    Secondary: HbA1c

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    End point title
    		 HbA1c [4]
    End point description
    Change from baseline in HbA1c (%) after 52 weeks of randomised treatment. This endpoint was summarised using the FAS. FAS included all randomised subjects. The statistical evaluation of the FAS was to follow the ITT principle and subjects contributed to the evaluation ‘as randomised’. For this endpoint, baseline and week 52 have been presented, where week 52 data is the end of trial containing last available measurement.
    End point type
    Secondary
    End point timeframe
    After 52 weeks of randomised treatment
    Notes
    [4] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
    Justification: The change from baseline in HbA1c after 52 weeks of randomised treatment is reported here. The subjects in the postmeal arm did not enter the additional 26-week treatment period and hence the data is provided for the faster aspart (meal) and the NovoRapid (meal) arm.
    End point values
    		 Faster aspart (meal) NovoRapid (meal)
    Number of subjects analysed
    381
    380
    Units: percentage
    arithmetic mean (standard deviation)
        Baseline
    7.62 ( 0.71 )
    7.58 ( 0.68 )
        Week 52
    7.51 ( 0.83 )
    7.58 ( 0.86 )
    No statistical analyses for this end point

    Secondary: Postprandial glucose (PPG)

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    End point title
    		 Postprandial glucose (PPG) [5]
    End point description
    Change from baseline in PPG and PPG increment (meal test) after 52 weeks of randomised treatment. This endpoint was summarised using the FAS. FAS included all randomised subjects. For this endpoint, baseline and week 52 have been presented, where week 52 data is the end of trial containing last available measurement. Here, 'n' specifies the number of subjects with data available for PPG at baseline [Faster aspart (meal) =379 and NovoRapid (meal) =379] and at week 52 [Faster aspart (meal) =380 and NovoRapid (meal) =380]. The number of subjects with data available for PPG increment at 120 mins at baseline [Faster aspart (meal) =379 and NovoRapid (meal) =379] and at week 52 [Faster aspart (meal) =380 and NovoRapid (meal) =380] is also presented.
    End point type
    Secondary
    End point timeframe
    After 52 weeks of randomised treatment
    Notes
    [5] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
    Justification: The change from baseline in PPG and PPG increment (meal test) for mealtime faster aspart group and the NovoRapid®/NovoLog® group after 52 weeks of randomised treatment is reported here. The subjects in the postmeal arm did not enter the additional 26-week treatment period and hence the data is provided for the faster aspart (meal) and the NovoRapid (meal) arm.
    End point values
    		 Faster aspart (meal) NovoRapid (meal)
    Number of subjects analysed
    381
    380
    Units: mmol/L
    arithmetic mean (standard deviation)
        PPG at 120 minutes (Baseline) (n=379,379)
    14.51 ( 6.09 )
    14.14 ( 5.69 )
        PPG at 120 minutes (Week 52) (n=380,380)
    14.26 ( 5.76 )
    14.51 ( 6.02 )
        PPG increment at 120 mins (Baseline) (n=379,375)
    6.06 ( 5.16 )
    6.24 ( 4.81 )
        PPG increment at 120 mins(Week 52) (n=381,380)
    5.71 ( 4.92 )
    6.14 ( 4.86 )
    No statistical analyses for this end point

    Adverse events

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    Adverse events information
    Timeframe for reporting adverse events
    Until 52 (26+26) weeks of treatment + 1 week of follow-up for faster aspart (meal) and NovoRapid®/NovoLog®(meal) or until 26 weeks of treatment + 1 week of follow-up for faster aspart (post).
    Adverse event reporting additional description
    All TEAEs are summarised.A TEAE defined as an event that had an onset date on or after first day of exposure to randomised treatment,and no later than 7 days after the last day of randomised treatment.Note:number of deaths causally related to treatment is the data considered to present under ‘total number of deaths resulting from adverse events'.
    Assessment type
    		 Systematic
    Dictionary used for adverse event reporting
    Dictionary name
    		 MedDRA
    Dictionary version
    17
    Reporting groups
    Reporting group title
    Faster aspart (meal)-as treated
    Reporting group description
    		 The subjects in this arm were administered mealtime faster aspart in combination with once or twice daily insulin detemir in a basal−bolus regimen. Mealtime faster aspart was administered subcutaneously 0−2 minutes before each main meal for 52 weeks. Subjects who, prior to screening, had used the principles of flexible dosing based on the meal carbohydrate content, and who were assessed by the investigator to be adequately trained in this method, were to continue using this method for bolus adjustment during the treatment period. All other subjects were to use a predefined bolus-dosing algorithm to adjust the bolus dose during the treatment period. Additional bolus dosing was allowed at the investigator’s recommendation. A total of 5 subjects were randomised to the postmeal faster aspart arm but had consistently throughout the trial taken their bolus insulin before the meal, hence were included as treated in the safety analysis set for this arm (number of subjects: 386)

    Reporting group title
    Faster aspart (post)-as treated
    Reporting group description
    		 The subjects in this arm were administered postmeal faster aspart in combination with once or twice daily insulin detemir in a basal−bolus regimen.Postmeal faster aspart was administered subcutaneously 20 minutes after the start of the meal for 26 weeks.Subjects who, prior to screening, had used the principles of flexible dosing based on the meal carbohydrate content, and who were assessed by the investigator to be adequately trained in this method, were to continue using this method for bolus adjustment during the treatment period.All other subjects were to use a predefined bolus-dosing algorithm to adjust the bolus dose during the treatment period. Additional bolus dosing was allowed at the investigator’s recommendation.A total of 5 subjects were randomised to the postmeal faster aspart arm but had consistently throughout the trial taken their bolus insulin before the meal, hence were included as treated and included in the mealtime faster aspart arm instead(number of subjects:377).

    Reporting group title
    NovoRapid (meal)-as treated
    Reporting group description
    		 The subjects in this arm were administered mealtime NovoRapid®/NovoLog® in combination with once or twice daily insulin detemir in a basal−bolus regimen. Mealtime NovoRapid®/NovoLog® was administered subcutaneously 0−2 minutes before each main meal for 52 weeks. Subjects who, prior to screening, had used the principles of flexible dosing based on the meal carbohydrate content, and who were assessed by the investigator to be adequately trained in this method, were to continue using this method for bolus adjustment during the treatment period. All other subjects were to use a predefined bolus-dosing algorithm to adjust the bolus dose during the treatment period. Additional bolus dosing was allowed at the investigator’s recommendation. Number of subjects in this arm: 380.

    Serious adverse events
    		 Faster aspart (meal)-as treated Faster aspart (post)-as treated NovoRapid (meal)-as treated
    Total subjects affected by serious adverse events
         subjects affected / exposed
    35 / 386 (9.07%)
    28 / 377 (7.43%)
    33 / 380 (8.68%)
         number of deaths (all causes)
    0
    1
    1
         number of deaths resulting from adverse events
    0
    0
    0
    Neoplasms benign, malignant and unspecified (incl cysts and polyps)
    Adenocarcinoma of colon
         subjects affected / exposed
    0 / 386 (0.00%)
    1 / 377 (0.27%)
    0 / 380 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Lung neoplasm malignant
         subjects affected / exposed
    1 / 386 (0.26%)
    0 / 377 (0.00%)
    0 / 380 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Papillary thyroid cancer
         subjects affected / exposed
    0 / 386 (0.00%)
    0 / 377 (0.00%)
    1 / 380 (0.26%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Vascular disorders
    Aneurysm
         subjects affected / exposed
    1 / 386 (0.26%)
    0 / 377 (0.00%)
    0 / 380 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Peripheral arterial occlusive disease
         subjects affected / exposed
    1 / 386 (0.26%)
    0 / 377 (0.00%)
    0 / 380 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Thrombosis
         subjects affected / exposed
    1 / 386 (0.26%)
    0 / 377 (0.00%)
    0 / 380 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Surgical and medical procedures
    Coronary arterial stent insertion
         subjects affected / exposed
    1 / 386 (0.26%)
    0 / 377 (0.00%)
    0 / 380 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Coronary revascularisation
         subjects affected / exposed
    0 / 386 (0.00%)
    1 / 377 (0.27%)
    0 / 380 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Reproductive system and breast disorders
    Uterine polyp
         subjects affected / exposed
    1 / 386 (0.26%)
    0 / 377 (0.00%)
    0 / 380 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Respiratory, thoracic and mediastinal disorders
    Nasal septum deviation
         subjects affected / exposed
    1 / 386 (0.26%)
    0 / 377 (0.00%)
    0 / 380 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Psychiatric disorders
    Mental status changes
         subjects affected / exposed
    0 / 386 (0.00%)
    0 / 377 (0.00%)
    1 / 380 (0.26%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Investigations
    Blood glucose decreased
         subjects affected / exposed
    0 / 386 (0.00%)
    0 / 377 (0.00%)
    1 / 380 (0.26%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Cardiovascular evaluation
         subjects affected / exposed
    0 / 386 (0.00%)
    0 / 377 (0.00%)
    1 / 380 (0.26%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Injury, poisoning and procedural complications
    Ankle fracture
         subjects affected / exposed
    1 / 386 (0.26%)
    1 / 377 (0.27%)
    0 / 380 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Fall
         subjects affected / exposed
    2 / 386 (0.52%)
    0 / 377 (0.00%)
    0 / 380 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Lower limb fracture
         subjects affected / exposed
    0 / 386 (0.00%)
    1 / 377 (0.27%)
    0 / 380 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Lumbar vertebral fracture
         subjects affected / exposed
    1 / 386 (0.26%)
    0 / 377 (0.00%)
    1 / 380 (0.26%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Overdose
         subjects affected / exposed
    0 / 386 (0.00%)
    1 / 377 (0.27%)
    0 / 380 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Radius fracture
         subjects affected / exposed
    1 / 386 (0.26%)
    0 / 377 (0.00%)
    0 / 380 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Road traffic accident
         subjects affected / exposed
    0 / 386 (0.00%)
    1 / 377 (0.27%)
    0 / 380 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Subdural haematoma
         subjects affected / exposed
    1 / 386 (0.26%)
    0 / 377 (0.00%)
    0 / 380 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Tendon rupture
         subjects affected / exposed
    1 / 386 (0.26%)
    0 / 377 (0.00%)
    0 / 380 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Wrong drug administered
         subjects affected / exposed
    1 / 386 (0.26%)
    1 / 377 (0.27%)
    0 / 380 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Cardiac disorders
    Angina pectoris
         subjects affected / exposed
    0 / 386 (0.00%)
    1 / 377 (0.27%)
    0 / 380 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Arrhythmia
         subjects affected / exposed
    0 / 386 (0.00%)
    1 / 377 (0.27%)
    0 / 380 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    Arteriosclerosis coronary artery
         subjects affected / exposed
    0 / 386 (0.00%)
    1 / 377 (0.27%)
    0 / 380 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Cardiac failure congestive
         subjects affected / exposed
    1 / 386 (0.26%)
    0 / 377 (0.00%)
    0 / 380 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Cardiac ventricular thrombosis
         subjects affected / exposed
    1 / 386 (0.26%)
    0 / 377 (0.00%)
    0 / 380 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Coronary artery disease
         subjects affected / exposed
    1 / 386 (0.26%)
    1 / 377 (0.27%)
    0 / 380 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Myocardial infarction
         subjects affected / exposed
    0 / 386 (0.00%)
    0 / 377 (0.00%)
    1 / 380 (0.26%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    Nervous system disorders
    Carotid artery stenosis
         subjects affected / exposed
    0 / 386 (0.00%)
    1 / 377 (0.27%)
    0 / 380 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Hypoglycaemic seizure
         subjects affected / exposed
    0 / 386 (0.00%)
    1 / 377 (0.27%)
    0 / 380 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Hypoglycaemic unconsciousness
         subjects affected / exposed
    5 / 386 (1.30%)
    3 / 377 (0.80%)
    4 / 380 (1.05%)
         occurrences causally related to treatment / all
    7 / 8
    3 / 3
    3 / 5
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Ischaemic stroke
         subjects affected / exposed
    0 / 386 (0.00%)
    0 / 377 (0.00%)
    1 / 380 (0.26%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Subarachnoid haemorrhage
         subjects affected / exposed
    1 / 386 (0.26%)
    0 / 377 (0.00%)
    0 / 380 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Transient ischaemic attack
         subjects affected / exposed
    1 / 386 (0.26%)
    0 / 377 (0.00%)
    0 / 380 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Eye disorders
    Diabetic retinopathy
         subjects affected / exposed
    0 / 386 (0.00%)
    0 / 377 (0.00%)
    1 / 380 (0.26%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Gastrointestinal disorders
    Abdominal pain
         subjects affected / exposed
    0 / 386 (0.00%)
    0 / 377 (0.00%)
    1 / 380 (0.26%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Anal fistula
         subjects affected / exposed
    0 / 386 (0.00%)
    0 / 377 (0.00%)
    1 / 380 (0.26%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Colitis microscopic
         subjects affected / exposed
    0 / 386 (0.00%)
    0 / 377 (0.00%)
    1 / 380 (0.26%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Diarrhoea
         subjects affected / exposed
    0 / 386 (0.00%)
    1 / 377 (0.27%)
    0 / 380 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Nausea
         subjects affected / exposed
    0 / 386 (0.00%)
    1 / 377 (0.27%)
    0 / 380 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Pancreatitis
         subjects affected / exposed
    1 / 386 (0.26%)
    0 / 377 (0.00%)
    1 / 380 (0.26%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Peritoneal fibrosis
         subjects affected / exposed
    0 / 386 (0.00%)
    1 / 377 (0.27%)
    0 / 380 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Vomiting
         subjects affected / exposed
    0 / 386 (0.00%)
    1 / 377 (0.27%)
    0 / 380 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Musculoskeletal and connective tissue disorders
    Compartment syndrome
         subjects affected / exposed
    0 / 386 (0.00%)
    0 / 377 (0.00%)
    1 / 380 (0.26%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Joint stiffness
         subjects affected / exposed
    0 / 386 (0.00%)
    0 / 377 (0.00%)
    1 / 380 (0.26%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Meniscal degeneration
         subjects affected / exposed
    0 / 386 (0.00%)
    0 / 377 (0.00%)
    1 / 380 (0.26%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Musculoskeletal pain
         subjects affected / exposed
    0 / 386 (0.00%)
    0 / 377 (0.00%)
    1 / 380 (0.26%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Infections and infestations
    Appendicitis
         subjects affected / exposed
    1 / 386 (0.26%)
    0 / 377 (0.00%)
    0 / 380 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Bronchitis
         subjects affected / exposed
    0 / 386 (0.00%)
    0 / 377 (0.00%)
    1 / 380 (0.26%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Cellulitis
         subjects affected / exposed
    0 / 386 (0.00%)
    0 / 377 (0.00%)
    1 / 380 (0.26%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Gastroenteritis
         subjects affected / exposed
    1 / 386 (0.26%)
    0 / 377 (0.00%)
    0 / 380 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Osteomyelitis
         subjects affected / exposed
    0 / 386 (0.00%)
    1 / 377 (0.27%)
    0 / 380 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Peritonsillar abscess
         subjects affected / exposed
    0 / 386 (0.00%)
    0 / 377 (0.00%)
    1 / 380 (0.26%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Pharyngitis
         subjects affected / exposed
    0 / 386 (0.00%)
    0 / 377 (0.00%)
    1 / 380 (0.26%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Pilonidal cyst
         subjects affected / exposed
    0 / 386 (0.00%)
    1 / 377 (0.27%)
    0 / 380 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Pneumonia staphylococcal
         subjects affected / exposed
    0 / 386 (0.00%)
    1 / 377 (0.27%)
    0 / 380 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Pyelonephritis
         subjects affected / exposed
    1 / 386 (0.26%)
    1 / 377 (0.27%)
    0 / 380 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Vestibular neuronitis
         subjects affected / exposed
    1 / 386 (0.26%)
    0 / 377 (0.00%)
    0 / 380 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Viral infection
         subjects affected / exposed
    0 / 386 (0.00%)
    0 / 377 (0.00%)
    1 / 380 (0.26%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Metabolism and nutrition disorders
    Diabetic ketoacidosis
         subjects affected / exposed
    1 / 386 (0.26%)
    0 / 377 (0.00%)
    2 / 380 (0.53%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    1 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Hypoglycaemia
         subjects affected / exposed
    12 / 386 (3.11%)
    11 / 377 (2.92%)
    10 / 380 (2.63%)
         occurrences causally related to treatment / all
    10 / 16
    7 / 11
    8 / 10
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Lactic acidosis
         subjects affected / exposed
    0 / 386 (0.00%)
    1 / 377 (0.27%)
    0 / 380 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Frequency threshold for reporting non-serious adverse events: 5%
    Non-serious adverse events
    		 Faster aspart (meal)-as treated Faster aspart (post)-as treated NovoRapid (meal)-as treated
    Total subjects affected by non serious adverse events
         subjects affected / exposed
    252 / 386 (65.28%)
    189 / 377 (50.13%)
    236 / 380 (62.11%)
    Injury, poisoning and procedural complications
    Wrong drug administered
         subjects affected / exposed
    22 / 386 (5.70%)
    18 / 377 (4.77%)
    23 / 380 (6.05%)
         occurrences all number
    31
    20
    28
    Nervous system disorders
    Headache
         subjects affected / exposed
    37 / 386 (9.59%)
    26 / 377 (6.90%)
    45 / 380 (11.84%)
         occurrences all number
    70
    41
    79
    Gastrointestinal disorders
    Diarrhoea
         subjects affected / exposed
    27 / 386 (6.99%)
    11 / 377 (2.92%)
    27 / 380 (7.11%)
         occurrences all number
    34
    11
    33
    Nausea
         subjects affected / exposed
    28 / 386 (7.25%)
    18 / 377 (4.77%)
    23 / 380 (6.05%)
         occurrences all number
    36
    29
    34
    Vomiting
         subjects affected / exposed
    19 / 386 (4.92%)
    15 / 377 (3.98%)
    25 / 380 (6.58%)
         occurrences all number
    23
    16
    30
    Respiratory, thoracic and mediastinal disorders
    Cough
         subjects affected / exposed
    17 / 386 (4.40%)
    12 / 377 (3.18%)
    20 / 380 (5.26%)
         occurrences all number
    21
    13
    21
    Oropharyngeal pain
         subjects affected / exposed
    17 / 386 (4.40%)
    16 / 377 (4.24%)
    23 / 380 (6.05%)
         occurrences all number
    22
    21
    30
    Musculoskeletal and connective tissue disorders
    Back pain
         subjects affected / exposed
    28 / 386 (7.25%)
    15 / 377 (3.98%)
    20 / 380 (5.26%)
         occurrences all number
    36
    17
    22
    Infections and infestations
    Gastroenteritis
         subjects affected / exposed
    20 / 386 (5.18%)
    8 / 377 (2.12%)
    17 / 380 (4.47%)
         occurrences all number
    25
    8
    21
    Influenza
         subjects affected / exposed
    22 / 386 (5.70%)
    11 / 377 (2.92%)
    37 / 380 (9.74%)
         occurrences all number
    30
    12
    54
    Nasopharyngitis
         subjects affected / exposed
    128 / 386 (33.16%)
    90 / 377 (23.87%)
    120 / 380 (31.58%)
         occurrences all number
    214
    111
    174
    Sinusitis
         subjects affected / exposed
    19 / 386 (4.92%)
    7 / 377 (1.86%)
    28 / 380 (7.37%)
         occurrences all number
    21
    7
    37
    Upper respiratory tract infection
         subjects affected / exposed
    56 / 386 (14.51%)
    28 / 377 (7.43%)
    40 / 380 (10.53%)
         occurrences all number
    75
    31
    61
    Urinary tract infection
         subjects affected / exposed
    20 / 386 (5.18%)
    15 / 377 (3.98%)
    18 / 380 (4.74%)
         occurrences all number
    25
    20
    29

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    Substantial protocol amendments (globally)
    Were there any global substantial amendments to the protocol? Yes
    Date
    Amendment
    26 Jul 2013
    A 30-day follow-up period was introduced in order to collect information on potential major cardiovascular events (MACE) to support cardiovascular risk assessment. Furthermore, collection of smoking history (to support cardiovascular risk analysis) and new diabetes treatment after end of trial treatment was introduced for all subjects at randomisation. The continuous glucose monitoring (CGM) data collection period was increased from 3−7 days to 10−14 days with the simultaneous decrease from 180 to 90 subjects in the CGM and frequently sampled meal test subgroup. This was done in order to improve data quality by having more CGM data from individual subjects at fewer clinical sites. The ADA classification of hypoglycaemia was updated to reflect the latest ADA classification. France was replaced by Finland.

    Interruptions (globally)
    Were there any global interruptions to the trial? No

    Limitations and caveats
    Limitations of the trial such as small numbers of subjects analysed or technical problems leading to unreliable data.
    None reported
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